Kurono Ohkuma 2016 Catalytic Asymmetric Cyanation Reactions

Review
pubs.acs.org/acscatalysis
Catalytic Asymmetric Cyanation Reactions

Nobuhito Kurono‡ and Takeshi Ohkuma*,†
†
Division of Applied Chemistry and Frontier Chemistry Center, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido
060-8628, Japan
‡
Department of Chemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
Downloaded via SHREENIVAS DESHPANDE LIBRARY IIT (BHU) VARANASI on October 23, 2023 at 12:35:44 (UTC).
ABSTRACT: Catalytic asymmetric cyanations of prochiral unsaturated compounds

affording the corresponding nitrile products in high enantiomeric excess (≥90% in
general) are summarized in this review. The nucleophilic cyanide addition onto
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aldehydes, ketones, and imines is promoted by chiral metal complexes and

organocatalysts. Recent progress in asymmetric conjugate cyanation of α,β-
unsaturated carbonyl compounds is also discussed. The asymmetric cyanation of
unactivated alkenes is catalyzed by chiral transition-metal complexes. Current topics
of intramolecular carbocyanation and aminocyanation in addition to the traditional
hydrocyanation are reviewed.
KEYWORDS: asymmetric cyanation, catalytic reaction, catalyst efficiency, chiral nitrile, cyanide reagent, enantioselectivity,
metal complex, organocatalyst
1. INTRODUCTION hydrocyanation of styrenes as well as intramolecular carbocya-

Catalytic asymmetric cyanations of prochiral unsaturated nation and aminocyanation of nitrile compounds carrying
compounds affording a variety of enantiomerically enriched alkenyl groups with high enantioselectivity have been reported.
nitriles have been extensively studied in recent years due to the Nickel and palladium complexes with chiral phosphinite,
significant utility of the products, which are readily convertible phosphoramidite, or phosphine-based ligands are typical
to the corresponding chiral carboxylic acids, ketones, amines, efficient catalysts. The H−CN, C−CN, and N−CN bonds
and so on (Scheme 1).1−3 These reactions are roughly divided are oxidatively cleaved by these metal complexes to add onto
into two categories. The first consists of nucleophilic additions the less-polar olefinic moieties.
to polarized compounds, such as aldehydes, ketones, and This review covers enantioselective cyanations promoted by
imines, utilizing the acid/base catalysis (Scheme 1-1)).1,2 artificial (not enzymatic) catalysts affording the corresponding
Conjugate cyanation of α,β-unsaturated carbonyl compounds nitrile products in high enantiomeric excess (ee >90% in
is included in this category. The protocol of bifunctional general). Previous reviews have elegantly presented the
catalysis (vide infra) is currently playing a vital role in the pioneering studies in this field.1−3 In the present review, the
application of these cyanations. 4 Trimethylsilylcyanide
features of each catalytic reaction are introduced with a
((CH3)3SiCN) is frequently used as a cyanide source, and
ethyl cyanoformate, acetyl cyanide, and acetone cyanohydrin representative reaction scheme involving the catalyst or ligand
are typical organo-cyanide reagents. Hydrogen cyanide (HCN) structure. For the range of applicable substrates, the individual
is the simplest reagent and has been utilized in the industrial articles should be consulted. The catalytic efficiency is primarily
processes. However, because HCN is highly toxic and volatile, estimated by the activity reflecting the amount of catalyst
HCN formed in situ by hydrolysis of (CH3)3SiCN or ethyl loading and enantioselectivity. Following the introductory
cyanoformate is often applied to these reactions rather than chapter, we discuss the nucleophilic cyanation of aldehydes,
isolated HCN. As another safe alternative, nonvolatile KCN is ketones, and imines in Chapter 2. Among these cyanations,
selected in some cases. Main group metal and early-transition- cyanosilylation has been the most intensively studied, although
metal complexes as well as lanthanide compounds act as the Strecker-type reaction (hydrocyanation of imines) is also a
efficient catalysts. Homo- and heterobimetallic systems have major topic. In Chapter 3, recent progress in the asymmetric
also been devised. Addition of nucleophilic cocatalyst activating conjugate cyanation of α,β-unsaturated carbonyl compounds is
the cyanide source sometimes increases the reaction rate. disclosed. Finally, enantioselective cyanation of unactivated
Application of a variety of organocatalysts derived from
alkenes is discussed. The current topics of intramolecular
peptides, (thio)ureas, and cinchona alkaloids, among others,
has notably improved and expanded this chemistry. Enzymatic carbocyanation and aminocyanation in addition to the
cyanation reactions are important practical processes, although traditional hydrocyanation are shown here.
they are outside the scope of this review.5
The other type of reactions are transition-metal-catalyzed Received: September 29, 2015
asymmetric cyanations of unactivated alkenes (Scheme 1-2)).3 Revised: December 24, 2015
Studies on these reactions are relatively rare yet, but Published: December 28, 2015
© 2015 American Chemical Society 989 DOI: 10.1021/acscatal.5b02184

ACS Catal. 2016, 6, 989−1023
ACS Catalysis Review
Scheme 1. Catalytic Enantioselective Cyanation Scheme 2. Asymmetric Cyanosilylation of Aldehydes with

Chiral Schiff Base−Titanium Catalyst
Scheme 3. Asymmetric Cyanosilylation of Aldehydes with

2. NUCLEOPHILIC CYANATION OF CARBONYL

COMPOUNDS AND IMINES
2-1. Cyanosilylation of Carbonyl Compounds. 2-1-
1. Aldehydes. In 1993, a pioneering work on the
enantioselective cyanosilylation of aldehydes using a chiral
titanium catalyst was reported by Oguni and co-workers
(Scheme 2).6 Some aromatic and α,β-unsaturated aldehydes efficient. Secondary alkyl aldehydes, 2-ethylbutanal and cyclo-
reacted with (CH3)3SiCN with high enantioselectivity in the hexanecarbaldehyde, as well as o-fluorobenzaldehyde were
presence of a catalyst prepared in situ from Ti(Oi-Pr)4 and a suitable for this catalytic reaction.
chiral Schiff base. Introduction of the tert-butyl group on the Camphor-derived Schiff base−titanium complexes were
phenolic moiety of the auxiliary was crucial to achieve high investigated by Bosiak and co-workers. Among five ligand
enantioselectivity. The reaction rate was remarkably enhanced candidates, the Schiff base prepared from 2-hydroxy-3-
by addition of the Schiff base to titanium alkoxide. The isopropylbenzaldehyde was the most efficient for this reaction
chemical structure of the chiral Schiff base−titanium alkoxide (Scheme 4).8 An excellent enantioselectivity of 99% was
complex was discussed on the basis of the 13C NMR spectra, achieved in the reaction of cinnamaldehyde.
field desorption mass spectra, and molecular weight measure-
ment. The 1:1 chiral Schiff base−titanium alkoxide monomeric
complex was considered to be the active species. Cyanide anion
approaches the aldehyde coordinated to the titanium of the
complex from the si-face side to avoid the bulky tert-butyl group
covering the carbonyl re-face.
Following on from Oguni’s report, Yoshinaga and Nagata
found that the catalytic activity was notably increased by using a
partially hydrolyzed titanium alkoxide as a catalyst precursor
(Scheme 3).7 The titanium species prepared from Ti(On-Bu)4,
water, and a chiral Schiff-base-catalyzed cyanosilylation of
aldehydes with high enantioselectivity in the low catalyst
loading (0.2−1.0 mol %). Ti(OEt)4 and Ti(On-Pr)4 were also
efficient titanium sources but bulky Ti(Oi-Pr)4 was less
990 DOI: 10.1021/acscatal.5b02184
ACS Catal. 2016, 6, 989−1023
Belokon and North and their co-workers have investigated reacted with (CH3)3SiCN under catalyst loadings of 0.01−0.02
the use of chiral (salen)titanium complexes to induce the mol % at ambient temperature to afford the corresponding
asymmetric addition of (CH3)3SiCN to aldehydes (Scheme 5).9 products in 87−99% yields and in 64−97% ees. The catalyst
was particularly effective for the reaction of aromatic aldehydes
Scheme 5. Asymmetric Cyanosilylation of Aldehydes with regardless of the presence of an electron-withdrawing or
Chiral Salen−Titanium Catalyst electron-donating group at either the para, meta, or ortho
position of the aromatic ring.
The in situ-formed titanium complexes bearing pyrrolidine-
based chiral salen ligands derived from natural L-tartaric acid
were evaluated as catalysts in the reaction of aromatic aldehydes
(Scheme 7).11 The catalysts with N-benzyl and N-cyclohexyl
pyrrolidine ligands showed higher activity and selectivity.

Chiral Salen−Titanium Catalyst
The optimal catalyst derived from (R,R)-1,2-diaminocyclohex-

ane and 3,5-di-tert-butyl-2-hydroxybenzaldehyde had a dimeric
structure of [(salen)Ti(μ-O)]2 in which the two Ti atoms were
bridged by two oxygen atoms. Addition of water was crucial to
generate the dimeric structure. The dimeric complex was more
active than that prepared from (salen)TiCl2. The reaction of m-
methoxybenzaldehyhde using 0.1 mol % of this complex
quantitatively gave the cyanohydrin silyl ether in up to 92% ee
at ambient temperature. The dimeric structure of a Ti complex
derived from (R,R)-1,2-diaminocyclohexane and 2-hydroxyben- Choi and co-workers synthesized N-sulfonylated β-amino-
zaldehyde was confirmed by an X-ray crystallographic analysis. alcohols with one or two stereocenters as chiral ligands.
The active dimeric species [(salen)Ti(μ-O)]2 reported by Titanium complexes prepared in situ from these ligands and
Belokon and North equilibrated with the less active monomeric Ti(Oi-Pr)4 efficiently catalyzed enantioselective cyanosilylation
form. In order to stabilize the dimeric structure, Ding and co- of aldehydes including benzaldehyde, 2-naphthaldehyde,
workers synthesized a (salen)titanium complex in which the cinnamaldehyde, and isobutylaldehyde (Scheme 8).12 Feng
two monomeric components were linked by a cis-5-
norbornene-endo-2,3-dicarboxylate bridge (Scheme 6).10 The Scheme 8. Asymmetric Cyanosilylation of Aldehydes with
linked complex acted as an excellent cyanation catalyst in terms Chiral N-Sulfonylated β-Aminoalcohol−Titanium Catalyst
of both activity and enantioselectivity. Various aldehydes,
including aromatic, α,β-unsaturated, and aliphatic substrates

Dimeric Chiral Salen−Titanium Catalyst
and co-workers used chiral β-aminoalcohol ligands prepared

through reduction of Schiff bases for the titanium-catalyzed
reaction (Scheme 9).13 The optimal complex showed high
activity and enantioselectivity in the cyanation of aromatic
aldehydes. The reaction pathway was proposed based on
Oguni’s report6 shown in Scheme 2. Benzaldehyde coordinates
to the titanium to avoid phenyl (complex)−phenyl (aldehyde)
repulsion. The cyanide anion preferentially attacks the carbonyl
991 DOI: 10.1021/acscatal.5b02184
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Scheme 9. Asymmetric Cyanosilylation of Aldehydes with bipyramidal in which the phosphine oxide moiety with
Chiral β-Aminoalcohol−Titanium Catalyst (CH3)3SiCN could be placed in a more favorable position to
react with the aldehyde. Cyanosilylation of aromatic, aliphatic,
and α,β-unsaturated aldehydes with this catalyst afforded the
products in excellent yields and enantioselectivities.
A bimetallic (salen)aluminum catalyst in the presence of a
phosphine oxide cocatalyst reported by North and co-workers
also efficiently promoted enantioselective cyanosilylation of
aldehydes (Scheme 11).15 Under optimized conditions,

