Catalysts: Epoxide Syntheses and Ring-Opening Reactions in Drug Development

catalysts
Review
Epoxide Syntheses and Ring-Opening Reactions in
Drug Development
Fotini Moschona, Ioanna Savvopoulou, Maria Tsitopoulou, Despoina Tataraki and
Gerasimos Rassias *
Department of Chemistry, University of Patras, 26504 Patra, Greece; fmoschona@windowslive.com (F.M.);
joanna_savv@hotmail.com (I.S.); mtsito@hotmail.com (M.T.); desptat@hotmail.com (D.T.)
* Correspondence: rassiasg@upatras.gr; Tel.: +30-2610997912

Received: 23 August 2020; Accepted: 23 September 2020; Published: 27 September 2020
Abstract: This review concentrates on success stories from the synthesis of approved medicines and
drug candidates using epoxide chemistry in the development of robust and efficient syntheses at large
scale. The focus is on those parts of each synthesis related to the substrate-controlled/diastereoselective
and catalytic asymmetric synthesis of epoxide intermediates and their subsequent ring-opening
reactions with various nucleophiles. These are described in the form of case studies of high profile
pharmaceuticals spanning a diverse range of indications and molecular scaffolds such as heterocycles,
terpenes, steroids, peptidomimetics, alkaloids and main stream small molecules. Representative
examples include, but are not limited to the antihypertensive diltiazem, the antidepressant reboxetine,
the HIV protease inhibitors atazanavir and indinavir, efinaconazole and related triazole antifungals,
tasimelteon for sleep disorders, the anticancer agent carfilzomib, the anticoagulant rivaroxaban
the antibiotic linezolid and the antiviral oseltamivir. Emphasis is given on aspects of catalytic
asymmetric epoxidation employing metals with chiral ligands particularly with the Sharpless and
Jacobsen–Katsuki methods as well as organocatalysts such as the chiral ketones of Shi and Yang,
Pages’s chiral iminium salts and typical chiral phase transfer agents.
Keywords: epoxides; drug development; catalytic asymmetric epoxidation; organocatalysis; process

development and manufacturing routes; Sharpless and Jacobsen–Katsuki asymmetric epoxidation;
chiral ketones/dioxiranes; iminium/oxaziridinium salts; epoxide ring opening
1. Introduction
Epoxides are versatile electrophiles that support the stereospecific formation of ring-opened
products with a wide array of nucleophiles. The implications of this reactivity in the context of drug
design and desired biologic action as well as manifestation of adverse effects has been reviewed
previously [1–4] although these are best exemplified by the plethora of natural products and the
14 approved drugs containing the epoxide functionality [5,6]. In the context of organic synthesis,
the ring strain-induced electrophilicity of epoxides renders them excellent reactive intermediates for
constructing in stereoselective/specific manner key bonds in larger and more complex molecules.
From an academic perspective, general aspects of epoxide synthesis and ring-opening reactions
spanning various levels of organic chemistry research have been reviewed extensively [7–9]. What is
lesser known is how pivotal has been the successful management of epoxide chemistry on scale
leading to robust, cost-effective and safe manufacturing processes. Emphasis is also given in the way
certain intermediates are handled due to safety, reactivity, inappropriate state (oils, low melting point
solids) or physical properties (hygroscopicity, poor filtration characteristics) or even time constraints.
For example, in several cases a “telescoped” process is implemented which is a process term to
describe a reaction that despite work up, washes, filtration of unwanted materials (inorganics, charcoal),
Catalysts 2020, 10, 1117; doi:10.3390/catal10101117 www.mdpi.com/journal/catalysts

Catalysts 2020, 10, x FOR PEER REVIEW 2 of 69

term to describe a reaction that despite work up, washes, filtration of unwanted materials
(inorganics,
term to describe charcoal), etc., avoids
a reaction thatany isolation
despite and up,
work a solution
washes,of the intermediate
filtration is carriedmaterials
of unwanted forward
Catalysts 2020, 10, 1117 2 of 65
in the next step, not necessarily in the same reactor. The more common term “one-pot”
(inorganics, charcoal), etc., avoids any isolation and a solution of the intermediate is carried forward implies no
processing/work
in the next step, not up and the reagents
necessarily in theforsame
the next stepThe
reactor. are added sequentially
more common termin“one-pot”
the same vessel.
impliesThe no
focus
etc., of this
processing/work review
avoids any isolation is
up and thethe
and implementation
reagents for the
a solution of
ofnext epoxide
the step chemistry from
are addedissequentially
intermediate a process
in the in
carried forward samedevelopment
thevessel. The
next step,
perspective
focus
not of thisand
necessarily in is
thepresented
review is the
same through
reactor. dedicated
implementation
The more discussions
of epoxide
common to highimplies
term chemistry
“one-pot” profile
from a noapproved
process drugs and
development
processing/work up
clinical
perspective
and candidates.
and for
the reagents is presented
the next stepthrough
are addeddedicated discussions
sequentially to high
in the same profile
vessel. approved
The focus of thisdrugs
reviewandis
clinical
the candidates. of epoxide chemistry from a process development perspective and is presented
implementation
1.1. LY459477—Development
through dedicated discussions of atoSelective Routeapproved
high profile via a Desymmetrization Process
drugs and clinical of a Meso-Epoxide
candidates.
1.1. LY459477—Development
LY459477 (1) is a potent of a(EC
Selective
50 1 nm)Route via a Desymmetrization
orthosteric Processand
agonist for rodent of a human
Meso-Epoxide
mGlu2 and
1.1. LY459477—Development of a Selective Route via a Desymmetrization Process of a Meso-Epoxide
mGlu3 receptors.
LY459477 (1)Development
is a potent (EC of an appropriate large-scale synthesis of LY459477 was required to
50 1 nm) orthosteric agonist for rodent and human mGlu2 and
support clinical
LY459477 (1) trials
is a for
potent
mGlu3 receptors. Development 50 schizophrenia,
(EC 1 nm) generalized
orthosteric
of an appropriate anxiety
agonist
large-scale disorder
forsynthesis
rodent andofand bipolar
human
LY459477 disorders
mGlu2
was [10].
and mGlu3
required to
Moreover,
receptors. the supply
Development
support clinical route
trials for for LY459477
of schizophrenia, served
an appropriate generalized as an excellent
large-scale synthesis platform
of LY459477
anxiety disorder for
andwas the development
required
bipolar of
to support
disorders [10].
subsequent
clinical
Moreover,trials structurally
theforsupply related
schizophrenia,
route formGlu2/3
generalized
LY459477 agonists
anxiety
served asasdrug candidates
disorder for neuropsychiatric
and bipolar
an excellent platform disorders disorders
[10]. Moreover,
for the development of
[11].
the supply route for LY459477 served as an excellent platform for the development
subsequent structurally related mGlu2/3 agonists as drug candidates for neuropsychiatric disorders of subsequent
[11]. The chemotype
structurally of LY459477
related mGlu2/3 agonistswasasbased
drugon a cyclopentene
candidates scaffold first introduced
for neuropsychiatric by Hodgson
disorders [11].
and The
scientists
The chemotypeat GlaxoSmithKline
chemotype of
ofLY459477
LY459477was (then
wasbased
basedGlaxo
onon aWellcome)
a cyclopentene
cyclopentene [12] where
scaffold the
firstfirst
scaffold key
introducedintermediate,
introducedby Hodgson chiral
by Hodgsonand
alcohol 2,
scientists was
at obtained
GlaxoSmithKline from desymmetrization
(then Glaxo Wellcome) of the meso
[12] whereepoxide
the key3 (Scheme
and scientists at GlaxoSmithKline (then Glaxo Wellcome) [12] where the key intermediate, chiral 1).
intermediate, chiral alcohol 2,
was obtained
alcohol 2, wasfrom desymmetrization
obtained of the mesoofepoxide
from desymmetrization the meso 3 (Scheme
epoxide 31).(Scheme 1).
Scheme 1. Retrosynthesis of LY459477 into the key alcohol and epoxide intermediates.
A team of process chemists from Eli Lilly developed the original synthesis further in order to
A
deliverteam of processprecursor
cyclopentene chemists from
5 on Eli Lilly developed
a multikilogram the original
scale (Scheme synthesis
2). The further incomprises
synthesis order to deliver
of six
A team of process chemists from Eli Lilly developed the original synthesis further in order to
cyclopentene precursor 5 on a multikilogram scale (Scheme 2). The synthesis comprises of six discreet
discreet steps but proceeds through several telescoped stages with only two isolable
deliver cyclopentene precursor 5 on a multikilogram scale (Scheme 2). The synthesis comprises of six intermediates;
steps but proceeds
monoacid 4 and through several
cyclopentene 5.telescoped stages with only two isolable
Peracid-mediated intermediates; monoacid 4
discreet steps but proceeds through several telescopedepoxidation
stages with of only5 two
delivers the intermediates;
isolable oxygen atom
and cyclopentene
preferentially 5. Peracid-mediated
on the same face of5.the epoxidation of
cyclopentene delivers
as5the NHBoc thesubstituent
oxygen atom preferentially
as result on the
monoacid 4 and cyclopentene Peracid-mediated epoxidation of 5 delivers the of a hydrogen
oxygen atom
same face
bonding of the cyclopentene
interaction as the NHBoc substituent as result of a hydrogen bonding interaction
preferentially on the between
same facethe of oxidant and the latter
the cyclopentene as thefunctionality.
NHBoc substituentA variety of conditions
as result were
of a hydrogen
between
examined thefor
oxidant and thediastereoselectivity
optimum latter functionality. in A variety
the of conditionsofwere
epoxidation 5 examinedthe
towards for optimum
desirable
bonding interaction between the oxidant and the latter functionality. A variety of conditions were
diastereoselectivity
diastereomer in the epoxidation of 5 monoperoxyphthalate
towards the desirable in diastereomer 6a, concluding to
examined for6a,optimum
concluding to magnesium
diastereoselectivity in the epoxidation of a biphasic
5 towardswater/ethyl acetate
the desirable
magnesium
mixture monoperoxyphthalate
with 6a,
n-Bu in a biphasic water/ethyl acetate mixture with
4NHSO4 as a phase transfer catalyst (Scheme 3). This method was successfully
n-Bu 4 NHSO 4 as a
diastereomer concluding to magnesium monoperoxyphthalate in a biphasic water/ethyl acetate
phase
scaled transfer catalyst (Scheme 3). This method was successfully scaled up to 11 kg and the final
mixtureupwith
to 11 kg 4and
n-Bu NHSO the4 as
final product
a phase was recrystallized
transfer from3).
catalyst (Scheme EtOAc/heptane
This method giving 6a at 75%
was successfully
product
yield was
with 3% recrystallized
of the from EtOAc/heptane
diastereomer 6b. giving 6a at 75% yield with 3% of the diastereomer 6b.
scaled up to 11 kg and the final product was recrystallized from EtOAc/heptane giving 6a at 75%
yield with 3% of the diastereomer 6b.
Scheme
Scheme 2. Synthesis of
2. Synthesis of meso-epoxide
meso-epoxide precursor
precursor 5.
5.
The desymmetrizationScheme 2. Synthesis of meso-epoxide precursor 5.

of epoxide 6a into chiral allylic alcohol 2 demanded a wide screen of
chiral lithiated mono- and diamines as well as amino alcohols, temperatures, additives, reaction
times and stoichiometry in order to achieve maximum yield and enantioselectivity. Best results were
obtained with diamine 7 (Scheme 4) affording the desired chiral allylic alcohol in 72% yield and >99%
ee, followed closely by the corresponding diamine with an ethylene linker between the nitrogen
atoms (71% yield and 89% ee) whereas the analog with the butylene spacer proved non selective.
Interestingly, under the same conditions diastereomeric epoxide 6b essentially does not rearrange.
Catalysts 2020, 10, 1117 3 of 65
The rearrangement of epoxides to allylic alcohols has been demonstrated to proceed via abstraction of
either the syn-β H or the anti-β H, with cyclopentane skeletons favoring the former mode. This was
also shown
Catalysts 2020, to
10, be thePEER
x FOR caseREVIEW
for 6a through deuterium labeling studies. 3 of 69
Scheme
Catalysts 2020, 10, x FOR Scheme Substrate-controlled diastereoselective
3. Substrate-controlled
PEER REVIEW
3. diastereoselective epoxidation
epoxidation of
of 5.
5. 4 of 69
The desymmetrization of epoxide 6a into chiral allylic alcohol 2 demanded a wide screen of
chiral lithiated mono- and diamines as well as amino alcohols, temperatures, additives, reaction
times and stoichiometry in order to achieve maximum yield and enantioselectivity. Best results were
obtained with diamine 7 (Scheme 4) affording the desired chiral allylic alcohol in 72% yield and
>99% ee, followed closely by the corresponding diamine with an ethylene linker between the
nitrogen atoms (71% yield and 89% ee) whereas the analog with the butylene spacer proved non
selective. Interestingly, under the same conditions diastereomeric epoxide 6b essentially does not
rearrange. The rearrangement of epoxides to allylic alcohols has been demonstrated to proceed via
abstraction of either the syn-β H or the anti-β H, with cyclopentane skeletons favoring the former
mode. This was also shown to be the case for 6a through deuterium labeling studies.
A transition state consistent with above findings was proposed and involves the complexation
of the lithiated diamine with both the (deprotonated under the reaction conditions) Boc group and
the epoxide. In the latter case the lithium cation serves as a Lewis acid activating the epoxide
towards ring opening with concomitant abstraction of the adjacent enantiotopic epoxide-syn-β H.
This epoxide activation would be absent in the analogous complex of the lithiated diamine and the
Boc group of diastereoisomer 6b (being in opposite sides) thus consistent with the inertness of the
latter. The proposed transition state also exemplifies the importance of the distance between the two
lithiated amino groups as this must match the distance between the epoxide and Boc oxygen atoms
so that a stable complex is formed. This in turn supports the alignment of one of the basic nitrogen
atoms with one of the two enantiotopic syn-β H atoms, abstraction of which leads to high
enantioselectivities.
Scheme 4. Desymmetrization of meso epoxide 6a with chiral bases.

Scheme 4. Desymmetrization of meso epoxide 6a with chiral bases.
A transition state consistent with above findings was proposed and involves the complexation
of theThe cost-effectiveness
lithiated diamine withand of the
both this(deprotonated
competitive synthesis
under thestems from
reaction the inexpensive
conditions) starting
Boc group and
materials including chiral diamine 7 which can be easily prepared from (R)-α-methyl benzylamine
the epoxide. In the latter case the lithium cation serves as a Lewis acid activating the epoxide
and is recovered
towards up to
ring opening 80%
with from the pilot-plant
concomitant abstraction operations. Overall,
of the adjacent an important
enantiotopic chiral and
epoxide-syn-β H.
pharmaceutically privileged scaffold is accessed in multikilogram quantities through
This epoxide activation would be absent in the analogous complex of the lithiated diamine and the Boc the
desymmetrization
group of a meso
of diastereoisomer epoxide.
6b (being in opposite sides) thus consistent with the inertness of the latter.
The proposed transition state also exemplifies the importance of the distance between the two lithiated
amino groups as this must match the distance between the epoxide and Boc oxygen atoms so that a
stable complex is formed. This in turn supports the alignment of one of the basic nitrogen atoms with
one of the two enantiotopic syn-β H atoms, abstraction of which leads to high enantioselectivities.
Catalysts 2020, 10, 1117 4 of 65
The cost-effectiveness and of this competitive synthesis stems from the inexpensive starting
materials including chiral diamine 7 which can be easily prepared from (R)-α-methyl benzylamine and is
recovered up to 80% from the pilot-plant operations. Overall, an important chiral and pharmaceutically
privileged
Catalysts 2020, scaffold is accessed
10, x FOR PEER REVIEW in multikilogram quantities through the desymmetrization5 of a
of 69
meso epoxide.
1.2. Tasimelteon
Tasimelteon—Comparison
—ComparisonofofLarge-Scale
Large-ScaleCatalytic
CatalyticAsymmetric
AsymmetricEpoxidation
EpoxidationProcesses
ProcessesTowards
Towardsa aChiral
Chiral
Dihydrobenzofuran Epoxide
Dihydrobenzofuran Epoxide
Agonism at
Agonism atthe
themelatonin
melatoninreceptors 1 and
receptors 2 has2produced
1 and drug molecules
has produced that havethat
drug molecules beenhave
approved
been
for the treatment of insomnia and circadian rhythms sleep–wake disorders (ramelteon,
approved for the treatment of insomnia and circadian rhythms sleep–wake disorders (ramelteon, tasimelteon) as
well as for depression
tasimelteon) as well as (agomelatine)
for depression[13]. During the[13].
(agomelatine) development
During theof tasimelteon,of
development (Scheme 5) by
10tasimelteon, 10
Bristol-Myers Squibb, provision of large quantities of 11, required the development
(Scheme 5) by Bristol-Myers Squibb, provision of large quantities of 11, required the development of a supply route.
of
aOne of theroute.
supply first syntheses
One of theexamined by process
first syntheses chemists
examined at BMS involved
by process chemists chiral
at BMS epoxide
involved12 as the
chiral
key intermediate
epoxide 12 as the askeythis could be transformed
intermediate to be
as this could acid 11 by reaction
transformed with11triethyl
to acid phosphonoacetate
by reaction with triethyl
followed by ester hydrolysis [14].
phosphonoacetate followed by ester hydrolysis [14].
Scheme 5. Retrosynthetic analysis of tasimelteon into key epoxide intermediate 12.

Scheme 5. Retrosynthetic analysis of tasimelteon into key epoxide intermediate 12.
Initially the Jacobsen–Katsuki asymmetric epoxidation (AE) [15–17] was attempted and its
Initially the Jacobsen–Katsuki asymmetric epoxidation (AE) [15–17] was attempted and its
optimization involved extensive screening of catalysts, solvents, oxidants, additives, reaction
optimization involved extensive screening of catalysts, solvents, oxidants, additives, reaction
temperature and time. It quickly became evident that the reaction needed to be carried out at
temperature and time. It quickly became evident that the reaction needed to be carried out at very
very low temperature in order to achieve significant enantioselectivity which never actually exceeded
low temperature in order to achieve significant enantioselectivity which never actually exceeded
76% ee. mCPBA (meta-chloroperoxybenzoic acid) provided higher enantioselectivities than MMPP
76% ee. mCPBA (meta-chloroperoxybenzoic acid) provided higher enantioselectivities than MMPP
(magnesium monoperoxyphthalate) or bleach and addition of NMO (N-methylmorpholine N-oxide)
(magnesium monoperoxyphthalate) or bleach and addition of NMO (N-methylmorpholine N-oxide)
was also beneficial. DCM proved the best solvent both in terms of conversion and enantioselectivities,
was also beneficial. DCM proved the best solvent both in terms of conversion and
yet this also proved the Achilles heel of the process since it caused significant safety and operational
enantioselectivities, yet this also proved the Achilles heel of the process since it caused significant
issues. Specifically, the moderate solubility of mCPBA in DCM exacerbated by the low reaction
safety and operational issues. Specifically, the moderate solubility of mCPBA in DCM exacerbated
temperature at −75 to −65 ◦ C, caused precipitation of the reagent leading to inconsistent reaction
by the low reaction temperature at −75 to −65 °C, caused precipitation of the reagent leading to
mixtures. More frequently than not, large exotherms and abrupt gas evolution were observed upon
inconsistent reaction mixtures. More frequently than not, large exotherms and abrupt gas evolution
addition of the mCPBA solution in the reaction mixture which caused serious safety concerns. Adjusting
were observed upon addition of the mCPBA solution in the reaction mixture which caused serious
for concentration, time and order of reagent addition did not solve these issues. Solvents in which
safety concerns. Adjusting for concentration, time and order of reagent addition did not solve these
mCPBA dissolves better, like EtOAc or ethanol were attempted as DCM replacements, but the reaction
issues. Solvents in which mCPBA dissolves better, like EtOAc or ethanol were attempted as DCM
did not proceed. Finally, by keeping DCM as the reaction and using the minimum amount of ethanol
replacements, but the reaction did not proceed. Finally, by keeping DCM as the reaction and using
to dissolve and transfer the mCPBA into the reaction mixture solved these issues and provided a fast
the minimum amount of ethanol to dissolve and transfer the mCPBA into the reaction mixture
reaction reaching 95% conversion within the three hours employed for addition of the mCPBA at
solved these issues and provided a fast reaction reaching 95% conversion within the three hours
−70 ◦ C. The optimized process involving catalyst M1 (Scheme 6) was successfully scaled up to 1 kg
employed for addition of the mCPBA at −70 °C. The optimized process involving catalyst M1
scale and delivered chiral epoxide 12 in 80% yield and 74% ee. This was deemed acceptable at this
(Scheme 6) was successfully scaled up to 1 kg scale and delivered chiral epoxide 12 in 80% yield and
point since a resolution step, using dehydroabietylamine (leelamine), was to be implemented later in
74% ee. This was deemed acceptable at this point since a resolution step, using dehydroabietylamine
the synthesis at the amine intermediate which upgraded the optical purity to 99% ee.
(leelamine), was to be implemented later in the synthesis at the amine intermediate which upgraded
Despite the temporary success in supplying the initially required quantities of drug substance,
the optical purity to 99% ee.
the necessity for a resolution step, the varying levels of manganese salts in the isolated intermediates
and the apparently unavoidable formation of benzofuran impurity 14 (>3%), undermined the potential
of this route in developing into a manufacturing process. Overoxidized impurity 14 in particular,
presumably formed by mCPBA or catalyst-induced hydroxylation at the benzylic position followed
by dehydration [18,19], posed significant quality issues as it transformed through the synthesis to
Catalysts 2020, 10, 1117 5 of 65
species that were difficult to purge, such as the acid 15, due to the high similarity with the desired
intermediates and ultimately with the final product.
Scheme 6. Catalytic asymmetric epoxidation of 13 and conversion to cyclopropane intermediate 11.

Scheme 6. Catalytic asymmetric epoxidation of 13 and conversion to cyclopropane intermediate 11.
This prompted the investigation of an alternative route to epoxide 12. Towards this end, Sharpless
Despite the temporary success in supplying the initially required quantities of drug substance,
Asymmetric Dihydroxylation on alkene 13 followed by transformation of the chiral diol 16 (Scheme 7) to
the necessity for a resolution step, the varying levels of manganese salts in the isolated intermediates
the epoxide was considered next [20]. Encouraging results were obtained from preliminary experiments
and the apparently unavoidable formation of benzofuran impurity 14 (>3%), undermined the
as diol 16 was isolated with high ee as a crystalline and easy to handle solid. Significant work was
potential of this route in developing into a manufacturing process. Overoxidized impurity 14 in
dedicated before selecting potassium ferricyanide as the osmium reoxidant over the less expensive
particular, presumably formed by mCPBA or catalyst-induced hydroxylation at the benzylic
NMO. Potassium ferricyanide requires larger solvent quantities to be suspended adequately, produces
position followed by dehydration [18,19], posed significant quality issues as it transformed through
a significant solid waste that must be removed during isolation and constitutes an additional burden in
the synthesis to species that were difficult to purge, such as the acid 15, due to the high similarity
terms of toxic materials in the process. Nevertheless, it provided consistently high enantioselectivities
with the desired intermediates and ultimately with the final product.
(98–99% ee) thus eliminating the necessity for a resolution step and robust reactions whereas the
This prompted the investigation of an alternative route to epoxide 12. Towards this end,
process with NMO proved sensitive to the rate of addition of alkene 13. The next issue that had to be
Sharpless Asymmetric Dihydroxylation on alkene 13 followed by transformation of the chiral diol 16
dealt with was the poor solubility of 13 in tert-butanol/water mixtures which was eventually solved by
(Scheme 7) to the epoxide was considered next [20]. Encouraging results were obtained from
replacing tert-butanol with isopropanol. Interestingly the reaction failed to proceed with commercially
preliminary experiments as diol 16 was isolated with high ee as a crystalline and easy to handle
available AD-Mix-α, and potassium persulfate was used and required the in situ preparation of the
solid. Significant work was dedicated before selecting potassium ferricyanide as the osmium
catalyst. The final problem intrinsically linked to the Asymmetric Dihydroxylation reaction was the
reoxidant over the less expensive NMO. Potassium ferricyanide requires larger solvent quantities to
reduction of the toxic osmium species to pharmaceutically acceptable levels which for the isolated diol
be suspended adequately, produces a significant solid waste that must be removed during isolation
intermediate was set at <10 ppm. Following a screening of resins, filter aids and reagents as well as the
and constitutes an additional burden in terms of toxic materials in the process. Nevertheless, it
development of an appropriate analytical method, the use of a sodium sulfite wash in the work up
provided consistently high enantioselectivities (98–99% ee) thus eliminating the necessity for a
reduced the osmium levels to less than 6 ppm as determined by inductively coupled plasma atomic
resolution step and robust reactions whereas the process with NMO proved sensitive to the rate of
emission spectroscopy (ICP-ES).
addition of alkene 13. The next issue that had to be dealt with was the poor solubility of 13 in
The optimized process (Scheme 7) was gradually scaled up to 1, 8 and 15 kg scale furnishing
tert-butanol/water mixtures which was eventually solved by replacing tert-butanol with
diol 16 in 90% yield, HPLC purity of 98% and >99% ee and as a crystalline solid, provided the water
isopropanol. Interestingly the reaction failed to proceed with commercially available AD-Mix-α, and
content of the organic solution after work up was <1% w/w.
potassium persulfate was used and required the in situ preparation of the catalyst. The final problem
Finally, diol 16 was transformed to the desired epoxide 12 through the Kolb -Sharpless method [21],
intrinsically linked to the Asymmetric Dihydroxylation reaction was the reduction of the toxic
by treatment with trimethyl orthoacetate and trimethylsilyl chloride followed by base. In this process,
osmium species to pharmaceutically acceptable levels which for the isolated diol intermediate was
the initially formed orthester 17 is converted in situ to chloroacetate intermediate 18 with inversion of
set at <10 ppm. Following a screening of resins, filter aids and reagents as well as the development of
configuration and after hydrolysis of the ester and ring closure, also with inversion of configuration,
an appropriate analytical method, the use of a sodium sulfite wash in the work up reduced the
osmium levels to less than 6 ppm as determined by inductively coupled plasma atomic emission
spectroscopy (ICP-ES).
Catalysts 2020, 10, 1117 6 of 65
provides the desired chiral epoxide 12. When the traditional conditions of K2 CO3 /MeOH were used
for the latter part of the process, significant amounts of impurity 19 were observed (up to 10%)
presumably via opening of the epoxide by methoxide anion. The epoxide stability issue surfaced
required investigation of appropriate solvents, bases, reaction temperature and times temperatures as
well as work up procedures in order to inhibit the formation of impurity 19. The optimum conditions
found involved confirming by HPLC the completion of chloroacetate formation, followed by charging
a solution of KOt Bu in THF at 0–5 ◦ C and maintaining at the same temperature until conversion to the
epoxide was complete (~ 1 h) (Scheme 7). No deterioration of the epoxide quality is observed under
The optimized process (Scheme 7) was gradually scaled up to 1, 8 and 15 kg scale furnishing
these conditions even after prolonged reaction times. The optimized process was successfully scaled
diol 16 in 90% yield, HPLC purity of 98% and >99% ee and as a crystalline solid, provided the water
up to 8 kg batches delivering the epoxide 90–95% yield and >98% ee.
content of the organic solution after work up was <1% w/w.
Scheme 7. Synthesis of chiral epoxide 12 via Sharpless asymmetric dihydroxylation of 13.

