Current Organic Chemistry, 2010, 14, 15-47 15

Naturally Occurring -Hydroxy-
-Lactones: Muricatacins and Related Compounds

M. Carmen Murcia,a Cristina Navarro,b Ana Moreno,b and Aurelio G. Csákÿb*

a
Pharma Mar, S.A., Avda de los Reyes 1, E-28770 Colmenar Viejo, Madrid, Spain
b
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense; E-28040 Madrid, Spain

Abstract: In this account we present and critically analyze the different stereoselective synthetic strategies that have been reported in the
literature for muricatacins [5-(1-hydroxytridecyl)dihydrofuran-2-ones], naturally occurring -hydroxy-
-lactones related to acetogenins,
which display cytotoxic activity towards human tumoral cell lines.

1. INTRODUCTION carboxylic acid 3 from the bacterium Erwinia quercina [7], the
causal agent of drippy nut disease of the California live oak. Com-
Muricatacins are the two syn (threo) natural enantiomers of 5-
pound 3 was found to be an active lateral root-inducer upon inocu-
(1-hydroxytridecyl)dihydrofuran-2-one (1) (Fig. 1). They constitute
lation of slices of carrots, turnips and beets.
the simplest of the known native acetogenins, as they bear only two
chiral centres and have no tetrahydrofuran moiety, unlike other O
members of this class of natural products [1]. They are considered O
oxidative degradation products of the monotetrahydrofuran annona- Ph OH CO2H
R
ceous acetogenins, compounds which exhibit a variety of important
biological activities, including cytotoxicities against various types OH
of cancer cells, immunosuppressant, antimalarial and pesticidal 2a, R = CH3 OH
activities [2]. 3
2b, R = nC5H11
2c, R = PhCH2
Natural syn (threo) isomers

O O Fig. (2).

O O Muricatacins were isolated in 1991 for the first time by

McLaughlin and co-workers as an approximate 62:38 mixture (25%
5
()10 4 ()10 ee) of the (-)-(4R,5R)-1 and (+)-(4S,5S)-1 enantiomers from the
OH OH seeds of Annona Muricata L. (Annonaceae) from the Dominican
Republic [8]. This plant, commonly known as soursop or guana-
(+)-(4S,5S)-1 (-)-(4R,5R)-1 bana, is endemic to the Caribbean and Central America, and is now
(+)-Muricatacin (-)-Muricatacin grown commercially as a fruit crop throughout the tropical regions
of the world. The chemical structure of the natural muricatacins was
Unnatural anti (erythro) isomers assigned as a mixture of the syn isomers (+)-(4S,5S)-1 and (-)-
O O (4R,5R)-1 on the basis of CI-MS, and 1D and 2D- 500 MHz 13C-
and 1H-NMR spectra. The enantiomeric composition was assessed
O O
by comparison with the optical rotation of the isolated sample with
()10
that of analogue 2b (Fig. 2), which had previously been prepared as
()10
an intermediate for the synthesis of disparlure, the pheromone of
OH OH the female gypsy moth [9]. It was also shown [8] that (-)-(4R,5R)-1
(+)-(4S,5R)-1 (-)-(4R,5S)-1 can be obtained by degradation (mCPBA, CHCl3, 48, rt) of annon-
(+)-epi-Muricatacin (-)-epi-Muricatacin acin (Fig. 3). Chemical syntheses carried out afterwards confirmed
all these preliminary observations. In addition, muricatacins have
Fig. (1).
also been isolated from the Formosan annonaceous plant Annona
Muricatacins constitute a representative example of the natu- montana [10], this time as an approximate 78 : 22 mixture (56 %
rally occurring -hydroxy-
-alkanolides, an ubiquitous skeleton ee) of the (-)-(4R,5R)-1 and (+)-(4S,5S)-1 enantiomers.
among natural products. Other closely related compounds of this
family that may be cited (Fig. 2) are solerol (2a), a constituent of
OH OH
wines and sherry [3] that has been also found in some fruits such as HO O
nectarines, figs and dates [4]; L-factor (2b), a -hydroxy lactone
which occurs temporarily before antibiotic production during the
fermentation of Streptomyces griseus [5, 6]; or compound 2c, which O
O
was obtained as an artefact during isolation of the corresponding

nC H
12 25
*Address correspondence to this author at the Departamento de Química Orgánica, HO
Facultad de Química, Universidad Complutense; E-28040 Madrid, Spain; Tel: 34 91 Annonacin
3945030; Fax: 34 91 3945030 E-mail: csaky@quim.ucm.es Fig. (3).