Chiral Bimetallic Salen−Aluminum Catalyst
si-face over the shielded re-face by the phenyl moiety of the

complex.
Shibasaki and co-workers devised a bifunctional chiral
catalyst consisting of aluminum as a Lewis acid and phosphine
oxide as a Lewis base moiety, which activated both aldehydes
(substrate) and (CH3)3SiCN (reagent) (Scheme 10).14 enantioselectivity of 96% was obtained by using 2 mol % of
Phosphine oxide moieties were introduced into the 3,3′- the catalyst in the reaction of m-anisaldehyde. An analysis of the
positions of the binaphthyl framework to avoid internal acid− reaction kinetics revealed that the reactions exhibited first-order
base interaction with the aluminum part. kinetics in which the rate of reaction was independent of the
Addition of tributylphosphine oxide was important to change aldehyde concentration.
the geometry of aluminum from tetrahedral to trigonal Based on the mechanistic understanding of asymmetric
cyanohydrin synthesis catalyzed by the chiral (salen)titanium
complex, Belokon, North, and Parsons developed a chiral
(salen)vanadium oxide complex (Scheme 12).16 The reaction
Chiral Bifunctional Aluminum Catalyst
Chiral Salen−Vanadium Catalyst
of m-methylbenzaldehyde with only 0.1 mol % of the catalyst

loading gave the cyanated product in 95% ee. Propylene
carbonate, a green solvent, was also usable for this reaction.
Uang and co-workers prepared a tridentate Schiff base ligand
from tert-butyl substituted salicylaldehyde and inexpensive (S)-
valine (Scheme 13).17 The vanadium oxide complex with the
chiral Schiff base and the salicylaldehyde-ligand-catalyzed
cyanosilylation of 2-naphthaldehyde in the presence of
992 DOI: 10.1021/acscatal.5b02184
ACS Catal. 2016, 6, 989−1023
Scheme 13. Asymmetric Cyanosilylation of Aldehydes with Scheme 15. Asymmetric Cyanosilylation of Aldehydes with
Chiral Schiff Base−Vanadium Catalyst Chiral Oxazaborolidinium Catalyst
tetrabutylammonium fluoride (TBAF) to afford the product in

95% yield and 90% ee.
Corey and Wang invented a sophisticated catalyst system
(Scheme 14).18 The two kinds of chiral bisoxazoline derived

Chiral Bisoxazoline−Magnesium Catalyst
the chiral oxazaborolidinium resulting in high enantioselectivity

and was suggested to have several key features: (1)
Nucleophilic attack on the formyl carbon is expected to
occur at the si face because the opposite face is shielded by the
neighboring π-eletctron-rich m-xylyl ring of the catalyst. (2)
The complex structure was fixed with regard to rotation by
using coordination links of the CO···B and the formyl C−
H···O hydrogen bond. Therefore, the absolute configuration of
the silylated cyanohydrin was predicted to be R. Addition of a
Lewis base phosphine oxide activated (CH3)3SiCN and formed
the corresponding isocyanide. The reaction of a variety of
aromatic and aliphatic aldehydes was demonstrated, and the
silylated cyanohydrins were obtained in high yield and in >90%
ee under mild conditions.
Kagan and Holmes studied cyanosilylation of aldehydes
using fundamental chiral lithium phenolate catalysis (Scheme
16).20 The reaction of m-tolaldehyde conducted by a catalyst
with a chiral salen structure afforded the cyanated product in
97% ee. The binaphtholate catalyst resulted in 59% ee.
Ishihara and co-workers improved the generation method for
the binaphthol−Li catalyst system (Scheme 17).21 A simple 1:1
mixture of (R)-BINOL and LiOi-Pr efficiently catalyzed

from (S)-phenylglycinol were used as a pair of synergistic chiral Chiral Lithium Phenolate Catalyst
reagents: The first one (bisoxazoline a) and HCN formed from
(CH3)3SiCN and a trace amount of water provided the
equivalent of a chiral cyanide source. The second one
(bisoxazoline b) coordinated to magnesium chloride acting as
the chiral Lewis acid. Thus, the enantioselective reaction may
have occurred between the chiral cyanide source and the
aldehyde activated by the chiral magnesium Lewis acid as
shown in the scheme. Effective catalysis was shown in the
reaction of aliphatic aldehydes such as heptanal.
Corey’s group later revealed that the oxazaborolidinium
bistriflimidate described in Scheme 15 behaved as a highly
enantioselective catalyst.19 The coordination of aldehyde onto
993 DOI: 10.1021/acscatal.5b02184
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Scheme 17. Asymmetric Cyanosilylation of Aldehydes with Scheme 19. Asymmetric Cyanosilylation of Aldehydes with
BINOL−Lithium Catalyst Chiral Metal−Organic Framework Catalyst
asymmetric cyanosilylation of aromatic aldehydes. A transition-

state model consisting of the lithium binaphtholate,
(CH3)3SiCN, and benzaldehyde was proposed. The aldehyde
coordinates to the hypervalent silicon atom in a manner that the chiral induction. Ce-MDIPs worked as heterogeneous
avoids steric hindrance. The attractive π−π interaction between catalysts and exhibited high catalytic activity and enantiose-
the phenyl ring of the aldehyde and binaphthyl plane of the lectivity for asymmetric cyanosilylation of four aromatic
catalyst was shown to be the major factor for high aldehydes.
enantioselectivity. A homochiral metal−organic framework (MOF) with an
Ohkuma and co-workers devised a highly active, robust, and enantiopure 2,2′-dihydroxy-1,1′-biphenyl unit was constructed
enantioselective catalyst consisting of Ru(phgly)2(binap) and by Cui’s group (Scheme 20).24 Replacing one proton of the
Li2CO3 (phgly = phenylglycinate) (Scheme 18).22 The reaction
Scheme 18. Asymmetric Cyanosilylation of Aldehydes with Chiral Metal−Organic Framework Catalyst
Chiral Ruthenium−Lithium Combined Catalyst
could be conducted with catalyst loading of 0.01 mol % to

convert the aldehydes quantitatively into the silylated
cyanohydrins in up to 98% ee. The ruthenium complex was
recognized as a chiral template and combination with lithium
cyanide formed the active catalytic species. The structure of the
Ru−Li combined complex was determined by a single-crystal
X-ray analysis. phenoxy groups with Li cations made the MOF a highly
Duan and co-workers examined the catalyst efficiency of their efficient and recyclable heterogeneous catalyst for asymmetric
homochiral porous metal−organic frameworks (MOFs) in cyanation of aldehydes with enantioselectivity as high as 99%.
asymmetric reactions (Scheme 19).23 The MOFs, Ce−MDIP1, The catalytic activity and enantioselectivity of the MOF were
were prepared through crystallization from a mixture of enhanced over the original homogeneous system, especially at a
methylenediisophthalic acid (H4MDIP), celium nitrate, and L- low catalyst loading.21 The rigid framework seemed to stabilize
N-tert-butoxycarbonyl-2-(imidazole)-1-pyrrolidine as a chiral the catalytically active monolithium salt of biphenol, avoiding
inducing agent in the presence of H2O and Et3N. The CD the formation of inactive and/or less active assemblies in the
spectrum of bulk crystals of Ce-MDIP2, which were prepared reaction.
from the opposite enantiomer of the chiral agent, exhibited 2-1-2. Ketones. In 2000, Shibasaki and co-workers
Cotton effects that were precisely opposite those of Ce-MDIP1, developed the first and highly enantioselective cyanosilylation
indicating that the homochiral crystallization was achieved by of ketones by designing bifunctional catalysts (Scheme 21).25
994 DOI: 10.1021/acscatal.5b02184
ACS Catal. 2016, 6, 989−1023
Scheme 21. Asymmetric Cyanosilylation of Ketones Scheme 22. Asymmetric Cyanosilylation of Ketones with
Catalyzed by Titanium Complexes with Carbohydrate- Chiral Schiff Base−Titanium Catalyst
Derived Chiral Ligands
Scheme 23. Asymmetric Cyanosilylation of Ketones

Catalyzed by Titanium Complex with Chiral Amide Ligand
The carbohydrate-derived chiral ligand A with a phosphine

oxide moiety and Ti(Oi-Pr)4 efficiently catalyzed the reaction
of 2′-acetonaphthone, providing the corresponding quaternary
cyanohydrin derivative in 95% ee. The NMR studies suggested
that the actual catalyst was a titanium monocyano mono-
isopropoxide complex with chiral ligand A which activated
ketonic substrate with titanium as well as (CH3)3SiCN with the
phosphine oxide.
The titanium complex derived from chiral ligand B showed
higher catalytic activity and enantioselectivity in the cyanation
of ketones. The reaction of acetophenone using 1 mol % of the
catalyst gave the product in 94% ee (10 mol %, 92% ee with
ligand A). Steric hindrance of the benzoyl group on the ligand
B was expected to reduce undesired coordination with the
ketones, and the electron-withdrawing ability seemed to and phenolic N-oxide (Lewis base), which exhibited high
stabilize the reaction intermediate. catalytic efficiency in the enantioselective cyanosilylation of
The titanium complex prepared from a partially hydrolyzed ketones (Scheme 24).27 In the presence of 2.5 mol % catalyst, a
titanium alkoxide and a chiral tridentate Schiff-base-ligand- variety of aromatic ketones were converted into the
catalyzed cyanosilylation of ketones in the low catalyst loading corresponding cyanohydrin silyl ethers in high yields and
(Scheme 22).7 The reaction of aldehydes with this catalyst was enantioselectivities (up to 96%).
discussed in the previous section. Shibasaki and co-workers devised a chiral gadolinium catalyst
Feng and co-workers developed an efficient tetraaza ligand, prepared from Gd(Oi-Pr)3 and a D-glucose-derived ligand for
(2S)-N-{(1R,2R)-2-[(S)-pyrrolidine-2-carboxamido]-1,2- asymmetric cyanosilylation of ketones (Scheme 25).28 The
diphenylethyl}pyrrolidine-2-carboxamide, for the addition of reaction of acetophenone provided the corresponding (S)-
(CH3)3SiCN to ketones (Scheme 23).26 This tetraaza ligand cyanohydrin silyl ether in 92% ee. As described above, a
was readily synthesized in two steps from commercial titanium catalyst with the same ligand selectively afforded the R
compounds. The titanium complex formed in situ seemed to enantiomer in this reaction. The features of these two catalyst
have a monometallic Ti(Oi-Pr)2 structure with the chiral ligand. systems were quite different, although both utilized the same
It could activate both ketones and (CH3)3SiCN with titanium chiral ligand. The active species of the titanium catalyst seemed
(also an amino proton) and an appropriately positioned to be monomeric, but the gadolinium one consisted of
pyrrolidine nitrogen, respectively. The reaction of ketones was gadolinium and the ligand in a ratio of 2:3. A bimetallic
catalyzed by this complex with enantioselectivity as high as catalysis was proposed.
94%. The chiral gadolinium catalyst was applied to a 100 g-scale
Feng’s group also reported another bifunctional catalyst reaction of cyclohexyl phenyl ketone, affording the cyanohydrin
system composed of (S)-prolinamide, Ti(Oi-Pr)4 (Lewis acid), silyl ether in 94% ee without loss of enantioselectivity.29 The
995 DOI: 10.1021/acscatal.5b02184
ACS Catal. 2016, 6, 989−1023
Scheme 24. Asymmetric Cyanosilylation of Ketones of asymmetric induction in the reaction of aliphatic substrates
Catalyzed by Titanium Complex with Chiral Amide Ligand (3-none-2-one: 95%; 2-nonanone: 86%) was noteworthy. The
chiral ligand had the benefits of being readily prepared and
easily modified.
Feng and co-workers utilized a bifunctional catalyst system
composed of a chiral (salen)aluminum complex and an achiral
N-oxide achieving high catalytic turnovers (200 for aromatic
ketones, 1000 for aliphatic ones) (Scheme 27).32 A wide range
Scheme 27. Asymmetric Cyanosilylation of Ketones with