Scheme 7. Synthesis of chiral epoxide 12 via Sharpless asymmetric dihydroxylation of 13.
Finally, diol 16 was transformed to the desired epoxide 12 through the Kolb -Sharpless method [21],
Finally, diol
by treatment with16 was transformed
trimethyl orthoacetate to the
anddesired epoxide
trimethylsilyl 12 through
chloride the Kolb
followed -Sharpless
by base. In this method
process,
[21], by treatment with trimethyl orthoacetate and trimethylsilyl chloride followed
the initially formed orthester 17 is converted in situ to chloroacetate intermediate 18 with inversion by base. In this
of
process, the initially
configuration and after formed orthester
hydrolysis of the17ester
is converted
and ring in situ toalso
closure, chloroacetate
with inversionintermediate 18 with
of configuration,
inversionthe
provides of configuration
desired chiral and after12.
epoxide hydrolysis
When theoftraditional
the ester and ring closure,
conditions of K2 COalso3 /MeOH
with inversion
were used of
configuration, provides the desired chiral epoxide 12. When the
for the latter part of the process, significant amounts of impurity 19 were observed (up to 10%) traditional conditions of
K2CO3/MeOH
presumably viawere used of
opening forthe
theepoxide
latter partby of the process,
methoxide significant
anion. amounts
The epoxide of impurity
stability 19 were
issue surfaced
observed (up to 10%) presumably via opening of the epoxide by methoxide
required investigation of appropriate solvents, bases, reaction temperature and times temperatures as anion. The epoxide
stability
well issueup
as work surfaced
proceduresrequired investigation
in order to inhibit theof formation
appropriate of solvents,
impurity 19. bases,
Thereaction
optimum temperature
conditions
and times
found temperatures
involved confirming as well as work
by HPLC up procedures
the completion in order to inhibit
of chloroacetate the formation
formation, followed by of impurity
charging
19. The optimum t conditions found ◦ involved confirming by HPLC the completion
a solution of KO Bu in THF at 0–5 C and maintaining at the same temperature until conversion to the of chloroacetate
formation,
epoxide was followed
complete by(~charging
1 h) (Schemea solution
7). Noofdeterioration
KOtBu in THF of at
the0–5 °C andquality
epoxide maintaining at theunder
is observed same
temperature
these conditionsuntileven
conversion to the epoxide
after prolonged reactionwas complete
times. (~1 h) (Scheme
The optimized 7). was
process No deterioration of the
successfully scaled
epoxide
up to 8 kgquality
batchesisdelivering
observedthe under
epoxidethese conditions
90–95% even
yield and >98%
afteree.prolonged reaction times. The
optimized
Overall, process was successfully
the efforts to develop a scaled up toroute
large-scale 8 kgtobatches delivering
tasimelteon the epoxide
culminated 90–95% yield
in interrogating the
and >98% ee.
performance and viability of two of the most popular asymmetric transformations, namely the
Overall, the efforts
Jacobsen–Katsuki to develop
Asymmetric a large-scaleand
Epoxidation routethe
to tasimelteon
Sharpless culminated
Asymmetricin Dihydroxylation.
interrogating the
performance
Both processes and viability
required of two
careful of the most
navigation popular
through safetyasymmetric
and product transformations, namelyfrom
quality issues arising the
Jacobsen–Katsuki Asymmetric Epoxidation and the Sharpless Asymmetric
reagents, catalysts and associated process impurities as well as technical difficulties in several unitDihydroxylation. Both
processes required
operations. Despite careful navigation
the shorter through
route offered bysafety and product
the Asymmetric quality issues
epoxidation process,arising from
the lower
reagents, catalystsachieved
enantioselectivity and associated
renders process
imperativeimpurities as well as technical
the implementation difficulties
of a resolution step andin several unit
in addition,
operations. Despite the shorter route offered by the Asymmetric epoxidation
suffers from a persistent impurity. The Asymmetric Dihydroxylation route although more process process, the lower
enantioselectivity achieved renders imperative the implementation of a resolution step and in
addition, suffers from a persistent impurity. The Asymmetric Dihydroxylation route although more
process intensive, provides excellent enantioselectivity, superior purity profile and higher overall
yield of the final drug substance (43% vs 22%).
Catalysts 2020, 10, 1117 7 of 65
intensive, provides excellent enantioselectivity, superior purity profile and higher overall yield of the
final drug substance (43% vs 22%).
1.3. Efinaconazole, Ravuconazole, Isavuconazole, Albaconazole—Synthesis via Two Successive Chiral Epoxide
Intermediates and Ring Opening Reactions
The introduction of fluconazole in 1988 was a major breakthrough in the treatment of fungal
Catalysts 2020,harming
infections 10, x FOR humans,
PEER REVIEW
animals and plants [22,23]. Fungal infections vary in severity from8 mild of 69
to fatal particularly when the people infected receive chemotherapy, immunosuppressant treatment or
to fatal
are particularly when the
immunocompromised people
such as HIV infected receive
patients. Azolechemotherapy,
antifungals work immunosuppressant
by inhibiting primarilytreatment the
or are immunocompromised such as HIV patients. Azole antifungals work
cytochrome P450-dependent lanosterol 14α-demethylase (Erg11p, CYP51) involved in the biosynthesis by inhibiting primarily
the cytochrome
of ergosterol P450-dependent
which is essential for lanosterol 14α-demethylase
fungi membrane integrity.(Erg11p,
Over the CYP51)
years, involved in the
issues related to
biosynthesis of ergosterol which is essential for fungi membrane integrity. Over
bioavailability, toxicity, resistance, limited spectrum activity and cost has prompted intense research the years, issues
related to bioavailability,
in antifungal toxicity,analogs
research including resistance,
of thelimited
triazolespectrum
class. This activity
effort and cost has prompted
has produced approved
intense
drugs such as efinaconazole [24], isavuconazole (in its prodrug form isavuconazonium sulfate) has
research in antifungal research including analogs of the triazole class. This effort [25]
produced
and clinicalapproved
candidates drugs such as efinaconazole
like ravuconazole [24], isavuconazole
[26] and albaconazole [27] (Scheme (in8).its prodrug
In the triazoleform
and
isavuconazonium
imidazole classes sulfate) [25] and
of antifungals clinical biologic
optimum candidates like ravuconazole
activity requires the R,R [26]stereochemistry
and albaconazole [27]
at both
(Scheme 8). In the triazole and imidazole classes of antifungals optimum biologic
the benzylic and adjacent stereocenter. In this context, epoxide 24 presents a key intermediate for the activity requires
the R,R stereochemistry
synthesis of these molecules,at both
butthe
alsobenzylic and adjacent
an attractive stereocenter.
diversification point forInthe
thispreparation
context, epoxide 24
of related
presents
analogs. aThe
keyR,Sintermediate for theofsynthesis
stereochemistry 24 ensures ofthat
these molecules,
regardless of but also an attractive
the nucleophile used, diversification
the subsequent
point for the preparation of related analogs. The R,S stereochemistry
ring opening of the epoxide which proceeds with inversion of configuration, will deliverof 24 ensures that regardless
the correctof
the nucleophile used, the subsequent
stereochemistry hence active analogs. ring opening of the epoxide which proceeds with inversion of
configuration, will deliver the correct stereochemistry hence active analogs.
Scheme 8. Approved triazole antifungals and their common synthetic precursor epoxide 24.
ThereScheme
have 8. Approved
been severaltriazole antifungals
approaches and their
in accessing keycommon
epoxidesynthetic precursor
24 over the years byepoxide
various24.academic
groups and pharma companies. Almost invariably the key feature of these efforts concentrated in
There have
establishing the Sbeen several approaches
stereochemistry in accessing
at the stereocenter key the
bearing epoxide
methyl24group
over sothethat
years
it isby various
inverted to
academic groups and pharma companies. Almost invariably the key feature
the correct R configuration in the subsequent reaction with the choice nucleophile, namely CN for of these efforts
−
concentrated in establishing
ravu/isavuconazole, the piperidine
methylene S stereochemistry at the stereocenter
for efinaconazole bearing the methyl group for
and 7-chloroquinazolin-4(3H)-one so
that it is inverted to the correct R configuration in the subsequent reaction
albaconazole. A summary of these routes outlined in Scheme 9 below. One of the early attempts to with the choice
nucleophile, namely CN- for
install the S stereochemistry ravu/isavuconazole,
in 24, involved the use ofmethylene piperidine
the Sharpless asymmetric for epoxidation
efinaconazole and
reaction
7-chloroquinazolin-4(3H)-one for albaconazole. A summary of these routes outlined
on allylic alcohol 25 to provide epoxy alcohol 26 in 95% yield and 76% ee [28]. Mesylation of the in Scheme 9
below.
primary One of thefollowed
alcohol early attempts to install
by triazole the S stereochemistry
displacement furnished the keyin 24, involved
epoxide 24. the use of the
A variation of
Sharpless asymmetric epoxidation reaction on allylic alcohol 25 to provide epoxy
this approach was reported in a recent synthesis of efinaconazole where the triazole analog alcohol 26 inrather
95%
yield and 76% ee [28]. Mesylation
than hydroxy-substituted alkene 25 was of subjected
the primary to thealcohol followed
Sharpless by triazole
asymmetric displacement
dihydroxylation [29].
furnished the key epoxide 24. A variation of this approach was reported in a recent synthesis of
efinaconazole where the triazole analog rather than hydroxy-substituted alkene 25 was subjected to
the Sharpless asymmetric dihydroxylation [29]. Despite the ability to upgrade the optical purity
downstream the synthesis, the issue with these routes is the preparation of the cis double bond in the
alkene substrate. In the case of 25 extensive manipulation was required to isomerize the
predominant trans isomer (formed by Wittig reaction on the corresponding acetoxy-acetophenone)
Catalysts 2020, 10, 1117 8 of 65
Despite the ability to upgrade the optical purity downstream the synthesis, the issue with these
routes is the preparation of the cis double bond in the alkene substrate. In the case of 25 extensive
manipulation was required to isomerize the predominant trans isomer (formed by Wittig reaction on
the corresponding
Catalysts acetoxy-acetophenone)
2020, 10, x FOR PEER REVIEW which negated further development work. 9 of 69
Scheme
Scheme 9. Summary of
9. Summary of approaches
approaches towards
towards an
an asymmetric
asymmetric synthesis
synthesis of
of 24.
24.
Earlier
Earlier than
thanthat,
that,chemists
chemists at Sankyo
at Sankyo(legacy company
(legacy of Daichi
company Sankyo)
of Daichi after proving
Sankyo) the viability
after proving the
of a synthesis with racemic lactic acid derivatives, switched to the chiral pool
viability of a synthesis with racemic lactic acid derivatives, switched to the chiral pool and usedand used D-(−)-lactic
acid [30–33].acid
D-(−)-lactic This was converted
[30–33]. to the THP-protected
This was converted morpholine
to the THP-protected amide and
morpholine reacted
amide andwith the
reacted
2,4-difluorophenyl GrignardGrignard
with the 2,4-difluorophenyl reagent producing ketone 27.ketone
reagent producing Corey–Chaykovsky epoxidation
27. Corey–Chaykovsky reaction
epoxidation
with
reaction with trimethyl sulfoxonium ylide yielded THP-protected epoxy alcohol 28 inratio
trimethyl sulfoxonium ylide yielded THP-protected epoxy alcohol 28 in 4:1 diastereomeric 4:1
favoring
diastereomeric ratio R,R
the desired stereochemistry.
favoring the desiredThe R, Rsame result was obtained
stereochemistry. fromresult
The same the mCPBA epoxidation
was obtained from
of
theterminal
mCPBAalkene 29 (produced
epoxidation via aalkene
of terminal Wittig29 reaction fromvia
(produced 27),a thus no reaction
Wittig advantage fromwas gained
27), thus byno
adding the extra step in the synthesis. Ring opening of the epoxide by triazole
advantage was gained by adding the extra step in the synthesis. Ring opening of the epoxide by to form 30 followed
by THP deprotection
triazole and mesylation
to form 30 followed by THPaffords hydroxyand
deprotection mesylate 31 which
mesylation affordsupon base treatment
hydroxy mesylatering 31
closes to the second epoxide of the synthesis and key intermediate 24. These
which upon base treatment ring closes to the second epoxide of the synthesis and key intermediate and subsequent steps
rectify the optical
24. These purity. Thesteps
and subsequent steps rectify
of triazole
the installation and mesylation
optical purity. The steps could be reversed
of triazole providing
installation and
mesylation could be reversed providing actually a cleaner profile overall, as the 1,2,4-triazole was
shown to react chemoselectively with 32 by ring opening the epoxide.
Interestingly, the corresponding triflate reacts with inversed chemoselectivity, giving the SN2
triflate substitution product when treated with the triazole. This aspect was investigated in the
context of inversing the configuration of that center if the L-(+)-lactic acid was initially employed.
Both enantiomers of lactic acid occur naturally, but the S enantiomer is much more abundant, and its
Catalysts 2020, 10, 1117 9 of 65
actually a cleaner profile overall, as the 1,2,4-triazole was shown to react chemoselectively with 32 by
ring opening the epoxide.
Interestingly, the corresponding triflate reacts with inversed chemoselectivity, giving the SN 2
triflate substitution product when treated with the triazole. This aspect was investigated in the
context of inversing the configuration of that center if the L-(+)-lactic acid was initially employed.
Both enantiomers of lactic acid occur naturally, but the S enantiomer is much more abundant, and its
utilization
Catalysts 2020,would
10, x FORreduce the cost of the triazole antifungals.
PEER REVIEW 10 of 69
In analogy to 27, its enantiomer, 33, would give the opposite and undesired stereochemistry
at theInstereogenic
analogy to epoxide
27, its enantiomer,
carbon in the 33, Corey–Chaykovsky
would give the opposite and undesired
epoxidation reaction. stereochemistry
For this reason, at
the stereogenic
ketone epoxide carbon
33 was converted to allylic inalcohol
the Corey–Chaykovsky
34 and subjected to epoxidation
vanadiumreaction.
catalyzedFor this reason,
epoxidation to
ketone 33
provide was alcohol
epoxy converted to allylic
35 [34]. The alcohol 34 and subjected
same transformation has to vanadium
also catalyzed
been reported withepoxidation
the use of the to
provide epoxy
Sharpless alcohol epoxidation
asymmetric 35 [34]. The reaction
same transformation
which gives has also 86%
35 with beenee reported
[35,36]. with the use
Inversion of of
thethe
S
Sharpless asymmetric
stereochemistry epoxidation reaction
at the hydroxyl-bearing which
carbon has gives 35 with 86%
been reported ee [35,36].
via both MitsunobuInversion of theon
conditions S
stereochemistry
the at the hydroxyl-bearing
alcohol and displacement its triflate by carbon
nitritehasorbeen reported
hydroxide via both
anions. SomeMitsunobu
degree of conditions
retention on of
the alcohol and
configuration displacement
is also its triflate
observed during these byextended
nitrite ormanipulations
hydroxide anions. Somethe
rendering degree
routes offrom
retention of
the less
configuration is also observed during these extended manipulations rendering
costly L-(+)-Lactic acid less efficient overall. It is worth noting that reducing the cost contribution of the routes from the
less costly L-(+)-Lactic
D-(−)-Lactic acid less
acid, particularly inefficient
the caseoverall. It is worth
of efinaconazole (anoting that reducing
full course the cost 10%,
of efinaconazole, contribution
therapy
of D-(−)-Lactic
for one-nail costs acid, particularly
$2,307) in the case
[37] has prompted of efinaconazole
intensive investigations(a full
forcourse of efinaconazole,
alternative preparations of 10%,
27
therapy for one-nail costs $2,307) [37] has prompted intensive investigations
and related derivatives. These include utilization of Evans’ auxiliary [38], asymmetric hydroxylation for alternative
preparations
of 2,4-difluoro of 27 and related
propiophenone [39],derivatives. These include
enzymatic resolution utilizationcyanohydrin
[40], asymmetric of Evans’ auxiliary
formation [38],[41],
asymmetric Henry hydroxylation of 2,4-difluoro propiophenone [39], enzymatic
reaction [42] and the oxidative ring opening of β-methyl-2,4-difluorostyrene resolution [40],
asymmetric
oxide [43]. Thecyanohydrin formation resourceful
latter is a particularly [41], asymmetricand rarelyHenry reaction transformation
encountered [42] and the oxidative
that deservesring
aopening
special of β-methyl-2,4-difluorostyrene oxide [43]. The latter is a particularly resourceful and rarely
mention.
encountered
In a styrenetransformation
oxide substratethat deserves
(Schemea 10), special mention.of the epoxide oxygen atom with TMS
activation
In a styrene
(trimethylsilyl) or oxide
TBDMS substrate
triflate (Scheme 10), activation of
(tert-butyldimethylsilyl the epoxide oxygen atomcauses
trifluoromethanesulfonate) with TMSring
(trimethylsilyl)
opening or TBDMSgeneration
with concomitant triflate (tert-butyldimethylsilyl trifluoromethanesulfonate)
of the benzylic cation (probably an equilibrium) thanks causestoringthe
opening with concomitant generation of the benzylic cation (probably
resonance stabilization provided by the aryl substituent. In the absence or more potent nucleophiles, an equilibrium) thanks to the
resonancesulfoxide
dimethyl stabilization provided
may engage theby the aryl
cation and substituent.
form a sulfoxoniumIn the absence or more
intermediate akinpotent
to thatnucleophiles,
encountered
in Swern-type oxidations of alcohols. Introduction of triethylamine at this advanced stagetoof that
dimethyl sulfoxide may engage the cation and form a sulfoxonium intermediate akin the
encountered
reaction in Swern-type
eliminates oxidations
triethylammonium of alcohols.
triflate Introduction
and dimethyl sulfide toof generate
triethylamine at this
the ketone. Theadvanced
starting
stage of geometry
cis/trans the reaction eliminates
of the epoxidetriethylammonium triflate and dimethyl
substituents is inconsequential sulfide to is
as this information generate
lost in the
ketone. The starting cis/trans geometry of the epoxide substituents
product. More important, the stereochemistry at the carbon preserving the original bond to the epoxide is inconsequential as this
information
oxygen is lost in
is retained in the
the alcohol
product. More important,
product. The generalitythe stereochemistry
of this reaction hasat the carbon
been preservingwith
demonstrated the
originalstilbene
several bond toand the epoxide oxygen is retained in the alcohol product. The generality of this reaction
styrene oxides.
has been demonstrated with several stilbene and styrene oxides.
Scheme
Scheme 10. Innovative oxidative
10. Innovative oxidative ring
ring opening
opening of
of epoxides
epoxides with
with electron
electron donating
donating substituents.
substituents.
The
The ring
ringopening
opening of epoxide
of epoxide24 with
24 various nucleophiles
with various has also been
nucleophiles investigated
has also extensively.
been investigated
Almost invariably, alkali and alkaline earth metal salts are reported as the optimum
extensively. Almost invariably, alkali and alkaline earth metal salts are reported as the optimum additives to aid the
nucleophile
additives to in thethe
aid ring opening ofin24the
nucleophile [44–47]. In a recent
ring opening iteration
of 24 (t-BuO)
[44–47]. 2 Mg was
In a recent found (t-BuO)
iteration to facilitate
2Mg
the reaction of 24 with a secondary amine used directly in its hydrochloride form [48].
was found to facilitate the reaction of 24 with a secondary amine used directly in its hydrochloride The first event
is the [48].
form neutralization of theissalt
The first event thetoneutralization
form the amine-free base,
of the salt to t-BuOH
form theand t-BuOMgCl
amine-free base,which
t-BuOH in turn
and
acts
t-BuOMgCl which in turn acts as Lewis acid to activate the epoxide. This was demonstrated on 700of
as Lewis acid to activate the epoxide. This was demonstrated on 700 g scale in the synthesis g
efinaconazole which was
scale in the synthesis isolated in 96%
of efinaconazole yield.
which was isolated in 96% yield.
From all interconnected routes discussed above (Scheme 9) and variations thereof, process
chemists at Bristol-Myers Squibb selected to develop further the process from 27, that leads to the
key epoxide 24 via intermediates 28, 32, 34 as the manufacturing route of choice for ravuconazole
[49]. This process that proceeds through the synthesis and ring opening of two epoxide
intermediates has its roots in Sankyo’s original approach towards triazole antifungals and ever since
Catalysts 2020, 10, 1117 10 of 65
From all interconnected routes discussed above (Scheme 9) and variations thereof, process chemists
at Bristol-Myers Squibb selected to develop further the process from 27, that leads to the key epoxide
24 via intermediates 28, 32, 34 as the manufacturing route of choice for ravuconazole [49]. This process
that proceeds through the synthesis and ring opening of two epoxide intermediates has its roots in
Sankyo’s original approach towards triazole antifungals and ever since has been regarded as the
standard method to prepare these and related scaffolds [50–54].
Catalysts 2020, 10, x FOR PEER REVIEW

1.4. AZD-4818—Development 11 of 69
of a Multikilogram Synthesis of a Chiral Epoxide Precursor to A CCR1 Antagonist
The CCR1
The CCR1 (chemokine
(chemokinereceptor
receptor1)1)isisa aGGprotein-coupled
protein-coupled receptor expressed
receptor on on
expressed a wide range
a wide of cell
range of
types including monocytes, NK cells, basophils, eosinophils, mast cells, osteoclasts
cell types including monocytes, NK cells, basophils, eosinophils, mast cells, osteoclasts and and predominantly
in neutrophils, dendritic
predominantly cells and dendritic
in neutrophils, T lymphocytes. cells Based
and Tonlymphocytes.
animal models, pharmacological
Based on animal blockade
models,
of CCR1 has been proposed to combat inflammatory and autoimmune diseases
pharmacological blockade of CCR1 has been proposed to combat inflammatory and autoimmune such as rheumatoid
arthritis, multiple
diseases such as sclerosis and more
rheumatoid recently
arthritis, cancersclerosis
multiple thus CCR1 andantagonists have attracted
more recently cancer thussignificant
CCR1
interest [55–57].
antagonists have attracted significant interest [55–57].
Astra Zeneca’s
Astra Zeneca’s compound
compound AZD-4818
AZD-4818 (Scheme
(Scheme 11)
11) is
is aa CCR1
CCR1 antagonist
antagonist and
and aa clinical
clinical candidate
candidate
for the treatment of immune and inflammation disorders
for the treatment of immune and inflammation disorders [56,58]. [56,58].
Scheme 11. Early medicinal chemistry route to AZD-4818.

Scheme 11. Early medicinal chemistry route to AZD-4818.
Initial modifications of the original medicinal chemistry route to CCR1 (Scheme 11), identified
Initial modifications of the original medicinal chemistry route to CCR1 (Scheme 11), identified
the formation of the intermediate 40 from 4-(acetylamino)-3-hydroxyphenyl acetate (39) and
the formation of the intermediate 40 from 4-(acetylamino)-3-hydroxyphenyl acetate (39) and
((2S)-2-methyloxiranyl)-methyl 3-nitrobenzenesulfonate (38) as the critical step of the synthesis [59].
((2S)-2-methyloxiranyl)-methyl 3-nitrobenzenesulfonate (38) as the critical step of the synthesis [59].
Epoxy nosylate 38 turned out to be a highly energetic material that decomposed in an autocatalytic
Epoxy nosylate 38 turned out to be a highly energetic material that decomposed in an autocatalytic
manner even at low temperatures. In addition, during the first 43 and 120 kg campaigns, robustness
manner even at low temperatures. In addition, during the first 43 and 120 kg campaigns, robustness
issues in the asymmetric Sharpless epoxidation of 2-methyl-2-propen-1-ol (36) became a concern which
issues in the asymmetric Sharpless epoxidation of 2-methyl-2-propen-1-ol (36) became a concern
prompted the investigation of alternative routes towards 40.
which prompted the investigation of alternative routes towards 40.
AstraZeneca process chemists considered connecting the aromatic moiety to an appropriate
AstraZeneca process chemists considered connecting the aromatic moiety to an appropriate
glycerol fragment that would bear a latent epoxide functionality to be revealed later in the synthesis.
glycerol fragment that would bear a latent epoxide functionality to be revealed later in the synthesis.
An acetonide-protected diol serves well this purpose [60] thus a chiral glycerol intermediate 42R was
An acetonide-protected diol serves well this purpose [60] thus a chiral glycerol intermediate 42R
prepared initially in the racemic form 42rac followed by enzymatic resolution of its succinate derivative
was prepared initially in the racemic form 42rac followed by enzymatic resolution of its succinate
(Scheme 12). Extensive optimization of this sequence enabled isolation of 42R in 22% overall yield
derivative (Scheme 12). Extensive optimization of this sequence enabled isolation of 42R in 22%
at >98% ee. Its subsequent nucleophilic aromatic substitution with 3-fluoro-4-nitrophenol was also
overall yield at >98% ee. Its subsequent nucleophilic aromatic substitution with
carefully optimized and demonstrated successfully in multikilogram batches (156 kg in two batches).
3-fluoro-4-nitrophenol was also carefully optimized and demonstrated successfully in
multikilogram batches (156 kg in two batches). Intermediate 43 however could not be isolated as a
solid hence its solution was used directly in the next reaction.
Catalysts 2020, 10, 1117 11 of 65
Intermediate 43 however could not be isolated as a solid hence its solution was used directly in the
Catalysts
next 2020, 10, x FOR PEER REVIEW
reaction. 12 of 69
Scheme 12.
Scheme Process route
12. Process route to
to key
key intermediate
intermediate 43;
43; carried
carried forward
forward as
as aa solution
solution thereof.
thereof.
At
At this
this point
point two
two options
options were
were considered
considered with
with respect
respect to
to the
the sequence
sequence ofof the
the following
following steps
steps
involving
involving the reduction of the nitro group and acetonide hydrolysis/epoxide formation(Scheme
the reduction of the nitro group and acetonide hydrolysis/epoxide formation (Scheme13).
13).
In Route A the solution of intermediate 43 was carried forward in a telescoped process to
hydrogenate the nitro group followed by N-acetylation. Inclusion of acetic anhydride at the onset
of the hydrogenation to trap the toxic aminophenol intermediate as it forms negatively affected the
performance of the hydrogenation reaction and led to mixtures of N-, O- and diacetylated products.
Attempts to isolate anilide 44 thus produced were not successful although TsOH (p-Toluenesulfonic acid)
catalyzed deprotection to the diol 45 allowed for isolation of a crystalline intermediate. Three batches
totaling 107 kg of the diol intermediate 45 were produced in this way. The subsequent formation of
bromide 46 proceeded smoothly although this intermediate too proved unstable to store or handle for
long times; best case scenario without degradation was 24 h at −5 ◦ C. Inevitably this was carried over
as a solution into the deacetylation of the hydroxyl group followed by the ring closure to form epoxide
40. An additional problem appeared in the consistent crystallization and purification of the epoxide
due to the nature of the reaction medium built over the telescoped process.
This aspect combined with the limited stability of bromide 46 led the Astra Zeneca process team
to examine Route B (Scheme 13), namely the reverse sequence of events where epoxide generation
from 43 precedes the reduction of the nitro group. The TsOH deprotection step to 47 and subsequent
conversion to the acetoxy bromide 48 followed by formation of epoxide 49 were accomplished using
the same conditions as in Route A for the anilide intermediates. In this sequence both bromide 48 and
nitrophenol epoxide 49 were much more stable than their anilide counterparts 46 and 44 from Route
A. Nitrophenol epoxide 49 could actually be isolated in good yield and quality. Initial attempts to
hydrogenate the nitro group produced significant amounts of reductive ring opening of the epoxide
hence a wide range of catalysts and conditions were screened for the selective hydrogenation to the
aniline. This was achieved with a Pt/C catalyst in THF (4 bar H2 ) which was telescoped with the
acetylation of both the aniline and phenol groups by addition of acetic anhydride. Despite the better
behaving intermediates of Route B, a number of impurities (Scheme 14) found in the key epoxide
intermediate 40 isolated from this process casted serious doubts over its potential as a manufacturing
route. One set of impurities (50–52) was shown to form by water attack on the terminal epoxide under
Scheme 13. Scaled-up routes to intermediate 40 from 43; route A was finally selected.
Catalysts 2020, 10, 1117 12 of 65
the processing conditions generating initially impurity 50. The generated primary alcohol participated
in a transesterification process producing deacetylated phenol impurity 51 which in turn is acetylated
again by acetic anhydride
Scheme giving
12. Process routerise to impurity
to key These
52.43;
intermediate impurities
carried forward aswere ultimately
a solution thereof.managed by
control of the water content and processing conditions. This was not however the case with a second set
At this point
of impurities twoThese
(53, 54). options
arisewere
fromconsidered with respect
the aniline reacting to the
with the sequence
epoxide of of
moiety theitsfollowing steps
nitro precursor
involving the reduction
thus generating dimer 53ofwhich
the nitro group
in turn and
gets acetonide
reduced to 54hydrolysis/epoxide formation
and associated acetylated (Scheme 13).
derivatives.
These side reactions became more pronounced in conditions simulating large-scale processing and
the dimeric impurities could not be purged in the already challenging crystallization of intermediate 40.
This issue rendered Route B inappropriate for future deliveries and exemplified Route A as the process
of choice which was subsequently optimized further. The final coupling of 40 and 41 (Scheme 11)
had been optimized in earlier campaigns and posed no issues in subsequent large-scale deliveries.
The successful preparation of AZD-4818, at the required specifications depends heavily on the purity of
the key epoxide intermediate 40 that the new process achieved in supplying at an appropriate quality.
The synthetic efforts towards Astra Zeneca’s CCR1 antagonist, highlights the quality of skills,
expertise and perseverance of process chemists in managing sensitive, non-crystalline intermediates
and multiple telescoped stages on scale.
generated primary alcohol participated in a transesterification process producing deacetylated
phenol impurity 51 which in turn is acetylated again by acetic anhydride giving rise to impurity 52.
These impurities were ultimately managed by control of the water content and processing
conditions. This was not however the case with a second set of impurities (53, 54). These arise from
the aniline reacting with the epoxide moiety of its nitro precursor thus generating dimer 53 which in
Catalysts 2020, 10, 1117 13 of 65
turn gets reduced to 54 and associated acetylated derivatives.
These side reactions became more pronounced in conditions simulating large-scale processing
and the dimeric impurities could not be purged in the already challenging crystallization of
intermediate 40. This issue rendered Route B inappropriate for future deliveries and exemplified
Route A as the process of choice which was subsequently optimized further. The final coupling of 40
and 41 (Scheme 11) had been optimized in earlier campaigns and posed no issues in subsequent
large-scale deliveries. The successful preparation of AZD-4818, at the required specifications
depends heavily on the purity of the key epoxide intermediate 40 that the new process achieved in
supplying at an appropriate quality.
The synthetic efforts towards Astra Zeneca’s CCR1 antagonist, highlights the quality of skills,
expertise and perseverance of process chemists in managing sensitive, non-crystalline intermediates
and multiple telescoped stages on scale.
1.5. BMS-960—Development and