1385-2728/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

16 Current Organic Chemistry, 2010, Vol. 14, No. 1
In addition to the natural syn enantiomers, both unnatural anti
(erythro) enantiomers (Fig. 1) have been synthesized and their bio-
logical activities have been evaluated. The unnatural diastereomers
are known as epi-muricatacins. Using NMR data, they can be easily
distinguished from the natural compounds in a downfield shift of
the H5-signal, and an upfield shift of the C5-signal [11].
The butyrolactones are known to exist in the envelope confor-
mation as an equilibrium of two conformers (Fig. 4) [12].
H3b R determine the pharmacophore of the muricatacin molecule (Fig. 5).
R O H4
H3a
O H3b
O philic methoxy group at the end of the alkyl chain (4) decreased the
O H4 R = CH(OH)nC12H25 H3a
Ia Ib
Fig. (4).
1
H-NMR study of (-)-(4R,5R)-1 in CDCl3 solution [13] showed
that (-)-muricatacin takes up a predominant conformation with the
4-hydroxyalkyl chain in the equatorial position (conformation Ia).
Thus, the expected values for 3J3,4 (ax,ax) and 3J3,4 (eq,eq) proton
coupling should be 10 Hz and 2 Hz respectively [12]. For the lac-
tone (-)-(4R,5R)-1, the experimental value 3J3,4 = 8 Hz (experimen-
tal error 0.5 Hz) may be interpreted as a slight contribution of Ib
which is evaluated as 25% by the equation: 2(1-
) + 10
= 8
(where
represents the molar concentration of configuration Ia).
2. BIOLOGICAL ACTIVITIES
Apart from other members of the naturally occurring -
hydroxy--lactone family, the Medicinal Chemistry interest in mu-
ricatacins (1) stems from their cytotoxic activities. This has led to
the proposal of muricatacins as lead compounds for the search of
new antineoplastic agents instead of the structurally more compli-
cated acetogenins isolated from the same natural sources.
The 62:38 mixture of syn enantiomers (-)-(4R,5R)-1 and (+)-
(4S,5S)-1 isolated from Annona Muricata L. showed cytotoxic ac-
tivity on tumour cell lines A-549 (lung carcinoma) with ED50 =
23.3 μg/mL, MCF-7 (breast carcinoma) with ED50 = 9.5 μg/mL,
and HT-29 (colon carcinoma) with ED50 = 14.0 μg/mL [8, 14].
Additionally, the mixture of muricatacins isolated from Annona
montana [10] (78 : 22 mixture of the syn enantiomers (-)-(4R,5R)-1
and (+)-(4S,5S)-1) have been subjected to a 3-day MTT cytotoxicity
assay toward three human cancer cell lines: A-549 (lung carci-
noma), Hep-G2, and Hep-3B (hepatoma). Although they showed
significant cytotoxicity towards Hep-G2 cells (ED50 = 0.31 μg/mL),
they displayed only moderate cytotoxic activities towards the Hep-
3B and A-549 lines (ED50 values of 7.41 and 16.52 μg/mL respec-
tively).
Yoon and co-workers have tested the four independently syn-
thesized muricatacin enantiomers (natural syn and unnatural anti)
against A-549 (lung carcinoma) and MCF-7 (breast carcinoma) cell
lines [15]. Values of IC50 [16] determined against A-549 were 18.5,
24.3, 23.7 and 29.8 μg/mL respectively for (-)-(4R,5R)-1, (+)-
(4S,5S)-1, (-)-(4R,5S)-1 and (+)-(4S,5R)-1; whereas values of IC50
determined against MCF-7 were 17.6, 15.9, 22.2 and 16.7 μg/mL
respectively. The four isomers exhibited weak and similar inhibi-
tion in both cell lines. This indicated that the stereochemistry at the
C4 and C5 positions did not affect the cytotoxicities significantly.
Also, Figadère and co-workers have shown that both synthetic natu-
ral syn enantiomers possessed the same activity on KB cell lines
Murcia et al.
(human epidermoid carcinoma) with ED50 = 5 μg/mL. However, for
VERO cell lines (African green kidney monkey cells) the values
were slightly different, with ED50 = 10 μg/mL for (+)-(4S,5S)-1 and
ED50 = 11 μg/mL for (-)-(4R,5R)-1 [17, 18]. The synthetic unnatu-
ral anti isomer (+)-(4S,5R)-1 (dr = 54%) was somewhat less active,
with values of ED50 = 7.5 μg/mL and ED50 = 14 μg/mL against KB
and VERO cell lines respectively.
Several structural modifications have been evaluated in order to
Thus, Yoon and co-workers, in their studies against A-549 and
MCF-7 cell lines [15, 19], have shown that inclusion of a hydro-
activity. On the other hand, Figadère and co-workers, in their stud-
ies of the inhibition of KB and VERO cell lines [17, 18, 20], have
put forward that cytotoxicity was dependent on the length of the
alkyl chain, and syn muricatacins (1, R = C12H25) were the more
active. A shorter chain dramatically decreased the activity (2, R =
H, C2H5, C5H11, C7H15, C10H21), whereas a longer chain (2, R =
C14H29) did not increase the activity. Unsaturation in the lactone
ring (5) improved the activity of the compounds with a short chain
(5, R = C5H11, C7H15), but had no effect on muricatacin (5, R =
C12H25). When other functionalities were present, such as an oxo
function (6, R = C12H25), the activity was about the same as for
muricatacin. Addition of a tetrahydrofuran ring (7, R = C12H25) did
not modify the activity as long as the length of the alkyl chain was
not shortened (7, 8, R = C10H21). In the cases of the pyrrolidones 9
(aza-muricatacins), the activity was either identical to that of muri-
catacin or even better, independently of the relative or absolute
configurations (ED50 values against KB and VERO cell lines, re-
spectively: (+)-(4S,5S)-9, ED50 = 1.5 and 7 μg/mL; (-)-(4R,5R)-9,
ED50 = 3.5 and 7 μg/mL; (-)-(4S,5R)-9, ED50 = 2 and 12 μg/mL).
In another study against the growth of human Hep-G2 hepato-
carcinoma and Hep-G2 transfected hepatitis B virus (2,2,15) cancer
cell lines, Wu and co-workers [21] have determined IC50 values of
22.0 and 21.8 μM respectively for the hydroxylated compound 10
(1:1 mixture of two diastereomers, epimers at C9). The IC50 of (+)-
muricatacin against the growth of these two cancer cell lines were
14.9 and 18.0 μM, respectively.
Popsavin and co-workers have studied [22, 23, 24] the antitu-
mour activity of the 7-oxa-muricatacin analogues (-)-(4R,5R)-11
and (+)-(4S,5S)-11, which were designed as possible muricatacin
bioisosteres. They have considered in vitro cytotoxicity against
K562 (human myelogenous leukaemia), HL60 (human promyelo-
cytic leukaemia), Jurkat (human T cell leukaemia), HT-29 (human
colon adenocarcinoma), and Raji (human Burkitt’s lymphoma) cell
lines after exposure to the test compounds for 24 h. This study
showed that the (–)-muricatacin analogue (-)-(4R,5R)-11 was inac-
tive against the HL60 and Raji malignant cells, but showed a sig-
nificant cytotoxic activity against K562 (IC50 = 0.18 μM) and HT-
29 (IC50 = 0.086 μM) cell lines. The activity of this compound to-
wards the Jurkat cells (IC50 = 1.95 μM) was comparable to that
observed for doxorubicin, which was used as reference compound
in this study. However, compound (-)-(4R,5R)-11 was found to be
significantly more active against the K562 and HT-29 cell lines,
being approximately 4.5- and sixfold more potent than doxorubicin,
respectively. The (+)-enantiomer (+)-(4S,5S)-11 showed a remark-
able cytotoxicity towards the K562 (IC50 = 0.45 μM) and HT-29
(IC50 = 0.18 μM) cell lines, being almost two and threefold, respec-
tively, more potent than doxorubicin. This analogue was also active
against Jurkat cells (IC50 = 10.80 μM), but it was more than eight-
fold less active with respect to the reference compound (DOX).
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 17

O O O O
O O O O
R R R
O ()11
OH OH OH O
1, 2 4 5 6
O O

O O O
HN

O O R

R R
OH

OH OH 9
7 8
O O
O O

()4 ()8 O
OH 10 OH 11 OH

O O
O O

HO HO
O O
O HO
()8 Ph
12 13

Fig. (5).

These authors have also studied furanolactone 12, which repre-
sents a conformationally constrained one-carbon homologue of (+)-
(4S,5S)-11, that may be also considered as a non-styryl analogue of
goniofufurone (13), a naturally occurring cytotoxic lactone that was
isolated from the stem bark of Goniothalamus giganteus (Annona-
ceae). The furanolactone 12 showed a potent cytotoxic activity
against the HL60 (IC50 = 4.14 μM) and Raji (IC50 = 7.37 μM) cells
after 24 h exposure, comparable to that observed for the reference
compound, doxorubicin. Thus, the cytotoxicity profile of 12 com-
plements the observed biological effects of (-)-(4R,5R)-11 and (+)-
(4S,5S)-11.
Compound 12, when tested against K562, HL60, Jurkat and
HeLa cell lines in a 72 h assay exhibited the same growth inhibition
pattern as (-)-muricatacin, and therefore represents a bioisostere of
(-)-(4R,5R)-1. As (-)-muricatacin itself, compound 12 was inactive
against Jurkat cells, but showed a potent antiproliferative activity
towards K562 (IC50 = 1.25 μM), HL-60 (IC50 = 0.14 μM) and HeLa
(IC50 = 0.30 μM) cells. These values are to be compared with those
shown by (-)-muricatacin in the same assays (IC50 = 0.04, 25.85 and
0.17 μM respectively).
When comparing (-)-muricatacin to analogues 11 and 12
against K562, HL60, Jurkat and HeLa cell lines in the 72 h assay, it
was shown that (-)-muricatacin was the most potent compound in
the K562 cell line (IC50 = 0.04 μM), while the most pronounced
antiproliferative activity of analogues 11 and 12 was recorded
against the HL-60 cell line (IC50 = 25.85, 0.15, 0.14 μM respec-
tively for (-)-(4R,5R)-1, (-)-11, 12). Compounds (-)-11 and 12 ex-
hibited 172- and 185-fold, stronger activities when compared to the
parent compound (-)-muricatacin. A sub-micromolar activity of 12
was also recorded against the HeLa malignant cells (IC50 = 0.30
μM), comparable to that observed for the reference compound (-)-
(4R,5R)-1 (IC50 = 0.17 μM).
It is worth mentioning that neither of the compounds (-)-
(4R,5R)-1, (-)-11 or 12 exhibited any antiproliferative activity to-
wards normal foetal lung MRC-5 cells.
Studies toward the determination of the mechanism of action of
muricatacins have not been yet conclusive [1, 18]. Since it has been
proposed that the related acetogenins of Annonaceae act as an in-
hibitor of complex I (NADH : ubiquinone redoxidase) in the mito-
chondrial respiratory system [25] as well as the NADH oxidase in
cancer cells, it has been postulated that muricatacins may act via an
identical mechanism. On the other hand, NMR experiments have
shown that muricatacins do not bind efficiently cations such as
Ca2+, Ba2+ and K+, whereas acetogenins of Annonaceae may have
ionophoric properties due to their complexation properties [26].
The biological activities reported for muricatacins and their
analogues have prompted the development of a wide variety of
approaches for the stereoselective synthesis of these compounds.
These will be analyzed in the following sections.
3. MURICATACIN SYNTHESES BASED ON RESOLUTION
The first synthesis of enantiomerically pure (-)-muricatacin was
reported by Tochtermann and Scholz [27] (Scheme 1). Diels-Alder
reaction between furan and cyclooctyne produced adduct 14, which
was hydrogenated regioselectively to 15 on a 20 g scale. Ozonolysis
18 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