Chiral Salen−Aluminum Catalyst
Scheme 25. Asymmetric Cyanosilylation of Ketones

Catalyzed by Gadolinium Complex with Carbohydrate-
Derived Chiral Ligand
chiral ligand could be recovered with a silica-gel short column of aliphatic and aromatic ketones were converted under mild
in the purification of the product. conditions into the cyanation products in high ees
The enantioselective cyanosilylation of 3′,5′-difluorophenacyl (acetophenone: 94%; 1-tetralone: 90%; methyl isopropyl
chloride was promoted by the gadolinium catalyst bearing a ketone: 90%). A double-activation catalysis model was
modified chiral ligand. The functionalized product was applied proposed. (CH3)3SiCN is activated by the tertiary aniline N-
to the synthesis of several chiral medicines.30 oxide to form the hypervalent-silicon isocyanide, and it reacts
Snapper and Hoveyda and their co-workers reported an with the ketone coordinated to the chiral (salen)aluminum
aluminum-catalyzed reaction of ketones using a peptide-based complex on the less-hindered side.
chiral ligand (Scheme 26).31 A variety of aromatic (cyclic and Zhou and co-workers reported a tandem process involving a
acyclic) and aliphatic ketones (saturated and unsaturated) were Wittig reaction that provided enone substrates and cyanosily-
converted to the cyanated products in high ees. The high level lation using a chiral (salen)aluminum catalyst (Scheme 28).33a
Phosphine oxide, a byproduct generated in the first Wittig step,
Scheme 26. Asymmetric Cyanosilylation of Ketones was utilized to activate (CH3)3SiCN as a Lewis base, and the
Catalyzed by Aluminum Complex with Peptide-Based Chiral following enantioselective cyanosilylation of enones afforded
Ligand the silylated cyanohydrins in up to 93% ee. The tandem
transformation using meta- and para-substituted benzaldehydes
showed high enantioselectivity. The ee value of the product was
somewhat decreased in the reaction of o-chlorobenzaldehyde
and n-butanal.
Very recently, they developed an improved ternary catalyst
system for cyanosilylation of ketones consisting of (salen)-
aluminum chloride (10 mol %), phosphorane (10 mol %), and
triphenyl phosphine oxide (50 mol %) through mechanistic
studies on the above tandem reaction (Scheme 28).33b This
catalyst system succeeded in the achievement, for the first time,
of excellent enantioselectivity up to 95% in the reaction of
linear aliphatic ketones and α,β,γ,δ-unsaturated ketones. They
proposed a reaction mechanism according to their experimental
996 DOI: 10.1021/acscatal.5b02184
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Scheme 28. Tandem Process of Wittig Reaction/Asymmetric Scheme 29. Asymmetric Cyanosilylation of Ketones with
Cyanosilylation with a Chiral Salen−Aluminum Catalyst and Chiral Oxazaborolidinium Catalyst
Cyanation with an Improved Ternary Catalyst System
Feng and co-workers reported a simple and highly

enantioselective cyanosilylation of ketones catalyzed by phenyl-
glycine sodium salt (Scheme 30).35 The corresponding lithium

observations and theoretical calculations: Phosphorane acts as Phenylglycine Sodium Salt
an efficient Lewis base that interacts with (salen)aluminum
chloride to form a cationic aluminum complex. The ketonic
substrate, which coordinates to the electrophilic aluminum
species, reacts with (CH3)3SiCN activated by phosphine
oxide.19
Corey and Ryu found that the chiral oxazaborolidinium
triflate with diphenylmethyl phosphine oxide was an excellent
catalyst for the reaction of methyl ketones and (CH3)3SiCN
(Scheme 29).34 The sense of enantioface selection of this
reaction was the same as that in the case of aldehydes described
in the former section. The cyanation of p-nitroacetophenone
gave an enantioselectivity of 96%, higher than that of 83% with
acetophenone itself. On the other hand, p-methoxyacetophe-
none was transformed to the product in 32% ee with the and potassium salts as well as proline sodium salt were much
opposite sense of enantioselection. The reaction mechanism less selective. The reaction of benzalacetone in the presence of
seemed to be similar to that of the aldehyde cyanation shown in 30 mol % of the catalyst gave the cyanated product in 96% yield
Scheme 15.19 The ketonic substrate was fixed on the and 97% ee. The reaction was proposed to proceed through the
oxazaborolidinium with coordination links of the CO···B hypervalent silicate intermediate.
and the α−C−H···O hydrogen bond. The π,π-interaction of Ishihara and co-workers examined the catalytic enantiose-
the binded ketonic carbonyl with the neighboring π-electron- lective cyanosilylation of aromatic ketones using chiral lithium
rich mexyl group of oxazaborolidinium was a major factor in salts of (R)-BINOL-derived phosphoric acid compounds
determining the enantioselectivity. Then, the intermediate (Scheme 31).36 In the presence of 10 mol % of the chiral
complex reacted with the in situ-formed Ph2MePOTMS(N lithium salt, the corresponding tertiary cyanohydrins were
C:). obtained in high yields with moderate to high enantioselectiv-
997 DOI: 10.1021/acscatal.5b02184
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Scheme 31. Asymmetric Cyanosilylation of Ketones with Scheme 32. Asymmetric Cyanosilylation of Ketones with
Chiral Phosphoric Acid Lithium Salt Chiral Ruthenium−Lithium Combined Catalysts
ities (up to 86%). This catalyst was not appropriate for the
aliphatic substrates. The reaction was proposed to proceed
through a cyclic transition state in which the chiral lithium
phosphate interacts with both ketone and (CH3)3SiCN. The
direction of ketonic substrate is controlled in a manner that
diminishes steric repulsion toward the phenyl group on the
BINOL skeleton.
Ohkuma and co-workers demonstrated that the ruthenium
complex−lithium phenoxide systems efficiently catalyzed
enantioselective cyanosilylation of various ketones, such as Scheme 33. Asymmetric Cyanosilylation of Ketones with
simple aromatic ketones, α-keto esters, α-alkoxy ketones, and Chiral Thiourea Catalyst
α,α- and β,β-dialkoxyketones (Scheme 32).37 The Ru-
(phgly)2(binap)−lithium phenoxide system showed high
enantioselectivity for the reaction of acetophenone derivatives
and α-keto esters to afford the cyanated products in up to 99%
ee. The reaction features were similar to those of the aldehyde
cyanation as discussed in the previous section. For the
cyanosilylation of dialkoxy ketones and α-alkoxy ketones, the
Ru(t-leu)2(BINAP)−lithium phenoxide system exhibited the
best catalyst performance to produce the cyanohydrin
derivatives in up to 99% ee and 98% ee, respectively (t-Leu =
tert-leucinate). The excellent catalytic activity resulted in
complete conversion in the reaction with 0.01 mol % in the
best cases. A cyanosilylation of α,α-dialkoxy ketones catalyzed by an
A bifunctional thiourea−amine-derivatives-catalyzed enantio- organic chiral Lewis base, (DHQ)2AQN, was demonstrated by
selective cyanosilylation of ketones was developed by Jacobsen Deng and co-workers (Scheme 34).39 The catalyst was
and Fuerst (Scheme 33).38 High enantioselectivities were commercially available and recyclable. A series of α,α-dialkoxy
obtained in the reaction of aromatic and α,β-unsaturated ketones with substituents, such as aromatic, vinylic, acetylenic,
ketones. Some α-heterosubstituted ketones were cyanated with and aliphatic groups, was converted to the cyanated products in
usable enantioselectivities. HCN formed in situ from >90% ee. Some amino alcohols with quaternary stereocenters
(CH3)3SiCN, and CF3CH2OH was necessary for the reaction were synthesized by using this reaction.
to proceed. The mechanism of this cyanation was investigated Feng and co-workers reported that the bifunctional N,N′-
using a combination of experimental and theoretical methods. dioxide compounds formed in situ catalyzed enantioselective
The kinetic analysis was consistent with a cooperative cyanosilylation of α,α-dialkoxy ketones (Scheme 35).40 This
mechanism in which both the thiourea and the tertiary amine catalyst seemed to activate both (CH3)3SiCN with two N-
of the catalyst were involved in the rate-limiting cyanide oxides and the ketone by hydrogen bonding with the amide
addition step. Density functional theory calculations indicated proton.
the most favorable transition structure involving addition of the 2-2. Carbocyanation. 2-2-1. Carbonyl Compounds.
amine-bound HCN to the thiourea-bound ketone with two Shibasaki and co-workers developed an asymmetric reaction
hydrogen bonds. of aldehyde and ethyl cyanoformate with a catalyst system
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Scheme 34. Asymmetric Cyanosilylation of Ketones Scheme 36. Asymmetric Reaction of Aldehydes and Ethyl
Catalyzed by An Organic Chiral Lewis Base Cyanoformate with YLB-Based Catalyst

Chiral Diamine Catalyst
was rather slow. To accelerate the initiation step, the addition

of a catalytic amount of acetone cyanohydrin was effective and
completed the reaction within 9 min using 5 mol % of the
catalyst at −78 °C.
Feng and co-workers found that 10 mol % (S)-aluminum
lithium bis(binaphthoxide) (ALB) with 10 mol % cinchonine
catalyzed the asymmetric cyanoethoxycarbonylation of alde-
hydes to afford the cyanohydrin ethyl carbonates in high yields
(up to 99%) with moderate to high enantioselectivities (up to
95%) under mild conditions (at −20 °C) according to
Shibasaki’s heterobimetallic catalysis concept (Scheme 37).42
consisting of YLi3[tris(binaphthoxide)] (YLB), water, n-
butyllithium, and [2,6-(CH3O)2C6H3]3PO (Scheme 36).41 Scheme 37. Asymmetric Reaction of Aldehydes and Ethyl
Achiral additives had a key role in the construction of a proper Cyanoformate with ALB−Cinchonine Catalyst
chiral environment of this catalyst system. No reaction was
observed without water. A variety of aromatic, aliphatic, and
α,β-unsaturated aldehydes were converted to the adducts in
high enantioselectivity. The catalyst system was able to perform
an asymmetric tandem reaction of the cyanation and nitro aldol
reaction by tuning with the achiral additives in each step.
The optically active allylic cyanohydrin carbonates prepared
from the asymmetric cyanation of α,β-unsaturated aldehydes
were converted into the γ-oxy-α,β-unsaturated nitriles through
[3,3]-sigmatropic rearrangement without racemization but with
partial E/Z isomerization. This method was applied to an
enantioselective total synthesis of (+)-patulolide C.
Detailed mechanistic studies suggested that the active species
was a 1:1:1:1 mixture of YLB:H2O:LiCN:phosphine oxide
derivative, and the initiation step to generate nucleophilic LiCN
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The ALB prepared from LiAlH4 in THF poorly catalyzed the Scheme 39. Asymmetric Reaction of Aldehydes and Ethyl
reaction. The use of solid ALB free of THF obtained from (S)- Cyanoformate with Bimetallic Salen−Titanium Catalyst
bi(2-naphthol), aluminum 2-propoxide, and n-butyllithium in
dichloromethane, which was insensitive to air and moisture,
was important to perform this reaction efficiently. Aluminum of
ALB could activate aldehyde and cinchonine coordinated with
the lithium could activate ethyl cyanoformate.
Belokon and North and co-workers found that the bimetallic
titanium complex [(salen)Ti(μ-O)]2, in which salen derived
from (R,R)-1,2-cyclohexanediamine and 3,5-di-tert-butyl-salicy-
laldehyde was the ligand, catalyzed the asymmetric reaction of
aromatic and α,β-unsaturated aldehydes and ethyl cyanofor-
mate to give the cyanated products in high enantiomeric
excesses (up to 99%) (Scheme 38).43 Aliphatic aldehydes were
Scheme 38. Asymmetric Reaction of Aldehydes and Ethyl

Cyanoformate with Bimetallic Salen−Titanium Catalyst

Cyanoformate with Salen−Titanium Catalyst
reacted with moderate to good enantioselectivities. This

catalyst was also effective for the asymmetric cyanosilylation
as discussed in the former section.
Moberg and co-workers reported that the bimetallic Lewis
acid [(salen)Ti(μ-O)]2 combined with the amine Lewis base
behaved as an efficient catalyst system for the addition of acetyl
cyanide or ethyl cyanoformate to aldehydes, affording the
enantio-enriched O-acylated or O-ethoxycarbonylated cyanohy-
drins in high yields, although the titanium complex or amine
alone poorly catalyzed the cyanation with acetyl cyanide
(Scheme 39).44 The reaction of benzaldehyde, p-Me-, p-MeO-,
or p-Cl-substituted benzaldehyde, cinnamaldehyde, and hexanal
proceeded with >90% enantioselectivity, but sterically hindered
pivalaldehyde was cyanated with a moderate selectivity.
Experimental data supported a mechanism involving attack of
the Lewis base on the carbonyl carbon of acetyl cyanide
coordinating to titanium of the complex, thereby providing
cyanide and the acylated ammonium compound reacted with
the aldehyde activated by the Lewis acid.
Feng and co-workers studied several Ti catalyst systems for
the cyanoethoxycarbonylation of aldehydes. The (salen)- ees were obtained in the reaction of a series of aromatic,
titanium complex was already known to form the dimeric aliphatic, and α,β-unsaturated aldehydes with 5 mol % catalyst
structure based on the report of Belokon’ and North. The in a 1:4 mixture of 2-propanol and chloroform at −20 °C. A
dimerization was avoided by the addition of 2-propanol in the transition-state model was proposed in which the aldehyde
preparation of the titanium complex, and the obtained coordinates to the titanium complex to avoid steric repulsion
mononuclear complex catalyzed the asymmetric cyanation toward an imino moiety of the complex, and the cyanide
(Scheme 40).45 The cyanohydrin ethyl carbonates in 76−91% approaches from the less-shielded carbonyl re-face.
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The multicomponent catalyst system prepared from Ti(Oi- Scheme 43. Asymmetric Reaction of Aldehydes and Ethyl
Pr)4, (S)-6,6′-dibromo-1,1′-bi-2,2′-naphthol, cinchonine, and Cyanoformate with Ternary Titanium Catalyst
(1R,2S)-N-methyl-ephedrine promoted the asymmetric reac-
tion to afford the cyanated products with moderate to high
enantioselectivity (up to 94%) (Scheme 41).46 This system was
regarded as a Lewis acid−Lewis base bifunctional catalyst.