Scheme 14. Impurities in ScaleB;up
Route 53ofand
a Chiral Epoxide
54 were Route
difficult through
to purge anRoute
hence Enzymatic
A was Reduction
selected.
Scheme 14. Impurities in Route B; 53 and 54 were difficult to purge hence Route A was selected.
Sphingosine 1-phosphate
1.5. BMS-960—Development (S1P)up
and Scale regulates
of a Chiralthrough
Epoxide five
Routehigh-affinity G protein-coupled
through an Enzymatic Reduction S1P
receptors multiple physiological and pathophysiological processes including cell proliferation and
Sphingosine
survival, 1-phosphate
cell migration, (S1P) regulates
inflammatory mediatorthrough
synthesisfive
andhigh-affinity G protein-coupled
tissue remodeling S1P
[61–63]. The S1P1
receptors
receptor multiple physiological
in particular and pathophysiological
has received processes
intensive investigation forincluding cell proliferation
the modulation and
of various
survival, cell migration, inflammatory mediator synthesis and tissue remodeling
autoimmune and inflammatory diseases with the products of this effort being two approved drugs [61–63]. The S1P1
receptor in particular
for multiple sclerosis:has received intensive
fingolimod investigation
and ozanimod [64–66].forResearch
the modulation
on S1P1ofagonists
various autoimmune
continues to
and inflammatory diseases with the products of this effort being two
unfold both in terms of novel molecules and additional indications. In this context approved drugsBristol-Myers
for multiple
sclerosis: fingolimod and ozanimod [64–66]. Research on S1P1 agonists continues
Squibb developed BMS-960 (Scheme 15, a potent agonist of the S1P1 receptor. For the ongoing to unfold both in
terms of and
biologic novel molecules and
toxicological additional indications.
investigations, a reasonableIn this context
supply Bristol-Myers
route was Squibb
required that developed
would address
BMS-960 (Scheme 15, a potent agonist of the S1P1 receptor. For the ongoing biologic
the issues of the original medicinal chemistry synthesis. These included the low yielding (36%) and toxicological
investigations, a reasonable
alkylation of amine 56 withsupply route was
bromoketone 55 required that wouldseparation
and the inefficient address the ofissues of the original
diastereomers of 58
medicinal chemistry
generated from NaBHsynthesis. These included the low yielding (36%) alkylation of amine 56 with
4 reduction of 57.
bromoketone 55 andSquibb
Bristol-Myers the inefficient
chemistsseparation
examinedofthe diastereomers
potential of ofan58 generatedroute
alternative fromthat
NaBH 4 reduction
could deliver
of 57.
enantiopure 58 via optically pure epoxide 59 [67].
Scheme
Scheme 15. Alternative syntheses
15. Alternative syntheses of
of key
key intermediate 58, precursor
intermediate 58, precursor of
of BMS-960.
BMS-960.
Initial efforts focused on the preparation of racemic 59 with a view to subject it to chiral
separation. The Corey–Chaykovsky reaction from the p-cyanobenzaldehyde and trimethyl
sulfonium iodide [68] met with low yields. In contrast, NaBH4 reduction of the commercially
Catalysts 2020, 10, 1117 14 of 65
Bristol-Myers Squibb chemists examined the potential of an alternative route that could deliver
enantiopure 58 via optically pure epoxide 59 [67].
Initial efforts focused on the preparation of racemic 59 with a view to subject it to chiral separation.
The Corey–Chaykovsky reaction from the p-cyanobenzaldehyde and trimethyl sulfonium iodide [68]
met with low yields. In contrast, NaBH4 reduction of the commercially available bromoketone 55
gave initially
available racemic bromohydrin
bromoketone 55 gave initially which was
60 racemic transformed
bromohydrin to racemic
60 which 59 in high yield
was transformed when
to racemic
subjected to mild base. The chiral separation of racemic 59 however proved
59 in high yield when subjected to mild base. The chiral separation of racemic 59 however proved unviable hence a two-step
asymmetric
unviable hence synthesis wasasymmetric
a two-step considered synthesis
next. After wascareful consideration
considered next. After ofcareful
asymmetric reduction
consideration of
methods, B-chlorodiisopinocampheylborane (DIP-chloride) was initially
asymmetric reduction methods, B-chlorodiisopinocampheylborane (DIP-chloride) was initially tested and provided good
yields
tested (85%) and enantiomeric
and provided good yields excess
(85%) (90%
andee) of chiral bromohydrin
enantiomeric excess (90%60. ee)Despite
of chiralthese encouraging
bromohydrin 60.
results, upgrade of the optical purity through chiral separation was still required
Despite these encouraging results, upgrade of the optical purity through chiral separation was still hence an enzymatic
reduction
required hencewas pursued.
an enzymatic reduction was pursued.
Towards
Towards this this end,
end, aa large
large array
array of of both
both NADH-
NADH- and and NADPH-dependent
NADPH-dependent ketoreductases
ketoreductases was was
screened for the reduction of 55 and several enzymes were identified
screened for the reduction of 55 and several enzymes were identified that could produce either that could produce either
enantiomer
enantiomer of of bromohydrin
bromohydrin 60 60 inin >99% yield and
>99% yield and enantiomeric
enantiomeric excesses
excesses of >99%.
of >99%.
In
In the
theend,
end,based on on
based its activity, selectivity
its activity, and substrate-to-enzyme
selectivity and substrate-to-enzyme ratio, ketoreductase enzyme
ratio, ketoreductase
KREDNADH-110
enzyme KREDNADH-110 (Codexis) was selected for the synthesis of the (S)-enantiomer ofboth
(Codexis) was selected for the synthesis of the (S)-enantiomer of 60. Though 60.
NADH
Thoughand NADPH
both NADH cofactors
and must NADPH be regenerated
cofactors formust
cost reduction, KREDNADH-110
be regenerated for cost also has the
reduction,
additional
KREDNADH-110 advantage alsoofhas
requiring the lower
the additional cost NADH
advantage cofactor.the lower cost NADH cofactor.
of requiring
The conversion of (S)-60 to the epoxide
The conversion of (S)-60 to the epoxide was optimized was optimized with sodium
with sodium tert-butoxide giving
tert-butoxide the best
giving the
results (>93%(>93%
best results and 100%and ee)
100%andee)eventually this wasthis
and eventually bolted
wasonbolted
the enzymatic reduction thus
on the enzymatic developing
reduction thus
adeveloping
telescoped process (Scheme
a telescoped 16). The
process next step
(Scheme in this
16). The synthesis
next stepwas in the
thisepoxide
synthesisring-opening reaction
was the epoxide
of the chiral (S)-60 with amino-ester 56 to give the desired key intermediate
ring-opening reaction of the chiral (S)-60 with amino-ester 56 to give the desired key intermediate 58. This reaction took
place in areaction
regiospecific ◦
58. This took manner
place inata 50 C with a catalytic
regiospecific manneramount
at 50 °Cofwith
DMAP (4-dimethylaminopyridine)
a catalytic amount of DMAP
in 77% yield.
(4-dimethylaminopyridine) in 77% yield.
Scheme 16.
Scheme Scale up
16. Scale up of
of enzymatic
enzymatic reduction
reduction to
to halohydrin
halohydrin and
and epoxide
epoxide formation
formation en
en route
route to
to 58.
58.
As will be further discussed below, halohydrins (and equivalent species) provide a powerful
As will be further discussed below, halohydrins (and equivalent species) provide a powerful
route to epoxide synthesis. In this case a chiral halohydrin produced via an enzymatic reduction of an
route to epoxide synthesis. In this case a chiral halohydrin produced via an enzymatic reduction of
appropriate bromoketone at 100 g scale gave access to the key epoxide and its ring opened product.
an appropriate bromoketone at 100 g scale gave access to the key epoxide and its ring opened
This approach was pivotal for the development of a cost effect and efficient route towards BM-960.
product. This approach was pivotal for the development of a cost effect and efficient route towards
BM-960.
1.6. Atazanavir (BMS-232632)—Process Research and Development towards an Efficient Synthesis of an HIV
Protease Inhibitor
Atazanavir (BMS-232632) (Scheme 17) is a potent HIV-1 protease inhibitor and an FDA
approved drug for HIV/AIDS both as monotherapy and in combination with other anti-HIV agents
[69–72]. Atazanavir (BMS-232632) is an aza-peptidomimetic transition state inhibitor for the HIV-1
protease that was discovered by Novartis [73], but after a preliminary investigation it was licensed to
Catalysts 2020, 10, 1117 15 of 65
1.6. Atazanavir (BMS-232632)—Process Research and Development towards an Efficient Synthesis of an HIV
Protease Inhibitor
Atazanavir (BMS-232632) (Scheme 17) is a potent HIV-1 protease inhibitor and an FDA approved
In order to do so, a reliable cost-effective and robust process had to be developed by the Bristol
drug for HIV/AIDS both as monotherapy and in combination with other anti-HIV agents [69–72].
Myers Squibb process department. The original medicinal chemistry route was unsuitable for
Atazanavir (BMS-232632) is an aza-peptidomimetic transition state inhibitor for the HIV-1 protease
large-scale deliveries due to a number of issues including hazardous reagents and solvents, several
that was discovered by Novartis [73], but after a preliminary investigation it was licensed to Bristol
protection/deprotection steps, expensive amide coupling reagents and elaborate chromatographic
Myers Squibb who developed it fully to the point of FDA approval.
purifications.
Scheme 17. Retrosynthetic analysis of atazanavir leading to key epoxide intermediate 62.
Scheme 17. Retrosynthetic analysis of atazanavir leading to key epoxide intermediate 62.
In order to do so, a reliable cost-effective and robust process had to be developed by the Bristol Myers
In order to develop a viable manufacturing route to atazanavir it was imperative that both
Squibb process department. The original medicinal chemistry route was unsuitable for large-scale deliveries
N,N’-bis-Boc-protected hydrazino–amino alcohol 61 and the chiral epoxide 62 intermediates were
due to a number of issues including hazardous reagents and solvents, several protection/deprotection
accessed in a scalable and robust manner.
steps, expensive amide coupling reagents and elaborate chromatographic purifications.
The synthesis of optically pure epoxide 62 in particular was of great concern as its quality
In order to develop a viable manufacturing route to atazanavir it was imperative that both
influences heavily the performance of the downstream chemistry and isolation/purification of
N,N’-bis-Boc-protected hydrazino–amino alcohol 61 and the chiral epoxide 62 intermediates were
subsequent intermediates. In the original route 62 was made in 80% ee by mCPBA epoxidation of the
accessed in a scalable and robust manner.
corresponding allylic Boc-protected amine. The main reason for the enantiomeric leakage was the
The synthesis of optically pure epoxide 62 in particular was of great concern as its quality influences
aldehyde precursor Boc-Phe-H which racemized to a significant extend even when the Wittig
heavily the performance of the downstream chemistry and isolation/purification of subsequent
reaction was performed at −78 °C. Additionally, the need for chromatographic purification for both
intermediates. In the original route 62 was made in 80% ee by mCPBA epoxidation of the corresponding
the aldehyde and epoxide intermediates combined with the low yield of the two-step sequence,
allylic Boc-protected amine. The main reason for the enantiomeric leakage was the aldehyde precursor
forced the development of a new, more robust and suitable for scale-up synthesis of 62.
Boc-Phe-H which racemized to a significant extend even when the Wittig reaction was performed at
The Bristol Myers Squibb process group responded to this challenge [74] by exploiting the
−78 ◦ C. Additionally, the need for chromatographic purification for both the aldehyde and epoxide
readily synthesized and also commercially available vicinal diol 63 (Scheme 18). Based on the work
intermediates combined with the low yield of the two-step sequence, forced the development of a new,
of Moyano and Pericàs [75], they developed further the three step process to access the key epoxide.
more robust and suitable for scale-up synthesis of 62.
The Bristol Myers Squibb process group responded to this challenge [74] by exploiting the readily
synthesized and also commercially available vicinal diol 63 (Scheme 18). Based on the work of Moyano
and Pericàs [75], they developed further the three step process to access the key epoxide.
Initial selective silylation of the primary alcohol followed by mesylation of the secondary alcohol
proceeded cleanly although the silyloxy mesylate 64 was not a crystalline intermediate. Using this oil
directly in the silyl deprotection step provided the crystalline and easy to purify hydroxy mesylate 64.
For this step they introduced the inexpensive and easier to handle ammonium fluoride in place of
TBAF (tetra-n-butylammonium fluoride) and isolated the mesylate intermediate 65 in 80% yield and
excellent quality. After extensive screening of bases and reaction conditions, KOt Bu in THF/IPA turned
out to be the most successful combination for the ring closure of hydroxy mesylate 65 to epoxide
62. The latter was isolated directly in 90% yield and in 100% ee without need for chromatography.
The regiospecific ring opening of the epoxide with protected hydrazine 66 was accomplished in
refluxing isopropanol and provided key intermediate 61 in >85% yield. Finally, deprotection of the Boc
groups telescoped into an EDCI-promoted (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide) coupling
with N-methoxycarbonyl-L-tert-leucine at both the amino and hydrazino termini, gave atazanavir-free
base which was ultimately converted to its bisulfate salt.
Scheme 18. Process route to atazanavir via asymmetric synthesis of epoxide 62.
Initial selective silylation of the primary alcohol followed by mesylation of the secondary
alcohol proceeded cleanly although the silyloxy mesylate 64 was not a crystalline intermediate.
Using this oil directly in the silyl deprotection step provided the crystalline and easy to purify
reaction was performed at −78 °C. Additionally, the need for chromatographic purification for both
the aldehyde and epoxide intermediates combined with the low yield of the two-step sequence,
forced the development of a new, more robust and suitable for scale-up synthesis of 62.
The Bristol Myers Squibb process group responded to this challenge [74] by exploiting the
readily synthesized
Catalysts 2020, 10, 1117 and also commercially available vicinal diol 63 (Scheme 18). Based on the16work
of 65
of Moyano and Pericàs [75], they developed further the three step process to access the key epoxide.
This process (Scheme 18) was scaled-up successfully and delivered 3.5 kg of atazanavir bisulfate
Initial selective silylation of the primary alcohol followed by mesylation of the secondary
thus demonstrating reproducibility and robustness in this epoxide-enabling manufacturing route to an
alcohol proceeded cleanly although the silyloxy mesylate 64 was not a crystalline intermediate.
approved drug.
Using this oil directly in the silyl deprotection step provided the crystalline and easy to purify
1.7. WAY-255719—Ring Opening of a Chiral Epoxide with Grignard Reagents
The 5-HT2c receptor is one of the 14 serotonin receptors and is located in several regions of the brain.
Activation of this G protein-coupled receptor by serotonin inhibits dopamine and norepinephrine
release in certain areas of the brain therefore 5-HT2c receptor agonism has demonstrated benefits in the
treatment of obesity (lorcaserin), substance use disorders (SUD) and impulse control disorders while
antagonism augments treatment of anxiety, depression and schizophrenia [76]. In this context Wyeth
(legacy company of Pfizer) discovered WAY-255719 [77] a potent 5-HT2C full agonist with greater
than 100-fold selectivity over the related 5-HT2A and 5-HT2B receptors. WAY-255719 demonstrated
anti-psychotic activity in several animal models thus was selected among several other analog
compounds to advance into development as a drug candidate.
The medicinal chemistry route to WAY-255719 (Scheme 19) had a number of issues including a
low yielding (<45%) Suzuki reaction to biaryl 67, extremely low temperature for phenol demethylation,
a thermally intensive and protracted Claisen rearrangement, racemic epoxide formation, hazardous
azide chemistry and a special hydrogenation to ensure chemoselectivity over the aromatic chlorides.
In addition to the nine steps, the racemic amine product had to be converted to its Cbz derivative in order
achieve chiral resolution and finally be subjected to hydrogenolysis to afford enantiopure WAY-255719.
Initial improvements, including chiral separation on the amine without Cbz derivatization
(on 100 g scale took one week to complete using a 25 cm × 3 cm column) succeeded in delivering
up to 100 g of the desired product, but clearly a much better synthesis was needed for larger scale
deliveries and commercial manufacturing. An asymmetric route that would negate the need for chiral
chromatography therefore became a critical objective for the viability of the project.
One of the ideas that prioritized high for the asymmetric synthesis of the chiral 2-substituted
dihydrobenzofuran domain involved the introduction of an appropriately functionalized enantiopure
three-carbon fragment directly at the position ortho to the methoxy group of 67. Reaction of the
corresponding aryl Grignard with glycidol surrogates presented an attractive option to access 70
directly because many of the latter are commercially available in enantiopure form and there is literature
precedence for their reaction with organometallic reagents, at least on small scales.
Catalysts 2020, 10, 1117 17 of 65
Scheme 19. Initial improvements made on the medicinal chemistry route to WAY-255719.
One of the ideas that prioritized high for the asymmetric synthesis of the chiral 2-substituted
dihydrobenzofuran domain involved the introduction of an appropriately functionalized
enantiopure three-carbon fragment directly at the position ortho to the methoxy group of 67.
Reaction of the corresponding aryl Grignard with glycidol surrogates presented an attractive option
to access 70 directly because many of the latter are commercially available in enantiopure form and
there is literature precedence for their reaction with organometallic reagents, at least on small scales.
Having first developed a much higher yielding Suzuki–cross coupling reaction for generating
67 and resolved HBr-induced demethylation issues in the subsequent bromination to 72 (Scheme 20)
attention was turned into the formation of the Grignard reagent 73 and reaction with glycerol
Scheme
tosylate 74Scheme
[78]. 19. Initialimprovements
19. Initial improvements made
made onon the
the medicinal
medicinal chemistry
chemistry route
route to
to WAY-255719.
WAY-255719.
Generation of the Grignard reagent 73 from the aryl bromide under standard conditions with
Having
One of first
the developed
ideas that a much higher
prioritized yielding
high for theSuzuki–cross
asymmetric coupling
synthesisreaction
of the for generating 67 and
chiral
magnesium metal was accompanied by magnesium oxidatively inserting into the 2-substituted
aryl-chloride
resolved HBr-induced
dihydrobenzofuran demethylation
domain issues
involved in
the the subsequent
introduction bromination
of an to 72 (Scheme
appropriately 20) attention
functionalized
bonds. Chemoselective formation of the desired organometallic reagent 73 was accomplished by a
was turned into
enantiopure the formation
three-carbon of the Grignard reagent
at the 73 and reaction
ortho with glycerol tosylate 74 [78].
Grignard exchange reactionfragment directly
with isopropyl magnesium position
bromide. to the methoxy group of 67.
Reaction of the corresponding aryl Grignard with glycidol surrogates presented an attractive option
to access 70 directly because many of the latter are commercially available in enantiopure form and
there is literature precedence for their reaction with organometallic reagents, at least on small scales.
Having first developed a much higher yielding Suzuki–cross coupling reaction for generating
67 and resolved HBr-induced demethylation issues in the subsequent bromination to 72 (Scheme 20)
attention was turned into the formation of the Grignard reagent 73 and reaction with glycerol
tosylate 74 [78].
magnesium metal was accompanied by magnesium oxidatively inserting into the aryl-chloride
bonds. Chemoselective formation of the desired organometallic reagent 73 was accomplished by a
Grignard exchange reaction with isopropyl magnesium bromide.
Scheme 20. Development of a telescoped process for multi-kilogram delivery of WY-255719.
magnesium metal was accompanied by magnesium oxidatively inserting into the aryl-chloride bonds.
Chemoselective formation of the desired organometallic reagent 73 was accomplished by a Grignard
exchange reaction with isopropyl magnesium bromide.
In the absence of Lewis acid catalysts, reactions between epoxides and organometallic reagents
are known to proceed slowly and with formation of side products. In this case copper(I) salts provided
optimum results with little difference among CuCN, Li2 CuCl4 and CuI at 5–10 mol%. Without the
copper catalyst the reaction did not proceed at all. Initially CuCN was selected due to its stability,
Scheme 20. Development of a telescoped process for multi-kilogram delivery of WY-255719.
In the absence of Lewis acid catalysts, reactions between epoxides and organometallic reagents
are known to proceed slowly and with formation of side products. In this case copper(I) salts
provided optimum
Catalysts 2020, 10, 1117 results with little difference among CuCN, Li2CuCl4 and CuI at 5–10 mol%. 18 of 65
Without the copper catalyst the reaction did not proceed at all. Initially CuCN was selected due to its
stability, nonhygroscopic nature and availability in small particle size although it was later replaced
nonhygroscopic
with CuI to avoidnatureissues and availability
associated in smalltoxicity.
with cyanide particleAnother
size although
critical it was later
process replaced
parameter waswiththe
reaction temperature leading to either incomplete reactions below −25 °C or significant formationthe
CuI to avoid issues associated with cyanide toxicity. Another critical process parameter was of
reaction temperature
impurities above −20 °C. leading
Within to either
the −25incomplete reactionsthe
to −20 °C window, below −25 ◦isCcomplete
reaction or significant
after formation
4–5 h giving of
impurities above −20 ◦ C. Within the −25 to −20 ◦ C window, the reaction is complete after 4–5 h giving
an oil consisting predominantly the hydroxy tosylate 75 with an approximately 10% (HPLC) of the
an oil consisting
terminal epoxide predominantly
76. This was notthe anhydroxy tosylate
issue because 75 with an
subsequent approximately
treatment 10% (HPLC)
of the crude productofwith the
terminal epoxidering
NaOH-induced 76. This wasofnot
closure 75antoissue because
epoxide subsequent treatment
76 quantitatively. of the crude
Theoretically, product with
the enantiomer of
NaOH-induced ring closure of 75 to epoxide 76 quantitatively. Theoretically,
epoxide 76 can form by direct displacement of the tosylate in 74 without epoxide opening. This the enantiomer of epoxide
76 can form
however does bynotdirect displacement
happen in practice of and
the tosylate
indeed 76 in 74 without
forms epoxideopening
via epoxide opening.of This 74 tohowever
75 and
does not happen in practice and indeed 76 forms via epoxide opening
subsequent closure on the other side by chloride displacement. This was confirmed as the Wyeth of 74 to 75 and subsequent
closure
team on the other
established thatsideno by chloride
loss displacement.
of enantiomeric purity This was confirmed
occurred, whereasasdirect
the Wyeth team
tosylate established
displacement
that no lead
would loss ofto enantiomeric
the terminal purity epoxide occurred,
of opposite whereas
stereo direct tosylate displacement
configuration and 76 withwould reduced lead ee.toThe
the
terminal epoxide of opposite stereo configuration and 76 with reduced
process was further streamlined by eliminating the separate step for the conversion of 75 to 76 since ee. The process was further
streamlined
this by eliminating
transformation could bethe separate step
accomplished for the conversion
quantitatively duringofalkaline
75 to 76washes
since thisin transformation
the work up of
could
the be accomplished
Grignard reaction with quantitatively
74. Thus, afterduring alkaline
solvent washesto
swapping inDMF
the work up of thesolution
the resulting Grignardofreaction
76 was
with
telescoped in the second epoxide ring-opening reaction with potassium phthalimide toingive
74. Thus, after solvent swapping to DMF the resulting solution of 76 was telescoped the
second epoxide
intermediate 77 inring-opening
53% yield with reaction
respectwith potassium
to 74, phthalimide
98.7% purity by HPLC toand
give99% intermediate
ee. Activation77 inof53%the
yield with respect to 74, 98.7% purity by HPLC and 99% ee. Activation
alcohol as its mesylate ester followed by treatment with BBr3 gave directly the cyclized of the alcohol as its mesylate
ester followed by treatment
dihydrobenzofuran with BBr
intermediate 78.3 gave directly the
Apparently, oncecyclized dihydrobenzofuran
the phenol is demethylated, intermediate
it cyclizes 78.
Apparently,
spontaneously onceviathethephenol is demethylated,
intramolecular SN2 reaction it cyclizes
on the spontaneously via the intramolecular
mesylate; the uncyclized phenol/mesylate SN 2
intermediate was never detected in this process. Deprotection and hydrochloride this
reaction on the mesylate; the uncyclized phenol/mesylate intermediate was never detected in salt
process. Deprotection andofhydrochloride
formation/crystallization the right polymorphsalt formation/crystallization
gives WAY-255719 with of the right>99.5%
purity polymorphand 98.6%gives
WAY-255719
ee. with purity >99.5% and 98.6% ee.
After a tremendousamount
After a tremendous amountofof workwork (including
(including withwith
modelmodel substrates)
substrates) the Wyeth
the Wyeth process process
team
team managed
managed to develop
to develop a robust
a robust manufacturing
manufacturing route
route for for WAY-255719without
WAY-255719 withoutthe thepitfalls
pitfalls ofof the
the
original synthesis The new route proceeds through a telescoped
original synthesis The new route proceeds through a telescoped process encompassing four process encompassing four chemical
transformations,
chemical namely twonamely
transformations, consecutivetwo epoxide
consecutive ring-opening/ring-closing reaction sequences
epoxide ring-opening/ring-closing and
reaction
has delivered
sequences and10 haskgdelivered
batches of10the kgAPI at specification.
batches of the API at specification.
1.8. Linezolid
1.8. Linezolid and
and Rivaroxaban
Rivaroxaban—Exploiting
—Exploiting Glycerol
GlycerolSurrogates
Surrogatesin
inChiral
ChiralOxazolidinone
OxazolidinoneSyntheses
Syntheses
Linezolid and
Linezolid and rivaroxaban
rivaroxaban (Scheme
(Scheme 21)
21) share
share striking
striking structural
structural similarity
similarity therefore
therefore common
common
synthetic strategies
synthetic strategies have
have been
been described
described for
for their
their syntheses. The chiral
syntheses. The chiral oxazolidine
oxazolidine moiety
moiety isis
accessed conveniently from the chiral pool, perhaps almost invariantly with the use of
accessed conveniently from the chiral pool, perhaps almost invariantly with the use of glycerol (79),glycerol
(79), epichlorohydrin
epichlorohydrin (80) conveniently
(80) and and conveniently functionalized
functionalized glycerol
glycerol derivatives
derivatives (81,
(81, 82 82 Scheme 21).
Scheme21).
Scheme 21. Structures of rivaroxaban, linezolid and glycerol equivalents from the chiral pool.
Scheme 21. Structures of rivaroxaban, linezolid and glycerol equivalents from the chiral pool.
In contrast to the high similarity of their chemical structure and syntheses, the biologic and
pharmaceutical profiles of linezolid and rivaroxaban could not be more different. Linezolid (trade name
Zyvox) discovered and developed by Pharmacia UpJohn (legacy company of Pfizer) is a protein
synthesis inhibitor and member of the oxazolidinone class of antibiotics [79]. It shows excellent
activity against major Gram-positive bacteria and is very effective in the treatment of infections of the
In contrast to the high similarity of their chemical structure and syntheses, the biologic and
pharmaceutical profiles of linezolid and rivaroxaban could not be more different. Linezolid (trade
name Zyvox) discovered and developed by Pharmacia UpJohn (legacy company of Pfizer) is a
protein synthesis inhibitor and member of the oxazolidinone class of antibiotics [79]. It shows
Catalysts 2020, 10, 1117 19 of 65
excellent activity against major Gram-positive bacteria and is very effective in the treatment of
infections of the respiratory tract and skin disorders. The rare, if any, cases of cross resistance with
other antibiotics
respiratory tract andis attributed to its The
skin disorders. unique
rare,mechanism
if any, casesof of action. In contrast
cross resistance toother
with common protein
antibiotics is
synthesis
attributed inhibitors
to its unique which halt protein
mechanism synthesis
of action. at thetoelongation
In contrast phase, synthesis
common protein linezolid inhibitors
inhibits protein
which
synthesis
halt protein at synthesis
the initiation at thephase. It doesphase,
elongation so by binding
linezolidatinhibits
the 23Sprotein
component of the
synthesis at 50S
the ribosome
initiation
subunit
phase. It does so by binding at the 23S component of the 50S ribosome subunit which is responsibleoffor
which is responsible for the peptidyl transferase activity thus preventing formation a
functional
the peptidyl70S initiationactivity
transferase complexthus[80]. Because
preventing of its action
formation on ribozymes,
of a functional linezolid
70S initiation has been
complex [80].
designated as a riboswitch [81,82]. Despite the high degree of structural
Because of its action on ribozymes, linezolid has been designated as a riboswitch [81,82]. Despite the resemblance, rivaroxaban
possesses
high degree noofantibiotic
structural activity whatsoever
resemblance, and doespossesses
rivaroxaban not bind tonoRNA molecules.
antibiotic Rivaroxaban
activity whatsoever (trade
and
name Xarelto) was discovered and developed by Bayer and Ortho-McNeil
does not bind to RNA molecules. Rivaroxaban (trade name Xarelto) was discovered and developed Pharmaceutical, Inc.
(legacy company of Johnson and Johnson). It was approved in Germany,
by Bayer and Ortho-McNeil Pharmaceutical, Inc. (legacy company of Johnson and Johnson). It was Canada and by the FDA in
2008 for the
approved treatment,Canada
in Germany, prevention
and byand thereduction
FDA in 2008 in for
thetherisktreatment,
of recurrent deep vein
prevention thrombosis,
and reduction in
stroke, systemic and pulmonary embolism. More recently it also obtained
the risk of recurrent deep vein thrombosis, stroke, systemic and pulmonary embolism. More recently it approval for reducing the
risk of major approval
also obtained cardiovascular events,the
for reducing such
riskasofdeath, myocardial infarction
major cardiovascular and as
events, such stroke.
death, Rivaroxaban
myocardial
inhibits
infarction both
andfree and Rivaroxaban
stroke. prothrombinase complex
inhibits bothbound
free and Factor Xa and prevents
prothrombinase thrombin
complex boundformation,
Factor Xa
but not its action [83]. It has a rapid onset of action and was the first approved
and prevents thrombin formation, but not its action [83]. It has a rapid onset of action and was the first oral Factor Xa
inhibitor.
approved oral Factor Xa inhibitor.
As
As aa consequence
consequenceofofthe thestructural
structural similarity
similarity between
between linezolid
linezolid andand rivaroxaban
rivaroxaban therethere is great
is great deal
deal of overlap in the respective reported syntheses. In fact, most of the
of overlap in the respective reported syntheses. In fact, most of the known syntheses for one molecule known syntheses for one
molecule
have beenhave testedbeen tested
in the in the preparation
preparation of the other ofwith
the other with modifications
modifications on the terminalon the terminal
aniline andaniline
amide
and amide as appropriate. The original Bayer synthesis of rivaroxaban
as appropriate. The original Bayer synthesis of rivaroxaban is described in Scheme 22 [84]. is described in Scheme 22
[84].
O O
O
N
O
O N NH OH O
O 82
O N NH2
N
83 84
O
CDI
O O O O
MeNH2 (aq) O
O O
O N N O N N
NH2 N
86 85 O
X = Cl or X
S Cl
p-NO2Ph-O
O
87
O O
O
O N N H
N Cl
S
Rivaroxaban O
Scheme 22.
Scheme Original Bayer
22. Original Bayer synthesis
synthesis of
of rivaroxaban.
rivaroxaban.
Bayer and others have since patented several other syntheses [85–87] yet over the years it was
the first route that attracted numerous suitors who put much effort in developing it further into a
viable large-scale process. In this context, all modifications reported concern reaction conditions,
solvents and reagents in each of the steps without changing any of the intermediates/transformations
of the Bayer route [88–90]. The reported syntheses for rivaroxaban and linezolid have been reviewed
Bayer and others have since patented several other syntheses [85–87] yet over the years it was
the first route that attracted numerous suitors who put much effort in developing it further into a
viable large-scale
Catalysts 2020, 10, 1117 process. In this context, all modifications reported concern reaction conditions, 20 of 65
solvents and reagents in each of the steps without changing any of the
intermediates/transformations of the Bayer route [88–90]. The reported syntheses for rivaroxaban
extensively
and linezolid [91] and been
have repetition of thisextensively
reviewed is beyond the scope
[91] and of the present
repetition work.
of this is The
beyondfollowing casesofwere
the scope the
selected simply because they exemplify the synthetic creativity and versatility
present work. The following cases were selected simply because they exemplify the synthetic that may be expressed
through
creativitythe andchemistry
versatilityof that
the epoxide functionality.
may be expressed through the chemistry of the epoxide functionality.
For
For example in the synthesis of Yuan et
example in the synthesis of Yuan et al.
al. [92]
[92] (Scheme
(Scheme 23),
23), the
the penultimate
penultimate intermediate
intermediate 85 85 of
of
the
the Bayer synthesis is targeted via a completely different strategy where the oxazolidinone ring is
Bayer synthesis is targeted via a completely different strategy where the oxazolidinone ring is
constructed
constructed firstfirst (92)
(92) followed
followed by by installment
installment of of the
the phthalimido group (93)
phthalimido group (93) and
and attachment
attachment of of the
the
oxazolidinone
oxazolidinone 93 93ononthethemorpholinone-substituted
morpholinone-substituted aromatic ring 91
aromatic via91
ring a Goldberg couplingcoupling
via a Goldberg reaction.
The same The
reaction. reaction
samewas used to
reaction wasinstall
usedthe to morpholinone 88 on the aromatic
install the morpholinone 88 on the ring. This and
aromatic other
ring. efforts
This and
attempt to address the synthesis of the morpholinone aryl moiety as this is a significant
other efforts attempt to address the synthesis of the morpholinone aryl moiety as this is a significant cost contributor
for
costrivaroxaban.
contributor for rivaroxaban.
Scheme 23. The