a b c d
+ O O O O

14 15
O
OH 16
CO2H e CO2CH3 f
O ()5 H3CO2C
O ()5
O O
17 18
OR* OR*
g
CO2CH3 CO2CH3
H3CO2C R ()5 H3CO2C ()5
O OH
(1´S,4R)-19 CO-
20
R* = S O
+
OR* h
O
CO2CH3
H3CO2C S
O CO2CH3
O ()5
(1´S,4S)-19 O
OR*
21

k CH2OH j CO2H
O ()5 O ()5
O O
OH OH
23 22
O

O O O O O
l m
CH2OH CHO
H3CO2C ()6 H3CO2C ()6 ()10

24 25 OH
(-)-(4R,5R)-1

Scheme 1. Reagents. a: 140ºC, 2h (50%); b: H2 / Pt; c: O3 (80%); d: O2; e: i. 2 M NaOH, 15 min, rt, ii. AgNO3 / H2O, 15 min, rt, iii. CH3I / Et2O,
; f: i. (-)-
camphanoyl chloride, pyridine, ii. Column chromatography on silica gel (Et2O : pentane = 2:1); g: L-Selectride, THF, -78ºC; h: Amberlyst-15, CH2 Cl2; i: i.
NaOH, MeOH, 2 h,
; ii. NaOH, H2O/MeOH, 5 h,
; iii. HCl; j: BH3-THF, -18ºC to rt; k: Me2C(OMe)2, MeOH, Amberlyst-15, 60 h, rt; l: PCC, CH2Cl2 , 2.5 h,
rt; m: i. [ nC5H11 PPh3]Br, KOtBu, Et2O, 1h,
; ii. H 2, Pt, iii. THF, HCl, H2 O, 1h,
.

of 15 furnished diketone 16, which was exposed to air oxidation in
large Petri dishes for 2-3 months to afford -lactone 17. Ring-
opening and esterification gave rise to 18. Resolution of 18 was
carried out by camphanoate ester formation, and the corresponding
diastereomers 19 were separated by column chromatography on
silica gel. This allowed for the establishment of the absolute con-
figuration of C4 in the final muricatacins. Reduction of the carbonyl
group of the open chain ketone (1´S,4R)-19 was highly syn selec-
tive, giving rise to 20, which already had the correct absolute and
relative configuration of both stereocentres of the target. Lactoniza-
tion of 20 under acidic conditions took place with simultaneous
migration of the camphanoate group to afford 21, which was
saponified to the advanced intermediate 22. The alkyl chain of (-)-
muricatacin was obtained from 22 by elongation of the aliphatic
chain using a Wittig reaction as key step. Therefore, in order to
provide the required aldehyde, the carboxylic acid group of 22 was
first transformed into alcohol 23. However, selective oxidation of
the primary OH group of 23 into the aldehyde group required pre-
vious protection of the secondary OH group. This was accom-
plished by treatment of 23 with acetone dimethyl acetal in acid,
which furnished the acetonide derivative 24 via ring opening of the
lactone moiety of 23 followed by transketalization of an intermedi-
ate 1,2-diol. Now, oxidation of the primary OH group in 24 af-
forded the key aldehyde 25. Wittig reaction, alkene hydrogenation,
and acid induced ketal hydrolysis with simultaneous lactonization
finally afforded (-)-(4R,5R)-1.
Although lengthy (18 steps), the authors reported that all steps
in the synthesis took place with yields between 65% and 98%, and
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 19

in particular, the chromatographic separation of diastereomers 19 Enzymatic resolution of racemic acetate 30 with PLE afforded
was amenable to multigram scale synthesis. enantiomerically enriched acetate (+)-30 (79% ee) and alcohol (-)-
Yoshimitsu, Nagaoka and co-workers have established a novel 28 (90% ee). Oxidation of the ´-C-H position of (+)-30 with ru-
diastereoselective -hydroxyalkylation reaction of tetrahydrofuran thenium tetroxide under modified Sharpless conditions gave (-)-
with aldehydes in which triethylborane-air or triethylborane-tert- acetylmuricatacin (32). Deprotection of 32 by transesterification
butyl hydroperoxide as the radical source are used (Scheme 2) [28]. with EtOH followed by acid treatment of the crude mixture pro-
The tetrahydrofuranyl radical thus generated was found to react duced (-)-(4R,5R)-1, which was obtained optically pure after recrys-
with aldehydes with syn-selectivity to afford -substituted tetrahy- tallization.
drofuran-2-methanols. The authors proposed a transition state Alternatively to the enzymatic procedure, (rac)-28 (Scheme 4)
model in which boron atoms tether radical 26 to aldehydes 27 as a was transformed into the diastereomeric carbonates 33 and 34 upon
plausible reaction explanation for this selectivity. reaction with (+)-menthyl chloroformate. -Oxidation of 33 and
removal of the menthoxycarbonyl group afforded optically pure (-)-
air or tBuOOH RCHO (27) R (4R,5R)-1.
O Et3B, rt O O
26 OH R a R R
+
O O O
O
Et OH OR* OR*
B H 33
Et rac-28 34
O H