Cyanoformate with Multicomponent Titanium Catalyst
Two types of ternary titanium catalyst systems were also

reported. One was the tridentate Schiff base−cinchonine−Ti co-workers catalyzed the cyanoacetylation of aryl and α,β-
system affording the cyanated products in up to 94% ee unsaturated aldehydes using NaCN as a cyanide source and
(Scheme 42).47 The other was prepared from a nitrogen- acetic anhydride as an acetyl source (Scheme 44).10 The
Scheme 42. Asymmetric Reaction of Aldehydes and Ethyl Scheme 44. Asymmetric Cyanoacetylation of Aldehydes
Cyanoformate with Ternary Titanium Catalyst Catalyzed by Dimeric Titanium Complex
containing (R)-3,3′-bis((methyl((S)-1-phenylethyl)amino)-
methyl)-1,1′-binaphthyl-2,2′-diol (a BINOL derivative), N-
[(1S,2R)-2-hydroxy-1,2-diphenyl ethyl]acetamide (a β-amino-
alcohol derivatives), and Ti(Oi-Pr)4, and gave the adducts in up
to 92% ee (Scheme 43).48 The chiral titanium complex formed reactions were conducted with very low catalyst loading of
in situ might activate ethyl cyanoformate with the tertiary 0.05−0.005 mol % to afford the adducts in up to 96% ee. This
amine group as a Lewis base, and then the liberated cyanide catalyst was also efficient for asymmetric cyanosilylation of
anion might attack the aldehyde coordinated to the titanium aldehydes (see the former section).
atom. Khan and co-workers carried out cyanoethoxycarbonylation
The dimeric titanium complex [(salen)Ti(μ-O)]2 bridged by of aromatic, aliphatic, and α,β-unsaturated aldehydes catalyzed
cis-5-norbornene-endo-2,3-dicarboxylate devised by Ding and by the chiral (salen)vanadium(V) complex with imidazole as a
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cocatalyst (Scheme 45).49 Imidazole catalytically activated ethyl Deng and Tian developed enantioselective cyanoethoxycar-
cyanoformate to react with aldehyde, which in turn interacted bonylation of ketones catalyzed by dihydroquinidyl phenan-
threne (DHQD-PHN), a cinchona alkaloid derivative that was
Scheme 45. Asymmetric Reaction of Aldehydes and Ethyl a commercially available and recyclable catalyst (Scheme 47).51
Cyanoformate with Salen−Vanadium Catalyst Cyclic and sterically hindered dialkyl ketones as well as α,α-
dialkoxy ketones were converted to the tertiary cyanohydrin
derivatives in up to 97% ee.
Scheme 47. Asymmetric Reaction of Ketones and Ethyl

Cyanoformate Catalyzed by a Cinchona Alkaloid Derivative
The chiral acyl-ammonium cyanide derived from the Lewis

base catalyst and the acyl cyanide induced the cyanation of
ketones to give the enantio-enriched cyanohydrin alkoxides
reversibly. Besides, the dynamic kinetic resolution through
with vanadium complex. The cyanation seemed to occur on the enantioselective acylation of the alkoxides increased the
less-hindered side in order to avoid repulsion with an imino enantiomeric purity of the products.
moiety of the complex. The products were obtained with good Sakakura and Ishihara and co-workers demonstrated the
to high enantioselectivity. Hydrocinnamaldehyde was con- enantioselective cyanoethoxycarbonylation of isatins by using
verted to the adduct in a notably high ee of 97%. the Lewis base−Brønsted acid cooperative catalyst (Scheme
An organocatalyst with two cinchonidine ammonium salts 48).52 N-p-Nitrobenzyl protected isatins having various
linked with an anthracenyl-dimethyl group showed high substituents at the aromatic ring were converted into the
catalytic activity for the enantioselective cyanomethoxycarbo- cyanated products with up to 99% ee. The reaction proceeded
nylation of aromatic aldehydes (Scheme 46).50 Chinchilla and in two steps. The first step was enantioselective but reversible
Nájera and co-workers found that the reaction proceeded with cyanation at the carbonyl group, and the second one was a rate-
1 mol % of the cinchonidine derivative in the presence of 20 determining acylation with kinetic resolution, resulting in high
mol % of triethylamine to provide the cyanated products in up ee of the products. The structures of two intermediates at the
to 96% ee. The organocatalyst was almost quantitatively first step involving the R and S cyanohydrin alkoxides,
recovered by ether-promoted precipitation without any loss of respectively, based on theoretical calculation were proposed
activity. as shown in the scheme. The intermediate of the R alkoxide
interacting with three hydrogen-bonds is more stable than that
of the S alkoxide with two hydrogen-bonding, and the former is
preferentially converted to the product.
Cyanoformate Catalyzed by Cinchonidine Ammonium Salt
2-2-2. Imines. List and co-workers developed an efficient
Brønsted acid-catalyzed reaction of imines with acetyl cyanide
(Scheme 49).53 The desired N-acetyl α-aminonitriles were
formed from a wide range of aromatic, aliphatic, and
unsaturated imines with 1−5 mol % of the Jacobsen-type
thiourea catalyst in high yields and enantioselectivities of >98%
in the best case. The reaction was proposed to proceed through
the N-acetyl iminium intermediate shown in the scheme. The
thiourea catalyst interacts with the cyanide to react in the
catalyst’s chiral environment. This acetylcyanation was applied
to a three-component Strecker-type reaction of in situ-
generated imines from the aldehydes and benzylamine in the
presence of MS 5 Å to give the cyanated products in up to 94%
ee.
2-2-3. N-Containing Hetroaromatics. The enantioselective
addition of cyanide to quinolines and isoquinolines (Reissert-
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Scheme 48. Asymmetric Reaction of Isatins and Ethyl Cyanoformate with Chiral Thiourea Catalyst
Scheme 49. Asymmetric Reaction of Imines and Acetyl Scheme 50. Asymmetric Reissert-Type Reaction with Chiral
Cyanide with Chiral Thiourea Catalyst Bifunctional Aluminum Catalyst
type reaction) using the BINOL-derived bifunctional catalysts

was developed by Shibasaki and co-workers (Scheme 50).54 tolyl-substituted phosphine oxide group in the catalyst was
The use of (CH3)3SiCN and 2-froyl chloride gave successful important in terms of reactivity and enantioselectivity. The
results. The reaction of (CH3)3SiCN with the acyl quinolinium bulkiness of the o-tolyl moiety prevented formation of the
intermediate was promoted by the bifunctional chiral aluminum intramolecular coordination of the phosphine oxide onto the
catalystthat is, the phosphine oxide moiety activated aluminum, resulting in low catalytic activity. The reaction of 4-
(CH3)3SiCN and the aluminum center interacted with the diallylamino-5,7-dichloroquinoline gave the corresponding N-
acyl quinolinium intermediate. The high Lewis basicity of the o- furoyl 2-cyanoquinoline, which was a synthetic intermediate of
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bioactive compound, in 96% ee. Less reactive substrates (e.g., 6- group as described above. The reaction of N,N-diisopropyl
dichloroquinoline) resulted in medium enantioselectivity. nicotinamide using (CH3)3SiCN and fluorenylmethoxycarbonyl
Shibasaki’s group expanded the applicability of the catalytic chloride proceeded with high 1,6-regioselectivity to afford the
Reissert-type reaction into the 1-substituted isoquinolines to corresponding product in 98% yield and in 96% ee.
provide the N-acyl 1-cyanodihydroisoquinolines with a 2-3. Hydrocyanation. 2-3-1. Aldehydes. Inoue and co-
quaternary stereocenter (Scheme 51).55 The catalyst was workers found that a chiral cyclic dipeptide, cyclo[(S)-
phenylalanyl-(S)-histidyl] (cyclo[(S)-Phe-(S)-His]), efficiently
Scheme 51. Asymmetric Cyanation Reaction of Isoquinoline catalyzed the transformation (Scheme 53).57 (R)-Mandeloni-
Derivatives with Chiral Bifunctional Aluminum Catalyst
Scheme 53. Asymmetric Hydrocyanation of Aldehydes
Catalyzed by a Chiral Cyclic Dipeptide
trile was obtained with enantiomeric excess of 97% in high yield

tuned to have two electron-withdrawing bromo groups at the in the reaction of benzaldehyde with 2 mol % of cyclo[(S)-Phe-
6- and 6′-position of the BINOL skeleton as well as a triflate (S)-His] in toluene at −20 °C. Some benzaldehydes with an
group on the aluminum, and thereby exhibited high Lewis acid electron-rich substituent and 2-naphthaldehyde were cyanated
behavior. Use of vinyl chloroformate gave the highest with high enantioselectivity. The reaction of heteroaromatic
enantioselectivity. The 1-alkyl, -alkenyl, and -aryl isoquinolines and aliphatic aldehydes proceeded with medium selectivity.
were cyanated with enantioselectivity as high as 98%. A dual- The origin of enantioselectivity was ascribed to bifunction-
activation transition state, in which (CH3)3SiCN and acyl ality of the dipeptide catalyst: The peptide hydrogen of the
isoquinolinium are activated by the Lewis base (phosphine histidine residue activated benzaldehyde with a hydrogen bond,
oxide) and the Lewis acid (aluminum), respectively, was and the imidazolyl moiety of the histidine residue interacted
proposed. with HCN to form cyanide ion, promoting the intramolecular
Shibasaki’s group also developed the enantioselective si-face-selecting nucleophilic addition. The re-face attack was
cyanation of nicotinic amides using the dual-activation protocol prevented by the aromatic ring of the phenylalanine residue.
(Scheme 52).56 In this case, a sulfoxide group was utilized as a Ohkuma and co-workers revealed that bimetallic complexes
Lewis base part of the catalyst instead of a phosphine oxide [Li{Ru[(S)-phgly]2[(S)-binap]}]X (X = Cl, Br) acted as
excellent catalysts for asymmetric hydrocyanation of aldehydes
Scheme 52. Asymmetric Cyanation Reaction of Nicotinic (Scheme 54).58 The reaction was successfully conducted with
Amides with Chiral Bifunctional Aluminum Catalyst 0.2 mol % of the Ru·Li catalyst. A series of aromatic,
heteroaromatic, and α,β-unsaturated aldehydes as well as
pivalaldehyde were converted to the corresponding cyanohy-
drins in up to 99% ee. The structure of [Li{Ru[(S)-phgly]2[(S)-
binap]}]Br was determined by an X-ray crystallographic
analysis: A lithium cation coordinated with the carbonyl
oxygen of PhGly and the bromide ion was located between
two amino protons interacting with the hydrogen bonds.
2-3-2. Imines. Snapper and Hoveyda and co-workers
reported that tripeptide Schiff base−titanium complexes
catalyzed the addition of cyanide to a series of aldimines with
high enantioselectivity (Scheme 55).59 The ligand structure was
systematically optimized to proceed in the order of Schiff base−
(S)-tert-leucine−(S)-O-tert-butyl threonine−glycine terminated
with methyl ester. The Schiff base structure was also tuned to
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Scheme 54. Asymmetric Hydrocyanation of Aldehydes with Scheme 56. Asymmetric Cyanation of Imines Catalyzed by
Chiral Ruthenium−Lithium Combined Catalyst Chiral Titanium Complex with Two Different Ligands
Scheme 55. Asymmetric Cyanation of Aldimines with Chiral