Scheme YuanYuan
23. The et al.etsynthesis of the
al. synthesis ofrivaroxaban N-Phth-intermediate
the rivaroxaban via a via
N-Phth-intermediate Goldberg reaction.
a Goldberg
reaction.
Similar to the reaction of epichlorohydrin with sodium cyanate, the Lewis acid or base catalyzed
cycloaddition
Similar toof the
epoxides withofisocyanates
reaction gives N-substituted
epichlorohydrin with sodiumrather than the
cyanate, the N–H
Lewisoxazolidinones
acid or base
(Scheme 24 upper portion). This transformation has been used by Bayer
catalyzed cycloaddition of epoxides with isocyanates gives N-substituted rather than as the last step in a convergent
the N–H
synthesis
oxazolidinones (Scheme 24 upper portion). This transformation has been used by Bayer an
of rivaroxaban where the 4-morpholinone-benzene isocyanate (94) is reacted with as epoxide
the last
(95)
stepbearing the domain
in a convergent of the target
synthesis moleculewhere
of rivaroxaban with the
thethiophene carboxamide already
4-morpholinone-benzene formed
isocyanate [86].
(94) is
In a variation of this strategy (Scheme 24 lower portion), the epoxide/isocyanate
reacted with an epoxide (95) bearing the domain of the target molecule with the thiophene cycloaddition was
used in the beginning
carboxamide already thus building
formed thearivaroxaban
[86]. In variation ofskeleton in a linear
this strategy fashion
(Scheme 24 [93].
lower portion), the
One of the earlier Bayer attempts involved the use of the anion of Cbz-(4-morpholino)-aniline
epoxide/isocyanate cycloaddition was used in the beginning thus building the rivaroxaban skeleton
to
in aring open
linear glycerol
fashion [93].butyrate (98). The resulting secondary alkoxide bites back on the carbamate
and displaces benzyl alcohol (Scheme 25) [94]. In this way the hydroxymethyl oxazolidinone 103a is
generated in a single step and with the butyrate is lost in the work up, two steps are eliminated from
the synthesis. In an improvement of this, the cryogenic BuLi deprotonation of the carbamate was
replaced Lit BuO at room temperature and 103a was isolated in 80% [95]. Further improvement that
saves the subsequent mesylation step of alcohol 103a was reported recently where glycerol butyrate/
Lit BuO is replaced with epibromohydrin (99)/Cs2 CO3 [96].
Catalysts 2020, 10, 1117 21 of 65
Scheme 24. Direct synthesis of chiral oxazolidinones via epoxide/isocyanate cycloadditions.
One of the earlier Bayer attempts involved the use of the anion of Cbz-(4-morpholino)-aniline to
ring open glycerol butyrate (98). The resulting secondary alkoxide bites back on the carbamate and
displaces benzyl alcohol (Scheme 25) [94]. In this way the hydroxymethyl oxazolidinone 103a is
replaced LitBuO at room temperature and 103a was isolated in 80% [95]. Further improvement that
saves theScheme
subsequent
Scheme mesylation
Direct
24. Direct
24. step
synthesis
synthesis of of alcohol
of chiral
chiral 103a wasvia
oxazolidinones
oxazolidinones reported
via recently where
epoxide/isocyanate
epoxide/isocyanate glycerol butyrate/
cycloadditions.
cycloadditions.
LitBuO is replaced with epibromohydrin (99)/Cs2CO3 [96].
One of the earlier Bayer attempts involved the use of the anion of Cbz-(4-morpholino)-aniline to
ring open glycerol butyrate (98). The resulting secondary alkoxide bites back on the carbamate and
displaces benzyl alcohol (Scheme 25) [94]. In this way the hydroxymethyl oxazolidinone 103a is
replaced LitBuO at room temperature and 103a was isolated in 80% [95]. Further improvement that
saves the subsequent mesylation step of alcohol 103a was reported recently where glycerol butyrate/
LitBuO is replaced with epibromohydrin (99)/Cs2CO3 [96].
Scheme 25.
Scheme Synthesis of
25. Synthesis of oxazolidinone
oxazolidinone intermediates
intermediates via
via condensation
condensation of
of carbamates
carbamates with
with epoxides.
epoxides.
Pharmacia Upjohn
Pharmacia Upjohn alsoalso tried
tried this
this approach
approach in in the
the early
early days
days of of linezolid
linezolid development
development where where
several carbamates of the linezolid aniline were screened in the-in-the
several carbamates of the linezolid aniline were screened in the-in-the reaction with epoxide 100 reaction with epoxide 100
with the view of accessing the drug substance directly [97] In this case however
with the view of accessing the drug substance directly [97] In this case however the deprotonation of the deprotonation
of the
the acetamide
acetamide sideside
chainchain competed
competed resulting
resulting in intramolecular
in an an intramolecular ringringopeningopening of epoxide
of the the epoxideand
and formation of 101. This issue was bypassed with the use of electrophile
formation of 101. This issue was bypassed with the use of electrophile 102 which also loses 102 which also loses the
the
acetate group
acetate group after
afterdisplacement
displacementand andthethesecondary
secondary alcohol
alcoholcyclizes
cyclizesontoontothethecarbamate
carbamate to produce
to producethe
oxazolidine
the oxazolidine thusthus
linezolid.
linezolid.
Scheme 25. Synthesis of oxazolidinone intermediates via condensation of carbamates with epoxides.
Arguably, either enantiomer
Arguably, either enantiomer [98][98] of
of any
any glycerol
glycerol derivative
derivative available
available in in bulk
bulk has
has been
been tested at
tested at
some point
somePharmacia in the
point in the synthesis
Upjohn of
alsoof
synthesis the
tried chiral
the this
chiral oxazolidinone
approach domains
in the early
oxazolidinone domains in
daysinof these two
linezolid
these important
development
two important medicines.
where
medicines.
Despite
several the entirely
Despite carbamates
the entirely of different pharmacology
the linezolid
different and
aniline were
pharmacology mode
screened
and mode of action, the
in the-in-the
of action, significant
reaction
the significant structural similarity
with epoxide
structural 100
similarity
between
with
between linezolid
the view
linezolid andrivaroxaban
of accessing
and rivaroxaban
the drug has hasbenefited
benefited
substance the
directly
the development
[97] In this case
development of of viable
however
viable large-scale processes
the deprotonation
large-scale processes of
for
for
the each since
eachacetamide in most
side chain
since in most cases the
competed
cases the respective
resulting
respective synthetic approaches
in anapproaches
synthetic intramolecular have
havering been
beenopening equally
equallyof applicable
the epoxide
applicable to
and
to both
both molecules.
formation
molecules. of 101. This issue was bypassed with the use of electrophile 102 which also loses the
acetate group after displacement and the secondary alcohol cyclizes onto the carbamate to produce
1.9. ACT-209905—Ring Opening of an Epoxide with Ammonia Surrogates
the oxazolidine thus linezolid.
ACT-209905
Arguably, is anenantiomer
either immunomodulating
[98] of any S1P1 agonist
glycerol underavailable
derivative development in bulk byhas
Actelion for the
been tested at
treatment
some pointofinautoimmune
the synthesis disorders. The oxazolidinone
of the chiral scope and potentialdomains of S1P1 agonism
in these was discussed
two important earlier
medicines.
under BMS-960.
Despite Onedifferent
the entirely of the key features in ACT-209905
pharmacology and mode(Schemeof action,26) theis significant
the chiral alcohol present
structural in the
similarity
pendant aliphatic
between linezolid chain attached to has
and rivaroxaban the phenol.
benefited The
theapproach
development was to ofform
viable the amide lastprocesses
large-scale from amine for
each since in most cases the respective synthetic approaches have been equally applicable to both
molecules.
accessed using phenol 106 and the inexpensive glycidol as the chiral building block.
This approach was adopted by the medicinal chemistry team who used the Mitsunobu reaction
to condense phenol 106 with glycidol into ether 105 and then excess ammonia in methanol to
generate 104.
Catalysts 2020, 10,this
Overall, 1117 constituted a 12-step synthesis that served the project team well for up to 22 of 65
half a
kilo drug substance deliveries. For larger scale demands this route presented several issues
particularly around the cost-effective synthesis of phenol 106, the workup difficulties and
104 resulting from ammonia-induced opening of epoxide 105 which in turn should be accessed using
chromatographic purification of the Mitsunobu reaction as well as amine dimers generated by the
phenol 106 and the inexpensive glycidol as the chiral building block.
reaction of amine 104 with epoxide 105.
Scheme 26. Retrosynthesis of the S1P1 agonist ACT-209905.
This approachprocess
The Actelion was adopted
team byhad thetomedicinal chemistry
respond with team whosupply
a reasonable used the Mitsunobu
route amid tightreaction to
project
condense phenol 106 with glycidol into ether 105 and then excess ammonia
deadlines which precluded extensive development and raw materials with long lead-times [99]. in methanol to generate 104.
Overall,
Having resolvedthis constituted
the synthesis a 12-step synthesis that
of the challenging served
phenol thefocus
106 projectwasteam
turnedwellon
foran
upalternative
to half a kilo
to
drug substance deliveries. For larger scale demands
Mitsunobu reaction for securing the epoxy intermediate 105. this route presented several issues particularly
around the cost-effective
Economics synthesis
and literature of phenol and
precedence 106, the workup alkylation
suggested difficulties ofandthechromatographic
phenol with
purification of the Mitsunobu
(R)-epichlorohydrin reactiona as
may provide well as
viable amine Cognizant
option. dimers generatedof thebyfact
the that
reaction of amine
reaction of 104
the
with epoxide 105.
phenoxide anion at the carbon bearing the chlorine atom in epichlorohydrin would produce the
The Actelion
undesired enantiomer process teamcareful
of 105, had to reaction
respond conditions
with a reasonable supply route
were employed amid tight
to safeguard project
that only
deadlines
epoxide ring which precluded
opening extensive development and raw materials with long lead-times [99]. Having
ensues.
resolved
In neatthe (10
synthesis of the challenging
equivalents) epichlorohydrin phenoland focus
106Me was turned on an alternative to Mitsunobu
4NCl as phase transfer catalyst, in the absence
reaction for securing the epoxy intermediate 105.
of base, it took two days for the phenol to be fully consumed at 25 °C. From the onset, a product
Economics
mixture and literature
of epoxide 105 and precedence
chlorohydrin and107
suggested alkylation
is observed whose of the phenol with
composition (R)-epichlorohydrin
shifted from 30:70 to
may provide a viable option. Cognizant of the fact that reaction
60:40 (105:107) as the reaction progressed. Increasing the temperature from 25 to of the phenoxide anion at the
30 and 40 carbon
°C the
bearing
reactionthe chlorine in
completed atom
1.5 in epichlorohydrin
days would produce
and 15 h, respectively althoughthe undesired enantiomer
a slight erosion of 105,
of ee was careful
observed
reaction
from 96 conditions were employed
to 94%. Addition to safeguard
of methanol that only
and aqueous NaOH epoxide
led toring
fullopening
conversionensues.
of the halohydrin
In neat (10 equivalents) epichlorohydrin
107 to epoxide 105 (Scheme 27). These conditions were and Me NCl as phase transfer catalyst,
4 successfully scaled up and delivered in the absence
17 kg of
of
base, it took ◦
epoxide 105.two days for the phenol to be fully consumed at 25 C. From the onset, a product mixture of
epoxide 105 and chlorohydrin 107 is observed whose composition shifted from 30:70 to 60:40 (105:107)
as the reaction progressed. Increasing the temperature from 25 to 30 and 40 ◦ C the reaction completed in
1.5 days and 15 h, respectively although a slight erosion of ee was observed from 96 to 94%. Addition of
methanol and aqueous NaOH led to full conversion of the halohydrin 107 to epoxide 105 (Scheme 27).
These conditions were successfully scaled up and delivered 17 kg of epoxide 105.
The use of glycerol derivatives bearing a latent amine group such as 81 in place of epichlorohydrin
may potentially eliminate the need for reaction of the epoxide with ammonia, but time constraints did
not allow this option to be explored or source this or equivalent reagent. The reaction of the epoxide
with ammonia typically produced up to 20% of the bis-alkylated amine impurity which could be
removed only by chromatography. An enormous excess of ammonia was required to suppress the
second alkylation and drive the reaction to amine 104.
Catalysts 2020, 10, 1117 23 of 65
Scheme 27. The ACT-209905 process including rectification of an undesired epoxide ring-opening.
Scheme 27. The ACT-209905 process including rectification of an undesired epoxide ring-opening.
Clearly a protected ammonia equivalent was required. The potassium salt of phthalimide reacted
The use of glycerol derivatives bearing a latent amine group such as 81 in place of
very slowly with 105 in DMF even at elevated temperatures. Sodium azide gave a fast and complete
epichlorohydrin may potentially eliminate the need for reaction of the epoxide with ammonia, but
reaction however its subsequent Pd-catalyzed hydrogenation was incompatible with oxadiazole ring.
time constraints did not allow this option to be explored or source this or equivalent reagent. The
No reaction occurred with hexamethyldisilazane (HMDS), but its lithium salt (LiHMDS) proved
reaction of the epoxide with ammonia typically produced up to 20% of the bis-alkylated amine
an excellent nucleophile in the opening of the epoxide ring and gave none of the dimeric impurity.
impurity which could be removed only by chromatography. An enormous excess of ammonia was
After solvent swapping to TBME and aqueous wok up the amine was isolated in 55% yield
required to suppress the second alkylation and drive the reaction to amine 104.
Further purification of amine 104 was not required and was treated directly with a mixture of
Clearly a protected ammonia equivalent was required. The potassium salt of phthalimide
glycolic acid, EDCI and HOBt in THF followed by crystallization from EtOAc afforded ACT-209905 in
reacted very slowly with 105 in DMF even at elevated temperatures. Sodium azide gave a fast and
49% yield with 98.6% purity and er 98.4:1. (Scheme 27) This chemistry was scaled up and delivered the
complete reaction however its subsequent Pd-catalyzed hydrogenation was incompatible with
desired active pharmaceutical ingredient at 12 kg scale.
oxadiazole ring. No reaction occurred with hexamethyldisilazane (HMDS), but its lithium salt
Undeterred by project constraints the Actelion process team delivered a scalable and efficient route
(LiHMDS) proved an excellent nucleophile in the opening of the epoxide ring and gave none of the
to ACT-209905 that apparently encompasses the first example of a large-scale epoxide ring opening
dimeric impurity. After solvent swapping to TBME and aqueous wok up the amine was isolated in
with LiHMDS as ammonia surrogate.
55% yield
1.10. Further purification of amine
SL65.0102–10—Refocusing 104 was
Attention not
from therequired and was treated
Active Pharmaceutical directly
Ingredient to with a mixture
the Chiral of
Epoxide
Starting
glycolic Material
acid, EDCI and HOBt in THF followed by crystallization from EtOAc afforded ACT-209905
in 49% yield with 98.6% purity and er 98.4:1. (Scheme 27) This chemistry was scaled up and
The 5-HT4 receptor is widely expressed in the periphery and development of 5-HT4R agonists has
delivered the desired active pharmaceutical ingredient at 12 kg scale.
led to approved drugs for gastrointestinal disorders. The 5-HT4 receptor is also highly expressed in the
Undeterred by project constraints the Actelion process team delivered a scalable and efficient
CNS in areas which are involved in cognitive functions (learning, memory) and their stimulation leads
route to ACT-209905 that apparently encompasses the first example of a large-scale epoxide ring
to production of acetylcholine and regulation of the neurotrophic soluble amyloid-protein precursor
opening with LiHMDS as ammonia surrogate.
alpha (sAPP) [100–103]. Consequently, 5HT4 receptor agonists have attracted attention for their
1.10. SL65.0102–10—Refocusing Attention from the Active Pharmaceutical Ingredient to the Chiral Epoxide
Starting Material
The 5-HT4 receptor is widely expressed in the periphery and development of 5-HT4R agonists
has led to approved drugs for gastrointestinal disorders. The 5-HT4 receptor is also highly expressed
in the 2020,
Catalysts CNS10,in1117
areas which are involved in cognitive functions (learning, memory) and24their of 65
stimulation leads to production of acetylcholine and regulation of the neurotrophic soluble
amyloid-protein precursor alpha (sAPP) [100–103]. Consequently, 5HT4 receptor agonists have
therapeutic potential in the treatment of Alzheimer’s Disease and cognitive impairment [104,105].
attracted attention for their therapeutic potential in the treatment of Alzheimer’s Disease and
SL65.0102–10 is a selective 5-HT4 partial agonist that was discovered and developed by Sanofi as
cognitive impairment [104,105]. SL65.0102–10 is a selective 5-HT4 partial agonist that was
promising agent for the treatment of cognitive impairment.
discovered and developed by Sanofi as promising agent for the treatment of cognitive impairment.
The Sanofi process team developed the original medicinal chemistry route by optimizing and
The Sanofi process team developed the original medicinal chemistry route by optimizing and
streamlining the first three steps involving epoxide 82 ring opening, mesylation of the resulting alcohol
streamlining the first three steps involving epoxide 82 ring opening, mesylation of the resulting
108 and intramolecular displacement of the mesylate 109 by the N-benzyl end of the piperazine
alcohol 108 and intramolecular displacement of the mesylate 109 by the N-benzyl end of the
(Scheme 28). This process was successfully scaled up to 60 kg batches affording intermediate 110
piperazine (Scheme 28). This process was successfully scaled up to 60 kg batches affording
directly in 74% yield.
intermediate 110 directly in 74% yield.
Scheme 28.
Scheme Initial improvements
28. Initial improvements to
to the
the medicinal
medicinal chemistry
chemistry route
route towards
towards SL65.0102–10.
SL65.0102–10.
The medicinal
The medicinalchemistry
chemistry 2-step deprotection
2-step of 110ofby 110
deprotection hydrogenolysis of the benzyl
by hydrogenolysis of ammonium
the benzyl
moiety followed by hydrazine treatment was replaced by a single
ammonium moiety followed by hydrazine treatment was replaced by a single step double step double deprotection in 20%
aqueous HCl. in
deprotection Despite the slow HCl.
20% aqueous rate and technical
Despite difficulties
the slow in removing
rate and technicalthe generatedinbenzyl
difficulties chloride
removing the
and benzyl alcohol this step performed well on scale and delivered the key amino
generated benzyl chloride and benzyl alcohol this step performed well on scale and delivered the methyl piperazine
key in
111 48.5%
amino yield in
methyl 35 kg batches.
piperazine 111 in The
48.5% final step
yield incoupling of 111The
35 kg batches. with acidstep
final was alsoof
112coupling optimized
111 with
and provided
acid SL65.0102–10
112 was also optimizedin and76.7% yield and
provided excellent quality
SL65.0102–10 in 76.7% even at and
yield 20 kgexcellent
batches quality
[106]. even at
20 kgNevertheless,
batches [106]. the lack of a reliable supplier of 82 at the quantities jeopardized the agreed
project deliveries hence
Nevertheless, theofSanofi
the lack process
a reliable chemists
supplier of 82 were
at theforced to develop
quantities a quickly
jeopardized a large-scale
the agreed project
synthesis for this starting material. The available conventional reactors however
deliveries hence the Sanofi process chemists were forced to develop a quickly a large-scale synthesis were inappropriate
to host
for safely the
this starting epichlorohydrin
material. The available involved in the reactors
conventional standard synthesis
however wereof inappropriate
82. (S)-(+)-solketal
to host
[(S)-(+)-1,2-isopropylideneglycerol] 113 and (R)-(-)-3-chloro-1,2-propanediol
safely the epichlorohydrin involved in the standard synthesis of 82. (S)-(+)-solketal 114 were identified
as suitable (S)-epichlorohydrin surrogates
[(S)-(+)-1,2-isopropylideneglycerol] 113 and which are cheap and available in
(R)-(-)-3-chloro-1,2-propanediol 114bulk.
were Respectively,
identified as
two alternative syntheses of 82 were investigated and evaluated at pilot plant
suitable (S)-epichlorohydrin surrogates which are cheap and available in bulk. Respectively, scale (Scheme 29). two
The (S)-(+)-solketal
alternative syntheses of 82 (10) route
were to 82 through
investigated and intermediates
evaluated at pilot 116 and
115,plant scale117a comprises
(Scheme 29). 6 steps
and was scaled up to 50 kg batches in the pilot plant thus enabling imminent deliveries of SL65.0102–10.
In parallel optimization of the (R)-(-)-3-chloro-1,2-propanediol route through the orthoformate
derivative of 115 [21,107] demonstrated significant benefits over the (S)-(+)-solketal route both in
terms of number of steps and required isolations of intermediates. The (R)-(-)-3-chloro-1,2-propanediol
became the method of choice and generated over 180 kg of 82 in excellent quality (98% purity and
>99% ee) for subsequent campaigns towards SL65.0102–10.
Catalysts 2020, 10, 1117 25 of 65
Scheme 29. Process development towards chiral epoxide 81 enabling a convergent API route.
Scheme 29. Process development towards chiral epoxide 81 enabling a convergent API route.
Overall, project deadlines combined with difficulties in sourcing convenient raw materials drove
The (S)-(+)-solketal (10) route to 82 through intermediates 115, 116 and 117a comprises 6 steps
the project team focus both on the API and the chiral epoxide starting material and succeeded
and was scaled up to 50 kg batches in the pilot plant thus enabling imminent deliveries of
at both fronts. The Sanofi process team developed a second-generation route to SL65.0102–10 by
SL65.0102–10. In parallel optimization of the (R)-(-)-3-chloro-1,2-propanediol route through the
improving the 12 steps/8 isolations in the first route to 10 steps/5 isolations capable of performing at
orthoformate derivative of 115 [21,107] demonstrated significant benefits over the (S)-(+)-solketal
multikilogram scale.
route both in terms of number of steps and required isolations of intermediates. The
(R)-(-)-3-chloro-1,2-propanediol
1.11. Carfilzomib—A Natural Epoxide became
Product theTurned
method intoofa choice
Drug andand thegenerated over
Challenge of Its 180 kg of 82 in
excellent quality Epoxidation
Diastereoselective (98% purity and >99% ee) for subsequent campaigns towards SL65.0102–10.
Overall, project deadlines combined with difficulties in sourcing convenient raw materials
Carfilzomib (trade name Kyprolis) is a highly selective irreversible inhibitor of the
drove the project team focus both on the API and the chiral epoxide starting material and succeeded
chymotrypsin-like activity of both the constitutive (β5c subunit) and the immuno-isoform (β5i or
at both fronts. The Sanofi process team developed a second-generation route to SL65.0102–10 by
LMP7 subunit) of the 20S proteasome [108,109]. It was approved by the FDA for multiple myeloma in
improving the 12 steps/8 isolations in the first route to 10 steps/5 isolations capable of performing at
2012 and by the European Medicines Agency in 2015. Carfilzomib is a great example of an anticancer
drug that was developed through a series of systematic modifications of a natural product, in this
case epoxomicin. Epoxomicin was discovered by Bristol Myers Squibb Research Institute (Tokyo) in
1.11. Carfilzomib —A Natural Epoxide Product Turned into a Drug and the Challenge of its Diastereoselective
1992 and demonstrated significant antitumor activity, but its development was abandoned because
Epoxidation
its mode of action was unclear and being a peptide did not have the appropriate pharmacokinetic
Carfilzomib
profile. Prof. CM Crews(trade (Yale
name Kyprolis)and
University) is Prof.
a highly selective
R Deshaies irreversible
(California inhibitor
Institute of the
of Technology)
chymotrypsin-like activity of both the constitutive (β5c subunit) and the
among others, founded Proteolix (later acquired by Onyx Pharmaceuticals; legacy company of Amgen) immuno-isoform (β5i or
LMP7 subunit) of the 20S proteasome [108,109]. It was approved by the
and decided to develop epoxomicin derivatives with desirable drug-like properties, particularlyFDA for multiple myeloma
in 2012 and
improved by theand
potency European Medicines
solubility. This effort Agency in 2015. Carfilzomib
born carfilzomib whose mechanismis a great example
of action wasofalsoan
anticancer drug
elucidated [110]. that was developed through a series of systematic modifications of a natural
product, in this case
Carfilzomib epoxomicin.
(Scheme 30) is aEpoxomicin
tetrapeptide was discoveredtwo
comprising by leucines,
Bristol Myers Squibb Research
phenylalanine and a
Institute
homo-phenylalanine with a the terminal morpholino cap benefiting the PK profile. Criticalwas
(Tokyo) in 1992 and demonstrated significant antitumor activity, but its development for
abandoned because
biologic activity its mode
however of action
is the was unclear and
chiral keto-epoxide being which
warhead a peptidewasdid not have the
maintained appropriate
throughout the
pharmacokinetic profile. Prof.
SAR work and constitutes CM Crews
the principle (Yale University)
synthetic challenge. The andsynthesis
Prof. R Deshaies (California
of the methyl Institute
or benzyl ester
of Technology) among others, founded Proteolix (later acquired by Onyx
of the tripeptide core hPheLeu-Phe 118 is achieved using standard solution phase peptide coupling Pharmaceuticals; legacy
company
conditionsof andAmgen)
only minor and improvements
decided to develop epoxomicin
have been made overderivatives with desirable drug-like
the years [111–116].
properties, particularly
In the original improved
synthesis potency[117]
of carfilzomib andthe solubility. Thiswas
keto-epoxide effort born carfilzomib
prepared whose
by lithium/halogen
mechanism of action was also elucidated [110].
exchange between t-BuLi (tert-Butyllithium) and 2-bomopropene and addition of the resulting vinyl
anionCarfilzomib
on the Weinreb (Scheme
amide30) 120isata−78
tetrapeptide comprising
◦ C thus affording vinyltwo leucines,
ketone phenylalanine
121 (Scheme and a
31). Hydrogen
homo-phenylalanine with a the terminal morpholino cap benefiting the PK profile. Critical for
biologic activity however is the chiral keto-epoxide warhead which was maintained throughout the
SAR work and constitutes the principle synthetic challenge. The synthesis of the methyl or benzyl
ester of the tripeptide core hPheLeu-Phe 118 is achieved using standard solution phase peptide
coupling conditions and only minor improvements have been made over the years [111–116].
Catalysts 2020, 10, 1117 26 of 65
peroxide oxidation
ester of the of thecore
tripeptide latterhPheLeu-Phe
produces the 118
Boc-protected amino
is achieved keto-epoxide
using 119a in aphase
standard solution 63:37 mixture
peptide
of diastereomers the desired isomer of which is obtained by column chromatography.
coupling conditions and only minor improvements have been made over the years [111–116].
Scheme 30. Retrosynthesis of carfilzomib into epoxyketone 119 and final coupling step.
In the original synthesis of carfilzomib [117] the keto-epoxide was prepared by lithium/halogen
anion on the Weinreb amide 120 at −78 °C thus affording vinyl ketone 121 (Scheme 31). Hydrogen
peroxide oxidation
Scheme 30.ofRetrosynthesis
the latter produces the Boc-protected
of carfilzomib into epoxyketoneamino keto-epoxide
119 and final coupling119a
final coupling step. in a 63:37
step.
mixture of diastereomers the desired isomer of which is obtained by column chromatography.
In the original synthesis of carfilzomib [117] the keto-epoxide was prepared by lithium/halogen
anion on the Weinreb amide 120 at −78 °C thus affording vinyl ketone 121 (Scheme 31). Hydrogen
peroxide oxidation of the latter produces the Boc-protected amino keto-epoxide 119a in a 63:37
mixture of diastereomers the desired isomer of which is obtained by column chromatography.
Scheme 31. Original and improved syntheses of the key chiral epoxyketone 119.
Scheme 31. Original and improved syntheses of the key chiral epoxyketone 119.
Obviously, the cryogenic temperatures, the pyrophoric t-BuLi and the chromatographic purification
Obviously,
render the unsuitable
this synthesis cryogenic for temperatures,
manufacturing. theThe pyrophoric
issue witht-BuLi and successfully
t-BuLi was the chromatographic
addressed
purification render this synthesis unsuitable for manufacturing. The
later by Onyx Pharmaceuticals, as they replaced it with the isopropenylmagnesium bromide thus issue with t-BuLi was
successfully addressed later by Onyx Pharmaceuticals,
enabling the formation of vinyl ketone 121 to proceed in THF at 0–5 C [111]. as ◦ they replaced it with the
isopropenylmagnesium
In the same bromide
work,31.marginal
Scheme thusimproved
enablingsyntheses
improvement
Original and the 2:1)
(dr formation
was of vinyl
of theachieved
key chiralinketone 121 to119.
the epoxidation
epoxyketone proceed in with
of 121 THF
at 0–5 °C [111]. ◦
calcium hypochlorite in aqueous NMP at −15 C or with bleach in aqueous pyridine at −5 C. ◦
In
As the same work,
Obviously,
carfilzomibthehad marginal
cryogenic improvement
grown astemperatures,
an Amgen asset (dr
the 2:1)
and was achieved
pyrophoric
established t-BuLiin the
marketed and epoxidation of 121
the chromatographic
product, Amgen with
process
calcium hypochlorite
purification
chemists made render inimprovements
aqueous
furtherthis NMP
synthesis toatthe
−15
unsuitable °C or
process forwith bleach in downstream
manufacturing.
upstream and aqueous
The pyridine
issue at
with
of the −5t-BuLi
°C.
pyridine/bleach was
As carfilzomib had grown as an Amgen asset and established marketed
epoxidation reaction and resolved issues related to a) the epimerization of 121 due to the interactionthe
successfully addressed later by Onyx Pharmaceuticals, as they replaced product,
it Amgen
with of
process
the chemists made
isopropenylmagnesium
enone/residual further improvements
bromide
inorganics/silica thus enabling
during to formation
the the process
its purification, of upstream
vinylyield
b) quality, and
ketoneand121downstream
to proceedissues
robustness ofTHF
in the
of
pyridine/bleach
at 0–5
the °C [111].
oxidation epoxidation
step reaction and
due to pH-dependent resolved issues
decomposition related c)
of bleach, toimpurity
a) the epimerization
built-up derived of 121
bydue
the
In the
solvent same work,
stabilizer [118]. marginal improvement (dr 2:1) was achieved in the epoxidation of 121 with
calcium
Other hypochlorite in aqueous
parties interested NMP at −15the
in improving °Csynthesis
or with bleach in aqueous
and optical pyridine
purity at −5carfilzomib
of the key °C.
As carfilzomib had grown as an Amgen asset and established marketed
intermediate 119, interrogated the influence of the 121 N-protecting group(s) in the Ca(OCl)2 epoxidation product, Amgen
process chemists made further improvements to the process upstream and downstream of the
pyridine/bleach epoxidation reaction and resolved issues related to a) the epimerization of 121 due
to the
to the interaction
interaction ofof the
the enone/residual
enone/residual inorganics/silica
inorganics/silica during
during its
its purification,
purification, b)b) quality,
quality, yield
yield and
and
robustness issues
robustness issues of
of the
the oxidation
oxidation step
step due
due to
to pH-dependent
pH-dependent decomposition
decomposition of of bleach,
bleach, c)
c) impurity
impurity
built-up derived
built-up derived byby the
the solvent
solvent stabilizer
stabilizer [118].
[118].
Other
Other
Catalysts parties
2020,parties interested in
10, 1117 interested in improving
improving the the synthesis
synthesis andand optical
optical purity
purity of
of the
the key
key carfilzomib
carfilzomib
27 of 65
intermediate 119,
intermediate 119, interrogated
interrogated the the influence
influence of of the
the 121
121 N-protecting
N-protecting group(s)
group(s) inin the
the Ca(OCl)
Ca(OCl)22
epoxidation reaction
epoxidation reaction [119].
[119]. Apparently,
Apparently, the the nature
nature and and number
number of of protecting
protecting groups
groups has
has aa great
great
reaction
impact on [119].
on the Apparently,
the yield
yield and the nature and
and diastereoselectivity number
diastereoselectivity of of the of protecting
the epoxidation groups
epoxidation since has
since this a great
this improved impact
improved from on
from 40% the
40% and yield
and dr
impact dr
and
2:1 diastereoselectivity
with the mono-Boc of the epoxidation
derivative 119a tosince
64% this
and improved
dr 10:1 from
with 40%
the and
bis-Boc dr 2:1
analog
2:1 with the mono-Boc derivative 119a to 64% and dr 10:1 with the bis-Boc analog 119b. The latter with the
119b. mono-Boc
The latter
derivative
was marginally
was 119a tobetter
marginally 64% and
better dr the
than
than 10:1 with
the bis-Cbzthe and
bis-Cbz bis-Boc
and mixed analog
mixed 119b. The
Boc/Cbz
Boc/Cbz latterstructures
analog
analog was marginally
structures 119c better
119c than
and 119d,
and 119d,
the bis-Cbz and
respectively (Scheme
respectively mixed
(Scheme 32).Boc/Cbz
32). analog structures 119c and 119d, respectively (Scheme 32).
Scheme 32.
Scheme
Scheme 32. Effect of
32. Effect
Effect of nitrogen
of nitrogen atom
nitrogen atom protection
atom protection on
protection on the
on the diastereoselectivity
the diastereoselectivity of
diastereoselectivity of the
of the enone
the enone epoxidation
enone epoxidation
epoxidation
Another approach
Another approach
approach waswas
was toto enhance
to enhance
enhance the the substrate
the substrate control
substrate control
control inin the
in the epoxidation
the epoxidation reaction
epoxidation reaction by
reaction by using
by using the
using the
the
Another
allylic
allylic alcohol(s)
alcohol(s) 122 as
122 the
as substrate
the (Scheme
substrate (Scheme33). The
33). Cbz
The substrate
Cbz generated
substrate the
generatedsyn and
the anti
syn alcohols
and anti
allylic alcohol(s) 122 as the substrate (Scheme 33). The Cbz substrate generated the syn and anti
122 in dr 122
alcohols 9:1 which
in dr were
dr 9:1
9:1 in turn
which wereepoxidized
in turn using vanadium
turn epoxidized
epoxidized using vanadium
vanadium The syn and
catalysis. catalysis. Theanti
synepoxides
and anti
anti
alcohols 122 in which were in using catalysis. The syn and
123 were
epoxides obtained
123 were in the same
obtained ratio
in thewhich
same was also
ratio maintained
which was in
also the subsequent
maintained in oxidation
the of the
subsequent
epoxides 123 were obtained in the same ratio which was also maintained in the subsequent
hydroxyl
oxidationgroups
of the back to the
the hydroxyl
hydroxyl ketoneback
groups state.
toInterestingly
the ketone the Boc-protected
ketone state.
state. Interestingly theketone 121 gave a 4:1
the Boc-protected
Boc-protected mixture
ketone 121
oxidation of groups back to the Interestingly ketone 121
of the syn
gave aa 4:1 and anti
4:1 mixture alcohols
mixture of of the 122,
the syn but
syn and this
and anti did not
anti alcohols transcend
alcohols 122,
122, but to the
but this
this didsyn
did notand anti epoxides
not transcend
transcend to 123.
to the
the synThese
syn and were
and anti
anti
gave
obtained
epoxides in a 1:1
123. ratiowere
These suggesting
obtained a mismatched
in a 1:1 ratioconformation
suggesting a of the major Boc
mismatched diastereoisomer
conformation of the122syn
major
epoxides 123. These were obtained in a 1:1 ratio suggesting a mismatched conformation of the major
exemplifying once more
Boc diastereoisomer
diastereoisomer the influence
122syn exemplifying exerted
onceby the protecting
more the influence
influence group in the
exerted bystereochemical
protectingcourse
the protecting of
group in
in
Boc 122syn exemplifying once more the exerted by the group
the epoxidation
the stereochemical [111,115,116].
stereochemical coursecourse of of the
the epoxidation
epoxidation [111,115,116].
[111,115,116].
the
Scheme 33. Effect of nitrogen atom protection on the diastereoselectivity of the allylic-OH epoxidation.
Scheme 33.
Scheme 33. Effect
Effect of
of nitrogen
nitrogen atom
atom protection
protection onon the
the diastereoselectivity
diastereoselectivity of of the
the allylic-OH
allylic-OH
epoxidation.
epoxidation.
In another attempt, the Sharpless asymmetric hydroxylation was applied on 121 although the
diastereoselectivity of this was not reported. In this case the synthesis of carfilzomib required additional
In another
In another attempt,
attempt, the
the Sharpless
Sharpless asymmetric
asymmetric hydroxylation
hydroxylation waswas applied
applied on
on 121
121 although
although the
the
steps associated with transforming the diol to the epoxide through protection as the diacetate prior
diastereoselectivity of this was not reported. In this case the synthesis of carfilzomib
diastereoselectivity of this was not reported. In this case the synthesis of carfilzomib required required
to Boc removal and coupling with the tripeptide, deprotection of the diol, activation of the primary
additional steps
additional steps associated
associated with
with transforming
transforming the
the diol
diol to
to the
the epoxide
epoxide through
through protection
protection as
as the
the
alcohol as mesylate followed by ring closure to the epoxide. The additional process intensity and
length render this approach unattractive for further development.
Other efforts involved the oxidation of the epoxyketone moiety at the dipeptide or tripeptide
stages post deprotection and coupling of 121 to the adjacent amino acids in carfilzomib or even
diacetate prior to Boc removal and coupling with the tripeptide, deprotection of the diol, activation
of the primary alcohol as mesylate followed by ring closure to the epoxide. The additional process
intensity and length render this approach unattractive for further development.
Catalysts 10, 1117 involved the oxidation of the epoxyketone moiety at the dipeptide or tripeptide
2020, efforts
Other 28 of 65
stages post deprotection and coupling of 121 to the adjacent amino acids in carfilzomib or even at
des-oxy
at des-oxy carfilzomib
carfilzomib itself. The
itself. Thediastereoselectivities
diastereoselectivities(where(wherereported)
reported)were
werenono better
better than those
than those
obtained with 121 [120–123]. This and other approaches are discussed in more
obtained with 121 [120–123]. This and other approaches are discussed in more detail in an excellent detail in an excellent
patent review by
patent review by D.L.
D.L. Hughes
Hughes [124].
[124].
The cause of carfilzomib
The cause of carfilzomib had had attracted
attracted the
the application
application of of alternative
alternative catalytic
catalytic epoxidation
epoxidation
methods.
methods. In one of them, epoxidation of 121 has been reported to occur with 93% de85%
In one of them, epoxidation of 121 has been reported to occur with 93% de and andyield
85%
with the lanthanum(III) BINOL complex, in toluene at ambient temperature
yield with the lanthanum(III) BINOL complex, in toluene at ambient temperature with TBHP (tert-Butyl with TBHP (tert-Butyl
hydroperoxide)
hydroperoxide) in in the presence of
the presence of triphenyl
triphenyl phosphine
phosphine [125] (the real
[125] (the real additive
additive being
being the
the triphenyl
triphenyl
phosphine oxide
phosphine oxidegenerated
generatedininsitu situ
byby thethe oxidant)
oxidant) [126].
[126]. ThisThis reaction
reaction waswas demonstrated
demonstrated at 100atg100
scaleg
scale nevertheless it requires a catalyst-loading of at least 20 mol%
nevertheless it requires a catalyst-loading of at least 20 mol% for best results. for best results.
In contrasttoto
In contrast thisthis requirement,
requirement, a chiral
a chiral manganese
manganese complexcomplex
(M2, Scheme(M2,34)Scheme 34) specifically
developed developed
specifically for the epoxidation
for the epoxidation of enones with of enones with H2at
H2 O2 , sufficed O20.2
, sufficed
mol% to at epoxidize
0.2 mol% to epoxidize
(S)-ketone (S)-ketone
121 in 96% yield,121
in 96% yield, but at dr 1:7 favoring the undesired diastereoisomer of 119a-syn (S at
but at dr 1:7 favoring the undesired diastereoisomer of 119a-syn (S at the ketone, R at the epoxide) [127]. the ketone, R at
the epoxide) [127].
Et H
N N N N O
H
N N BocHN
Mn Et N N Mn N Et
N O
Et N N OTf 119a-syn
OTf OTf OTf dr 95 : 5
M2 M3
DBU 20 mol%
Amgen Process TBME, 20 oC
50% overall
1. morpholine
CDI, TBME M3 0.04 mol% O
N 2. Mg, Br MeCN, AcOH
BocHN BocHN BocHN
THF/ H2O2, -20 oC
O 2-MeTHF O O
Boc-D-leucine-OH ent-121 119a-anti