R R = nC12H25 b,c
R* = O=CO
Scheme 2.
R
Application of these principles to the synthesis of (-)- O O
muricatacin [29] represented a novel route to -(hydroxyalkyl)-- OH
(-)-(4R,5R)-1
butyrolactones via -C-H hydroxyalkylation and ´-C-H oxidation
of THF (Scheme 3). Therefore, -C-H hydroxyalkylation of THF Scheme 4. Reagents. a: (+)-menthyl chloroformate, py, 0ºC to rt (50% 7,
with tridecanal using triethylborane-TBHP provided alcohols 28 50% 8); b: i. RuCl3.nH2O, NaHCO 3, NaIO4 , CCl4, CH 3CN-H2O, rt (66%), ii.
and 29 whose subsequent acetylation gave racemic acetates 30 and K2CO3 , EtOH, rt, iii. PPTS, benzene,
(94%).
31 in 65:35 ratio. As 30 had the syn stereochemistry of the target [(-
)-(4R,5R)-1], the anti acetate 31 was recycled into 30 via reduction 4. MURICATACIN SYNTHESES FROM THE CHIRAL
of the ester to alcohol followed by inversion of the alcohol centre POOL
(C4 in the final target) using a Mitsunobu reaction with acetic acid.
Several compounds from the chiral pool such as L-glutamic
a acid, D-isoascorbic acid, tartaric acids, mannitol, glyceraldehyde,
R R
+ D-glucose, D-xylose, and their derivatives have been used as suit-
O O O able starting materials for the synthesis of muricatacins. In these
OAc OAc
rac-28 rac-29 approaches, the chiral centres already present in the starting mate-
R = nC12H25 b rial will become part of the product, and the stereochemistry will be
retained or inverted to furnish C4 and C5 of the muricatacin di-
R R astereomers.
+
O O Larchevêque and co-workers [30] have shown that 4-acyl-4-
OAc OAc butanolides may be obtained in good yield (Scheme 5) by a low
rac-30 rac-31 temperature reaction of a Grignard reagent in THF or a magnesium
homocuprate with the acid chloride 36 derived from L-glutamic
d acid by nitrous acid deamination [31], a reaction known to proceed
c
with a full retention of the configuration of the initial -amino acid
R R due to participation of the neighboring carboxylate group [32].
+
O O The reduction of the ketone group in these type of acyl lactones
OAc OH 37 with chelating reducing agents, such as Zn(BH4)2, afforded the
(+)-30 (-)-28
protected anti -diols, although the diastereoselectivity of the proc-
e ess was not very high. In contrast, hindered reducing agents, such
as L-Selectride, afforded protected syn -diols in very good di-
R f R astereomeric purity. The high syn-selectivity of the reduction with
O O L-Selectride was explained by the authors by the operation of Fel-
O O
OAc OH kin-Ahn model. In addition, as D-glutamic acid is also available,
32 (-)-(4R,5R)-1 the corresponding enantiomers can also be prepared by the same
diastereoselective route.
Scheme 3. Reagents. a: i. tridecanal, Et3B, tBuOOH, 0ºC to rt (64%, rac-28
: rac-29 = 65 : 35); b: Ac2O, Et3N, DMAP, CH2 Cl2 , rt (84%); c: i. LiAlH 4 , The synthesis of (+)-muricatacin according to these guidelines
THF, 0ºC to rt (84%), ii. DEAD, Ph3P, AcOH, toluene, -15ºC (76%); d: required reacting the acid chloride 36, derived from L-glutamic
PLE, CH 3CN, phosphate buffer (pH = 8), rt (79% ee, 49% (+)-30; 90% ee, acid, with dodecylmagnesium bromide to give 37a (R = nC12H25)
47% (-)-28); e: i. RuCl3.nH2O, NaHCO 3, NaIO4, CCl4, CH3CN-H2O, rt [17]. The authors pointed out that the yield of this step could be
(66%), ii. K 2CO3 , EtOH, rt; f: PPTS, benzene,
(94%).
20 Current Organic Chemistry, 2010, Vol. 14, No. 1
O O
HO
NH2
L-Glu
O b
O O
OH
35
d, e or f
O + O
(+)-(4S,5S)-1
Scheme 5. Reagents. a: NaNO2, H2 SO4, H 2O, 20 h, 5ºC (50%); b: i. ClCOCOCl, benzene, 4h, 60ºC or ClCOCOCl, CH 2Cl2, DMF (cat), 20ºC (90%); c: i.
RMgBr, THF, -85ºC, ii. 3N HCl (65%); d: i. L-Selectride, THF, 1h, -80ºC, ii. 3N HCl (90:10 syn/anti, 88%); e: i. NaBH4, EtOH, 2 h, 0ºC, ii. 3N HCl (40:60
syn/anti, 95%); f: Bu3 SnH, SiO2 (28:72 syn/anti, 80%).
improved up to 92% by using the corresponding organomanganese
compound instead of the Grignard reagent [33]. Reduction of 37a
with L-Selectride gave rise to a mixture of (+)-(4S,5S)-1 with the
anti diastereomer (+)-(4S,5R)-1 in 90:10 ratio, which could be sepa-
rated by flash chromatography on silica gel. Also, reduction with
sodium borohydride afforded a mixture of (+)-muricatacin and (+)-
epi-muricatacin in 40:60 ratio.
The same methodology has also been reported for the synthesis
of (+)-epi-muricatacin by reduction of 37a with Bu3SnH in the
presence of SiO2 (80% yield, 44% de) [18, 34].
L-Ascorbic and D-isoascorbic acids have been used as starting
materials for the preparation of the four possible stereoisomers of
epoxybutanediol acetonide 38 [35]. These molecules may be for-
mally considered as synthetic equivalents of the bis-epoxide
[2,2´]bioxyranyl (Fig. 6), as they contain one epoxide function and
the other one is masked into the protected glycol of 38.
HO HO
O O O O
HO HO
HO OH HO OH
Ascorbic acid D-Isoascorbic acid
[2,2´]Bioxyranyl
Fig. (6).
In particular, (R,R)-38, prepared from D-isoascorbic acid, has
been used for the synthesis of (-)-muricatacin (Scheme 6) [36]. In
this approach, the absolute stereochemistry of C5 in (-)-muricatacin
was concealed in the secondary carbon of the epoxide ring, and that
of C4 in the secondary carbon of the acetonide. Both configurations
were preserved throughout the synthesis.
Nucleophilic ring opening of the epoxide in (R,R)-38 with un-
decylmagnesium bromide in the presence of dilithium tetrachloro-
cuprate led to the alcohol 44a. Protection of the free OH and selec-
tive acidic hydrolysis of the acetal was followed by a Mitsunobu
reaction in which the activated primary OH of 45b acted as leaving
group. These manipulations unmasked the second epoxide ring
embedded in (R,R)-38. Ring-opening of the epoxide 46b with the
sodium enolate of diethyl malonate afforded 47b as a mixture of
Murcia et al.
O O
a
OH HO OH
OH
O c O
O O O O
Cl R
36 37
OH OH
O O
R R
(+)-(4S,5R)-1
R = nC12H15
epimers at C2, which upon decarbethoxylation and alcohol depro-
tection with simultaneous lactonization afforded (-)-(4R,5R)-1. The
authors noted that it was also possible to carry out the Mitsunobu
step directly on the triol (45a, R2 = H) which resulted upon hy-
drolysis of 44a, thus avoiding the PMB-protection/deprotection
steps. However, the overall yield of the synthesis decreased without
PMB-protection (28% starting from 44b vs. 14% starting from
44a).
Reversal of the sequence allowed for a more simple synthesis
(Scheme 7) [13]. This time, the secondary carbon of the epoxide
became C4 in the final target, and the secondary carbon of the ace-
tonide became C5. As before, both configurations were preserved
throughout the synthesis. Ring-opening of the epoxide (R,R)-38
with the sodium enolate of diethylmalonate afforded
-
ethoxycarbonyl--butyrolactones 48 (70:30 epimeric mixture at
C2). Simultaneous decarbethoxylation and acetonide hydrolysis
gave rise to 49. A Mitsunobu reaction furnished the epoxide 50,
O
which upon nucleophilic opening of the epoxide by undecylmagne-
O sium bromide in presence of dilithium tetrachlorocuprate led to (-)-
O
muricatacin.
38
Scharf and co-workers have carried out the synthesis of both
epi-muricatacin enantiomers from D-isoascorbic acid [37]. First,
O O they prepared 2,3-O-isopropylidene-D-erythrose 53, which was
used as common precursor for both targets (Scheme 8). This was
made possible by the reaction sequence for the introduction of the
two different side chains, which were interchangeable. Thus, D-
isoascorbic acid 53 was oxidized with aqueous hydrogen peroxide
to give D-erythronolactone 51, which was acetalized to afford 52.
Compound 52 was reduced diastereoselectively to give 53 as the -
anomer.
The synthesis of (-)-epi-muricatacin from 53 started with a Wit-
tig reaction with the ylide derived from undecyltriphenylphospho-
niumbromide, followed by a Pfitzner-Moffat oxidation to aldehyde
55. Subsequent Wittig reaction of 55 with methyl (triphenylphos-
phoranylidene)acetate, hydrogenation and deprotection-cyclization
under acidic conditions gave (-)-(4R,5S)-1. Conversely, the synthe-
sis of (+)-epi-muricatacin from 53 started with a Wittig reaction
with the methyl (triphenylphosphoranylidene)acetate, to give 57. In
order to introduce the aliphatic side-chain of the target, the hydroxy
group in 57 was activated as a tosylate 58 to enable a cuprate cou-
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 21