Tripeptide Schiff Base−Titanium Catalyst
have 5-methoxy, 3,5-dichloro, or 3,5-dibromophenyl groups. N- Vilaivan and co-workers demonstrated that titanium
Benzhydryl (diphenylmethyl)-protected aldimines derived from complexes with tridentate N-salicyl-β-aminoalcohols acted as
aromatic aldehydes and pivalaldehyde were cyanated with up to effective catalysts for enantioselective Strecker reaction of
97% enantioselectivity. The titanium complex with the aromatic aldimines (Scheme 57).61 The configuration as well as
tridentate peptide ligand was proposed as a chiral Lewis acid the bulkiness of the β-substituent significantly influenced the
catalyst. enantioselectivity. Use of the most efficient ligand, (S)-N-(2-
The regio- (1,2- over 1,4-) and enantioselective cyanation of hydroxybenzyl)alaninol, allowed the reaction to proceed,
α,β-unsaturated imines was also achieved by using the affording the α-arylaminonitriles in >98% ee in the best cases.
titanium−tripeptide Schiff base catalyst.
Feng and co-workers found that a titanium complex with two Scheme 57. Asymmetric Cyanation of Aldimines with Chiral
different ligands, one of cinchonine and one of achiral 3,3′- Aminoalcohol−Titanium Catalyst
bis(naphth-2-yl)-2,2′-biphenol, catalyzed cyanation of N−Ts
protected aldimines and ketimines enantioselectively (Scheme
56).60 A range of aromatic aldimines and cyclohexyl aldimine
were cyanated with 5 mol % of catalyst with up to 97%
selectivity. A titanium complex with two chiral ligands was
proposed to be the catalytic species. The imine substrate
coordinates to this complex to avoid the large RL−2-naphthyl
(complex) repulsion, and HCN activated by the tertiary amine
of cinchonine reacts with the imine on the re-face.
The catalyst system was applied to the reaction of various
aromatic ketimines as well as cyclohexyl and α,β-unsaturated
imines to afford the α-aminonitriles with quaternary stereo-
centers in up to 99% ee.
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Seayed and Chai and co-workers reported that the partially Scheme 60. Asymmetric Cyanation of Aldimines with Chiral
hydrolyzed titanium alkoxide (PHTA) coordinated with N- Bifunctional Aluminum Catalyst
salicyl-tert-leucinol catalyzed the cyanation of N-benzyl, N-
benzhydryl, or N-Boc aldimines (Scheme 58).62 Aromatic and

Aminoalcohol−Titanium Catalyst
heteroaromatic N-benzhydryl aldimines were converted to the

α-aminonitriles in up to 98% ee at room temperature. The
homogeneous titanium complex was converted to the
heterogeneous cluster, which acted as a recyclable catalyst 10
times. The catalyst cluster was utilized in the flow reactor
system for the three-component Strecker reaction.
A chiral (salen)aluminum-complex-catalyzed enantioselective phosphine oxide activates (CH3)3SiCN and the Lewis acidic
hydrocyanation of N-allyl aldimines was reported by Jacobsen aluminum interacts with the imine.
and Sigman (Scheme 59).63 They were able to suppress the Yamamoto and Abell achieved the asymmetric Strecker
reaction of aldimines and ketimines based on a dual-activation
Scheme 59. Asymmetric Cyanation of Aldimines with Chiral protocol in which the tethered bis(8-quinolinolato) aluminum
Salen−Aluminum Catalyst complex described in Scheme 61 and Et3N were employed as a
chiral Lewis acid and achiral Lewis base, respectively.65 Ethyl
Scheme 61. Asymmetric Cyanation of Imines with Chiral

Bifunctional Aluminum Catalyst
uncatalyzed cyanation that gave racemic products by the

reaction at −70 °C, which occurred rapidly at room
temperature. Under the optimized conditions, the hydro-
cyanation of an aldimine prepared from benzaldehyde and allyl
amine followed by the amidation with trifluoroacetic anhydride
(TFAA) gave the corresponding product in 91% yield and 95%
ee. The reaction of aromatic aldimines resulted in high
enantioselectivity, but medium selectivity was observed by
using aliphatic substrates.
Shibasaki and co-workers developed an asymmetric Strecker
reaction catalyzed by the bifunctional Lewis acid−Lewis base
catalyst (Scheme 60).64 The reaction of N-fluorenyl aromatic
and α,β-unsaturated aldimines was catalyzed by the chiral
aluminum complex with high enantioselectivity, although the
aliphatic aldimines reacted with medium selectivity. The
cyanation occurred with (CH3)3SiCN followed by slow
addition of phenol or HCN to afford the protonated products.
A bifunctional catalysis was proposed in which the Lewis base
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cyanoformate was the cyanide source of choice in terms of Scheme 63. Asymmetric Cyanation of Aldimines with Chiral
yield, enantioselectivity, toxicity and availability. Under the Macrocyclic Dinuclear Manganese Catalyst
optimized conditions, this catalyst system exhibited high
enantioselectivity in the reaction of aromatic, heteroaromatic,
and tert-butyl N-diarylphosphinoyl aldimines. In addition,
various ketimines, such as acetophenone-, propiophenone-,
butyrophenone-, and α-tetralone-derived ketimines, were
converted to the quarternary α-aminonitriles in up to 96% ee
with the same catalytic system.
Li and co-workers established an enantioselective Strecker
reaction of N-phosphonyl aldimines with nonvolatile
(C2H5)2AlCN and a catalytic amount of primary amino acid
(Scheme 62).66 Phenylglycine, which was the optimized amino
Scheme 62. Asymmetric Cyanation of Aldimines Using

(C2H5)2AlCN and an Amino Acid Catalyst
Scheme 64. Asymmetric Three-Component Strecker

Reaction with Chiral Zirconium Catalyst
acid, connected in a bidentate manner to the Al−CN moiety,
forming the catalytically active species (phgly)AlCN. (C2H5)(i-
C3H7O)AlCN formed from (C2H5)2AlCN and 2-propanol
acted as the cyanide source. The reaction of N-phosphonyl
imines derived from benzaldehydes gave the corresponding
products in excellent ee of 99.7% in the best case. The N-
phosphonyl group was readily removed from the products by
treatment with aqueous HCl, and N,N′-bis(naphthalen-1-
ylmethyl)ethane-1,2-diamine could be quantitatively recovered.
Khan’s group synthesized macrocyclic dinuclear (salen)-
manganese linked with two triethylene glycol tethers and
utilized it as a catalyst of enantioselective Strecker reaction with
4-phenylpyridine N-oxide (4PPyNO) as a cocatalyst (Scheme
63).67 4PPyNO was considered to be an axial ligand on the
(salen)manganese complex. The macrocyclic manganese
catalyst system worked with a catalyst loading of 5 mol % on
the cyanation of N-benzhydryl aryl and tert-butyl aldimines.
The substituent on the aromatic ring of the substrate affected
the enantioselectivity (p-H, 94%; p-CH3O, >99%; p-Br, 91%).
The reaction using ethyl cyanoformate as a cyanide source
catalyzed by the diethyl tartrate linked macrocyclic (salen)-
manganese was also reported.
Kobayashi and co-workers developed a zirconium-catalyzed
asymmetric reaction of aldimines and tributyltin cyanide
(Scheme 64).68 The unique Zr complex shown in the scheme
was formed from Zr(Ot-Bu)4, (R)-6,6′-dibromo-BINOL, (R)-
3,3′-dibromo-BINOL, and N-methyl imidazole in a 2:2:1:2
ratio. N-(2-Hydroxy)phenyl aromatic and heteroaromatic The zirconium catalyst was also effective for the asymmetric
aldimines were cyanated in up to 92% enantioselectivity. The three-component reaction of aldehyde, 2-amino-3-methylphe-
hydroxyl group on the protective group was important to nol, and HCN. A range of aromatic and aliphatic aldehydes was
achieve high reactivity and enantioselectivity. converted to the α-aminonitriles in up to 94% ee. This is the
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pioneering study showing the one-pot three-component Scheme 66. Asymmetric Cyanation of Hydrazones with Ph-
protocol. pybox−Europium Catalyst
A chiral lanthanum-binaphthyldisulfonate-complex-catalyzed
Strecker reaction of aldimines was reported by Ishihara’s group
(Scheme 65).69 The catalyst prepared in situ from La(OPh)3
Scheme 65. Asymmetric Cyanation of Aldimines Catalyzed

by Chiral Lanthanum Binaphthyldisulfonate Complex

Ruthenium−Lithium Combined Catalyst
and the chiral disulfonate promoted the reaction of N-

benzhydryl aryl and heteroaryl aldimines in up to 92%
enantioselectivity. Addition of 3-methylbutanoic acid was
important in terms of catalytic activity. A transition-state
model was proposed as shown in the scheme. The lanthanum
complex with a chiral binaphthyldisulfonate and a carboxylate
interacts with the imine substrate avoiding remarkable repulsive
interactions, and a sulfonate moiety activates HCN, resulting in
the internal re-face attack of the cyanide.
Jacobsen’s group reported that the asymmetric hydro-
cyanation of hydrazones derived from aromatic aldehydes was
catalyzed by Er(Ph-pybox) to furnish the corresponding
hydrazino nitrile in up to 97% ee (Scheme 66).70 Europium Scheme 68. Asymmetric Cyanation of Aldimines with Chiral
was selected as the metal center in terms of yield and Dipeptide Catalyst
enantioselectivity according to the lanthanide source screening.
The substrates with electron-rich phenyl rings were cyanated
with high reactivity and selectivity, although the electron-
deficient ones reacted slowly.
Ohkuma and co-workers found that the Ru(phgly)2(binap)−
PhOLi system or the bimetallic complex [Li{Ru-
(phgly) 2 (binap)}]Cl acted as an efficient catalyst for
enantioselective hydrocyanation of N-carbamoyl-protected
aldimines (Scheme 67).71 A variety of N-Cbz aryl and
heteroaryl aldimines as well as primary-, secondary-, and
tertiary-alkyl substrates were quantitatively converted to the α-
amino nitriles in up to 98% ee with 0.2 mol % of the catalyst
under 0 °C in 30 min. In some cases, the reaction was carried
out with catalyst loading of 0.02 mol % with maintenance of the
enantioselectivity.
Lipton and co-workers devised a chiral dipeptide catalyst
prepared from (S)-phenylalanine and (S)-α-amino-γ-guanidi- substituents were reacted with excellent enantioselectivity.
nobutyric acid for asymmetric Strecker reaction (Scheme 68).72 The enantioface selection did not work well for the electron-
The N-benzhydryl aryl aldimines with electron-donating deficient aryl imines and the aliphatic substrates.
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Scheme 69. Asymmetric Cyanation of Imines with Chiral Urea and Thiourea Catalyst
Jacobsen’s group developed urea or thiourea derivatives The simpler amido−thiourea catalyst C promoted the
containing a substituted salicylimine group linked by a chiral Strecker reaction of N-benzhydryl aldimines at −30 to 0 °C.
1,2-cyclohexyldiamine and a chiral N-substituted tert-leucine The catalyst was applicable to the gram-scale reactions using
terminal for the Strecker reaction of aldimines and ketimines HCN formed in situ from KCN and acetic acid.76
(Scheme 69).73 The catalyst structure was optimized by using a On the basis of Jacobsen’s report,73−75 Kunz and co-workers
combinatorial method. Presence of two tert-butyl groups, one synthesized the chiral urea catalysts using glucosamine
each at the amino acid position and the C3-position of the derivatives instead of chiral 1,2-cyclohexyldiamine for enantio-
salicylimine group of catalyst A and B was required for the high selective hydrocyanation of aldimines (Scheme 70).77 The
enantioselectivity. After the elaboration, a pivaloyl group was
introduced into the C5-position of the salicylimine moiety. A Scheme 70. Asymmetric Cyanation of Aldimines with Chiral
proposed transition state using catalyst C was shown in the Urea Catalyst
scheme. The amido−thiourea-induced imine protonation by
HCN generates the catalyst interacting with the iminium−
cyanide ion pair, and this interaction promotes the smooth
carbon−carbon bond formation.
The urea catalyst A was suggested to have a wide substrate
scope.74 A variety of N-allyl or N-benzyl aldimines with
aromatic, aliphatic, and 1-cyclohexenyl substituents was
cyanated with high enantioselectivity at −70 °C. The reaction
of imines with less bulky alkyl groups afforded the products in
somewhat lower ee. This problem was solved by using the
thiourea catalyst B. The catalyst B also effectively catalyzed the
cyanation of ketimines derived from acetophenone and
pinacolone, yielding the products in 96% ee and 86% ee,
respectively.75
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optimized catalyst showed high enantioselectivity of 95% in the Scheme 73. Asymmetric Cyanation of N-Aryl α-CF3- and α-
reaction of the imine derived from benzaldehyde. Other aryl CF2H-Substituted Ketimines with Chiral Dihydroqunine/
imines were reacted with moderate to good stereoselectivity. Urea Catalyst
Palacios and co-workers found that cinchonidine catalyzed
the enantioselective reaction of α-ketiminophosphonates and
acetyl cyanide to give the α-phosphono-α-amino nitriles in up
to 92% ee (Scheme 71).78 Substitution on the phenyl ring of
Scheme 71. Asymmetric Cyanation of α-