dr 91 : 9
Scheme 34. Catalytic asymmetric (substrate-controlled) epoxidation followed by epimerization.

Scheme 34. Catalytic asymmetric (substrate-controlled) epoxidation followed by epimerization.
The Amgen process chemists took notice of this and decided to investigate if the diastereoselectivity
The Amgen process chemists took notice of this and decided to investigate if the
of this excellent performing catalytic epoxidation could be reversed. A thorough optimization led to a
diastereoselectivity of this excellent performing catalytic epoxidation could be reversed. A thorough
more efficient Mn ligand/active catalyst M3 nevertheless the diastereoselectivity of this process remained
optimization led to a more efficient Mn ligand/active catalyst M3 nevertheless the
overwhelmingly substrate-controlled producing the undesired diastereoisomer of 119a-anti in 91:9
diastereoselectivity of this process remained overwhelmingly substrate-controlled producing the
ratio. This was ingeniously exploited by employing the enantiomer of enone 121 (i.e., the R enantiomer)
undesired diastereoisomer of 119a-anti in 91:9 ratio. This was ingeniously exploited by employing
to generate the correct epoxide stereochemistry (S) followed by epimerization of the α-carbon into the
the enantiomer of enone 121 (i.e., the R enantiomer) to generate the correct epoxide stereochemistry
S stereochemistry for which DBU (1,8-Diazabicyclo[5.4.0] undec-7-ene) emerged as the optimum base
(S) followed by epimerization of the α-carbon into the S stereochemistry for which DBU
(79% yield, dr 95:5).
(1,8-Diazabicyclo[5.4.0] undec-7-ene) emerged as the optimum base (79% yield, dr 95:5).
The higher crystallinity of the R,S diastereoisomer allowed also for the development of a
The higher crystallinity of the R,S diastereoisomer allowed also for the development of a
crystallization process which obviated the need for chromatography. The Amgen process group
crystallization process which obviated the need for chromatography. The Amgen process group
transformed entirely the synthesis of 119a by developing a continuous process for the Grignard
transformed entirely the synthesis of 119a by developing a continuous process for the Grignard
addition of 2-propenyl to the Boc-D-leucine morpholine amide instead of the Weinreb amide 120
addition of 2-propenyl to the Boc-D-leucine morpholine amide instead of the Weinreb amide 120
and telescoping this into the catalytic epoxidation reaction. This remarkably innovative process
and telescoping this into the catalytic epoxidation reaction. This remarkably innovative process was
was demonstrated at 2 kg scale and delivered enantiopure 119a-syn in 50% yield in a much greener,
safer and efficient manner [128].
The development of carfilzomib has been established as a point of reference in anticancer drug
research and has inspired the development of several other related and unrelated natural products
for various indications most notably cancers. After years of research and development by various
demonstrated at 2 kg scale and delivered enantiopure 119a-syn in 50% yield in a much greener, safer
and efficient manner [128].
The
Catalysts development
2020, 10, 1117 of carfilzomib has been established as a point of reference in anticancer29drug
of 65
research and has inspired the development of several other related and unrelated natural products
for various indications most notably cancers. After years of research and development by various
groups, Amgen
Amgenprocess
processchemists
chemistsachieved a highly
achieved diastereoselective
a highly and viable
diastereoselective and in large-scale
viable catalytic
in large-scale
epoxidation process for the terminal vinyl ketone moiety.
catalytic epoxidation process for the terminal vinyl ketone moiety.
1.12. Diltiazem—A
1.12. Diltiazem—A Rare
Rare Example
Example of
of Chiral
Chiral Epoxide
Epoxide Industrial
Industrial Synthesis
Synthesis via
via Asymmetric
Asymmetric Organocatalysis
Organocatalysis
Followed by Ring Opening with Retention of Configuration
Followed by Ring Opening with Retention of Configuration
Diltiazem (Cardizem) is a calcium channel blocker and is FDA approved for atrial arrhythmia,
Diltiazem (Cardizem) is a calcium channel blocker and is FDA approved for atrial arrhythmia,
hypertension, paroxysmal supraventricular tachycardia and chronic stable angina. Diltiazem is a chiral
hypertension, paroxysmal supraventricular tachycardia and chronic stable angina. Diltiazem is a
1,5-benzothiazepine with the threo (2S,3S)-isomer demonstrating superior vasodilating properties.
chiral 1,5-benzothiazepine with the threo (2S,3S)-isomer demonstrating superior vasodilating
The end game in the various syntheses of diltiazem almost invariably involves the attachment of the
properties. The end game in the various syntheses of diltiazem almost invariably involves the
dimethylamino-ethyl side chain on the amide nitrogen of intermediate 124 (Scheme 35) followed by
attachment of the dimethylamino-ethyl side chain on the amide nitrogen of intermediate 124
O-acetylation. Lactam 124 is obtained by cyclisation of an appropriate carboxyl derivative 125 such as
(Scheme 35) followed by O-acetylation. Lactam 124 is obtained by cyclisation of an appropriate
an ester or amide.
carboxyl derivative 125 such as an ester or amide.
Scheme 35.
Scheme Retrosynthesis of
35. Retrosynthesis of diltiazem
diltiazem to
to chiral
chiral precursor
precursor 125.
125.
Initially, development of manufacturing routes to diltiazem were based on both chemical [129]
Initially, development of manufacturing routes to diltiazem were based on both chemical [129]
and enzymatic [130] resolutions of appropriate intermediates. The route based on resolution of
and enzymatic [130] resolutions of appropriate intermediates. The route based on resolution of
(2S,3S)-3-(4-methoxyphenyl)
(2S,3S)-3-(4-methoxyphenyl) glycidic glycidic acidacid methyl
methyl ester,
ester, (126
(126 Scheme
scheme 36) 36) inin particular,
particular, provided
provided
significant cost benefits [131]. In the context of asymmetric
significant cost benefits [131]. In the context of asymmetric synthesis, setting up synthesis, setting up the
the correct
correct
stereochemistry of
stereochemistry of the
thethio-
thio-and
andacetoxy-
acetoxy-substituents
substituentsprecipitates
precipitatesa amajor
majorchallenge
challenge in in
thethe
synthesis
synthesisof
diltiazem. Standard ring opening of the trans-epoxide 126 by nucleophilic attack
of diltiazem. Standard ring opening of the trans-epoxide 126 by nucleophilic attack of 2-amino-(or of 2-amino-(or 2-nitro)
thiophenol
2-nitro) with inversion
thiophenol of configuration
with inversion at the benzylic
of configuration at the carbon
benzylicwould
carbon generate
wouldthe undesired
generate the
erythro isomer
undesired One strategy
127.isomer
erythro 127. Oneto overcome
strategy tothis issue was
overcome demonstrated
this by Jacobsen who
issue was demonstrated used the
by Jacobsen
who used the cis-epoxide
corresponding corresponding 128 thus starting with
cis-epoxide inverted
128 thus stereochemistry
starting with inverted at the benzylic carbonat[132].
stereochemistry the
Indeed, ring opening of the cis-epoxide 128 (R = i Pr) with 2-nitrothiophenol provided intermediate
benzylic carbon [132]. Indeed, ring opening of the cis-epoxide 128 (R = Pr) with 2-nitrothiophenol
i
129 (X = O,
provided R = i Pr, Scheme
intermediate 129 (X36).
= O,Reduction of the 36).
R = iPr, Scheme nitro group followed
Reduction by the
of the nitro standard
group endby
followed game
the
yielded diltiazem. The synthesis of cis-epoxide
standard end game steps yielded diltiazem. The synthesis of cis-epoxide 128 was realized in 96% by
steps 128 was realized in 96% ee (10:1 cis/trans ratio) ee
applying the Jacobsen–Katsuki epoxidation protocol with a chiral salen complex
(10:1 cis/trans ratio) by applying the Jacobsen–Katsuki epoxidation protocol with a chiral salen on the corresponding
cis-cinnamate
complex on theester. The availability
corresponding of the latter
cis-cinnamate alkene
ester. The constitutes
availabilitythe Achilles’
of the heel ofconstitutes
latter alkene this route astheit
is obtained by photoisomerization of the trans isomer.
Achilles’ heel of this route as it is obtained by photoisomerization of the trans isomer.
An alternative
An alternative strategy
strategy had
had been
been developed
developed aa decade
decade earlier
earlier by
by chemists
chemists at at Tanabe
Tanabe Seiyaku
Seiyaku
(legacy company of Mitsubishi Tanabe Pharma), the inventors of
(legacy company of Mitsubishi Tanabe Pharma), the inventors of diltiazem, who recognized diltiazem, who recognized thatthat
the
the easy-to-access trans epoxide 126 could be exploited in a ring-opening
easy-to-access trans epoxide 126 could be exploited in a ring-opening reaction with retention of reaction with retention of
configuration at
configuration at the
the benzylic
benzylic carbon
carbon [133].
[133].
This transformation is largely facilitated by the p-methoxy phenyl substituent supporting the
opening of the ring by virtue of its electron donating capacity (Scheme 37) and ability to stabilize
the resulting benzylic cation (other less electron donating substituents do not work as well, if at
all). This reaction is further assisted by Lewis acid activation of the epoxide, presumably in a
form involving prior complexation with the nucleophile, thus allowing the reaction to proceed in a
pseudo-intramolecular fashion. A similar case culminating the reduction of a chiral epoxide with
retention of configuration has been described by Merck chemists in the synthesis of the PDE IV inhibitor
CDP840 [134].
Catalysts 2020, 10, 1117 30 of 65
Scheme 36. Ring opening of epoxides 126 and 128 with retention and inversion of configuration.
opening of the ring by virtue of its electron donating capacity (Scheme 37) and ability to stabilize the
resulting benzylic cation (other less electron donating substituents do not work as well, if at all). This
reaction is further assisted by Lewis acid activation of the epoxide, presumably in a form involving
prior complexation with the nucleophile, thus allowing the reaction to proceed in a
retention of configuration has been described by Merck chemists in the synthesis of the PDE IV
36. Ring opening
Scheme 36.
Scheme opening of
of epoxides
epoxides 126 and 128
126 and with retention
128 with retention and
and inversion
inversion of
of configuration.
inhibitor CDP840Ring[134]. configuration.
opening of the ring by virtue of its electron donating capacity (Scheme 37) and ability to stabilize the
resulting benzylic cation (other less electron donating substituents do not work as well, if at all). This
reaction is further assisted by Lewis acid activation of the epoxide, presumably in a form involving
prior complexation with the nucleophile, thus allowing the reaction to proceed in a
Scheme 37. Mechanism of epoxide ring opening with retention of configuration.
retention of configuration has been described by Merck chemists in the synthesis of the PDE IV
inhibitor
The CDP840chemists
The Tanabe
Tanabe [134]. later
chemists laterexpanded
expanded their original
their originalwork
workand screened
and a wide
screened array
a wide of catalysts
array and
of catalysts
solvents for this transformation [135]. Best results (90% yield 129c, 92:8 threo/erythro ratio)
and solvents for this transformation [135]. Best results (90% yield 129c, 92:8 threo/erythro ratio) were were obtained
with iron (III)
obtained withsalts,
ironparticularly
(III) salts, with the chloride
particularly withandthethechloride
sulfate, at
and10−4
themol% catalyst-loading
sulfate, at 10–4 mol% in
refluxing xylene in
catalyst-loading (Scheme
refluxing38, xylene
upper).(Scheme 38, upper).
Chemists at Roche, in their effort to develop diltiazem analogs such as naltiazem, accomplished
this thermally (Scheme 38, lower) in the presence of 2-aminothiophenol alone which is acidic enough
to support protonation of the epoxide and self-ring opening to the stabilized benzylic cation thus
inviting the attack
Schemeby 37.
theMechanism
thiolate anion [136].ring
of epoxide Thisopening
process was
with demonstrated
retention on kg scale affording
of configuration.
intermediate 129* in 98% yield. In this case, the prerequisite chiral epoxide was synthesized via
The Tanabe
employing a chiralchemists
auxiliary later
in aexpanded their original
diastereoselective Darzenswork and screened
reaction betweenap-anisaldehyde
wide array of catalysts
and the
and solvents for
chloroacetate this
ester oftransformation [135]. Best results
(1R,2S)-2-phenylcyclohexanol (90%
130*. yield
This 129c, 92:8
reaction threo/erythro
produces a 62:38 ratio)
mixturewere
of
obtained
the with iron (III)
two diastereomeric salts, 131*
epoxides particularly
from whichwiththethe chloride
desired and the sulfate,
diastereoisomer at 10
is isolated –4 mol%
by simple
catalyst-loading
crystallization inin refluxing
54% xylene
yield (400 (Scheme 38, upper).
g scale).
In terms of preparation of the appropriate chiral epoxy cinnamate ester 129a, the Tanabe chemists
addressed an occupational health issue in their original enzymatic resolution process [131]. Because
the epoxy ester intermediate was shown to be a severe irritant, the enzymatic resolution was modified
to produce optically pure and safe to handle epoxy amide 129c either directly using ammonia or by
converting resolved methyl ester 129a to the primary amide. The epoxy amide 129c performed well in
the ring opening and the subsequent acid-catalyzed lactamization, eventually allowing for successful
preparation of diltiazem in multigram scale.
Catalysts 2020, 10, 1117 31 of 65
Scheme 38. Alternative synthesis of diltiazem intermediate 129 via asymmetric Darzen reaction.
Scheme 38. Alternative synthesis of diltiazem intermediate 129 via asymmetric Darzen reaction.
In order to improve further on the efficiency of the synthesis of the chiral epoxide the Tanabe
Chemists at Roche, in their effort to develop diltiazem analogs such as naltiazem, accomplished
chemists investigated alternative routes that would preclude the >50% yield loss associated with
this thermally (Scheme 38, lower) in the presence of 2-aminothiophenol alone which is acidic enough
resolution methods (either chemical or enzymatic). Thus, a catalytic asymmetric epoxidation of
to support protonation of the epoxide and self-ring opening to the stabilized benzylic cation thus
p-methoxy cinnamate esters (132) became the next objective of the Tanabe investigation. Given the
inviting the attack by the thiolate anion [136]. This process was demonstrated on kg scale affording
electron deficient nature of the alkene potion in the cinnamic substrate, a powerful electrophilic oxidant
intermediate 129* in 98% yield. In this case, the prerequisite chiral epoxide was synthesized via
must be used in order for the epoxidation to take place. For this reason, chiral dioxiranes generated in
employing a chiral auxiliary in a diastereoselective Darzens reaction between p-anisaldehyde and
situ from appropriate chiral ketones were considered for this task [137,138].
the chloroacetate ester of (1R,2S)-2-phenylcyclohexanol 130*. This reaction produces a 62:38 mixture
Yang’s chiral ketone 133 (Scheme 39) emerged as the optimum organocatalyst for this
of the two diastereomeric epoxides 131* from which the desired diastereoisomer is isolated by
transformation in terms of ease of preparation, catalyst-loading and stability [139]. The process
simple crystallization in 54% yield (400 g scale).
was gradually scaled up to 100 g with 5 mol% of the ketone catalyst in the presence of OxoneTM as
In terms of preparation of the appropriate chiral epoxy cinnamate ester 129a, the Tanabe
the terminal oxidant and delivered the crude chiral epoxy cinnamate in 89% yield and 78% ee [139].
chemists addressed an occupational health issue in their original enzymatic resolution process [131].
A special recrystallization process was developed for isolating the product without contamination from
Because the epoxy ester intermediate was shown to be a severe irritant, the enzymatic resolution was
the catalyst which not only upgraded the quality of the intermediate to 99% ee (64% yield), but also
modified to produce optically pure and safe to handle epoxy amide 129c either directly using
allowed for the recovery of the catalyst. In a subsequent effort, the crystallization process was coupled
ammonia or by converting resolved methyl ester 129a to the primary amide. The epoxy amide 129c
to a lipase-catalyzed transesterification step that also allowed for recycling of the unwanted epoxide
performed well in the ring opening and the subsequent acid-catalyzed lactamization, eventually
enantiomer [140].
allowing for successful preparation of diltiazem in multigram scale.
The asymmetric epoxidation of α,β-unsaturated ketones may be accomplished by the Julia Colona
In order to improve further on the efficiency of the synthesis of the chiral epoxide the Tanabe
protocol with nucleophilic oxidants such as hydrogen peroxide. In this, the substrate associates with
chemists investigated alternative routes that would preclude the >50% yield loss associated with
polyleucine catalyst via hydrogen bonding and becomes activated towards a conjugate addition by the
resolution methods (either chemical or enzymatic). Thus, a catalytic asymmetric epoxidation of
oxidant within the chiral environment of the catalyst. This approach was demonstrated in the synthesis
p-methoxy cinnamate esters (132) became the next objective of the Tanabe investigation. Given the
of diltiazem via the catalytic asymmetric epoxidation of ketone 134 (Scheme 39) followed by a Bayer
electron deficient nature of the alkene potion in the cinnamic substrate, a powerful electrophilic
Villiger reaction on epoxide 135 to generate the t-butyl cinnamate ester 136 [141]. Using the conditions
oxidant must be used in order for the epoxidation to take place. For this reason, chiral dioxiranes
developed by Roche and the established endgame reactions, a second alternative synthesis of diltiazem
generated in situ from appropriate chiral ketones were considered for this task [137,138].
based on an organocatalyst was achieved. It is worth noting that this synthesis was performed three
Yang’s chiral ketone 133 (Scheme 39) emerged as the optimum organocatalyst for this
consecutive times at 4 g scale with reuse of the immobilized polyleucine catalyst each time, without
transformation in terms of ease of preparation, catalyst-loading and stability [139]. The process was
deterioration of the yield or ee.
gradually scaled up to 100 g with 5 mol% of the ketone catalyst in the presence of Oxone™ as the
terminal oxidant and delivered the crude chiral epoxy cinnamate in 89% yield and 78% ee [139]. A
special recrystallization process was developed for isolating the product without contamination
from the catalyst which not only upgraded the quality of the intermediate to 99% ee (64% yield), but
also allowed for the recovery of the catalyst. In a subsequent effort, the crystallization process was
The asymmetric epoxidation of α,β-unsaturated ketones may be accomplished by the Julia
Colona protocol with nucleophilic oxidants such as hydrogen peroxide. In this, the substrate
associates with polyleucine catalyst via hydrogen bonding and becomes activated towards a
conjugate addition by the oxidant within the chiral environment of the catalyst. This approach was
demonstrated in the synthesis of diltiazem via the catalytic asymmetric epoxidation of ketone
Catalysts 2020, 10, 1117 134
32 of 65
(Scheme 39) followed by a Bayer Villiger reaction on epoxide 135 to generate the t-butyl cinnamate
ester 136 [141]. Using the conditions developed by Roche and the established endgame reactions, a
secondOverall, the process
alternative development
synthesis effortsbased
of diltiazem towards
ondiltiazem encompasswas
an organocatalyst two rare aspectsItofisepoxide
achieved. worth
chemistry performed on scale, namely the asymmetric synthesis of an epoxide
noting that this synthesis was performed three consecutive times at 4 g scale with using an organocatalyst
reuse of the
and its subsequent
immobilized ring opening
polyleucine catalystwith
eachretention of configuration.
time, without deterioration of the yield or ee.
Scheme 39.
Scheme Synthesis of
39. Synthesis of chiral
chiral epoxy
epoxy cinnamate
cinnamate intermediates
intermediates using
using asymmetric
asymmetric organocatalysis.
organocatalysis.
1.13. Reboxetine—Epoxide Intermediates Transcending from a Racemic to an Asymmetric Synthesis

Overall, the process development efforts towards diltiazem encompass two rare aspects of
CNSchemistry
epoxide disorders performed
are largely associated with deregulation
on scale, namely of neurotransmitter
the asymmetric synthesis of anand neurohormone
epoxide using an
signaling. Prominent
organocatalyst members of
and its subsequent the
ring formerwith
opening category include
retention the biogenic amines serotonin,
of configuration.
norepinephrine (noradrenaline) and dopamine. Depression encompasses several disorders with
1.13. Reboxetine—Epoxide
various symptoms, ailments Intermediates Transcending
and disabilities from aaffect
that may Racemic
ourtoemotions,
an Asymmetric Synthesis
thoughts, actions and
physical condition of the entire human body. Intervention at the serotoninergic and noradrenergic
CNS disorders are largely associated with deregulation of neurotransmitter and neurohormone
signaling has produced the state of the art of antidepressants (SSRIs, NRIs and SNRIs) [142,143]
signaling. Prominent members of the former category include the biogenic amines serotonin,
primarily through inhibition of the reuptake of the respective neurotransmitters in the synaptic cleft.
norepinephrine (noradrenaline) and dopamine. Depression encompasses several disorders with
Reboxetine is a highly potent and selective norepinephrine reuptake inhibitor that is approved in many
various symptoms, ailments and disabilities that may affect our emotions, thoughts, actions and
countries, but not the FDA, for the acute treatment of depressive illness/major depression. Its efficacy
physical condition of the entire human body. Intervention at the serotoninergic and noradrenergic
for these indications has been a matter of controversy instead clearer benefit is observed in cases with
signaling has produced the state of the art of antidepressants (SSRIs, NRIs and SNRIs) [142,143]
symptoms of anhedonia and somatic pain. Furthermore, reboxetine appears to be widely endorsed
primarily through inhibition of the reuptake of the respective neurotransmitters in the synaptic cleft.
(off label) for SSRI-resistant panic disorder and attention deficit hyperactivity disorder (ADHD).
Reboxetine is a highly potent and selective norepinephrine reuptake inhibitor that is approved in
Reboxetine was discovered by Farmitalia which was acquired by Pharmacia in 1993 and succeeded in
many countries, but not the FDA, for the acute treatment of depressive illness/major depression. Its
obtaining regulatory approvals. Pharmacia merged with Upjohn in 1995 forming Pharmacia-Upjohn
efficacy for these indications has been a matter of controversy instead clearer benefit is observed in
which in turn was acquired by Pfizer in 2003.
cases with symptoms of anhedonia and somatic pain. Furthermore, reboxetine appears to be widely
Reboxetine has two stereogenic centers and consequently there are four diastereoisomers, two sets
endorsed (off label) for SSRI-resistant panic disorder and attention deficit hyperactivity disorder
of enantiomers, associated with its structure. The registered NRI antidepressant, reboxetine mesylate
(ADHD). Reboxetine was discovered by Farmitalia which was acquired by Pharmacia in 1993 and
(trade name Edronax, Scheme 40), comprises actually one set enantiomers the (S,S and the R,R), namely
the set of syn diastereomers and is therefore marketed in a diastereomerically pure yet racemic form.
For this reason, the initial synthesis of reboxetine were racemic. More recent studies have shown
that the (S,S)-enantiomer (esreboxetine, Scheme 40) is more active than its enantiomer in certain
biologic assays [144] and (S,S)-reboxetine succinate is under development at Pfizer for the treatment of
fibromyalgia. A number of reboxetine syntheses have been described over the years and these have
been recently reviewed [145]. The discussion that follows focuses on the relevant epoxide-involving
routes particularly those of large scale/manufacturing potential.
Pharmacia-Upjohn which in turn was acquired by Pfizer in 2003.
Reboxetine has two stereogenic centers and consequently there are four diastereoisomers, two
sets of enantiomers, associated with its structure. The registered NRI antidepressant, reboxetine
mesylate (trade name Edronax, Scheme 40), comprises actually one set enantiomers the (S, S and the
Catalysts 2020, 10, the
R, R), namely 1117set of syn diastereomers and is therefore marketed in a diastereomerically pure
33 ofyet
65
racemic form.
40. Stereochemistry of reboxetine (approved drug) and esreboxetine

Scheme 40.
Scheme esreboxetine (clinical
(clinical candidate).
candidate).
The first reason,

For this synthesis theforinitial
reboxetine mesylate
synthesis (the racemic
of reboxetine wereapproved
racemic. drug)
More was
recentreported
studiesby its
have
inventors Farmitalia-Carlo Erba. By the time the drug became a Pfizer asset it
shown that the (S,S)-enantiomer (esreboxetine, Scheme 40) is more active than its enantiomer in had grown in demand
and a more
certain efficient
biologic route
assays wasand
[144] needed, but there was
(S,S)-reboxetine limited freedom
succinate is underfor changes dueatthe
development restrictions
Pfizer for the
that apply to registered processes with regulatory bodies. Pfizer process
treatment of fibromyalgia. A number of reboxetine syntheses have been described over the yearschemists made several
modifications
and these have (Scheme 41) to thereviewed
been recently Farmitalia routeThe
[145]. anddiscussion
developed that
a process which
follows involves
focuses 12 chemical
on the relevant
transformations yet only three isolations improving the yield of the
epoxide-involving routes particularly those of large scale/manufacturing potential. drug substance from 11 to about
25% [146].
The first synthesis for reboxetine mesylate (the racemic approved drug) was reported by its
inventors Farmitalia-Carlo Erba. By the time the drug became a Pfizer asset it had grown in demand
and a more efficient route was needed, but there was limited freedom for changes due the
restrictions that apply to registered processes with regulatory bodies. Pfizer process chemists made
several modifications (Scheme 41) to the Farmitalia route and developed a process which involves 12
chemical transformations yet only three isolations improving the yield of the drug substance from 11
to about 25% [146].
In particular, due to work up difficulties, long processing times and size of waste, the reagent
for the epoxidation of cinnamyl alcohol 137 was switched from monoperoxyphthalic acid (prepared
from H2O2 and phthalic anhydride) to peracetic acid (Scheme 41). The epoxide 138 was telescoped
into the ring-opening reaction with 2-ethoxyphenol which was now run in water in the presence of a
phase transfer catalyst instead of dioxane. Diol 139 was isolated after the telescoped epoxidation and
ring-opening process in 65% yield at > 0.3 ton scale. The protecting group for the primary alcohol in
the next step was changed from p-nitrobenzoyl to TMS in order to limit the extensive migration of
the acyl group (>20%) to the secondary alcohol which would ultimately lead to the wrong API
diastereomer. The regioselectivity of the TMS protection towards exclusive formation of 140 was
carefully controlled before addition of mesyl chloride to generate mesylate 141. Acid treatment
removes the silyl group revealing hydroxy mesylate 142 followed by base-induced epoxide
formation. Ring opening of epoxide 143 with ammonia required large excess of the latter to suppress
further reaction of the generated amine 144 with a second molecule of epoxide. The dimeric amine
generated in this way was difficult to purge down downstream if formed at >8% at this stage. After
careful optimization of these steps the telescoped process from diol 139 spanning 5 steps was run at
275 kg batches and delivered key intermediate amine 144 as its mesylate salt in 63% yield and
excellent quality.
Scheme 41. Pfizer’s manufacturing route for reboxetine.