HO O
O O
O O a O b
O CO2Et
HO
O
HO OH HO 39 OH 40 OH
D-Isoascorbic acid
c d

O
O
O O e
O OH
O
MeO OMe 42 OH
41
f

O
OBn
O
43 OTs

HO O O
j h
R1 R1
HO O O
OR2 OR2 O

45a,b 44a, R2 = H (R,R)-38

i
44b, R2 = PMB
R1 = nC12H25 k
EtO2C
l m
O R1 R1 R1
O O
O O
OR2 OR2 OH
46b 47b (-)-(4R,5R)-1

Scheme 6. Reagents. a: Me2 C(OMe)2, dry HCl, acetone, 20ºC; b: i. H2O 2, K2CO3 , acetone,
, ii. EtI, CH3CN,
; c: Me2 SO4, K2CO 3, acetone,
; d: LiAlH4 ,
THF, 1h,
; e: i. O3 , CH 2Cl2, -78ºC, ii. LiAlH4, THF (50 – 60% overall yield from D-isoascorbic acid); f: i. PhCOCl, py, CH2Cl2, -78ºC, ii. TsCl, py, 0ºC to
20ºC; g: K2 CO3 , MeOH, CH2Cl2, 20ºC; h: nC11H 23 MgBr, Li2 CuCl4 , THF, -35ºC (80%); i: i. NaH, DMF, imidazole, 20ºC, ii. p-methoxybenzyl chloride, Bu4NI,
20ºC (93%); j: AcOH/H2O 4:1, 20ºC; k: Ph3 P, DIAD in vacuo (80% 18b from 16b); l: (EtO 2C) 2CH, NaOEt, EtOH, 60ºC; m: i. MgCl2.6H2O, CH 3CONMe2, ii.
DDQ, CH 2Cl2 /H2O 18:1 (37% from 18b).
CO2Et
O
a
O O
O O
O
O
48
(R,R)-38

R1 d c
O O HO O
O O O O
HO 50 HO
(-)-(4R,5R)-1 49

R1 = nC12H25

Scheme 7. Reagents. a: (EtO 2C)2 CH2, NaOEt, EtOH, 6 h, 60ºC (80%); b: MgCl2.6H2O, CH 3CONMe2, 4 h,
(90%); c: Ph3P, DIAD in vacuo (67%); d:
n
C11 H23 MgBr, Li2CuCl4, THF, -35ºC (38% (-)-1, together with 34% of unreacted 50 which could be easily recovered by flash column chromatography: 58%
yield of 1 based on 66% conversion of 50).
22 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

D-Isoascorbic acid

O b O O
O

HO OH O O
51

52

R1 O
OH CO2Me
HO d h HO

O O O O O O

54 53 57

e i
R1 CO2Me
OHC TsO

O O O O

55 58

f j

MeO2C R1 CO2Me
R3
g TsO
O O
HO
O O O O
(-)-(4R,5S)-1

56 59

k
R1 = nC10H21
R2 = nC11H22 R2 CO2Me
R3 = nC12H25 R3 l
O O
HO
O O
(+)-(4S,5R)-1

60

Scheme 8. Reagents. a: i. H2O2 , Na2CO3 , ii. HCl; b: Me2C(OMe) 2, acetone (76% from D-isoascorbic acid); c: DIBAL-H, 3 h, -72ºC (89%); d: [nC11 H23 PPh3]Br,
KOtBu, THF, 18 h, -20ºC to rt (61%); e: TFA, py, DMSO - toluene (1:1), 18 h, rt (88%); f: Ph3P=CHCO2 Me, CH2Cl2, 24 h,
(57%); g: i. H2 (5 bar),
Pd/C(10%), EtOH (99%), ii. HCl, THF - H2O (10:1.5) (89%); h: Ph3P=CHCO2Me, CH2 Cl2 , 3 days,
(60%); i: TsCl, Et3N, DMAP, CH2Cl2, 1 h, 0ºC and 2 h, rt
(96%); j: H2 (5 bar), Pd/C(10%), EtOH (99%); k: i. R2I, Li, pentane, ultrasound, 2 h, 0ºC, ii. CuI, Et2O, 2 h, -78ºC to rt (42%); l: aq HCl (cat), THF, 2 h, rt
(98%).

pling. Avoidance of competition with a possible conjugate addition
of the cuprate to the unsaturated system was solved by hydrogenat-
ing the double bond prior to cuprate coupling. Alkylation of the
tosylate 59 with lithium di(undecyl)cuprate gave 60, which was
transformed into (+)-(4S,5R)-1 in acidic media.
Tartaric acids and their derivatives have been used as starting
materials for various muricatacin syntheses.
Thus, lactone 66, precursor of (+)-muricatacin, has been pre-
pared by Southard and co-workers from L-(+)-tartaric acid [38] by
conventional stereoselective transformations (Scheme 9).
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 23

O OH
OH a O O b O O
HO
OH O HO OH BnO OH
L-tartaric acid 61 62

O O d O O

BnO BnO CHO

64 63
EtO2C
e
O O
O O
f
BnO BnO
OH OH
65 66

Scheme 9. Reagents. a: i. Me2 C(OMe) 2, MeOH, TsOH (cat), rt (70%), ii. LiAlH4 , Et2O, 35ºC (88%); b: BnBr, NaH, THF, 66ºC (70%); c: (COCl) 2, DMSO,
Et3N, CH2 Cl2 , -78ºC to 0ºC (53%); d: Ph3 P=CHCO2 Et, MeOH, 0ºC (Z : E = 9 : 1); e: 3N HCl, 25ºC, 24 h (47% from 8); f: H2 (1 atm), Pd/C (100%).

L-(+)-tartaric acid was transformed into the corresponding ace-
tonide, which was subsequently reduced to the chiral L-threitol
derivative 61. Monobenzylation, oxidation and Wittig reaction af-
forded esters 64 as a 9:1 mixture of Z- and E- diastereomers. Acidic
treatment of the unseparated mixture followed by extraction and
crystallization afforded the unsaturated lactone 65 together with
(E)-ethyl 7-benzyloxy-5,6-dihydroxyhept-2-enoate, which was
present as by-product from the deprotection of the E-isomer 64.
Compound 65 was finally debenzylated to 66, which had already
been used in the literature [13] as precursor of (+)-(4S,5S)-1.
Quayle and co-workers have developed a different approach to
(+)-(4S,5S)-1 from L-(+)-tartaric acid [39]. The key step consisted
in a transition metal acetylene-vinylidene rearrangement (Scheme
10) that was previously developed by these authors for the synthesis
of
-butyrolactones [40].
Cr(CO)5
a b
O O
OH
R1
R2 R1
R2
M = Cr, W
Scheme 10. Reagents. a: Cr(CO)5 THF or W(CO)5 THF, 500 W medium
pressure Hg lamp, 16 h, 55ºC; b: CAN, acetone.
Towards the stereospecific synthesis of (+)-muricatacin
(Scheme 11), L-(+)-tartaric acid was transformed into the bis-
mesylate 67 [41], which was used as starting material. Treatment of
67 with lithium acetylide – ethylenediamine complex afforded 68.
This was subjected to the acetylene-vinylidene rearrangement proc-
ess with either Cr(CO)5-THF or Mn(CO)5-THF giving rise to 69
without loss of stereochemical integrity. It is worth mentioning the
observation by the authors that the
-butyrolactone ring was formed
in preference to the -valerolactone ring, and that protection of the
other hydroxyl group in 68 was not required. Coupling of 69 with
1-iodonon-1-yne afforded the conjugated acetylene 70, which was
transformed into (+)-muricatacin by exhaustive hydrogenation of
the triple bonds.
Using (+)-diethyl L-tartrate as starting material, Somfai [42] has
reported another preparation of (+)-muricatacin (Scheme 12). The
O synthesis started [43] with the conversion of (+)-diethyl L-tartrate
into the corresponding p-methoxybenzylidene acetal 71. Reduction
of the ester groups in 71 was followed by reductive opening of the
acetal moiety to furnish compound 72 in excellent yield. Selective
R1 protection of the 1,2-diol moiety in compound 72 gave acetal 73
R2 [44].
Tosylation of the primary OH group of 73 followed by reaction
with undecylmagnesium bromide under Cu(I)-catalysis allowed for
a C-C coupling reaction which led to 74, thus installing the twelve-