Ketiminophosphonates Catalyzed by Cinchonidine
Lewis base (quinidine part) in the catalyst remarkably increased

the enantioselectivity. Addition of a stoichiometric amount of
(CF3)2CHOH (HFIP) sped up the reaction rate. Under the
optimized conditions the α-CF3- and α-CF2H-substituted
amino nitriles were obtained in up to 96% ee and 92% ee,
respectively.
Ma’s group and Wang’s group independently reported an
asymmetric Strecker reaction of cyclic N-acyl trifluoromethyl
ketimines with the cinchona alkaloid-based thiourea catalysts
(Scheme 74).81 Although their experiments were carried out
under different conditions, the stereoselective outcomes were
similar, achieving enantioselectivity as high as 97%. It was
proposed that the thiourea moiety interacted with the N-acyl
ketimine through two hydrogen bonds, and the acid−base
interaction between the tert-amine moiety of the catalyst and
substrates somewhat decreased the enantioselectivity. Cincho- HCN increased the nucleophilicity.
nidine was considered to activate the imine with a hydrogen Cinchona alkaloid-based thioureas also catalyzed the reaction
bond of the hydroxyl group, and also to activate acetyl cyanide of N-Boc isatin-derived ketimines, which were independently
with the Lewis basic tert-amine moiety. reported by Zhou’s group and Yan and Wang’s group (Scheme
Chiral-thiourea-catalyzed asymmetric Strecker reaction of N- 75).82 The quinine-derived thiourea (10 mol %) catalyzed the
aryl α-trifluoromethylated ketimines was developed by Enders cyanation at −25 °C with medium to high enantioselectivity.
and co-workers (Scheme 72).79 The reaction rate was relatively The reaction with the cinchonidine-derived catalyst (5 mol %)
at −70 °C gave the products in >99% ee in the best case,
Scheme 72. Asymmetric Cyanation of N-Aryl α- although a long reaction time (2−4 days) was required.
Trifluoromethylated Ketimines Catalyzed by Chiral Addition of (CF3)2CHOH (HFIP) increased the reactivity. The
Thiourea one-pot aza-Wittig−Strecker reaction sequence from the
corresponding keto-amide substrate was also examined.
Tian and Shao reported that the quinine-based thiourea also
catalyzed the hydrocyanation of cyclic (Z)-aldimines such as
3H-indoles and 2H-benzo[b][1,4]thiazines (Scheme 76).83 The
cyclic aminonitriles in up to 98% ee were obtained in the
reaction using HCN generated from ethyl cyanoformate with
10 mol % of the catalyst at 10 °C. The catalyst and HCN
seemed to form the ammonium salt shown in the scheme. The
cyclic imine was activated by the ammonium with hydrogen
bonding, and the cyanide interacted with the thiourea group,
which in turn reacted with imine in an intramolecular manner.
slow, but several aryl, alkenyl, and alkyl ketimines were Du’s group devised the quinine-squaramides to catalyze the
converted to the α-quaternary α-trifluoromethylated amino enantioselective cyanation of N-(benzothiazol-2-yl)aldimines
nitriles in 83−95% ee. Selection of the thiourea-catalyst (Scheme 77).84 The N-protected benzaldimines were converted
structure was crucially important for achieving high chemical to the α-aminonitriles in up to 98% ee. The catalyst was
yield and enantioselectivity. considered to activate the substrate with the two NH groups
Zhou and co-workers reported that dihydroqunine-derived through hydrogen bonding, and HCN formed in situ from
urea catalyzed the asymmetric Strecker reaction of N-aryl α- (CH3)3SiCN and ethanol interacted with the quinuclidine
CF3- and α-CF2H-substituted ketimines (Scheme 73).80 The moiety as shown in the scheme. Then the reaction occurred
bifunctional character of Brønsted acid (urea moiety) and under the catalyst’s chiral environment.
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Scheme 74. Asymmetric Cyanation of Cyclic N-Acyl Scheme 75. Asymmetric Cyanation of N-Boc Isatin-Derived
Trifluoromethyl Ketimines with Cinchona Alkaloid-Based Ketimines with Cinchona Alkaloid-Based Thiourea Catalysts
Thiourea Catalysts
Scheme 76. Asymmetric Cyanation of Cyclic Aldimines with

Quinine-Based Thiourea Catalyst
Feng and co-workers synthesized several chiral N,N′-dioxides

derived from proline derivatives and found that the N,N′-
dioxide of trans-4-hydroxy-L-proline linked with 1,2-diphenyle-
thylenediamine showed catalytic activity for the one-pot three-
component Strecker reaction of an aldehyde, benzhydrylamine,
and (CH3)3SiCN (Scheme 78).85 A series of aromatic and
aliphatic aldehydes were converted to the α-aminonitriles in
around 90% ee. High enantioselectivity of 95% was obtained in
the reaction of 2-ethylbutanal. The catalysis was shown to
proceed in a bifunctional manner. The imine generated in situ
was activated through the hydrogen bond with amide N−H,
and (CH3)3SiCN was simultaneously activated with two N-
oxides with fixing of the chiral structure.
Khan’s group developed chiral amide-based or chiral Dughera and co-workers synthesized a sulfonimide derivative
oxazoline-based sulfonamide catalysts for the Strecker reaction with an atropisomeric p-terphenyl structure (Scheme 80).87
of aldimines (Scheme 79).86 Catalyst A and B showed good to The C2 chiral compound catalyzed the three-component
high enantioselectivity in the reaction of a series of N- Strecker reaction of aromatic aldehydes or methylketones,
benzhydryl aryl, alkenyl, and alkyl aldimines. The electronic aniline derivatives, and (CH3)3SiCN to give the aminonitrile
properties of substituents and their positions on the phenyl ring products in moderate yield and in up to 97% ee.
of aryl substrates affected the enantioselectivity. Catalyst C Rueping and co-workers reported the chiral BINOL
showed a broader substrate scope than the other two catalysts. phosphate-catalyzed enantioselective Strecker reaction of N-
Every sulfonamide catalyst was considered to activate imine benzyl aromatic aldimines (Scheme 81).88 The phosphate with
substrates strongly through the hydrogen bond of the 9-phenanthryl groups at the 3,3′-positions showed high
sulfonamide moiety. enantioselectivity with medium to high chemical yield. The
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Scheme 77. Asymmetric Cyanation of Aldimines with Scheme 79. Asymmetric Cyanation of Aldimines with Chiral
Quinine-Squaramide Catalyst Sulfonamide Catalysts
Scheme 78. Asymmetric Three-Component Strecker

Reaction with Chiral N,N′-Dioxide Catalyst
phosphate derivative was considered to be a Brønsted acid

catalyst.
Tsogoeva’s group used 3,3′-bis(p-nitrophenyl)-substituted
BINOL-phosphate as a catalyst for the asymmetric hydro-
cyanation of aliphatic hydrazones (Scheme 82).89 The α-
hydrazinonitriles were obtained in up to 93% ee. The 4-nitro
substituent on the benzoyl protective group was important in
terms of both reactivity and enantioselectivity. The active
catalyst was proposed to be the O-TMS BINOL-phosphate
generated in situ, in which the silicon atom interacted with the
nitrogen or oxygen atom of hydrazone to activate it.
A chiral ammonium salt-catalyzed enantioselective Strecker
reaction was reported by Corey’s group (Scheme 83).90 The
cinchona alkaloid-derived ammonium salt may have activated
the imine substrate with the ammonium proton in the U-
shaped chiral environment of the catalyst, and the cyanide
attacked on the less-shielded re-face. A series of N-
allylbenzaldimines was cyanated with 10 mol % of catalyst
loading to give the aminonitriles in >99% ee in the best cases.
Maruoka and Ooi’s group developed the asymmetric Strecker
reaction of aldimines in a toluene−water two-phase system
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Scheme 80. Asymmetric Three-Component Strecker Scheme 83. Asymmetric Cyanation of Aldimines Catalyzed
Reaction with Chiral Sulfonimide Catalyst by a Chiral Ammonium Salt

BINOL Phosphate Catalyst
using aqueous KCN with chiral phase transfer catalysts

(Scheme 84).91,92 The quaternary ammonium salt with a
tetranaphthyl backbone possessing an axial chirality catalyzed
the reaction of N-mesitylenesulfonyl aliphatic aldimines with 1
mol % catalyst loading to give the cyanated products in high ee.
Among them, the tert-alkyl aldimines were reacted with up to
98% enantioselectivity.91
This catalysis protocol was expanded into the cyanation of in
situ-generated aldimines from the N-mesitylenesulfonyl α-
amido sulfones. This method improved the yield and
enantioselectivity (up to 99% enantioselectivity) by diminution
Scheme 82. Asymmetric Cyanation of Hydrazones with
of the imine hydrolysis and background cyanation under the
Chiral BINOL Phosphate Catalyst
biphasic conditions. Reducing the amount of KCN to 1.05
equiv was appropriate for the practical usage.92
Lee and co-workers devised chiral BINOL-based bishydroxy
polyethers for the asymmetric Strecker reaction by using KCN
as a reagent (Scheme 85).93 The 3,3′-diiodo-substitution, three-
ether tether unit, and phenolic hydroxy groups of the catalyst
were all important in terms of reactivity and enantioselectivity.
The reaction of in situ-generated benzaldimines from the
corresponding N-tert-butoxycarbonyl α-amido sulfones afforded
the α-amino nitriles in up to 99% ee. The reaction of primary
alkyl imines was less enantioselective. KCN coordinated by the
polyether may have reacted with the α-amido sulfone to
generate the aldimine, HCN, and potassium benzenesulphinate.
Then activated imine and HCN reacted via the polyether
catalyst through hydrogen bonding under the chiral circum-
stance as shown in the scheme.
Kunz and co-workers synthesized a chiral N-galactosyl[2,2]-
paracyclophane aldimine bearing a methoxycarbonyl group and
applied the aldimine as a catalyst for the enantioselective
Strecker reaction (Scheme 86).94 The aldimine moiety of this
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Scheme 84. Asymmetric Cyanation of Aldimines with Chiral Scheme 86. Asymmetric Cyanation of Aldimines with
Phase Transfer Catalyst Galactopyranose-Cyclophane Catalyst
nitrogen and the pivaloyl oxygen at the C2 position of the

galactose moiety, providing the Brønsted acidic site. Then the
substrate imine was dragged electrophilically into the chiral
pocket of the catalyst.
Scheme 85. Asymmetric Cyanation of In Situ-Generated
Benzaldimine with Chiral Bishydroxy Polyether Catalyst 3. CONJUGATE CYANATION OF α,β-UNSATURATED
CARBONYL COMPOUNDS
Jacobsen and Sammis developed the (salen)aluminum-
catalyzed conjugate addition of HCN to α,β-unsaturated imides
(Scheme 87).95 The use of HCN generated in situ from
Scheme 87. Asymmetric Conjugate Cyanation of α,β-