Scheme 41. Pfizer’s manufacturing route for reboxetine.
The construction of the morpholine ring was realized via a telescoped three step sequence
involving amidation of 144 with chloroacetyl chloride, cyclisation of 145 and reduction of the
resulting morpholinone. Features of this process such as the dimethyl carbonate solvent in the
amidation step and the final Vitride reduction were maintained in order to avoid major deviations
from the registered process. Modifications in the reduction step nevertheless led to significant
Catalysts 2020, 10, 1117 34 of 65
In particular, due to work up difficulties, long processing times and size of waste, the reagent
for the epoxidation of cinnamyl alcohol 137 was switched from monoperoxyphthalic acid (prepared
from H2 O2 and phthalic anhydride) to peracetic acid (Scheme 41). The epoxide 138 was telescoped
into the ring-opening reaction with 2-ethoxyphenol which was now run in water in the presence of a
phase transfer catalyst instead of dioxane. Diol 139 was isolated after the telescoped epoxidation and
ring-opening process in 65% yield at > 0.3 ton scale. The protecting group for the primary alcohol in the
next step was changed from p-nitrobenzoyl to TMS in order to limit the extensive migration of the acyl
group (>20%) to the secondary alcohol which would ultimately lead to the wrong API diastereomer.
The regioselectivity of the TMS protection towards exclusive formation of 140 was carefully controlled
before addition of mesyl chloride to generate mesylate 141. Acid treatment removes the silyl group
revealing hydroxy mesylate 142 followed by base-induced epoxide formation. Ring opening of epoxide
143 with ammonia required large excess of the latter to suppress further reaction of the generated
amine 144 with a second molecule of epoxide. The dimeric amine generated in this way was difficult
to purge down downstream if formed at >8% at this stage. After careful optimization of these steps
the telescoped process from diol 139 spanning 5 steps was run at 275 kg batches and delivered key
intermediate amine 144 as its mesylate salt in 63% yield and excellent quality.
The construction of the morpholine ring was realized via a telescoped three step sequence
involving amidation of 144 with chloroacetyl chloride, cyclisation of 145 and reduction of the resulting
morpholinone. Features of this process such as the dimethyl carbonate solvent in the amidation step
and the final Vitride reduction were maintained in order to avoid major deviations from the registered
process. Modifications in the reduction step nevertheless led to significant minimization of certain
impurities and improved the work up. These were implemented in 125 kg batch processes delivering
reboxetine mesylate at specification in 62% yield over the three steps.
The progression of esreboxetine succinate to clinical candidate status precipitated the need for
kilogram scale deliveries of enantiopure reboxetine. Initially this was achieved by resolution of
reboxetine mesylate itself involving conversion to the free base, resolution with (S)-mandelic acid,
conversion to the free base and succinate salt formation [147]. Despite delivering 100 kg this process was
deemed highly inefficient as 3 kg of reboxetine mesylate were required to produce 1 kg of esreboxetine
succinate. In addition, using an established drug substance as a starting material carried several
supply and regulatory issues. For these reasons, resolution at the stage of amino alcohol 144 was
considered next.
A wide range of resolving agents and solvent systems were screened with (R)-camphanic acid
providing the most robust, scalable and efficient resolution. Unfortunately, it is the (S)-camphanic acid
that is cheaper and more widely available which conversely induces crystallization of the undesired
enantiomer of reboxetine as its (S)-camphanate salt. A process was thus developed that removed the
unwanted diastereomeric salt by filtration and the synthesis progressed with the desired enantiomer
retained in the liquors as free base in 88% ee; this was upgraded to 99% ee to upon its isolation as the
benzoate salt. This process was scaled up to 150 kg batches and delivered close to perfect yields for a
resolution step (47% on average) rendering the overall route to esreboxetine three times more efficient
and cost-effective than the process implementing the resolution at the reboxetine mesylate stage [147].
Following this logic, a resolution further upstream in the synthesis could increase the efficiency of
the synthesis and such an attempt has been described by Reddy et al. the resolution of epoxide 146
catalyzed by Jacobsen cobalt salen complex M4 (Scheme 42) [148].
Resolved epoxide 147, following ring opening with ammonia, was converted to the morpholine
derivative 148 via the standard 3-step procedure and protected with Boc. In this approach whatever
advantage was gained by conducting the resolution early, is lost in the manipulation of the Bn and
Boc protecting groups and necessity to invert the stereochemistry of the benzylic alcohol 148 and then
again of the benzylic bromide 149 with 2-ethoxyphenol.
close to perfect yields for a resolution step (47% on average) rendering the overall route to
esreboxetine
Catalysts 2020, 10,three
1117 times more efficient and cost-effective than the process implementing
35 ofthe
65
resolution at the reboxetine mesylate stage [147].
Scheme 42. Reddy’s kinetic resolution of an early epoxide intermediate using Jacobsen’s catalyst M4.
It must be noted
Following that all
this logic, reported syntheses
a resolution that involve
further upstream thesynthesis
in the formationcould of theincrease
O-aryl bond from the
the efficiency
benzylic alcohol do so with the use Mitsunobu or equivalent reactions
of the synthesis and such an attempt has been described by Reddy et al. the resolution of epoxide or chromium tricarbonyl arene
146
complexes
catalyzed by depending
Jacobsenon the stereochemistry
cobalt salen complex M4 at the benzylic
(Scheme 42)alcohol.
[148]. Such methods may be acceptable
for the preparation
Resolved of analog
epoxide structuresring
147, following in small
openingscale withbutammonia,
are renderwas the converted
synthesis uncompetitive
to the morpholine and
practically invalid in a large scale/manufacturing set up due to waste
derivative 148 via the standard 3-step procedure and protected with Boc. In this approach whatever and toxicity issues of the reagents
involved
advantage(Cr, was azodicarboxylates)
gained by conducting [149–155].
the resolution early, is lost in the manipulation of the Bn and
From a process chemist’s
Boc protecting groups and necessity to invertperspective, the best
the approach for constructing
stereochemistry the aryl-benzylic
of the benzylic alcohol 148etherand
fragment in reboxetine is to install this
then again of the benzylic bromide 149 with 2-ethoxyphenol. by using the phenol in a nucleophilic substitution reaction
at theIt benzylic centerthat
must be noted preferably
all reportedearlysyntheses
on. It is therefore
that involve notthe a coincidence
formation ofthat the both
O-arylracemic
bond fromand
asymmetric syntheses of reboxetine by the process team of Pfizer
the benzylic alcohol do so with the use Mitsunobu or equivalent reactions or chromium tricarbonylemploy this very strategy. The Pfizer
team
arene considered
complexes that an asymmetric
depending synthesis that could
on the stereochemistry at theoffset
benzylicthe 50% yieldSuch
alcohol. reduction
methods associated
may be
with their nearly perfect resolution processes would be ever more
acceptable for the preparation of analog structures in small scale but are render the synthesis efficient and cost saving. With more
freedom to operate now in the context of esreboxetine development,
uncompetitive and practically invalid in a large scale/manufacturing set up due to waste and toxicity the racemic route was modified
into anofasymmetric
issues the reagents one simply (Cr,
involved by replacing the racemic[149–155].
azodicarboxylates) epoxidation of cinnamyl alcohol in the first
step by a Sharpless asymmetric epoxidation
From a process chemist’s perspective, the best approach of the very same allylic alcohol in 92%
for constructing theeearyl-benzylic
(Scheme 43) ether[156].
Without
fragment in reboxetine is to install this by using the phenol in a nucleophilic substitution reactionthe
isolation, chiral epoxide 150 was subjected to the ring-opening reaction by the phenol as in at
previous process and recrystallization of the diol 151 allowed the
the benzylic center preferably early on. It is therefore not a coincidence that both racemic and upgrade of optical purity to >98%.
In this first iteration,
asymmetric synthesesonly minor modifications
of reboxetine by the process wereteam madeoftoPfizer
the rest of thethis
employ stagesvery(Scheme
strategy. 41)The
in
order
Pfizertoteam
accommodate
considered thethat
differences in solubility
an asymmetric and behavior
synthesis that couldof theoffset
enantiopure
the 50% intermediates
yield reductionfrom
those
associated with their nearly perfect resolution processes would be ever more efficient and next
of the racemic ones. Still, it was possible to improve the asymmetric process further in the cost
iteration
saving. With [147]. In particular,
more freedom to the −20 ◦ Cnow
operate TMSinprotection
the contextofofthe primary alcohol
esreboxetine in 151 suffered
development, from
the racemic
moderate
route wasyields and incomplete
modified regiocontrol one
into an asymmetric (either by direct
simply by silylation
replacingofthe the racemic
secondary alcohol or via
epoxidation of
TMS migration) and lacked robustness in larger scale processing.
cinnamyl alcohol in the first step by a Sharpless asymmetric epoxidation of the very same allylic
An in
alcohol innovative
92% ee protection
(Scheme 43) step[156].
was introduced using anchiral
Without isolation, enzyme-catalyzed
epoxide 150acetylation
was subjected to formto 152
the
which occurred consistently with almost complete regiocontrol even at 20 ◦ C. This was telescoped
ring-opening reaction by the phenol as in the previous process and recrystallization of the diol 151
into the mesylation
allowed the upgradestep and mesylate
of optical purity to153 was In
>98%. subjected
this firstdirectly
iteration, in only
the base-induced
minor modifications acetate were
ester
hydrolysis
made to the and ring-closure
rest of the stages to epoxide
(Scheme154. 41) inThis sequence
order saved one step/operation
to accommodate the differencesfrom the synthesis
in solubility and
since the corresponding TMS intermediate 141 required acidic deprotection
behavior of the enantiopure intermediates from those of the racemic ones. Still, it was possible to prior to epoxide formation.
Another
improvestep the was eliminated
asymmetric from the
process synthesis
further in thebynext ringiteration
opening [147].
of epoxide 154 to intermediate
In particular, the −20 °C155 TMSby
using 2-aminoethyl
protection of the primaryhydrogen alcoholsulfate instead
in 151 of ammonia.
suffered from moderate This reagent
yields bears the ethylene
and incomplete portion of
regiocontrol
the morpholine already preinstalled at the nitrogen atom and more
(either by direct silylation of the secondary alcohol or via TMS migration) and lacked robustness important, at the correct oxidationin
state, obviating the
larger scale processing. need for a reduction step. The ring opening of epoxide 154 had to be optimized
against formation dimeric impurities (amine 155 reacting with a second epoxide molecule) by careful
control of reagent stoichiometry, reaction temperature, order and duration of additions. Morpholine
ring closure under basic conditions was telescoped into the succinate salt generation thus providing
esreboxetine succinate in 81% yield at specification.
Catalysts 2020, 10, 1117 36 of 65
Scheme 43. Pfizer’s final process for the asymmetric synthesis of esreboxetine.
Scheme 43. Pfizer’s final process for the asymmetric synthesis of esreboxetine.
The new asymmetric process for reboxetine succinate afforded a 58% improvement in overall
An innovative protection step was introduced using an enzyme-catalyzed acetylation to form
yield,
152 reduced processing
which occurred times, significant
consistently cost savings
with almost completeand regiocontrol
waste reduction evenbyat90% 20 hence it received
°C. This was
a Green Chemistry Award [157].
telescoped into the mesylation step and mesylate 153 was subjected directly in the base-induced
Although
acetate ester ahydrolysis
number ofand syntheses have been
ring-closure reported
to epoxide 154.for racemic
This and enantiopure
sequence reboxetine and
saved one step/operation
derivatives,
from the synthesis since the corresponding TMS intermediate 141 required acidic deprotectionthe
including several of questionable merit [130], there are two efforts that also employ early
prior
installation
to epoxideofformation.
the phenolAnother
and proceed through
step was epoxide
eliminated intermediates
from the synthesisandby deserve to be of
ring opening mentioned.
epoxide
154Aparicio et al. reported
to intermediate 155 byan asymmetric
using synthesis
2-aminoethyl of reboxetine
hydrogen sulfate based
insteadonofa ammonia.
chiral auxiliary approach
This reagent
to facilitate
bears the aethylene
diastereoselective
portion of Darzens/Corey−Chaykovsky
the morpholine already preinstalled reactionat(Scheme 44) using
the nitrogen atom chiral amido
and more
important,
sulfonium saltat156
the [158].
correctThe
oxidation state, obviating
corresponding the need
ylide was for with
reacted a reduction step. Theand
benzaldehyde ringgenerated
opening ofthe
twoepoxide 154 had to
diastereomeric be optimized
epoxides against
(only the formation
desired dimeric157)
one is shown, impurities (amine
in dr 73:27. 155 were
These reacting with a
inseparable,
second epoxide molecule) by careful control of reagent stoichiometry, reaction
so they were progressed into the epoxide ring-opening reaction with 2-ethoxyphenol which, as expected temperature, order
and duration of additions. Morpholine ring closure under basic conditions was
occurred at the benzylic position with inversion of configuration. This time the diastereomeric hydroxytelescoped into the
succinate
amides weresalt generation
separable thus providing esreboxetine
by chromatography succinate
and the desired one in
158 81%
wasyield at specification.
isolated as a crystalline solid.
The new asymmetric process for reboxetine succinate afforded a 58% improvement
Optimization of the amide reduction step followed by the three-step process (via the morpholinone) in overall
yield, reduced processing times, significant cost savings and waste reduction
for morpholine formation and hydrogenolysis of the chiral auxiliary provided enantiopure reboxetine. by 90% hence it
received a Green Chemistry Award [157].
Although a number of syntheses have been reported for racemic and enantiopure reboxetine
and derivatives, including several of questionable merit [130], there are two efforts that also employ
Catalysts 2020, 10, 1117

the early installation of the phenol and proceed through epoxide intermediates and deserve37toof be
65
mentioned.
Scheme 44. Aparicio’s approach to esreboxetine using a diastereoselective Darzens reaction.

Scheme 44. Aparicio’s approach to esreboxetine using a diastereoselective Darzens reaction.
Another innovative and efficient approach has been reported by Yu and Ko who applied the
Aparicio
Sharpless’ et al. reported
asymmetric an asymmetric
dihydroxylation reactionsynthesis of reboxetine
on protected cinnamylbased on137
alcohol a chiral auxiliary
generating the
approach
cis-diol 160to(Scheme
facilitate45).
a diastereoselective Darzens/Corey−Chaykovsky
Formation of the cyclic sulfate 161 followed by TBAF reaction (Schemereveals
treatment 44) using
the
chiral amido sulfonium salt 156 [158]. The corresponding ylide was reacted with
terminal alkoxide which ring opens intramolecularly the cyclic sulfate with inversion of configurationbenzaldehyde and
generated
at the two
the adjacent diastereomeric
carbon forming epoxy epoxides
sulfate(only the desired
162. Azide oneatisthis
addition shown,
point157)
ringinopens
dr 73:27. These
the newly
were inseparable,
formed so theyintermediate
epoxide generating were progressed into the
163 in which the benzylic
epoxidealcohol
ring-opening reaction form
is in an activated with
2-ethoxyphenol which, as expected occurred at the benzylic position with inversion
ready for displacement. The latter is realized by the addition of 2-ethoxyphenol which affords key of configuration.
This time the164
intermediate diastereomeric
whose conversionhydroxy amides were
to esreboxetine separable
is straight by chromatography
forward. Optimization ofand thesteps
these desired
led
one
to 158 was
an impressive
Catalysts
isolated as
one-pot
2020, 10, x FOR
a crystalline
PEER telescoped
REVIEW
solid. Optimization of the amide
process from 161 to 164 in 84% yield. reduction step followed by the
39 of 69
three-step process (via the morpholinone) for morpholine formation and hydrogenolysis of the
chiral auxiliary provided enantiopure reboxetine.
Another innovative and efficient approach has been reported by Yu and Ko who applied the
Sharpless’ asymmetric dihydroxylation reaction on protected cinnamyl alcohol 137 generating the
cis-diol 160 (Scheme 45). Formation of the cyclic sulfate 161 followed by TBAF treatment reveals the
terminal alkoxide which ring opens intramolecularly the cyclic sulfate with inversion of
configuration at the adjacent carbon forming epoxy sulfate 162. Azide addition at this point ring
opens the newly formed epoxide generating intermediate 163 in which the benzylic alcohol is in an
activated form ready for displacement. The latter is realized by the addition of 2-ethoxyphenol
which affords key intermediate 164 whose conversion to esreboxetine is straight forward.
Optimization of these steps led to an impressive one-pot telescoped process from 161 to 164 in 84%
yield.
Scheme
Scheme 45. Yu and
45. Yu and Ko’s
Ko’s approach
approach to
to esreboxetine
esreboxetine using
using Sharpless’
Sharpless’ asymmetric
asymmetric dihydroxylation.
dihydroxylation.
Both of the syntheses described above required chromatographic purifications nevertheless,

they were conducted in gram scale and represent inspiring epoxide-mediated synthesis of
reboxetine who are novel and aligned with the Pfizer strategy therefore rank highest among
academic routes.
1.14. FK-788—Replacement of an Asymmetric Synthesis by a Resolution Process with Recycling of the

Catalysts 2020, 10, 1117 38 of 65
Both of the syntheses described above required chromatographic purifications nevertheless,

they were conducted in gram scale and represent inspiring epoxide-mediated synthesis of reboxetine
who are novel and aligned with the Pfizer strategy therefore rank highest among academic routes.
1.14. FK-788—Replacement of an Asymmetric Synthesis by a Resolution Process with Recycling of the

Undesired Enantiomer; the Meinwald Rearrangement on Scale
Prostaglandin I2 (PGI2 p), commonly known as prostacyclin, is a lipid product of arachidonic acid
metabolism and is generated in greatest abundance by vascular tissues primarily by COX1 [159,160].
It is arguably the most potent endogenous vasodilator and exerts its signaling through the IP
receptor, a GPCR. Although primarily recognized for protection against vascular remodeling and
platelet formation, PGI2 has been found to regulate both the innate and adaptive immune systems
and this has been aimed mainly at anti-inflammatory or immunosuppressive applications [161].
More recently, prostacyclin was directly linked with obesity treatment [162] and inhibition of lung
tumor progression [163].
Prostaglandin I2 (PGI2 ) has been approved as a medicine under the name of epoprostenol,
but its short half-life (42 s) has prompted intense research for more appropriate alternatives which
has produced the synthetic analogs iloprost and treprostinil [164]. Improved selectivity among
prostaglandin receptors and desirable pharmacokinetic profile continue to be at the heart of research
for novel IP agonists.
FK-788 (Scheme 46) is a prostacyclin structurally unrelated IP agonist with significant potency,
selectivity, solubility and bioavailability that was discovered by Fujisawa (legacy company of Astellas
Pharma) [165]. In the medicinal chemistry route (Scheme 46), the chiral center was introduced at
intermediate 165 by an asymmetric dihydroxylation at the unsaturated ester 166. Besides the toxicity
of osmium and cyanide reagents involved in this step, persistent impurities formed both in the
downstream chemistry and in the reactions leading to 166 from 167, forced Astellas chemists to develop
Catalysts
an 2020, 10,route
alternative x FOR to
PEER REVIEW
FK-788 that could be used for large-scale deliveries. 40 of 69
Scheme 46. Retrosynthetic analysis of FK-788.

Scheme 46. Retrosynthetic analysis of FK-788.
Initial attempts aimed at alternative asymmetric syntheses, for example using the Jacobsen–Katsuki
Initial attempts aimed at alternative asymmetric syntheses, for example using the
asymmetric epoxidation on appropriate substrates, had limited success. In the end it was envisaged
Jacobsen–Katsuki asymmetric epoxidation on appropriate substrates, had limited success. In the end
that the racemic key intermediate, diol 174, could be accessed relatively easily and that a diastereomeric
it was envisaged that the racemic key intermediate, diol 174, could be accessed relatively easily and
resolution of this would enable the provision of FK-788 in enantiomerically pure form [166]. Astellas’
that a diastereomeric resolution of this would enable the provision of FK-788 in enantiomerically
process team initially developed and scaled up a process capable of converting 1-tetralone 168 to
pure form [166]. Astellas’ process team initially developed and scaled up a process capable of
2-tetralone 169.
converting 1-tetralone 168 to 2-tetralone 169.
Accordingly, 168 was protected, reduced and dehydrated to furnish intermediate 153 (Scheme 47).
Accordingly, 168 was protected, reduced and dehydrated to furnish intermediate 153 (Scheme
Epoxidation of this to 170 followed by TsOH-catalyzed Meinwald rearrangement gave 2-tetralone
47). Epoxidation of this to 170 followed by TsOH-catalyzed Meinwald rearrangement gave
171. It must be noted that the latter transformation was attempted by hydroxide-ring opening of the
2-tetralone 171. It must be noted that the latter transformation was attempted by hydroxide-ring
epoxide 170 to diol 171 followed by dehydration of the benzylic alcohol towards the enol tautomer of
opening of the epoxide 170 to diol 171 followed by dehydration of the benzylic alcohol towards the
172 (Scheme 47). The yield of 171 by this sequence however did not exceed 48% even after stringent
enol tautomer of 172 (Scheme 47). The yield of 171 by this sequence however did not exceed 48%
optimization. In contrast screening of several acids for the Meinwald rearrangement produced several
even after stringent optimization. In contrast screening of several acids for the Meinwald
good yielding hits with TsOH being the best (73%). Interestingly, the Corey−Chaykovsky epoxidation
rearrangement produced several good yielding hits with TsOH being the best (73%). Interestingly,
of 171 with trimethyl sulfonium iodide did not work, but did so, with the sulfoxonium analog which
the Corey−Chaykovsky epoxidation of 171 with trimethyl sulfonium iodide did not work, but did so,
provided epoxide 173 in 74% yield. Acid-catalyzed ring opening of epoxide 173 in aqueous THF
with the sulfoxonium analog which provided epoxide 173 in 74% yield. Acid-catalyzed ring opening
furnished racemic diol 174. This ring opening was also attempted under alkaline conditions which
of epoxide 173 in aqueous THF furnished racemic diol 174. This ring opening was also attempted
under alkaline conditions which needed to be harsh and gave 174 in reduced yield (58%). Again,
among several acids TsOH proved the best in catalyzing the ring opening of 173 to 174. Several
chiral acids were screened for the derivatization of 174 into diastereomeric esters yet only
(-)-camphanate esters 175 proved crystalline. Double recrystallization of diastereomeric esters 175
from ethanol provided enantiopure camphanate ester 176 in 34% yield and in >99% ee. Hydrolysis of
Catalysts 2020, 10, 1117 39 of 65
needed to be harsh and gave 174 in reduced yield (58%). Again, among several acids TsOH proved
the best in catalyzing the ring opening of 173 to 174. Several chiral acids were screened for the
derivatization of 174 into diastereomeric esters yet only (-)-camphanate esters 175 proved crystalline.
Double recrystallization of diastereomeric esters 175 from ethanol provided enantiopure camphanate
ester 176 in 34% yield and in >99% ee. Hydrolysis of the chiral auxiliary (and recycling thereof)
generated the key intermediate, chiral diol 176 which was converted to FK-788 using established
conditions (Scheme 47). It is worth noting that the Astellas team managed to develop an impressive
telescoped process for converting 168 to 174, spanning 7 chemical steps which was run at 25 kg scale
producing 11 kg (25%) of 174 as the only isolable intermediate in the entire sequence. The resolution
Catalysts
and 2020, 10, x FOR
subsequent PEER
steps REVIEW
towards FK-788 were performed successfully at 10–15 kg scale. 41 of 69
Scheme 47. Astellas’ process route to FK-788 via resolution of diol 174.
Obviously, the maximum achievable yield for standard resolution processes cannot exceed 50%
Obviously,
unless the maximum
the undesired isomer couldachievable yield fortransformed
be somehow standard resolution processes
in the desire one. cannot exceedteam
The Astellas 50%
unless the undesired isomer could be somehow transformed in the desire one.
decided to explore this scenario by isolating the remaining 175 present in the liquors of 176 and The Astellas team
decided to52%
recovered explore thisthat
of this scenario by isolating
was found the remaining
to be enriched in the175 present diastereomer
unwanted in the liquors in
of dr
17631:69.
and
recovered 52% of this that was found to be enriched in the unwanted diastereomer
Hydrolysis of this gave 178 in er 31:69 (Scheme 48, only major isomer is shown). Two strategies were in dr 31:69.
Hydrolysis ofinthis
investigated gave 178
recycling thein er 31:69 (Scheme
S-enantiomer of the48, only
diol major
into isomer R.
the desired is shown). Two strategies were
investigated in recycling the S-enantiomer of the diol into the
The first (Scheme 48 upper) involved periodate cleavage of the diol desired R.back into the 2-tetralone 155
which was subjected to the same Corey−Chaykovsky epoxidation O and acid catalyzed ring opening
OH
O
of 173 to furnish the same racemic diol 174 Meas in the mainstream synthesis.
3SOI
The overall yield for
MsOH(cat) OHthis
three-step
NaIO4 sequence was 49%, namely 25% t-BuOK
from the recovered esters, which DME (aq) meant that applying the
sameTBAHS
resolution with camphanic acid (34%) THFwould giveOBn an additional 8.5% 49% of the desired R-diol 177.
OBn OBn
PhMe/H2O 173 over 3 steps 174rac
Alternatively (Scheme 48 lower)171 mesylation of the primary alcohol in 178 followed by based-induced
OH
OH
178 R:S = 31:69

OBn
Catalysts 2020, 10, 1117 40 of 65
Obviously, the maximum achievable yield for standard resolution processes cannot exceed 50%
unless the undesired isomer could be somehow transformed in the desire one. The Astellas team
ring closure
decided of 179 tothis
to explore epoxide 180 and
scenario by acid-catalyzed ring opening
isolating the remaining 175gave diol 177
present enriched
in the in of
liquors the176
desired
and
R-enantiomer (er 2:1) in 66% yield (33% from the recovered esters). Resolution of the
recovered 52% of this that was found to be enriched in the unwanted diastereomer in dr 31:69. scalemic diol
mixture viaof
Hydrolysis the camphanate
this gave 178 inesters furnished
er 31:69 (Schemethe
48, enantiopure diol 177
only major isomer in 11.2%Two
is shown). from the recycling
strategies were
process thus in 44% overall.
investigated in recycling the S-enantiomer of the diol into the desired R.
O OH
O
Me3SOI MsOH(cat) OH
NaIO4 t-BuOK DME (aq)
TBAHS THF OBn 49%
OBn OBn
PhMe/H2O 173 over 3 steps 174rac
171
OH
OH
178 R:S = 31:69

OBn
MsCl
NMM OH O OH
THF OMs KOtBu MsOH(cat) OH
DME DME (aq)
66%
OBn OBn OBn
179 180 over 3 steps
177
R:S = 67:33
Scheme 48. Recycling of unwanted diol enantiomer 178 into scalemic diol 177.
Scheme 48. Recycling of unwanted diol enantiomer 178 into scalemic diol 177.
It is worth noticing that the acid-catalyzed ring opening of 180 to 177 (Scheme 48 lower) proceeds
with water attack on tertiary carbon on which more positive charge is built when the epoxide oxygen
is protonated and the tertiary C–O bond is weekend thus facilitating the ring opening with inversion
of configuration at that stereogenic center. This stereochemical/ mechanistic information is lost in
the reaction with the racemic counterpart (172 to 174 in Schemes 47 and 48 upper) since the racemic
epoxide gives racemic diol irrespective of which epoxide end is attacked.
1.15. A Lead Candidate for Asthma—Improved Synthesis via a Decarboxylative Rearrangement of an