HO OH HO OH
a b or c

MsO OMs O
O
67 68 69 OH
d e
R2
O O
O R1 O
OH OH
70 (+)-(4S,5S)-1
R1 = nC7H15 R2 = nC12H25

Scheme 11. Reagents. a: Lithium acetylide-EDAcomplex (4 equiv), DMSO; 0 ºC (95% ee, 87%,); b: i. Cr(CO)5,.THF (2 equiv), THF, 21.5 h, 20 ºC, ii. CAN
(1 equiv), acetone, 3 h, 20 ºC (68%); c: i. W(CO)5,.THF (2 equiv), THF, 6.5 h, 20 ºC, ii. CAN (1 equiv), acetone, 3 h, 20 ºC (74%); d: 1-iodonon-1-yne,
(Ph3P) 2PdCl2 (3 mol%), CuI (3 mol%), i Pr2NH (1.8 equiv), THF, 1.25 h, 45ºC (82%); e: H2 (4 atm), 10% Pd/C, EtOAc, 16 h, 20ºC (94%).
24 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

O OH CO2Et OCH2Ar
O b,c
OEt a OH
EtO Ar HO
O
OH O CO2Et OH
L-DET 3 72
Ar = pMeO-C6H4

OCH2Ar OCH2Ar OCH2Ar

d OH e R f R
O O
O
O O
Et Et 75
Et Et
73 74
R= nC H
11 13
OCH2Ar
g R

EtO OH
76

H OCH2Ar OCH2Ar
H
H R R
C
O OH O OH

OCH2Ar
OH R
i
O O O
R
O
(+)-(4S,5S)-1 77

Scheme 12. Reagents. a: p-MeO-C 6H4-CH(OMe) 2, TsOH, DMF, 10 mm Hg, 5 h, 50ºC; b: NaBH4 , LiCl, THF-EtOH, 24 h, rt (100%); c: BH 3.THF, THF, 6 h,

(94%); d: 3-pentanone, TsOH, THF, TLC-following, rt (89%); e: i. TsCl, py, 0ºC, ii. n C11H 23 MgBr, CuI, THF, 90 min, -30ºC (82%); f: i. 2% aq H2 SO4 , MeOH,
2 days (91%), ii. TsCl, py, 13 h, 0ºC, iii. K2CO3 , MeOH, 30 min, 0ºC (83%); g: ethoxyacetylene, BuLi, BF3.OEt2, THF, 1 h, -78ºC (79%); h: xylenes, 25 h

(79%); i: DDQ, CH2 Cl2 , H2O, 45 min, rt (89%).

carbon aliphatic chain of (+)-muricatacin. Acetal deprotection fol-
lowed by selective tosylation of the primary OH group transformed
it into the leaving group for a subsequent intramolecular epoxida-
tion, which afforded 75.
Lactone formation was foreseen by application of MaGee´s
procedure [45], which consists in the intramolecular trapping of
ketenes, themselves available from alkynylethyl ethers by a thermal
retro-ene reaction, useful for the construction of small, medium an
large ring lactones from primary, secondary or tertiary alcohols.
The requisite ethyl-(4-hydroxyalkyl)ether 76 was prepared by ring
opening of the epoxide in 75 with the lithium anion of ethoxyacety-
lene. Slow addition of 76 to carefully dried refluxing xylenes re-
sulted in the formation of lactone 77, which was O-deprotected to
give (+)-(4S,5S)-1.
In a new approach from tartaric acid, Prasad and co-workers
have shown that a series of -hydroxy aldehydes could be obtained
in high enantiomeric purity from L-(+)-tartaric acid involving sim-
ple stereoselective transformations. The authors anticipated that the
1,2-diol unit of tartaric acid could be used as a masked aldehyde
synthon by oxidative cleavage of the C2-C3 bond, after stereoselec-
tive manipulations of the carboxylate groups [46]. Applying this
strategy [47], which hinged upon the preparation of the -
hydroxyaldehyde 83 as the key step, they have developed an effi-
cient synthesis of (-)-muricatacin (Scheme 13). Following this ap-
proach, both chiral centres of the starting material were used to
produce carbon C5 of (-)-muricatacin, whereas the stereochemistry
of carbon C4 was induced by a diastereoselective Grignard addition
to the key -hydroxyaldehyde intermediate 83.
L-(+)-tartaric acid was readily transformed to dimethyl-2,3-O-
isopropylidene tartrate diester 78 in one step on a 100 g scale [48].
Conversion of 78 to the bis-Weinreb amide 79 could be achieved
with N-methoxymethylamine hydrochloride either using trimethy-
laluminum activation [49] or via the corresponding magnesium salt
[50]. Addition of excess dodecylmagnesium bromide to 79 afforded
diketone 80, which was reduced under conditions previously opti-
mized by the authors for such type of diketones [46]. Compound 81
was produced as a single diastereomer. Protection of the alcohols as
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 25

OMe
N O
CO2Me
O O O O R
a or b c d

O O O O R
CO2Me
78 N O
OMe
80
79
HO BnO
OBn
O R HO R
e f
O
R
O R HO R
H
HO BnO
83
81 82
g

OH OBn
i h OBn
O O
O O
R R R

(-)-(4R,5R)-1 85 OH

R = nC12H25 84

Scheme 13. Reagents. a: HN(OMe)Me.HCl, AlMe3, CH2Cl2, 2 h, -78ºC (83%); b: HN(OMe)Me.HCl, iPrMgCl, THF, 20 min, -10ºC (83%); c: nC12H25MgBr,
THF, 1.5 h, 0ºC (96%); d: K-Selectride, THF, 2.5 h, -78ºC (90%); e: i. BnBr, NaH, DMF, 0ºC to rt, 2.5 h (92%), ii. FeCl3.6H2O, CH2 Cl2 , 3 h, rt (87%); f:
Pb(OAc)4, benzene, 1.5 h, rt; g: CH2=CHCH 2CH2 MgBr, MgBr2 .OEt2, CH 2 Cl2, 4 h, -78ºC; h: i. O3 /O2 , Me2 S, CH2Cl2 : MeOH, 4.5 h, 0ºC, ii. PCC, NaOAc,
Celite, CH2Cl2, 1.5 h, rt (55% from 5); i: H 2, Pd/C, MeOH, 3 h, rt (83%).
OMe
N O BnO

O O O R O R
a b c

O O O O O O

N N N
OMe OMe OMe
79 86 87
BnO BnO BnO

O R O R HO R
d e f

O OH O I

88 89 90
OBn OBn OH
O O O
O g O h O
R R R

92 (-)-(4R,5R)-1
91 R = nC12H25

Scheme 14. Reagents. a: nC12H25MgBr, THF, 30 min, -15ºC (82%); b: i. K-Selectride, THF, 2.5 h, -78ºC, ii. BnBr, Ag2 O, Tol, 26 h,
(94%); c: NaBH4,
MeOH, 3 h, 0ºC to rt (92%); d: I2 , PPh3 , imidazole, Tol, 3 h,
(86%); e: Zn, EtOH, 1 h
(99%); f: acryloyl chloride, Et3N, DMAP (cat), CH 2Cl2, 1 h, 0ºC
(88%); g: Grubbs-2nd generation catalyst, Tol, 5 h,
(91%); h: H2 , Pd/C, EtOAc, 2 h (97%).

the corresponding benzyl ethers was followed by deprotection of
the acetal in 82 and oxidative cleavage of the intermediate diol to
give aldehyde 83. Chelation controlled addition of a Grignard rea-
gent to the key -hydroxyaldehyde 83 in the presence of MgBr2
afforded the syn-alcohol 84 in a highly diastereoselective fashion.
Ozonolysis of alcohol 84 yielded an intermediate lactol, which
upon oxidation afforded lactone 85. Finally, debenzylation of lac-
tone 85 gave (-)-(4R,5R)-1.
In an alternative approach [51], controlled addition of dodecyl-
magnesium bromide to 79 afforded monoketone 86 (Scheme 14).
26 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