Unsaturated Imides with Salen−Aluminum Catalyst
(CH3)3SiCN and 2-propanol was important for the reaction to

catalyst was sterically shielded from nucleophilic reactions. N- proceed. No reaction was observed with the use of HCN alone
benzyl or ally aldimines with isopropy, cyclohexyl, or isoamyl as a cyanide source. The reaction of the imide substrates
groups were cyanated with high enantioselectivity (up to 99%). bearing aliphatic β-substituents achieved a good result, but the
The reaction of aromatic aldimines was somewhat less substrates with unsaturated substituents such as aryl, vinyl, and
stereoselective. Although the aldimine catalyst contained alkynyl groups were unreactive. The enantioselectivity was far
neither a hydrogen-bond donor nor a Brønsted acidic site, less sensitive to the steric properties of the substituent,
the proton of HCN was trapped with the Lewis base imine affording the cyanide adducts in up to 98% ee.
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Weck and Madhavan synthesized a polymer-supported Scheme 90. Asymmetric Conjugate Cyanation of α,β-
(salen)aluminum catalyst showing comparable enantioselectiv- Unsaturated N-Acylpyrroles Catalyzed by Gadolinium
ity with the original one and demonstrated that the catalyst Complex with D-Glucose-Derived Ligand
could be recycled five times.96
Jacobsen’s group also devised a cooperative heterobimetallic
catalyst system for the same reaction (Scheme 88).97 The two

Unsaturated Imides with Heterobimetallic Catalyst System
of (CH3)3SiCN (0.5−1 equiv) and HCN (2 equiv) gave the

best result. Various α,β-unsaturated N-acylpyrroles with β-alkyl,
aryl, and vinyl substituents were converted to the 1,4-adducts in
up to 98% ee.
Mechanistic studies suggested that the active species had
polymetallic structures of gadolinium and the chiral ligand with
hydroxide moieties as proton donors. The reaction proceeded
through an intramolecular cyanide transfer from the gadolinium
cyanide to the activated N-acylpyrrole substrate by the Lewis
chiral metal complexes, (salen)aluminum and (pybox)- acidic gadolinium. (CH3)3SiCN participated in the regeneration
europium, were considered to activate imides and HCN, of the active species.
respectively, and promoted the conjugate addition in a highly The modified gadolinium complex successfully catalyzed the
enantioselective manner. The dual catalyst system improved the conjugate cyanation of α,β-unsaturated ketones (Scheme
reactivity over the (salen)aluminum catalyst described above 91).100 The combination of (t-C4H9)(CH3)2SiCN (TBSCN,
with similar or better enantioselectivity.
The chiral (salen)aluminum catalyst was applied to Scheme 91. Asymmetric Conjugate Cyanation of α,β-
asymmetric conjugate cyanation of nitroalkenes by Khan and Unsaturated Ketones Catalyzed by Gadolinium Complex
co-workers (Scheme 89).98 The β-nitronitriles in up to 91% ee with D-Glucose-Derived Ligand
Scheme 89. Asymmetric Conjugate Cyanation of

Nitroalkenes with a Salen−Aluminum Catalyst System
2 equiv) and 2,6-dimethylphenol (2 equiv) was effective in this

reaction. A range of linear and branched alkyl ketones as well as
were obtained at −25 °C in the presence of 4-phenylpyridine cyclic ketones was quantitatively converted to the 1,4-adducts
N-oxide (4-PPNO) as a cocatalyst. A series of nitroalkenes with in high ee (up to 98% ee). The gadolinium complex also
β-alkyl substituents was cyanated with good to high catalyzed transformation of the allylic cyanohydrin (1,2-adduct)
enantioselectivity. Based on the spectroscopic studies, the N- into the 1,4-adduct, which could assist the excellent 1,4-
oxide seemed to act as an axial ligand to the (salen)aluminum addition over 1,2-addition selectivity.
complex as well as a Lewis base activator of (CH3)3SiCN. The proposed mechanism was somewhat different from the
Shibasaki and Kanai and co-workers developed enantiose- previous reaction of α,β-unsaturated N-acylpyrroles. The
lective conjugate addition of cyanide to various β-substituted polymetallic gadolinium complex with the (t-C4H9)(CH3)2SiO
α,β-unsaturated N-acylpyrroles catalyzed by a chiral complex moiety (not with hydroxide) was the active species. HCN (not
prepared in situ from Gd(Oi-Pr)3 and an electronically tuned D- silyl cyanide) was used for regeneration of the active species
glucose-derived ligand (Scheme 90).99 Use of the combination with release of the product.
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Shibasaki’s group extended the conjugate cyanation to β,β- Scheme 93. Asymmetric Conjugate Cyanation of Alkylidene
disubstituted α,β-unsaturated carbonyl compounds using a Malonates Catalyzed by Chiral Titanium Complex with Two
strontium catalyst (Scheme 92).101 A variety of β,β- Ligands
Scheme 92. Asymmetric Conjugate Cyanation of β,β-

Disubstituted α,β-Unsaturated Carbonyl Compounds with
Chiral Strontium Catalyst

Unsaturated Ketones with Dinuclear Bis(prophenol)−
Magnesium Catalyst
disubstituted α,β-unsaturated ketones and N-acylpyrroles

bearing alkyl and aryl groups reacted with the combination of
(t-C4H9)(CH3)2SiCN (2 equiv) and 2,6-dimethylphenol (2
equiv) using 0.5 mol % of the catalyst to afford the β-cyano
carbonyl compounds with quaternary carbon centers in up to
99% ee. The E/Z stereoisomers of the substrate were converted
to the opposite enantiomers of one another’s products. The
strontium complex also catalyzed asymmetric rearrangement of
the cyanohydrin (1,2-adduct) to the 1,4-cyanation product.
The catalytic species was the Sr/ligand = 3:5 complex, which
was observed as a single species in the ESI-MS analysis. It
activated both enone and HCN formed in situ, and
intramolecular conjugate cyanation occurred irreversibly. This
catalyst may also promote the 1,2-cyanation, but the 1,2-adduct
readily returned to the enone, and then was converted to the 2,6-di-tert-butylphenol (1.5 equiv) at 30 °C with 20 mol % of
1,4-adduct. catalyst to afford the 1,4-adducts in up to 97% ee.
Feng and co-workers devised enantioselective conjugate A ruthenium−lithium combined system devised by Ohkuma
cyanation of alkylidene malonates catalyzed by an in situ- and co-workers exhibited remarkable catalyst performance in
formed titanium complex coordinated by cinchonidine and asymmetric conjugate cyanation of α,β-unsaturated ketones and
3,3′-(9-phenanthrenyl)-substituted biphenol (Scheme 93).102 the N-acylpyrroles with various alkyl, heterosubstituted alkyl,
The axial chirality of the biphenol ligand could be induced at and aryl groups at the β position to afford the 1,4-adducts in up
the formation of the complex. Alkylidene malonates with β- to 98% ee and 99% ee, respectively (Scheme 95).104 In both
alkyl and -aromatic groups were cyanated with good to high cases, even 0.2 mol % of the ruthenium complex and LiOPh
enantioselectivity (up to 94%) under a solvent-free condition. worked effectively under mild conditions. The ruthenium
Use of ethyl cyanoformate as a cyanide source resulted in better complex was so robust that it could be recovered with a silica-
enantioselectivity than that with (CH3)3SiCN. gel column and was reused five times without loss of catalytic
According to the bifunctional catalyst concept, Wang and co- efficiency. On the basis of the X-ray and NMR spectroscopic
workers designed a dinuclear bis(prophenol)−magnesium analyses, a reaction mechanism was proposed in which Li+
catalyst for conjugate cyanation of α,β-unsaturated ketones interacting with the carbonyl oxygen of phenylglycine on the
(Scheme 94).103 The dual-mode coordination in the dinuclear ruthenium complex-activated substrate enone and CN− located
catalyst could activate both enone and cyanide, and then the between two amino protons with hydrogen bonding attacked
cyanation occurred in a stereospecific manner while avoiding the β-position of the enone.
the substrate rotation expected in a mononuclear catalysis. Chen and co-workers reported asymmetric conjugate
Chalcone derivatives reacted with (CH3)3SiCN (2 equiv) and cyanation of less-reactive chalcone analogues with benzophe-
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Scheme 95. Asymmetric Conjugate Cyanation of α,β- Shibata and co-workers reported that the ammonium salt of
Unsaturated Carbonyl Compounds with Chiral Ruthenium− cinchona alkaloid methyl ether, N-[2,5-bis(trifluoromethyl)-
Lithium Combined Catalyst phenyl] methyl-O-methylquinidinium bromide, catalyzed the
enantioselective conjugate cyanation of β-aryl-β-trifluorometh-
yl-substituted enones (Scheme 97).106 The O-methylquinidi-
Scheme 97. Asymmetric Conjugate Cyanation of β-Aryl-β-

trifluoromethyl-Substituted Enones Catalyzed by
Ammonium Salt of Cinchona Alkaloid
nium catalyst was more enantioselective than the conventional

hydroxy cinchona alkaloids. Use of diisopropyl ether as a
solvent was also important. The reaction using acetone
cyanohydrin with 10 mol % of the catalyst at 0 °C gave the
β-cyano ketones bearing a quaternary stereocenter in up to 97%
ee.
Chiral phase-transfer catalysis has been developed as an
effective strategy for the activation of practical cyanation
reagents, such as KCN and acetone cyanohydrin.
none cyanohydrin in the presence of a ternary catalyst system Deng’s group utilized accessible cupreine- or cupreidine-
of the 6,6′-adamantyl-substituted BINOL-derived phospholic derived salt as the catalyst and acetone cyanohydrin as a
acid, NaNH2, and 2-tert-butylphenol (Scheme 96).105 A series cyanide source for asymmetric conjugate cyanation of β-alkyl-
of substituted chalcones was transformed to the β-cyano substituted α,β-unsaturated ketones and N-acylpyrroles with
ketones in 92−98% ee with 5−10 mol % of the catalyst at 80 enantioselectivities as high as 97% and 98%, respectively
°C. The sodium BINOL-derived phosphate was proposed as (Scheme 98).107 They designed the catalyst on the basis of the
the catalytic species activating the HCN formed in situ.
Scheme 96. Asymmetric Conjugate Cyanation of Chalcones Unsaturated Carbonyl Compounds with Chiral Phase-
with BINOL-Derived Phosphate Catalyst Transfer Catalyst
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bifunctional (quaternary ammonium moiety and hydrogen- obtained in the reaction of styrenes under the optimized
bond-donor group) catalyst concept and optimized the conditions.
structure with careful analysis of the X-ray data. The nickel catalysts with C1-chiral diarylphosphinites
Maruoka and co-workers devised an enantioselective prepared from D-fructofranoside with two electronically differ-
conjugate cyanation of alkylidene malonates with a simple ent P-aryl groups promoted the hydrocyanation to yield the R
cyanide source, KCN, in the presence of a chiral bifunctional products in up to 95% ee.
ammonium bromide under cyclopentane−water biphasic Mechanistic studies of the reaction with MVN suggested that
conditions (Scheme 99).108 Addition of Brønsted acids such the chiral nickel(0) complex suffered an HCN oxidative
addition and MVN coordination followed by formation of an
Scheme 99. Asymmetric Conjugate Cyanation of Alkylidene (η3-benzyl)nickel cyanide complex with a nickel-hydride
Malonates with Chiral Phase-Transfer Catalyst migration onto MVN, and then an irreversible reductive
elimination of the product nitrile regenerated the catalytic cycle
intermediate.
Nickel-catalyzed hydrocyanation of 1,3-cyclohexadiene using
a chiral phosphite ligand with a binaphthol backbone was
investigated by Vogt and co-workers (Scheme 101).110 The
Scheme 101. Asymmetric Hydrocyanation of 1,3-

Cyclohexadiene with Nickel Catalyst Bearing a Chiral
Phosphinite Ligand
as NH4Cl and HCl was essential to accelerate the slow

ammonium cyanide regeneration from the intermediate
malonyl anion ammonium salt. The reaction of di-tert-butyl
alkylidene malonates and KCN was promoted with 2 mol % of
the phase-transfer catalyst to provide the cyanated products in
up to 93% ee.
4. CYANATION OF UNACTIVATED ALKENES