α-Carboxyl Epoxide
Asthma is a lifelong respiratory disease which is characterized by a huge variety of symptoms,
especially concerning the lungs. As there is no treatment for asthma, it is a great challenge for the
pharmaceutical companies to find APIs capable of lifelong management of the disease.
One of Novartis’ recent entries in this area was the lead compound 181, a triaryl thiazole [167].
The original medicinal chemistry route followed the retrosynthetic analysis shown in Scheme 49
where the imidazole ring was introduced last by SN Ar on thiazole intermediate 182 which in turn was
constructed after α-bromination of the ketone 183 and condensation with N-acetyl thiourea. Ketone
183 was synthesized from nitroethane condensation on aldehyde 184 followed by reduction of the
nitro group. In addition to chromatographic purifications and low yields, these steps were hampered
by serious process safety concerns that ultimately rendered this reaction sequence unsuitable for
large-scale preparations of 181.
The process group at Novartis decided to develop a synthesis that would involve the same starting
materials (registered and raw) and the same end game transformations. This shifted the focus on an
alternative synthesis of 183 from 184 that would not succumb to safety and purification issues.
Reaction of aldehyde 184 with sodium thiomethoxide generated substituted aldehyde 185 which
was subjected to a Darzens condensation with α-chloro methyl propionate to generate initially
epoxide 186 (Scheme 50). Hydrolysis of the ester followed by heating in acidic conditions drove the
decarboxylative rearrangement to ketone 187 presumably via transition state 188. Oxidation of the
thiomethyl substituent to the corresponding sulfone was achieved by tungstate catalysis as reported
pharmaceutical companies to find APIs capable of lifelong management of the disease.
One of Novartis’ recent entries in this area was the lead compound 181, a triaryl thiazole [167].
The original medicinal chemistry route followed the retrosynthetic analysis shown in Scheme 49
where the imidazole ring was introduced last by SNAr on thiazole intermediate 182 which in turn
was constructed
Catalysts 2020, 10, 1117after α-bromination of the ketone 183 and condensation with N-acetyl thiourea.41 of 65
Ketone 183 was synthesized from nitroethane condensation on aldehyde 184 followed by reduction
of the nitro group. In addition to chromatographic purifications and low yields, these steps were
by Noyori [168].
hampered Impressively,
by serious process the conversion
safety concernsofthat to 183 was rendered
184 ultimately developedthis
as telescoped process
reaction sequence
encompassing five chemical steps performed
unsuitable for large-scale preparations of 181. on 100 g scale delivering 73% of 183 99.5% pure.
telescoped process
Scheme
Scheme encompassing
Retrosynthesis
49. Retrosynthesis
49. of five chemical
of clinical
clinical steps
candidate
candidate performed
into
181 into
181 on 100183
pivotal ketone
pivotal ketone g scale
183 delivering
and its
and its precursor73%
precursor 184. of 183
184.
99.5% pure.
The process group at Novartis decided to develop a synthesis that would involve the same
starting materials (registered and raw) and the same end game transformations. This shifted the
focus on an alternative synthesis of 183 from 184 that would not succumb to safety and purification
issues.
Reaction of aldehyde 184 with sodium thiomethoxide generated substituted aldehyde 185
which was subjected to a Darzens condensation with α-chloro methyl propionate to generate
initially epoxide 186 (Scheme 50). Hydrolysis of the ester followed by heating in acidic conditions
drove the decarboxylative rearrangement to ketone 187 presumably via transition state 188.
Oxidation of the thiomethyl substituent to the corresponding sulfone was achieved by tungstate
catalysis as reported by Noyori [168]. Impressively, the conversion of 184 to 183 was developed as
Scheme 50. Large-scale synthesis of clinical candidate 181 via a decarboxylative Darzens reaction.
Scheme 50. Large-scale synthesis of clinical candidate 181 via a decarboxylative Darzens reaction.
It is worth pointing out that this two-step construction of the sulfone was much more efficient and
It is worth
cost-effective pointing
than out that
introducing it inthis
onetwo-step construction
step by means of SN Arofon
the185
sulfone was much
with sodium more efficient
methanesulfinate.
and cost-effective than introducing it in one step by means of S NAr on 185 with sodium
Furthermore, the Noyori oxidation could be performed on aldehyde 185, but for reasons yet unclear
methanesulfinate.
the corresponding Furthermore, the Noyori benzaldehyde
3-fluoro-4-methylsulfone oxidation could be performed
failed to give theon aldehyde
Darzens 185, but for
reaction.
reasons yet unclearand
Development theofcorresponding
the α-chlorination 3-fluoro-4-methylsulfone
of ketone 183 proved benzaldehyde
a much better failed to give
choice than the
its
Darzens reaction.
bromination due to significant side product formation with the latter. Formation of chloroketone
Development
189 was telescoped and
in theofthiazole
the α-chlorination
forming step of(Scheme
ketone 183 provedsome
50) where a much better
degree choice than its
of N-deacetylation
bromination
proved due to significant
unavoidable side product
hence the treatment withformation with the latter.
acetic anhydride Formation
after the of chloroketone
installation 189
of the imidazole
was telescoped in the thiazole
substituent in the last step. forming step (Scheme 50) where some degree of N-deacetylation
proved unavoidable
Overall, hence thesolution
an innovative treatment to with acetic anhydride
the safety, efficiency after
and the installation
purity issues inofaccessing
the imidazole
key
substituent in the last step.
intermediate 183 was developed by a decarboxylative rearrangement of an epoxide generated by a
Overall,
Darzens an innovative
reaction. This furthersolution to the the
demonstrates safety, efficiency
versatility and chemistry
and rich purity issues in accessing
of epoxides key
in robust,
intermediate
large-scale 183 wasofdeveloped
synthesis by a decarboxylative rearrangement of an epoxide generated by a
pharmaceuticals.
Darzens reaction. This further demonstrates the versatility and rich chemistry of epoxides in robust,
large-scale synthesis of pharmaceuticals.
1.16. Δ-9-Tetrahydrocannabinol—From 3-carene to 2-carene Oxide and Δ-9-THC in Large Scale

(-)-trans-Δ-9-tetrahydrocannabinol (Δ-9-THC) is the primary psychoactive compound among
the 113 cannabinoids found in the female marijuana plant and is a partial agonist of the CB1
Catalysts 2020, 10, 1117 42 of 65
1.16. ∆-9-Tetrahydrocannabinol—From 3-Carene to 2-Carene Oxide and ∆-9-THC in Large Scale

(-)-trans-∆-9-tetrahydrocannabinol (∆-9-THC) is the primary psychoactive compound among
the 113 cannabinoids found in the female marijuana plant and is a partial agonist of the CB1
receptor. In its medicinal form is known as dronabinol and is FDA approved under the trade names
of Marinol (gelatin capsules) and Syndros (oral solution) for the treatment of HIV/AIDS-induced
anorexia and chemotherapy-induced nausea and vomiting. Its 1:1 mixture with cannabidiol, known as
nabiximols (trade name Sativex), is approved in Europe for treating spasticity associated with multiple
sclerosis [169]. United States federal law currently registers dronabinol as a Schedule III controlled
substance, but all other cannabinoids remain Schedule I under the Single Convention on Narcotic
Drugs., except synthetics like nabilone. Current research is focusing on expanding the medicinal
applications of (-)-trans-∆-9-THC and synthetic analogs to treating body weight disorders, neuropathic
disorders, neuropathic and cancer associated pain, but negating potential psychotropic and
and cancer associated pain, but negating potential psychotropic and tolerance effects [170–172].
tolerance effects [170–172].
Current and projected requirements for (-)-trans-∆-9-THC warrant a robust scalable process for its
Current and projected requirements for (-)-trans-Δ-9-THC warrant a robust scalable process for
production which is primarily based on the Friedel–Crafts alkylation/cyclisation between olivetol and
its production which is primarily based on the Friedel–Crafts alkylation/cyclisation between olivetol
p-menth-2-ene-1,8-diol which in turn is accessed from 2-carene oxide (Scheme 51) [173–175].
and p-menth-2-ene-1,8-diol which in turn is accessed from 2-carene oxide (Scheme 51) [173–175].
Scheme 51. Synthesis of ∆-9-THC from p-menth-2-ene-1,8-diol and its retrosynthesis to 2-carene.
Scheme 51. Synthesis of Δ-9-THC from p-menth-2-ene-1,8-diol and its retrosynthesis to 2-carene.
As this process evolved over the years there have been two lingering issues that undermined its
As this
efficacy and process evolved over
cost-effectiveness. Thethe years
first there havewith
is associated beenthe two lingering
starting issues2-carene
material that undermined
(Scheme 51)its
efficacy and cost-effectiveness. The first is associated with the starting material
which is relatively expensive. The second issue is related with the isolation and purification of 2-carene (Scheme 51)
which is relatively expensive.
p-menth-2-ene-1,8-diol The second
from the other terpenoid issue is related
products of the with
processtheoften
isolation andchromatography
requiring purification of
p-menth-2-ene-1,8-diol
and/or extensive extractions fromand the other terpenoid
evaporation products
of its solutions of the process often requiring
to dryness.
chromatography and/or extensive extractions and evaporation
Process chemists from Cedarburg Pharmaceuticals (legacy company of its solutions
of Albanyto dryness.
Molecular Research,
Inc., AMRI) focused on solving these issues by assessing other starting materials andAlbany
Process chemists from Cedarburg Pharmaceuticals (legacy company of ways to Molecular
crystallize
Research,
p-menth-2-ene-1,8-diol directly as it was produced [176]. In contrast to 2-carene, 3-carene is and
Inc., AMRI) focused on solving these issues by assessing other starting materials ways
relatively
to crystallize p-menth-2-ene-1,8-diol directly as it was produced [176].
cheap and available in bulk. 3-Carene is equilibrated to 2-carene when heated with base at high In contrast to 2-carene,
3-carene is relatively
temperature resulting cheap and available
in approximately in bulk.
a 60/40 3-Carene
mixture is equilibrated
of the 3/2-carene to 2-carene
isomers (Scheme when heated
52). This was
with base at high temperature resulting in approximately a 60/40 mixture
conducted at 85 kg scale and the mixture of isomers after separation from the aqueous phase was of the 3/2-carene isomers
(Scheme 52). This
distilled thus was conducted
providing at 85tokg
quick access scale and
technical the mixture
grade 2-carene.ofFollowing
isomers after separation
a screening of from the
reagents
aqueous phase was of
for the epoxidation distilled thus providing
the 3/2-carene isomers,quick accessacid
peracetic to technical
emerged gradeas the 2-carene.
optimumFollowing
oxidant for a
screening of reagents for the epoxidation of the 3/2-carene isomers, peracetic
this transformation. The epoxidation reaction was carried out in 60 kg scale and after work up, acid emerged as the
optimum
the solutionoxidant
of the for thisoxides
carene transformation.
was subjected The directly
epoxidation reaction wasring
to acid-catalyzed carried out in
opening. 60 kgmildly
Under scale
and after work up, the solution of the carene oxides was subjected directly to acid-catalyzed ring
opening. Under mildly acidic conditions only 2-carene oxide ring opens via participation of the
cyclopropane ring which also ring opens itself to support the built up of positive charge at the
adjacent carbon of the protonated epoxide (Scheme 52). This neighboring group assistance by the
cyclopropane moiety cannot take place with the remotely positioned epoxide in 3-carene oxide
Catalysts 2020, 10, 1117 43 of 65
acidic conditions only 2-carene oxide ring opens via participation of the cyclopropane ring which also
ring opens itself to support the built up of positive charge at the adjacent carbon of the protonated
epoxide (Scheme 52). This neighboring group assistance by the cyclopropane moiety cannot take place
with the remotely positioned epoxide in 3-carene oxide which survives intact under these conditions.
Screening of antisolvents at this stage of the process identified heptane as the optimum choice enabling
crystallization of p-menth-2-ene-1,8-diol directly from the reaction mixture while retaining the more
soluble 3/2-carene oxides.
Scheme 52. Process route to p-menth-2-ene-1,8-diol from 2-carene via epoxidation/rearrangement.

Scheme 52. Process route to p-menth-2-ene-1,8-diol from 2-carene via epoxidation/rearrangement.
In this way a much-improved process for the large-scale synthesis of p-menth-2-ene-1,8-diol, a key
In this way a much-improved process for the large-scale synthesis of p-menth-2-ene-1,8-diol, a
intermediate in the synthesis of ∆-9-THC, was accomplished based on manipulation of inexpensive
key intermediate in the synthesis of Δ-9-THC, was accomplished based on manipulation of
feedstock and a selective epoxide rearrangement.
inexpensive feedstock and a selective epoxide rearrangement.
1.17. Oseltamivir—Development of Three Manufacturing Routes via the Same Key Epoxide Intermediate
1.17. Oseltamivir —Development of Three Manufacturing Routes via the Same Key Epoxide Intermediate
Oseltamivir phosphate (trade name Tamiflu) is an antiviral drug indicated for the treatment of
Oseltamivir
influenza A and phosphate
influenza B. (trade
It was name Tamiflu)atisGilead
discovered an antiviral drugbut
Sciences, indicated for the to
was licensed treatment
Roche forof
influenza A and influenza
clinical development, B. Itand
approval wasmarketing.
discoveredGlaxoSmithKline’s
at Gilead Sciences,zanamivir
but was (Relenza)
licensed to(discovered
Roche for
clinical development, approval and marketing. GlaxoSmithKline’s zanamivir
by the Australian company Biota) was the first neuraminidase inhibitor to be FDA approved (1999), (Relenza) (discovered
by the Australian
followed company
by oseltamivir laterBiota)
in the was
samethe firstOseltamivir
year. neuraminidase inhibitor
however to be
was the FDA
first approved
orally (1999),
active product
followed byisoseltamivir
(zanamivir inhaled) hence later itinbecame
the same moreyear. Oseltamivir
popular. Over however
the years,was the first to
in addition orally active
the Roche
product (zanamivir is inhaled) hence it became more popular. Over the years,
processes, there have been dozens of oseltamivir syntheses published by prominent academic research in addition to the
Roche
groupsprocesses,
[177] that there have beenthe
have expanded dozens of oseltamivir
synthetic creativitysyntheses
in organicpublished
chemistryby andprominent
continue academic
to inspire
research groups [177] that have expanded the synthetic creativity in organic
the next generation of chemists. Nevertheless, a comparison of all major syntheses published chemistry and continue
up to
to
2008inspire the nextthat
demonstrated generation
the Rocheofrouteschemists. Nevertheless,
are superior a comparison
with respect of all major
to length, complexity andsyntheses
across a
published
number of up greento chemistry
2008 demonstrated
and efficiency that parameters
the Roche [178];
routesthearemost
superior with
efficient respectroute
academic to length,
up to
complexity and across a number of green
that point was the latest from the Fang group [179]. chemistry and efficiency parameters [178]; the most
efficient academic
A number of route
otherup to that
routes point
have been waspublished
the latest from
since the
thenFang group [179].
[180–187] yet the Roche shikimic
A number of other routes have been published since then
acid-based manufacturing process remains the most viable and proficient to date. [180–187] yet the Roche shikimic
acid-based manufacturing process remains the most viable and proficient to date.
Consequently, the following discussion concentrates on the Roche manufacturing route to the
key epoxide intermediate 190 (Scheme 53) and the subsequent ring-opening step by amine
nucleophiles.
Catalysts 2020, 10, 1117 44 of 65
Consequently, the following discussion concentrates on the Roche manufacturing route to the key
epoxide intermediate
Catalysts 2020, (Scheme 53) and the subsequent ring-opening step by amine nucleophiles.
190REVIEW
10, x FOR PEER 46 of 69
Scheme 53. Retrosynthesis of oseltamivir into quinic and shikimic acid.

Scheme 53. Retrosynthesis of oseltamivir into quinic and shikimic acid.
Both quinic and shikimic acid provide an appropriately functionalized carbocyclic framework and
Both quinic and shikimic acid provide an appropriately functionalized carbocyclic framework
were used to deliver oseltamivir on 100 kg scale. Quinic acid however requires an additional series of
and were used to deliver oseltamivir on 100 kg scale. Quinic acid however requires an additional
dehydration steps to generate the double bond which is already present in the shikimic acid. Despite
series of dehydration steps to generate the double bond which is already present in the shikimic
intense optimization efforts, the dehydration-associated steps have not been particularly straight
acid. Despite intense optimization efforts, the dehydration-associated steps have not been
forward or high yielding hence shikimic acid emerged as the ideal starting material [188]. Gilead’s
particularly straight forward or high yielding hence shikimic acid emerged as the ideal starting
original preference for the quinic acid route [189] was based on the limited supply of shikimic acid at
material [188]. Gilead’s original preference for the quinic acid route [189] was based on the limited
that time. During Roche’s development efforts shikimic acid became available in multi-hundred-ton
supply of shikimic acid at that time. During Roche’s development efforts shikimic acid became
quantities by extraction of star anis and by a fermentation process using a genetically engineered E. coli
available in multi-hundred-ton quantities by extraction of star anis and by a fermentation process
strain [190].
using a genetically engineered E. coli strain [190].
Shikimic acid esterification, acetonide protection and mesylation were telescoped to provide
mesylate 191 in 82% yield after recrystallization (Scheme 54). Acid catalyzed transketalization with
excess 3-pentanone gave new mesylate 192 almost quantitatively. The regioselective reductive
ring opening of the ketal required extensive optimization since the original Gilead conditions
involving BH3 ·Me2 S and TMSOTf (trimethylsilyl trifluoromethanesulfonate) were not attractive
for manufacturing (safety, cost and availability). A thorough screening was undertaken to identify
suitable Lewis acids to facilitate the ring opening of the acetal to the corresponding oxenium cation
and compatible reducing agents to reduce the latter to the desired hydroxy ether 193. The combination
of TES (triethyl silane) and TiCl4 proved a viable option as it worked well provided the reaction
temperature was kept between −32 to −36 ◦ C (no reaction at lower temperatures and significant
deprotection to the diol at higher temperatures). After work up of this stage the solution of 193 was
treated directly with base which induced the ring closure of the hydroxy mesylate to the desired epoxide
190 in 80% for the latter two steps and 64% overall from shikimic acid. The direct ketal formation of
shikimic acid ethyl ester with 2-pentanone would save one step from the synthesis (the transketalization
of the acetonide intermediate) and naturally this was also investigated. In contrast to the hydroxy-
and mesyl-acetonide intermediates which are crystalline and allow for upgrade of their purity by
recrystallization, the pentylideneketal analog derivatives are oils and had to be progressed impure
downstream with significant yield penalty in downstream purification. Nevertheless, an improvement
of the direct pentylideneketal process was reported by Roche that enables pure 194 to be generated
and progressed without isolation in the formation of 192 [191].
Interestingly the strategy to pursue the installation of the 2-pentyl ether in 190 via the reductive
ring opening of the pentylideneketal ketal 192 was enforced by the failure of the corresponding epoxy
alcohol 195 to undergo alkylation with 2-pentyl iodide. All attempts led to aromatized products
presumably via base-induced epoxide isomerization/ring opening to the corresponding allylic alcohol
followed by dehydration.
This undesired aromatization process was frequently encountered in subsequent reactions of 190
with various amines/nitrogenous nucleophiles and posed a significant issue in the progression of the
synthesis via the ring opening of the epoxide.
Scheme 54. Process development of an efficient route to key epoxide intermediate 190.
Shikimic acid esterification, acetonide protection and mesylation were telescoped to provide
mesylate 191 in 82% yield after recrystallization (Scheme 54). Acid catalyzed transketalization with
excess 3-pentanone gave new mesylate 192 almost quantitatively. The regioselective reductive ring
opening of the ketal required extensive optimization since the original Gilead conditions involving
BH3·Me2S and TMSOTf (trimethylsilyl trifluoromethanesulfonate) were not attractive for
acid. Despite intense optimization efforts, the dehydration-associated steps have not been
particularly straight forward or high yielding hence shikimic acid emerged as the ideal starting
material [188]. Gilead’s original preference for the quinic acid route [189] was based on the limited
supply of shikimic acid at that time. During Roche’s development efforts shikimic acid became
Catalysts
available in10,
2020, 1117
multi-hundred-ton 45 of 65
quantities by extraction of star anis and by a fermentation process
using a genetically engineered E. coli strain [190].
In the original Gilead synthesis this was achieved with sodium azide producing a 9:1 mixture of
Shikimic acid azido
the corresponding esterification,
alcohols acetonide protection
195a/b although and mesylation
this selectivity were telescoped
is inconsequential to isomers,
as both provide
mesylate
upon treatment with trimethyl phosphine, convert to the same aziridine 197 (Scheme 55). Aziridinewith
191 in 82% yield after recrystallization (Scheme 54). Acid catalyzed transketalization ring
excess 3-pentanone gave new mesylate 192 almost quantitatively. The regioselective reductive
opening again with azide attack, followed by acetylation, azide reduction with Raney Ni and addition ring
opening of theacid,
of phosphoric ketal required
gave extensive
oseltamivir. Thisoptimization since delivered
part of the process the original Gilead conditions
successfully involving
multiple kilograms
BH 3·Me2S and TMSOTf (trimethylsilyl trifluoromethanesulfonate) were not attractive for
of the drug substance, but the azide chemistry raised concerns for long term manufacturing. Pressed
by competition from GlaxoSmithKline who at that time were slightly ahead with the development
of zanamivir, a decision was made to render the azide route fit for manufacturing and registration
rather than initiate the development of an azide-free route as this could take much longer and would
be probably best to investigate it later. Working together with process safety and azide chemistry
experts the Roche team quickly determined operating windows that ensured safety and precluded
decomposition of the azide intermediates and consequently yield losses. This, combined with other
improvements in this latter part of the synthesis, precipitated the manufacturing route to oseltamivir
(Scheme 55) [192].
In particular, the ring opening of the epoxide 190 to 196a/b required excess azide to drive the
reaction to completion and avoid aromatization of the substrate; for safety reasons this was conducted
at less than 70 ◦ C. The hazardous trimethyl phosphine was replaced with the less reactive yet safer
triphenyl analog which assisted by MsOH facilitated the Staudinger reduction of the azide and
subsequent formation of aziridine 197; for safety reasons this was conducted at less than 50 ◦ C.
Aziridine formation was coupled with aziridine ring opening by azide to generate 198 followed by
acetylation of the amine. For safety reasons these steps were conducted at less than 50, 35 and 25 ◦ C,
respectively. Thus, acetamido azide 199 was isolated directly after a three-stage telescoped process in
DMSO in 70% yield from 196a/b (Scheme 55). The reduction of azide by hydrogenation and hydride
Catalysts 2020, 10, 1117 46 of 65
methods was found to generate several impurities related to double bond reduction and isomerization.
Raney Ni was replaced with tributyl phosphine for an extremely selective Staudinger reduction/reaction
which was coupled to the final salt forming step with phosphoric acid. This provided oseltamivir in
Catalysts
55% 2020,
yield 10, x epoxide
from FOR PEER190
REVIEW
which translates to 35% overall yield from shikimic acid. 48 of 69
CO2Et
O N3
OH
Et Et
CO2Et CO2Et
196a 9
NaN3, NH4Cl Ph3P, MsOH
:
O EtOH, H2O Et3N, DMSO O
1 196b
O 86% 50 oC, 1h NH
Et Et Et Et
CO2Et
190 197
O OH
N3
55% from 190 Et Et NaN3, DMSO
35% from shikimic acid H2SO4, 35 oC, 4h
CO2Et CO2Et
CO2Et
.
H3PO4 1. EtOH, H2O
Bu3P, 5-20 oC Ac2O
AcOH(cat) O N3 70% O N3
O NH2 2. H3PO4 NHAc NH2
NHAc EtOH, 50 oC Et Et Et Et
Et Et
90%
oseltamivir 199 198
Scheme 55. Roche’s manufacturing route to oseltamivir.

Scheme 55. Roche’s manufacturing route to oseltamivir.
Roche followed this with two azide-free processes (Scheme 56). In the first one, a wide screen of
In particular,
appropriate the ringammonia
amines/latent opening of the epoxide
nucleophiles 190Lewis
and to 196a/b
acidsrequired
were screenedexcessinazide
ordertotodrive the
identify
reaction to completion and avoid aromatization of the substrate; for
conditions that led to efficient epoxide ring opening with minimum aromatization of 190 [193]. safety reasons this was
conducted
From at less thanin
this, allylamine 70the
°C.presence
The hazardous trimethyl
of magnesium phosphine
bromide was replaced
etherate with the less
was demonstrated reactive
to provide
yet safer triphenyl analog which assisted by MsOH facilitated the Staudinger
the amino alcohol 200 in 97% yield (dr 9:1) with only traces aromatization products being formed. reduction of the azide
Pd-catalyzed de-allylation, followed by protection of the amine as its benzaldehyde imine allowed °C.
and subsequent formation of aziridine 197; for safety reasons this was conducted at less than 50 for
Aziridine formation was coupled with aziridine ring opening by azide to generate
clean formation of mesylate 201. Further treatment with allylamine causes a transimination reaction 198 followed by
acetylation of the amine. For safety reasons these steps were conducted
to occur, freeing up the amino group next to the mesylate. The thus produced amino mesylate,at less than 50, 35 and 25 °C,
respectively.
cyclizes to theThus, acetamidoaziridine
corresponding azide 199 was is
which isolated
furtherdirectly
attacked,after
andaring
three-stage
opened telescoped
by allylamine process
with
in DMSO of
inversion inconfiguration.
70% yield from 196a/b
Careful (Scheme of
adjustment 55).theThe reduction
apparent of azide
pH allows for by hydrogenation
selective acetylation and
of
hydride methods was found to generate several impurities related to double
the primary amino group while the secondary is deactivated in its protonated form to give the trans bond reduction and
isomerization.
vicinal diamineRaney Ni was replaced
intermediate withthe
202. Despite tributyl phosphine
complexity fordomino
of this an extremely
process selective
involvingStaudinger
several
reduction/reaction which was coupled to the final salt forming step with
equilibria, ring closing and opening events, 202 is the only intermediate isolated in relatively phosphoric acid. good
This
provided oseltamivir in 55% yield from epoxide 190 which translates to
yield. Pd-catalyzed de-allylation followed by phosphate salt formation afforded oseltamivir in 35%35% overall yield from
shikimic
yield from acid.
190 (23% from shikimic acid).
Roche followed this
Based primarily with
on the two azide-free
discovery processes
of the efficient (Scheme
Mg(II) 56). Inring
promoted the opening
first one,ofa wide
190 byscreen of
amines,
appropriate amines/latent ammonia nucleophiles and Lewis acids were screened
a second generation route was developed [194]. In this, allylamine was replaced with t-butylamine and in order to identify
conditions that led to efficient epoxide ring opening with minimum aromatization of 190 [193]. From
the magnesium bromide etherate with the cheaper magnesium chloride. Interestingly the performance
this, allylamine in the presence of magnesium bromide etherate was demonstrated to provide the
of the ring opening was highly dependent on the order of addition with pre-mixing the amine and the
amino alcohol 200 in 97% yield (dr 9:1) with only traces aromatization products being formed.
catalyst leading to superior yield of 203 whereas premixing the epoxide with magnesium chloride led
Pd-catalyzed de-allylation, followed by protection of the amine as its benzaldehyde imine allowed
for clean formation of mesylate 201. Further treatment with allylamine causes a transimination
reaction to occur, freeing up the amino group next to the mesylate. The thus produced amino
mesylate, cyclizes to the corresponding aziridine which is further attacked, and ring opened by
allylamine with inversion of configuration. Careful adjustment of the apparent pH allows for
selective acetylation of the primary amino group while the secondary is deactivated in its protonated
Catalysts 2020, 10, 1117 47 of 65
to significant amounts of the corresponding chlorohydrin. The bulky group on nitrogen allowed for
clean activation of the alcohol as the mesylate which eventually cyclized to aziridine 204. Ring opening
of the latter with bis-allyl-amine followed by acetylation gave after HCl treatment the hydrochloride
process involving several equilibria, ring closing and opening events, 202 is the only intermediate
salt 205. Pd-catalyzed de-allylation followed by phosphate salt formation afforded oseltamivir in 58%
isolated in relatively good yield. Pd-catalyzed de-allylation followed by phosphate salt formation
yield from 190 (37% from shikimic acid) which compares favorably with the azide route.
afforded oseltamivir in 35% yield from 190 (23% from shikimic acid).
Scheme 56.
Scheme Roche’s second
56. Roche’s second generation
generation manufacturing
manufacturing routes
routes to
to oseltamivir
oseltamivir (azide-free).
(azide-free).
Overall, under tremendous pressure for an expedited registration, a remarkable joined effort by
Based primarily on the discovery of the efficient Mg(II) promoted ring opening of 190 by
process groups at Gilead, Roche and external contractors led to the development of a safe azide-based
amines, a second generation route was developed [194]. In this, allylamine was replaced with
manufacturing process for the complex molecule of oseltamivir. Innovative navigation through epoxide
t-butylamine and the magnesium bromide etherate with the cheaper magnesium chloride.
and aziridine chemistry led to an azide-free, second generation route that also delivers the drug
Interestingly the performance of the ring opening was highly dependent on the order of addition
substance at specification and with improved efficiency.
with pre-mixing the amine and the catalyst leading to superior yield of 203 whereas premixing the
epoxide with magnesium
1.18. Indinavir—A Member ofchloride
Approvedled HIVtoProtease
significant amounts
Inhibitors of the by
Synthesized corresponding
Chiral Epoxidechlorohydrin.
Intermediates
The bulky group on nitrogen allowed for clean activation of the alcohol as the mesylate which
Highlycyclized
eventually active antiretroviral therapy
to aziridine 204. Ring(HAART)
opening of is the
the current
latter withstandard in HIV treatment
bis-allyl-amine followedandby
involves combination of drugs targeting different stages of viral infection such
acetylation gave after HCl treatment the hydrochloride salt 205. Pd-catalyzed de-allylation followed as entry, reverse
transcription,
by phosphate integration
salt formationandafforded
maturation/release
oseltamivir[195].
in 58% HAART
yield fromhas revolutionized
190 (37% from HIV treatment
shikimic acid)
and increased considerably the life expectancy
which compares favorably with the azide route. to the point that is now considered a manageable
chronic disease.
Overall, Keytremendous
under contributionpressure
to the combination treatment
for an expedited is provided
registration, in the form
a remarkable of a effort
joined protease
by
inhibitor which is represented in 10 of the approximately 30 approved drugs
process groups at Gilead, Roche and external contractors led to the development of a safe for HIV [196–198]. Merck’s
indinavir (trade
azide-based name Crixivan,
manufacturing Scheme
process for 57)
the was the third
complex HIV protease
molecule inhibitor
of oseltamivir. to be FDA-approved,
Innovative navigation
one year epoxide
through after Roche’s
and saquinavir and Abbott’s
aziridine chemistry led (now
to anAbbVie) ritonavir;
azide-free, secondthese were followed
generation in quick
route that also
delivers the drug substance at specification and with improved efficiency.
1.18. Indinavir—A Member of Approved HIV Protease Inhibitors Synthesized by Chiral Epoxide Intermediates
(GlaxoSmithKline/Vertex) and lopinavir (also by Abbott).
Protease inhibitors aim to halt maturation and release of viral particles by inhibiting certain
cleaving events performed by the protease on the viral polyprotein, a process that releases mature,
essential viral proteins (p7, 9, 17, 24) and active viral enzymes (protease, reverse-transcriptase and
integrase
Catalysts among
2020, 10, 1117others). 48 of 65
HIV protease inhibitors have been designed primarily as transition state inhibitors equipped
with a non-hydrolysable peptidomimetic isostere. Arguably, the 1,2-aminoalcohol motif has
succession by nelfinavir (Eli Lilly/Agouron), amprenavir (GlaxoSmithKline/Vertex) and lopinavir
emerged the most successful consequently epoxide intermediates (Scheme 57) have been recruited
(also by Abbott).
extensively in the synthesis of this essential domain in HIV protease inhibitors [199].
Scheme 57. HIV protease inhibitors and their retrosynthesis into key epoxide intermediates.
Scheme 57. HIV protease inhibitors and their retrosynthesis into key epoxide intermediates.
Protease inhibitors aim to halt maturation and release of viral particles by inhibiting certain
Indinavir
cleaving eventsisperformed
synthesized byvia
theepoxide
protease206on (Scheme
the viral 57) the stereochemistry
polyprotein, of which,
a process that including
releases mature,
that at the amide α-carbon, are induced by the aminoindanol portion which therefore
essential viral proteins (p7, 9, 17, 24) and active viral enzymes (protease, reverse-transcriptase acts as a chiral
and
auxiliary in their
integrase among others). generation [200]. Cis-aminoindanol (1S,2R)-AI and its enantiomer are key
components in several
HIV protease drug have
inhibitors molecules, chiral auxiliaries
been designed primarilyand catalysts and
as transition stateare conveniently
inhibitors accessed
equipped with
a non-hydrolysable peptidomimetic isostere. Arguably, the 1,2-aminoalcohol motif has emergedleft)
by indene [201]. One of the earlier large-scale synthesis of (1S,2R)-AI by Sepracor (Scheme 58, the
involved
most the catalytic
successful asymmetric
consequently epoxide epoxidation of indene
intermediates (Scheme using (R,R)-M5
57) have to give (1S,2S)-indene
been recruited extensively in
oxide
the 207. Ring
synthesis of opening by ammonia
this essential domain in followed by benzamide
HIV protease formation
inhibitors [199]. and exposure to strong acid
Indinavir is synthesized via epoxide 206 (Scheme 57) the stereochemistry of which, including that
at the amide α-carbon, are induced by the aminoindanol portion which therefore acts as a chiral
auxiliary in their generation [200]. Cis-aminoindanol (1S,2R)-AI and its enantiomer are key components
in several drug molecules, chiral auxiliaries and catalysts and are conveniently accessed by indene [201].
One of the earlier large-scale synthesis of (1S,2R)-AI by Sepracor (Scheme 58, left) involved the catalytic
asymmetric epoxidation of indene using (R,R)-M5 to give (1S,2S)-indene oxide 207. Ring opening
by ammonia followed by benzamide formation and exposure to strong acid generates oxazoline 206
which is hydrolyzed to (1S,2R)-AI. Both the ring opening, and the cyclisation step occur with inversion
of configuration.
Merck developed an alternative synthesis (Scheme 58, right) that uses (1R,2R)-indene oxide 209 and
proceeds with retention of configuration through oxazoline 210 generated by a Ritter reaction (Scheme 58,
right). This transformation probably proceeds through the benzylic cation 211 (formed by protonation of
the epoxide or the associated diol) followed by attack of the most competent nucleophile present in the
reaction, namely acetonitrile. This can take place at either diastereotopic side of the planar benzylic cation,
Catalysts 2020, 10, 1117 49 of 65
but only the cis adduct may cyclize to a bicyclic oxazoline with a cis ring junction. The instability of the
nitrilium intermediate 212 renders its formation reversible and given the inability of the trans adduct to
cyclize, all reaction is channeled through the cyclisation of the cis adduct. It is worth mentioning that in
the Merck epoxidation process, P3 NO, 4-(phenylpropyl)pyridine N-oxide (Scheme 58) was found to be a
superior external ligand to those employed regularly and at 4 mol%, it supported a robust reaction with
Catalysts 2020,
reduced 10, x FOR PEER(0.7
catalyst-loading REVIEW 51 of
mol% (R,R)-M3, Scheme 58) capable of delivering (1R,2R)-indene oxide 69
209
in 90% yield and 88% ee at multikilogram scale. After hydrolysis of oxazoline 210 and recrystallization
generates
of (1S,2R)-AI oxazoline 206 salt,
as its tartrate whichtheis hydrolyzed
optical purity isto (1S,2R)-AI.
upgraded Both the ring opening, and the
to >99%.
cyclisation step occur with inversion of configuration.
Scheme 58. Syntheses of (1S,2R)-aminoindanol via Jacobsen–Katsuki asymmetric epoxidation.