O OH OTBS

a b
H O O O
O O O O O
O O
(R)-93 94 95

OTBS OH

c d
CHO R
O O
O O
ent-96a
(-)-(4R,5R)-1
R = nC12H25

Scheme 15. Reagents. a: i. 2-[(tbutyldimethylsilyl)oxy]furan (TBSOF), BF3.OEt2, 6 h, -80ºC (75%), ii. chromatography, hexanes : EtOAc (3 : 2); b: i. H2 (1
atm), Pd/C(10%), THF, NaOAc (cat), 24 h (90%), ii. TBS-Cl, imidazole, DMF, 36 h (90%); c: i. 70% aq AcOH, 8 h, 50ºC (95%), ii. aq NaIO4, SiO 2, CH2Cl2,
20 min, rt (85%); d: i. nC10H21CH=PPh3, THF, 3 days, -80ºC to rt (9 : 1 Z/E-mixture, 60%), ii. H2 (1 atm), Pd/C, NaOAc (cat), 24 h (93%), iii. BF3OEt2, CHCl3 ,
8 h, rt (90%).
O
O
M
O
d O
O O
H
OH O
OH O
(R,R)-100 (R,S)-99
c

O
O
O

a b (R,R)-98a
H O O +
O O O

O
(R)-93 97 O

(S,R)-98b

O
H
O

(S,S)-99

Scheme 16. Reagents. a: i. cyclopropylmagnesiumbromide, NaH, THF, 6 h, 70ºC, ii. addition of (R)-93 in THF, tris[2-(2-methoxyethoxy)ethyl]amine
(10%), 14 h, 70%; b: mCPBA, CH 2Cl2 , 0ºC to rt (49% 98a, 21% 99b); c: LiI (1%), CH 2Cl2 , 5h,
(90% de, 81%); d: i. mCPBA, CH 2Cl2 , rt, 2 h (68%), ii.
FeCl3-SiO 2, CH2Cl2, 48 h, rt (96%); e: LiClO4 (2 equiv), benzene, 24 h,
(80% de, 85%).

Stereoselective reduction of the keto group in 86 with was fol-
lowed by protection of the hydroxyl group as the corresponding
benzyl ether and reduction of the remaining Weinreb amide to af-
ford the primary alcohol 88. This was transformed into the corre-
sponding iodide 89. Treatment of 89 with activated Zn promoted a
-elimination of the intermediate organometallic and produced the
allylic alcohol 90. Reaction of 90 with acryloyl chloride afforded
ester 91, which was subjected to a ring-closing metathesis reaction
furnishing the butenolide 92. Hydrogenation of the double bond
gave rise to (-)-(4R,5R)-1.
D-mannitol can be readily transformed in bulk quantities to (R)-
D-isopropylideneglyceraldehyde [(R)-93] by selective transforma-
tion to 1,2:5,6-di-O-isopropylidene-D-mannitol followed by oxida-
tive cleavage of the diol moiety [52], and therefore has been used as
starting chiral material for a wide variety of stereoselective synthe-
ses.
Naturally Occurring  -Hydroxy-
-Lactones
O OH
a b
H O R O + R
O O
101 102a
OTBDPS
R OH
OH
104
OTBDPS
g R
R O
O O
OH TBSO
107
106
Scheme 17. Reagents. a: nC12H25MgBr, 0ºC to rt (76%); b: PCC, rt (75%); c: i. LiAlH4, THF, 0ºC (70% de, 94%), ii. chromatography; d: i. TBDPSCl, imida-
zole, rt, ii. TFA, H2 O, 0ºC (88%); e: i. TsCl, py, 0ºC, ii. K 2CO3 , MeOH, rt (85%); f:allylmagnesium bromide, CuBr, -40ºC to rt (78%); g: O3, NaOH, MeOH, -
15ºC (75%); h: TBAF, THF, rt (72%).
Rassu, Casiraghi and co-workers have adapted their Lewis-acid
catalyzed conjugate Mukaiyama-aldol addition of 2-[(tert-
butyldimethylsilyl)oxy]furan (TBSOF) to aldehydes for the di-
astereoselective synthesis of both enantiomers of muricatacin [53]
using (R)-93 as starting material (Scheme 15).
The chiral centre of the starting material was used to induce the
stereochemistry of both C4 and C5 of the targets, and was de-
stroyed afterwards by conversion into an aldehyde. This aldehyde
group was employed to build the twelve-carbon aliphatic chain of
muricatacins by a Wittig strategy. Thus, addition of TBSOF to (R)-
93 under BF3-catalysis was highly syn selective (formation of 94,
88% de). This step already generated the future (4R,5R)-
configuration of (-)-muricatacin. Saturation of the C=C bond in 94
and protection of the OH group was followed by selective acetal
hydrolysis and oxidative fission of the C6-C7 bond in 95 to afford
aldehyde ent-96a. Finally, homologation of the aldehyde group in
ent-96a by a Wittig reaction followed by hydrogenation and desily-
lation gave (-)-(4R,5R)-1.
The same synthetic sequence, but using (S)-L-isopropyl-
ideneglyceraldehyde [(S)-93] as starting material, allowed for the
synthesis of the anti isomer (+)-(4S,5S)-1.
In a different application of (R)-93, Piras and co-workers have
synthesized [54] the oxaspiropentanes (R,R)-98a and (S,R)-98b
(Scheme 16) by the diastereoselective epoxidation of (S)-4-
cyclopropylidene-2,2-dimethyl-1,3-dioxolane 97, in turn prepared
by an improved Wittig reaction using cyclopropylidenetriphenyl-
phosphorane under PTC-conditions [55].
Compound (R,R)-98a has been transformed into lactone (R,R)-
100, thus allowing for a formal synthesis of (-)-muricatacin [56].
The key step of this method consisted in the stereoselective ring
expansion of oxaspiropentanes to cyclobutanones, which could be
regioselectively transformed into
-lactones. Coordination of a
Current Organic Chemistry, 2010, Vol. 14, No. 1 27
OH O
O R O
O O
102b 103
OTBDPS
e f
R
O
105
h R
O
HO
(-)-(4R,5R)-1
R = nC12H25
Lewis acid with both the oxygen atom of the epoxide and an alkoxy
group in the vicinal position of the lateral chain may create an elec-
tronic deficiency on the non-cyclopropylic carbon of the epoxide
ring. At this point the oxaspiropentane undergoes a ring expansion
to the corresponding cyclobutanone. The stereospecificity of this
rearrangement strongly depended on the type of acid used. When
Li-salts were employed as Lewis acids, the stereoselectivity de-
pended on the particular Li-salt used and on the stereochemistry of
the starting oxaspiropentane [57].
When this procedure was applied to (R,R)-98a using LiI as
Lewis acid in CH2Cl2 solution, the ring expansion took place with
inversion of configuration, and cyclobutanone (R,S)-99 was ob-
tained (>90% de). Baeyer-Villiger oxidation with retention of con-
figuration at the migrating carbon, followed by deprotection of the
acetal moiety gave rise to lactone (R,R)-100, which had been previ-
ously transformed into (-)-muricatacin [13, 58]. On the other hand,
using LiClO4 as the Lewis acid reagent for the ring expansion of the
oxaspiropentane (S,R)-98b led preferentially to the cyclobutanone
(S,S)-99 with retention of configuration. As the latter result was
complementary to that obtained with LiI and (R,R)-98a, the authors
pointed out that following the same sequence used for the synthesis
of (-)-muricatacin should also make possible the synthesis of the
(+)-epi-(4S,5R)-muricatacin enantiomerically pure form.
The related (R)-2,3-cyclohexylideneglyceraldehyde 101 [59]
has been used by Chattopadhyay and co-workers in a simple and
efficient synthesis of (-)-muricatacin [60] (Scheme 17).
Reduction of ketone 103 with LiAlH4 took place with good syn
selectivity (70% de), which was explained by operation of the Fel-
kin-Ahn model aided by the bulky cyclopropyl group, with negligi-
ble participation of a chelated model. Silylation of 102a and
deketalization of the intermediate silylether afforded diol 104,
which was converted to epoxide 105 by tosylation of the primary
28 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