4-1. Hydrocyanation. Casalnuovo and RajanBabu and co-
workers found that C2-chiral diarylphosphinites derived from D- reaction with 0.2 mol % of the catalyst afforded 2-cyclohexene-
glucose were efficient ligands for the nickel-catalyzed 1-carbonitrile in moderate yield and in high ee of 86%. Styrene
asymmetric hydrocyanation of vinylarenes (Scheme 100).109 derivatives were cyanated with moderate enantioselectivity.
Mechanistic studies including deuterium-labeling experiments
Scheme 100. Asymmetric Hydrocyanation of Vinylarenes revealed that the enantioselectivity was determined at the
with Nickel Catalyst Bearing a Chiral Diarylphosphinite reductive elimination process.
Ligand Schmalz and co-workers devised TADDOL-derived phos-
phine−phosphite as a tunable chiral ligand, and utilized it in the
nickel-catalyzed asymmetric hydrocyanation of vinylarenes,
yielding chiral nitriles with good to high enantioselectivity
(Scheme 102).111 The reaction of indene gave the highest
enantioselectivity of 97%. p-Isobutyl-substituted styrene was
also cyanated in 92% enantioselectivity. The ligand structure,
reaction conditions, and cyanide source should be carefully
chosen. Slow addition of (CH3)3SiCN to the methanol solution
while maintaining a low concentration of HCN through the
reaction was important to obtain high enantioselectivity.
4-2. Intramolecular Carbocyanation. Jacobsen and a co-
worker accomplished the enantioselective intramolecular
arylcyanation of benzonitriles linked with an alkenyl moiety
The enantioselectivity was highly dependent on electronic through a tether via Caryl−CN bond activation using 5−10 mol
features of the phosphinite ligands. When the ligand had % of nickel catalyst and 10−20 mol % of BPh3 cocatalyst
electron-deficient 3,5-(CF3)2C6H3 as a P-aryl substituent, the (Scheme 103).112 The chiral alkyl diphosphine TangPHOS
hydrocyanation of 6-methoxy-2-vinylnaphthalene (MVN) gave the highest enantioselectivity. This method generated two
afforded the S-configured branched nitrile in up to 91% ee. new C−C bonds and one new quaternary carbon stereogenic
The catalyst with the P-3,5-(CH3)2C6H3 moiety gave the center in a single synthetic step, affording the 1,1-disubstituted
product in only 16% ee. Moderate enantioselectivities were indanes in 49−85% yield and 92−97% ee. The corresponding
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Scheme 102. Asymmetric Hydrocyanation of Vinylarenes Scheme 104. Asymmetric Intramolecular Arylcyanation with
with Nickel Catalyst Bearing a Chiral Phosphine−Phosphite Nickel Catalysts Bearing Chiral Phosphine-Based Ligands
Ligand
Scheme 103. Asymmetric Intramolecular Arylcyanation with

TangPHOS−Nickel Catalyst
Scheme 105. Asymmetric Intramolecular Cyanoamidation

with Palladium Catalyst Bearing a Chiral Phosphoramidite
Ligand
cyanated benzopyran was obtained in lower ee, and the

benzofuran analogue could not be obtained due to the
formation of an inactive π-allyl−nickel complex. The addition
of Lewis acidic BPh3 contributed to oxidative cleavage of the
Caryl−CN bond by the nickel(0) complex, and the identity of
the Lewis acid affected the enantioselectivity. Subsequent
migratory insertion resulted in construction of an indane
structure with a quaternary chiral center, and then reductive
elimination formed the Csp3−CN bond with regeneration of the
nickel(0) species.
Nakao, Hiyama, Ogoshi, and co-workers successfully utilized
a nickel catalyst having a chiral phosphinoxazoline ligand, i-Pr-
Foxap or i-Pr-Fox, and AlMe2Cl as a cocatalyst for the
enantioselective intramolecular arylcyanation (Scheme 104).113
The reaction occurred in an exclusive exo-dig manner to give a
range of cyanated indoline derivatives bearing a benzylic
quarternary stereogenic center in high yields and in up to 97% The reaction appeared to proceed through oxidative addition of
ee. The Chiraphos−nickel complex effected the enantioselec- the CO−CN bond to palladium, followed by amidopalladation
tive formation of a six-membered ring. AlMe2Cl seemed to of the olefin and reductive elimination.
promote the formation of the η2-nitrile−nickel intermediate. 4-3. Aminocyanation. Recently, two groups independently
This procedure was applied to the asymmetric synthesis of the reported the intramolecular aminocyanation of alkenes with
bioactive compound and the intermediate. N−CN bond cleavage.
Takemoto and co-workers reported a chiral palladium- Douglas and co-workers devised a Lewis acid-promoted
catalyzed intramolecular cyanoamidation of alkenyl cyanofor- reaction of alkenes including an N-cyano-N-phenyl-p-toluene
mamides to give the enantio-enriched 3,3-disubstituted sulfonamide group.115 The reaction with a stoichiometric
oxindoles (Scheme 105).114 The reaction using a catalyst amount of B(C6F5)3 in toluene at 90 °C afforded the racemic
system consisting of Pd(dba)2, a chiral phosphoramidite ligand, cyanomethyl-substituted indolines and tetrahydroquinolines in
and N,N-dimethylpropylene urea (DMPU) in decalin at 100 °C high yield. The reaction was proposed to proceed through
provided a series of 3,3-disubstituted oxindoles in up to 86% ee. nucleophilic addition of the alkene to the nitrile carbon, which
1019 DOI: 10.1021/acscatal.5b02184
ACS Catal. 2016, 6, 989−1023
was activated by coordination of the nitrile onto B(C6F5)3, required. A recently devised catalyst connected in a metal−
followed by the C−N bond cleavage. organic framework (MOF) would be a candidate for realizing
Nakao’s group developed the aminocyanation of alkenes with these goals.
an N-Boc-N-cyano-aniline moiety catalyzed by a palladium/ The cyanation of unactivated alkenes was efficiently catalyzed
triorganoboron cooperative system with N−CN bond cleavage by chiral transition metal complexes. The reaction proceeds
to give the indoline derivatives.116 The high chemo- and through oxidative cleavage of H−CN, C−CN, and N−CN
regioselectivities were achieved with an optimized catalyst bonds followed by insertion of carbon−carbon double bonds.
consisting of CpPd(allyl), 4,5-Bis(diphenyl phosphino)-9,9- Less-polar olefinic substrates are appropriate for this reaction.
dimethylxanthene (Xantphos), and triethyl- or triphenylborane. Addition of Lewis acidic compounds interacting with the CN:
A series of substituted indolines and pyrrolidines with both moiety promotes activation of the C−CN and N−CN bonds.
tetra- or trisubstituted carbon and cyano functionalities were Chiral nitrile products with tertiary or quaternary stereocenters
readily obtained by this procedure. In regard to the mechanism, are available in high ee. Studies on this type of reaction are
it was considered that oxidative addition of the N−CN bond to relatively rare and may constitute a novel class of chemical
palladium(0) catalyst was promoted by the cyano-group research as in the case of catalytic C−CN and N−CN bond
coordination to the boron Lewis acid cocatalyst. Amino- cleavage. We expect that the catalyst efficiency, substrate scope,
palladation in an exo-trig manner was followed by reductive and variety of reactions could be improved in the near future.
elimination with formation of the C−CN bond to release the
boron-bound indoline product, and then transfer of the boron
compound to the unreacted cyanamide substrate regenerated
■ AUTHOR INFORMATION
Corresponding Author
the palladium catalyst and the cyanamide−boron complex. *E-mail: ohkuma@eng.hokudai.ac.jp.
An asymmetric version of this reaction was furnished by
using a chiral bisphosphine ligand (R,R,R)-Ph-SKP (Scheme Notes
106).116 The indoline product in 93% ee was obtained The authors declare no competing financial interest.
successfully.
Scheme 106. Asymmetric Intramolecular Aminocyanation

■ ACKNOWLEDGMENTS
This work was supported in part by Grants-in-Aid from the
with Palladium Catalyst Bearing a Chiral Bisphosphine Japan Society for the Promotion of Science (JSPS) (No.
Ligand 15H03802 and No. 25410031) and the MEXT (Japan)
program “Strategic Molecular and Materials Chemistry through
Innovative Coupling Reactions” of Hokkaido University.
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1023 DOI: 10.1021/acscatal.5b02184

ACS Catal. 2016, 6, 989−1023

Kurono Ohkuma 2016 Catalytic Asymmetric Cyanation Reactions

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Kurono Ohkuma 2016 Catalytic Asymmetric Cyanation Reactions

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Review

Catalytic Asymmetric Cyanation Reactions

ABSTRACT: Catalytic asymmetric cyanations of prochiral unsaturated compounds

aldehydes, ketones, and imines is promoted by chiral metal complexes and

1. INTRODUCTION hydrocyanation of styrenes as well as intramolecular carbocya-

© 2015 American Chemical Society 989 DOI: 10.1021/acscatal.5b02184

Scheme 1. Catalytic Enantioselective Cyanation Scheme 2. Asymmetric Cyanosilylation of Aldehydes with

Scheme 3. Asymmetric Cyanosilylation of Aldehydes with

2. NUCLEOPHILIC CYANATION OF CARBONYL

Scheme 7. Asymmetric Cyanosilylation of Aldehydes with

The optimal catalyst derived from (R,R)-1,2-diaminocyclohex-

Scheme 6. Asymmetric Cyanosilylation of Aldehydes with

and co-workers used chiral β-aminoalcohol ligands prepared

Scheme 11. Asymmetric Cyanosilylation of Aldehydes with

si-face over the shielded re-face by the phenyl moiety of the

of m-methylbenzaldehyde with only 0.1 mol % of the catalyst

tetrabutylammonium ﬂuoride (TBAF) to aﬀord the product in

Scheme 14. Asymmetric Cyanosilylation of Aldehydes with

the chiral oxazaborolidinium resulting in high enantioselectivity

Scheme 16. Asymmetric Cyanosilylation of Aldehydes with

asymmetric cyanosilylation of aromatic aldehydes. A transition-

could be conducted with catalyst loading of 0.01 mol % to

Scheme 23. Asymmetric Cyanosilylation of Ketones

The carbohydrate-derived chiral ligand A with a phosphine

Scheme 27. Asymmetric Cyanosilylation of Ketones with

Scheme 25. Asymmetric Cyanosilylation of Ketones

Feng and co-workers reported a simple and highly

Scheme 30. Asymmetric Cyanosilylation of Ketones with

Scheme 35. Asymmetric Cyanosilylation of Ketones with

was rather slow. To accelerate the initiation step, the addition

Scheme 38. Asymmetric Reaction of Aldehydes and Ethyl

Scheme 40. Asymmetric Reaction of Aldehydes and Ethyl

reacted with moderate to good enantioselectivities. This

Scheme 41. Asymmetric Reaction of Aldehydes and Ethyl

Two types of ternary titanium catalyst systems were also

Scheme 47. Asymmetric Reaction of Ketones and Ethyl

The chiral acyl-ammonium cyanide derived from the Lewis

type reaction) using the BINOL-derived bifunctional catalysts

trile was obtained with enantiomeric excess of 97% in high yield

Scheme 55. Asymmetric Cyanation of Aldimines with Chiral

Scheme 58. Asymmetric Cyanation of Aldimines with Chiral

heteroaromatic N-benzhydryl aldimines were converted to the

Scheme 61. Asymmetric Cyanation of Imines with Chiral

uncatalyzed cyanation that gave racemic products by the

Scheme 62. Asymmetric Cyanation of Aldimines Using

Scheme 64. Asymmetric Three-Component Strecker

Scheme 65. Asymmetric Cyanation of Aldimines Catalyzed

Scheme 67. Asymmetric Cyanation of Aldimines with Chiral

and the chiral disulfonate promoted the reaction of N-

Scheme 71. Asymmetric Cyanation of α-

Lewis base (quinidine part) in the catalyst remarkably increased

Scheme 76. Asymmetric Cyanation of Cyclic Aldimines with

Feng and co-workers synthesized several chiral N,N′-dioxides

Scheme 78. Asymmetric Three-Component Strecker

phosphate derivative was considered to be a Brønsted acid

Scheme 81. Asymmetric Cyanation of Aldimines with Chiral

using aqueous KCN with chiral phase transfer catalysts

nitrogen and the pivaloyl oxygen at the C2 position of the

Scheme 87. Asymmetric Conjugate Cyanation of α,β-

(CH3)3SiCN and 2-propanol was important for the reaction to

Scheme 88. Asymmetric Conjugate Cyanation of α,β-

of (CH3)3SiCN (0.5−1 equiv) and HCN (2 equiv) gave the

Scheme 89. Asymmetric Conjugate Cyanation of