Scheme 58. Syntheses of (1S,2R)-aminoindanol via Jacobsen–Katsuki asymmetric epoxidation.
1.19. Metal-Catalyzed Asymmetric Epoxidations in Drug Development—Further Examples of the Sharpless
Merck developed
and Jacobsen–Katsuki an alternative synthesis (Scheme 58, right) that uses (1R,2R)-indene oxide 209
Methodologies
and proceeds with retention of configuration through oxazoline 210 generated by a Ritter reaction
The 58,
(Scheme Sharpless asymmetric
right). This epoxidation
transformation of proceeds
probably allylic alcohols
throughand thethe Jacobsen–Katsuki
benzylic salen
cation 211 (formed
complexes-catalyzed epoxidation of cyclic and cis alkenes have dominated the
by protonation of the epoxide or the associated diol) followed by attack of the most competentfield of metal catalyzed
asymmetric
nucleophile epoxidations
present in theemployed
reaction, at various
namely development
acetonitrile. Thisstages of pharmaceuticals.
can take Examples of
place at either diastereotopic
these are highlighted below.
side of the planar benzylic cation, but only the cis adduct may cyclize to a bicyclic oxazoline with a
Ono
cis ring Pharmaceutical
junction. developed
The instability of the and performed
nitrilium a Sharpless
intermediate asymmetric
212 renders epoxidation
its formation of allylic
reversible and
alcohol
given the 213 on 678 of
inability g scale to access
the trans adduct thetokey chiral
cyclize, allepoxide
reaction214 en route tothrough
is channeled the highly
the selective
cyclisation EP2
of
receptor
the cis agonist
adduct.215It (Scheme
is worth 59) [202].
mentioning that in the Merck epoxidation process, P3NO,
Eisai used the Sharpless
4-(phenylpropyl)pyridine method
N-oxide to develop
(Scheme an innovative
58) was found to be approach
a superiorforexternal
the chiral tertiary-alkyl
ligand to those
nitrile motif present in the calcium channel blockers enopamil, norenopamil
employed regularly and at 4 mol%, it supported a robust reaction with reduced catalyst-loading and verapamil(0.7
(Scheme 59) [203]. Accordingly, asymmetric epoxidation of 216 to 217 followed
mol% (R,R)-M3, Scheme 58) capable of delivering (1R,2R)-indene oxide 209 in 90% yield and 88% ee by protection of
the alcohol provided
at multikilogram theAfter
scale. epoxide substrateof218
hydrolysis for the rearrangement
oxazoline to aldehydeof219.
210 and recrystallization This involved
(1S,2R)-AI as its
the MAD-catalyzed migration of the isopropyl
tartrate salt, the optical purity is upgraded to >99%. group onto the benzylic carbon atom with concomitant
epoxide ring opening and formation of the aldehyde.
1.19. Metal-Catalyzed Asymmetric Epoxidations in Drug Development—Further Examples of the Sharpless
and Jacobsen–Katsuki Methodologies
The Sharpless asymmetric epoxidation of allylic alcohols and the Jacobsen–Katsuki salen
complexes-catalyzed epoxidation of cyclic and cis alkenes have dominated the field of metal
catalyzed asymmetric epoxidations employed at various development stages of pharmaceuticals.
Examples of these are highlighted below.
Ono Pharmaceutical developed and performed a Sharpless asymmetric epoxidation of allylic
alcohol 213 on 678 g scale to access the key chiral epoxide 214 en route to the highly selective EP2
Catalysts 2020, 10, 1117 50 of 65
Scheme 59.
Scheme Application of
59. Application of Sharpless’
Sharpless’ asymmetric
asymmetric epoxidation
epoxidation to
to the
the synthesis
synthesis of
of drug
drug candidates.
candidates.
GlaxoSmithKline’s
Eisai used the Sharpless effortmethod
for a toscalable
develop synthesis of GSK966587,
an innovative approach for antheantimicrobial clinical
chiral tertiary-alkyl
candidate [204],
nitrile motif presentpivoted
in theon the asymmetric
calcium epoxidation
channel blockers of allylic
enopamil, alcohol 220
norenopamil andusing the Sharpless
verapamil (Scheme
method
59) [203]. Accordingly, asymmetric epoxidation of 216 to 217 followed by protection of thethe
which delivered epoxide 221 in 81% yield and 90% ee in 10 g scale (Scheme 60). Under basic
alcohol
ring-opening
provided theconditions of 221 with
epoxide substrate 218amine the undesired intramolecular
222,rearrangement
for the to aldehyde 219. SN ArThis
reaction between
involved the
the primary alcohol and the adjacent aryl fluoride in the product was observed
MAD-catalyzed migration of the isopropyl group onto the benzylic carbon atom with concomitant thus an alternative way
was sought
epoxide ringtoopening
install the
andamine portion.
formation Thealdehyde.
of the ring opening of 221 with HCl gave initially chlorohydrin
223 which cyclized thermally
GlaxoSmithKline’s effortunder
for aneutral conditions
scalable synthesisto 224 with concomitant
of GSK966587, O-demethylation.
an antimicrobial clinical
candidate [204], pivoted on the asymmetric epoxidation of allylic alcohol 220 usingwas
Activation of the primary alcohol triggered cyclisation to epoxide 225 which theultimately
Sharpless
opened
method by amine
which 222 to furnish
delivered epoxide GSK966587.
221 in 81% yield and 90% ee in 10 g scale (Scheme 60). Under the
basic ring-opening conditions of 221optimized
GlaxoSmithKline process group with amine the222,
Jacobsen–Katsuki
the undesired method for epoxidizing
intramolecular 226 to
SNAr reaction
227 en route to the potassium channel opener BRL 55834 (Scheme 61, left) [205].
between the primary alcohol and the adjacent aryl fluoride in the product was observed thus an The reaction initially
required
alternativeat way
least was
8 mol% of the
sought to Jacobsen
install thesalen complex/catalyst
amine portion. The ring (R,R)-M5
opening in order
of 221towith
complete and
HCl gave
produce 227 with high enantioselectivity. Lower catalyst loadings led to
initially chlorohydrin 223 which cyclized thermally under neutral conditions to 224 with erosion of ee and incomplete
reaction
concomitantevenO-demethylation.
after 50 h. This was attributed to catalyst decomposition with active degradants
potentially promoting racemic product formation. Examination of several additives known to benefit
catalyst stability identified 4-Ph-pyridine N-oxide and isoquinoline N-oxide with the latter allowing
the catalyst-loading to be lowered to 0.1 mol% and, in contrast to the former, could be removed by in
the aqueous washes. This enabled the synthesis of BRL 55834 in multikilogram scale.
Catalysts 2020, 10, 1117 51 of 65
Scheme
Catalysts 2020, 10, x FOR PEER 60. Synthesis of GSK966587 via two chiral epoxide intermediates.
Synthesis
REVIEW 54 of 69
Activation of the primary alcohol triggered cyclisation to epoxide 225 which was ultimately
opened by amine 222 to furnish GSK966587.
GlaxoSmithKline process group optimized the Jacobsen–Katsuki method for epoxidizing 226 to
227 en route to the potassium channel opener BRL 55834 (Scheme 61, left) [205]. The reaction initially
required at least 8 mol% of the Jacobsen salen complex/catalyst (R,R)-M5 in order to complete and
produce 227 with high enantioselectivity. Lower catalyst loadings led to erosion of ee and
incomplete reaction even after 50 h. This was attributed to catalyst decomposition with active
degradants potentially promoting racemic product formation. Examination of several additives
known to benefit catalyst stability identified 4-Ph-pyridine N-oxide and isoquinoline N-oxide with
the latter allowing the catalyst-loading to be lowered to 0.1 mol% and, in contrast to the former,
could be removed by in the aqueous washes. This enabled the synthesis of BRL 55834 in
Scheme 61. Application of Jacobsen’s asymmetric epoxidation to the synthesis of drug candidates.
Scheme 61. Application of Jacobsen’s asymmetric epoxidation to the synthesis of drug candidates.
Several years later, Pfizer reported the same approach to prepare 229 from 228 en route to a
Several yearschannel
similar potassium later, Pfizer reported
opener, the same
230 (Scheme approach
61, right) [206].toInprepare
this case229 from 228
4-phenyl en route
pyridine to a
N-oxide
similar potassium channel opener, 230 (Scheme 61, right) [206]. In this case 4-phenyl pyridine
N-oxide proved the optimum external ligand for the epoxidation process which was demonstrated
successfully at a scale of 225 g. Under the oxidative conditions the diaryl sulfide in 228 is also
transformed to the sulfone.
Catalysts 2020, 10, 1117 52 of 65
proved the optimum external ligand for the epoxidation process which was demonstrated successfully
at a scale of 225 g. Under the oxidative conditions the diaryl sulfide in 228 is also transformed to
the sulfone.
1.20. Organocatalytic Asymmetric Epoxidation in Drug Development—Chiral Ketones, Iminium Salts and
Phase Transfer Catalysts
The advent of organocatalysis has provided additional options in both normal and
asymmetric epoxidation where a variety of organocatalytic systems have been developed including
ketone/dioxirane, iminium/oxaziridinium salt, polyleucine/H2 O2 and phase transfer catalysts/inorganic
oxidants [137,138,207,208]. Two such systems were discussed in the diltiazem synthesis with Yang’s
chiral ketone/dioxirane selected as the system of choice for the large-scale process. Among academic
efforts Shi’s fructose-derived chiral ketone (commonly known as epoxone) has been established as the
broadest scope organocatalytic system imparting high enantioselectivities in the epoxidation of various
alkene substrates [137,138]. This prompted DSM process chemists to challenge its application in the
large-scale synthesis of a key intermediate associated with a scaffold exhibiting significant antiviral
activity2020,
Catalysts (231,10,Scheme 62) REVIEW
x FOR PEER [209]. 55 of 69
Scheme 62.
Scheme Development of
62. Development of aa large-scale
large-scale organocatalytic
organocatalytic asymmetric
asymmetric epoxidation/lactonization.
epoxidation/lactonization.
It was envisaged that 231 could be accessed from amino lactone 232 which in turn can be
It was envisaged that 231 could be accessed from amino lactone 232 which in turn can be
derived from hydroxy lactone 233. The latter was shown to form spontaneously upon epoxidation of
derived from hydroxy lactone 233. The latter was shown to form spontaneously upon epoxidation of
unsaturated acid 234 under basic conditions. Having earlier optimized the synthesis of the chiral ketone
unsaturated acid 234 under basic conditions. Having earlier optimized the synthesis of the chiral
catalyst, DSM chemists looked into the tandem epoxidation/lactonization process. Oxirane formation
ketone catalyst, DSM chemists looked into the tandem epoxidation/lactonization process. Oxirane
from this ketone-catalyst requires a pH range of 10–11, at which the decomposition of catalyst, primarily
formation from this ketone-catalyst requires a pH range of 10–11, at which the decomposition of
via a Baeyer-Villiger reaction, becomes competitive hence the high catalyst loadings. The reaction also
catalyst, primarily via a Baeyer-Villiger reaction, becomes competitive hence the high catalyst
needs to be run under dilute conditions due to the low solubility of Oxone. After careful optimization
loadings. The reaction also needs to be run under dilute conditions due to the low solubility of
of the reaction conditions and mode of reagent addition this process delivered more than 100 kg of 233
Oxone. After careful optimization of the reaction conditions and mode of reagent addition this
over several batches nevertheless issues related to process robustness and reproducibility persisted.
process delivered more than 100 kg of 233 over several batches nevertheless issues related to process
Substrate-controlled epoxidations may be subject to match/mismatched interactions with chiral
robustness and reproducibility persisted.
catalysts/promoters therefore more efficient processes can be designed when a matched case is identified.
Substrate-controlled epoxidations may be subject to match/mismatched interactions with chiral
Epoxone has also been used to install the epoxide functionality in cryptophycin 51, a synthetic analog
catalysts/promoters therefore more efficient processes can be designed when a matched case is
of the natural product cryptophycin 1 (Scheme 63). Cryptophycin 51 was advanced to Phase I/II clinical
identified. Epoxone has also been used to install the epoxide functionality in cryptophycin 51, a
studies by Eli Lilly but was terminated due to adverse effects; research on this scaffold continues with
synthetic analog of the natural product cryptophycin 1 (Scheme 63). Cryptophycin 51 was advanced
analog structures [210,211]. In the effort to support early supplies of the drug substance a battery of
to Phase I/II clinical studies by Eli Lilly but was terminated due to adverse effects; research on this
epoxidation protocols was tested with the ultimate intermediate 236 and epoxone emerged as the most
scaffold continues with analog structures [210,211]. In the effort to support early supplies of the drug
diastereoselective agent giving a β/α ratio of 3.5:1 (mCPBA, Jacobsen methods 1.9:1) [212]. Eli Lilly
substance a battery of epoxidation protocols was tested with the ultimate intermediate 236 and
epoxone emerged as the most diastereoselective agent giving a β/α ratio of 3.5:1 (mCPBA, Jacobsen
methods 1.9:1) [212]. Eli Lilly chemists considered investigating a better matched case in the
substrate-controlled epoxidations of earlier non-macrocyclic intermediates such as 237, 238 and 239
(Scheme 63). The former gave the most diastereoselective epoxidation, but low conversions made
purification difficult and this option was abandoned. Optimization of 240 epoxidation increased the
Catalysts 2020, 10, 1117 53 of 65
chemists considered investigating a better matched case in the substrate-controlled epoxidations of

earlier non-macrocyclic intermediates such as 237, 238 and 239 (Scheme 63). The former gave the most
diastereoselective epoxidation, but low conversions made purification difficult and this option was
abandoned. Optimization of 240 epoxidation increased the diastereoselectivity from 5:1 to 6.5:1 with
>95% conversion and this was achieved with less epoxone (2 instead of 4 equivalents typically used in
this work). Although not a true catalytic process, it enabled an improved synthesis for this complex
drug candidate.
Scheme
Scheme 63. Application of
63. Application of Shi’s
Shi’s chiral
chiral ketone
ketone (epoxone)
(epoxone) to
to the
the synthesis
synthesis of
of cryptophycin
cryptophycin 51.
51.
A similar requirement for enhanced substrate control has been reported by Novartis in the
A similar requirement for enhanced substrate control has been reported by Novartis in the
synthesis of epothilone and analogs thereof where epoxone provided the highest diastereoselectivity
synthesis of epothilone and analogs thereof where epoxone provided the highest diastereoselectivity
in the epoxidation of the macrocyclic alkene (8–10:1) in the final step [213].
in the epoxidation of the macrocyclic alkene (8–10:1) in the final step [213].
Another interesting case of matched substrate-controlled epoxidation was reported by Rusinov
Another interesting case of matched substrate-controlled epoxidation was reported by Rusinov
and Chertorizhskii in the synthesis of the contraceptive mifepristone who used a chiral phase transfer
and Chertorizhskii in the synthesis of the contraceptive mifepristone who used a chiral phase
catalyst (Q1, Scheme
transfer catalyst 64) to enhance
(Q1, Scheme the desired
64) to enhance diastereoselectivity
the desired in the
diastereoselectivity in epoxidation
the epoxidationof 240 to
of 240
14:1 from 3.5:1 typically seen in the absence of the chiral species [214]. The diastereoselectivity
to 14:1 from 3.5:1 typically seen in the absence of the chiral species [214]. The diastereoselectivity was
was heavily dependent on the protecting group of the alcohol (7.75:1 with TMS in place of TBDMS).
heavily dependent on the protecting group of the alcohol (7.75:1 with TMS in place of TBDMS). The
The stereochemistry
stereochemistry of epoxide
of epoxide 241241 is critical
is critical in in installing
installing the
the arylgroup
aryl groupwith
withthe
thecorrect
correctstereochemistry
stereochemistry
as this is dictated by the prerequisite antiperiplanar geometry in the SN 2’ ring opening of the allylic
as this is dictated by the prerequisite antiperiplanar geometry in the SN2’ ring opening of the allylic
epoxide.
epoxide. TheTheresulting
resultingalcohol 242 is242
alcohol dehydrated removing
is dehydrated thus the initial
removing thus stereochemical information
the initial stereochemical
of the epoxide intermediate, but the stereochemistry at the carbon atom bearing
information of the epoxide intermediate, but the stereochemistry at the carbon atom bearing aryl group constitutes
aryl
chiral memory of this process.
group constitutes chiral memory of this process.
In contrast, in the synthesis of the osteoporosis drug candidate 243 (Scheme 65) of Aventis
(legacy company of Sanofi), process chemists found that this could form with the desired stereochemistry
following isomerization of 244 and several unsaturated intermediates including those with the opposite
stereochemistry, generated in previous steps. The initial focus from enhancing the substrate controlled
epoxidation of 245 to 246 was shifted in the equilibration/isomerization process post the SN 2’ Grignard
addition (247) and culminated the development of a robust and more efficient process that avoided
the losses associated with the rejection of the α-epoxide isomer. Consequently, the epoxidation
Catalysts 2020, 10, 1117 54 of 65
process mediated by hexachloroacetone and hydrogen peroxide (β/α 1.8:1) was retained (β/α 2.1:1
Catalysts
with 2020, 10, x FOR PEER[215].
hexafluoroacetone) REVIEW 57 of 69
Scheme 64. Application of chiral phase transfer catalyst-mediated asymmetric epoxidation.
(legacy company of Sanofi), process chemists found that this could form with the desired
stereochemistry following isomerization of 244 and several unsaturated intermediates including
those with the opposite stereochemistry, generated in previous steps. The initial focus from
enhancing the substrate controlled epoxidation of 245 to 246 was shifted in the
equilibration/isomerization process post the SN2’ Grignard addition (247) and culminated the
development of a robust and more efficient process that avoided the losses associated with the
rejection of the α-epoxide isomer. Consequently, the epoxidation process mediated by
Scheme 64. Application
hexachloroacetone of chiral phase
and hydrogen transfer
peroxide catalyst-mediated
(β/α 1.8:1) wasasymmetric
retained epoxidation.
(β/α 2.1:1 with
Scheme 64. Application of chiral phase transfer catalyst-mediated asymmetric epoxidation.
hexafluoroacetone) [215].
(legacy company of Sanofi), process chemists found that this could form with the desired
stereochemistry following isomerization of 244 and several unsaturated intermediates including
those with the opposite stereochemistry, generated in previous steps. The initial focus from
enhancing the substrate controlled epoxidation of 245 to 246 was shifted in the
equilibration/isomerization process post the SN2’ Grignard addition (247) and culminated the
development of a robust and more efficient process that avoided the losses associated with the
rejection of the α-epoxide isomer. Consequently, the epoxidation process mediated by
hexachloroacetone and hydrogen peroxide (β/α 1.8:1) was retained (β/α 2.1:1 with
hexafluoroacetone) [215].
Scheme 65. Application of the catalytic ketone/dioxirane epoxidation system in drug development.
The iminium/oxaziridinium salt system is analogous to the ketone/dioxirane system and possesses
significant reactivity as an electrophilic oxygen transfer agent by virtue of the positively charged
nitrogen atom bonded to the oxygen in the oxaziridinium intermediate. The Page group was among
the pioneers in developing this system in organocatalytic asymmetric epoxidations [216–219].
Scheme 65. Application of the catalytic ketone/dioxirane epoxidation system in drug development.
The iminium/oxaziridinium salt system is analogous to the ketone/dioxirane system and

possesses significant reactivity as an electrophilic oxygen transfer agent by virtue of the positively
charged nitrogen
Catalysts 2020, 10, 1117 atom bonded to the oxygen in the oxaziridinium intermediate. The Page group
55 of 65
was among the pioneers in developing this system in organocatalytic asymmetric epoxidations
[216–219].
In the synthesis of GlaxoSmithKline’s former drug candidate for hypertension (−)-cromakalim
In the synthesis of GlaxoSmithKline’s former drug candidate for hypertension (−)-cromakalim
(or levcromakalim, the active enantiomer of cromakalim) the asymmetric catalytic epoxidation of 248
(or levcromakalim, the active enantiomer of cromakalim) the asymmetric catalytic epoxidation of
to 249 was achieved with Iminium salt 250 (Scheme 66) [220].
248 to 249 was achieved with Iminium salt 250 (Scheme 66) [220].
Scheme 66. Application of chiral iminium salt-catalyzed epoxidation system in drug synthesis.
Scheme 66. Application of chiral iminium salt-catalyzed epoxidation system in drug synthesis.
Standard iminium salt-catalyzed epoxidations require aqueous solutions of the inorganic triple
Standard
salt Oxone, theiminium salt-catalyzed
stoichiometric oxidant,epoxidations
thus limitingrequire aqueous solutions
the temperature of the the
range at which inorganic triple
epoxidation
salt Oxone,
reaction maythebestoichiometric
performed. Inoxidant,
this work,thus
thelimiting the temperature
organic-solvent range(tetraphenylphosphonium
soluble TPPP at which the epoxidation
reaction may be performed. In this work, the
peroxymonosulfate; the latter anion is the active component in Oxone) was used organic-solvent soluble
allowing TPPPthe
(tetraphenylphosphonium peroxymonosulfate; the latter anion is the active component
reaction to be conducted in pure organic solvent (CHCl3 ) at lower temperatures. This afforded higher in Oxone)
was used allowingin the
enantioselectivities reactionwith
comparison to the
be typical
conducted in pure
conditions organicaqueous
involving solventacetonitrile.
(CHCl3) atWith lower
the
temperatures. This afforded higher enantioselectivities in comparison with the
modified protocol the desired epoxide 249 was obtained in 62% yield and 97% ee and its ring opening typical conditions
involving aqueous acetonitrile.
with pyrrolidin-2-one With the modified
gave levcromakalim protocol the desired epoxide 249 was obtained in
in 52% yield.
62% yield and 97% ee and its ring opening with pyrrolidin-2-one gave levcromakalim in 52% yield.
2. Conclusions
2. Conclusions
This work may be viewed as a tribute to process development chemists who respond to the
challenge work
This may beseemingly
to transform viewed asimpossible
a tribute toor process
problematicdevelopment
syntheseschemists
into robust,who respond to and
reproducible the
challenge to transform
safe manufacturing seemingly
routes. Arguably,impossible
this couldornot
problematic syntheses
be demonstrated intothan
better robust, reproducible
by cases and
of successful
safe manufacturing routes. Arguably, this could not be demonstrated better
management of epoxide synthesis and ring-opening reactions at the highest level which has enabled than by cases of
successful management of epoxide synthesis and ring-opening reactions at the highest
the manufacturing of drugs and clinical candidates at specification to support pivotal clinical trials level which
has
and enabled the manufacturing
the availability of medicines of to drugs
society.and clinical
From candidatesperspective,
an educational at specification to support
the chemistry pivotal
discussed
clinical
provides an insight on the synthetic options generated by epoxides and how these are affectedthe
trials and the availability of medicines to society. From an educational perspective, by
chemistry
the ability discussed
to control provides
reactant andan insight
productonregio-
the synthetic options generated
and stereochemistry as wellby as epoxides and how
side reactions and
these are affected
impurity formation.by the
Theability to control
established reactant
syntheses and product
described in thisregio-
reviewand stereochemistry
may as well asa
potentially constitute
side
point of reference and inspiration for academic and industrial research in this and related fields. may
reactions and impurity formation. The established syntheses described in this review
potentially constitute a point of reference and inspiration for academic and industrial research in this
Author
and Contributions:
related fields. F.M., I.S., M.T., D.T., G.R. selected the case studies, drew the relevant reaction/structure
schemes and provided descriptions of the key chemical transormations. In addition, F.M. managed all references.
G.R. added
Author process development
Contributions: details
F.M., I.S., M.T., in each
D.T., G.R. case and the
selected alsocase
wrote the introduction
studies, and conclusion
drew the relevant sections.
reaction/structure
All authors have read and agreed to the published version of the manuscript.
schemes and provided descriptions of the key chemical transormations. In addition, F.M. managed all
references. G.R.research
Funding: This added process
receiveddevelopment details in each case and also wrote the introduction and conclusion
no external funding.
sections. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest: The authors declare no conflict of interests.
Catalysts 2020, 10, 1117 56 of 65
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© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Catalysts: Epoxide Syntheses and Ring-Opening Reactions in Drug Development

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Catalysts: Epoxide Syntheses and Ring-Opening Reactions in Drug Development

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Keywords: epoxides; drug development; catalytic asymmetric epoxidation; organocatalysis; process

Catalysts 2020, 10, 1117; doi:10.3390/catal10101117 www.mdpi.com/journal/catalysts

Catalysts 2020, 10, x FOR PEER REVIEW 2 of 69

The desymmetrizationScheme 2. Synthesis of meso-epoxide precursor 5.

Scheme 4. Desymmetrization of meso epoxide 6a with chiral bases.

Scheme 5. Retrosynthetic analysis of tasimelteon into key epoxide intermediate 12.

Scheme 6. Catalytic asymmetric epoxidation of 13 and conversion to cyclopropane intermediate 11.

Scheme 7. Synthesis of chiral epoxide 12 via Sharpless asymmetric dihydroxylation of 13.

Catalysts 2020, 10, x FOR PEER REVIEW

Scheme 11. Early medicinal chemistry route to AZD-4818.

Catalysts 2020, 10, x FOR PEER REVIEW 14 of 69

1.5. BMS-960—Development and

Scheme 20. Development of a telescoped process for multi-kilogram delivery of WY-255719.

Scheme 23. The

Scheme 24. Direct synthesis of chiral oxazolidinones via epoxide/isocyanate cycloadditions.

Scheme 26. Retrosynthesis of the S1P1 agonist ACT-209905.

Boc-D-leucine-OH ent-121 119a-anti

Scheme 34. Catalytic asymmetric (substrate-controlled) epoxidation followed by epimerization.

1.13. Reboxetine—Epoxide Intermediates Transcending from a Racemic to an Asymmetric Synthesis

40. Stereochemistry of reboxetine (approved drug) and esreboxetine

The first reason,

Scheme 41. Pfizer’s manufacturing route for reboxetine.

Catalysts 2020, 10, 1117

Scheme 44. Aparicio’s approach to esreboxetine using a diastereoselective Darzens reaction.

Both of the syntheses described above required chromatographic purifications nevertheless,

1.14. FK-788—Replacement of an Asymmetric Synthesis by a Resolution Process with Recycling of the

Both of the syntheses described above required chromatographic purifications nevertheless,

1.14. FK-788—Replacement of an Asymmetric Synthesis by a Resolution Process with Recycling of the

Scheme 46. Retrosynthetic analysis of FK-788.

178 R:S = 31:69

178 R:S = 31:69

1.15. A Lead Candidate for Asthma—Improved Synthesis via a Decarboxylative Rearrangement of an

Catalysts 2020, 10, x FOR PEER REVIEW 43 of 69

1.16. Δ-9-Tetrahydrocannabinol—From 3-carene to 2-carene Oxide and Δ-9-THC in Large Scale

1.16. ∆-9-Tetrahydrocannabinol—From 3-Carene to 2-Carene Oxide and ∆-9-THC in Large Scale

Scheme 52. Process route to p-menth-2-ene-1,8-diol from 2-carene via epoxidation/rearrangement.

Scheme 53. Retrosynthesis of oseltamivir into quinic and shikimic acid.

Scheme 55. Roche’s manufacturing route to oseltamivir.

Scheme 58. Syntheses of (1S,2R)-aminoindanol via Jacobsen–Katsuki asymmetric epoxidation.

chemists considered investigating a better matched case in the substrate-controlled epoxidations of

Scheme 64. Application of chiral phase transfer catalyst-mediated asymmetric epoxidation.

The iminium/oxaziridinium salt system is analogous to the ketone/dioxirane system and

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