OMe
OH O OAc
O OH O Br
a O O

O OH O O
O Br
OH O OAc
108 OMe

OBn
O
O HO R1 OBn
b c
R1 O
O HO R
O H
OBn 111
109
110
OBn OBn OBn
d e f
R1 R1 R1

OH O O
112 O
O 114
113

g HO R1 = nC11H23
O O R2 = nC12H25
R2
(-)-(4R,5R)-1

Scheme 18. Reagents. a: i. CH 3C(OMe) 3 (3.0 equiv), PPTS (cat), 3 h, 25ºC, ii. AcBr, Et3 N (cat), CH 2Cl2 , 3 h, 0ºC to 25ºC, iii. K 2CO 3 (3.5 equiv), MeOH, 1
n
h, 20ºC (85%); b: i. C11 H 23 MgBr, CuI, THF, rt (93%), ii. NaH, THF, 1 h,
, iii. BnBr, Bu4NI (cat), THF, 12 h
(85%); c: Pb(OAc)4, benzene, 4 – 5 h, rt
(aprox. 80%); d: i. MgBr2OEt2, CH2Cl2, 1 h, -78ºC, ii. vinylmagnesiumbromide, CH2Cl2, 12 h, -78ºC (60% from 19); e: acryloyl chloride, Et3N, DMAP (cat),
CH2Cl2, 3 h, 0ºC (70%); f: Grubbs-2nd generation catalyst, degassed Tol, 24 – 30 h, 80ºC (80%); g: H2 (1 atm), Pd(OH)2 /C(20%) (Pearlman´s catalyst), EtOH,
48 h, rt (89%).

OH group followed by intramolecular base-induced SN2 reaction.
Regioselective ring-opening of the epoxide 105 with allylmagne-
sium bromide produced 106. Ozonolysis of 106 under basic condi-
tions afforded directly the -lactone 107, which was finally desily-
lated to produce (-)-(4R,5R)-1.
The authors pointed out that, compared to the corresponding
isopropylidene derivative 93, the use of 101 was advantageous due
to the better stability of the cyclohexylidene ketal functionality and
to the easy column chromatographic separation of the carbinol epi-
mers 102a and 102b.
Carda, Marco and co-workers have developed the synthesis of
various naturally occurring lactones using ring-closing metathesis
(RCM) reactions as one of the key steps [61]. In particular, they
have adapted their methodology for the synthesis of (-)-muricatacin
[62] using the -benzyloxyaldehyde 111 as starting material
(Scheme 18). In turn, compound 111 was prepared from the known
bisepoxide 109, which could be synthesized from 3,4-O-
isopropylidenemannitol (108) [63].
Diastereoselective reaction of 111 with excess vinylmagnesium
bromide in CH2Cl2 in the presence of MgBr2 allowed inducing C4
of the target molecule. Esterification of 112 with acryloyl chloride
furnished the key intermediate 113, which upon RCM with
Grubbs´second generation Ru-catalyst yielded the
,-unsaturated
lactone 114. Hydrogenation of the C=C bond in 114 took place with
concomitant cleavage of the benzyl group to afford (-)-(4R,5R)-1.
Also starting from D-mannitol and using a RCM-CM reaction
as key step, Quinn and co-workers have developed [64] a concise
total synthesis of (-)-muricatacin (Scheme 19). D-Mannitol was
transformed into 116 by known procedures [65] consisting in selec-
tive transformation of the primary OH groups into bromide fol-
lowed by acetylation of the secondary OH groups, and double se-
lective elimination using Zn and methanolysis of the crude material.
Desymmetrization of 116 by monobenzylation of the
stannylene acetal was followed by esterification to afford the key
intermediate 117. This was subjected to RCM using 2nd-generation
Grubbs´catalyst, giving rise to the selective formation of lactone
118. Sequential cross metathesis (CM) of 117 with 1-dodecene
afforded 119, which upon hydrogenation gave rise to (-)-(4R,5R)-1.
Alternatively, a tandem RCM-CM was developed: syringe-pump
addition of the metathesis catalyst to a mixture of 4 and 1-dodecene
gave rise directly to lactone 119.
Trost and co-workers [66] have developed an alternative proce-
dure for the synthesis of the key intermediate 123 for RCM. A mix-
ture of dl- and meso-divinylethylene carbonates, obtained by the
reductive dimerization of acrolein followed by cyclization in neat
diethylcarbonate [67], was used as electrophile in a dynamic kinetic
asymmetric transformation (DYKAT) by palladium-catalyzed al-
lylic alkylation reactions. From the diastereomeric mixture of meso
and chiral racemic starting materials, a single product (122) was
obtained in high optical purity (Scheme 20). This methodology has
been used for the synthesis of (+)-muricatacin using 2,3-
dimethylphenol as nucleophile.
Butenolide 124 was obtained by RCM of 123 with 2nd-
generation Grubbs catalyst. However, a lack of reactivity of 124 in
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 29

OH OAc

HO OH AcO Br HO
a b

HO OH AcO Br HO

OH OAc 116
D-Mannitol 115
OBn OBn
c d

O O
O
O 118
117
e

f OBn

f HO
H13nC10
O
O O
H25nC12
O
(-)-(4R,5R)-1
119

Scheme 19. Reagents. a: i. AcBr, 1,4-dioxane, ii. Ac 2 O, py (63%); b: i. Zn, NaOAc, AcOH,
, ii. NaOMe, MeOH (88%); c: i. Bu 2SnO, Bu 4 NI, BnBr, ben-
i nd
zene (84%), ii. acryloyl chloride, Pr 2 Net, CH 2Cl2 (83%); d: Grubbs-2 generation catalyst (10%), CH 2Cl2 , 24 h, 40ºC (58%); e: 1-dodecene, CH 2Cl2, 24 h,
nd
40ºC (55% from 117); f: 1-dodecene (5 equiv.), syringe-pump addition of Grubbs-2 generation catalyst (10%), CH 2Cl2 , 12 h, 40ºC (65%).
O O
O OAr
a O O O O b
H +
OH
rac-120 121 122

ArO HO
OAr R
c d e

O O O

O O O
123 124 125

f OH
O R = nC10H21
O R

(-)-(4S,5S)-1

O O
Ph2P NH NH PPh2

(R,R)-126
Scheme 20. Reagents. a: i. Zn, THF, aq NH 4Cl, ii. (EtO) 2CO (70%, 120 + 121 (1 : 1)); b: 2,3-dimethyl-4-methoxyphenol (0.77 equiv.), (C3 H 5PdCl) 2 (1.0 %),
nd
(R,R)-126 (3 %), CH 2Cl2 , 72 h, 0ºC (98% ee, 85%); c: acryloyl chloride, Et3 N, DMAP (cat), CH 2Cl2 , 0ºC to rt (71%); d: 10% Grubbs-2 generation cata-
nd
lyst, CH 2Cl2 , 2.5 h,
(70%); e: i. CAN, CH 3CN-H 2 O (70%), ii. dodecene (5 equiv), 10% Grubbs-2 generation catalyst, CH 2Cl2 , 1 h,
(84%); f: H 2, Pd/C
(93%).
30 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

O O O
O O O
BnO BnO BnO
a b

BnO BnO OH BnO R

O
O OH 129
128
127
OH
OH CO2Bn
BnO BnO
c d e

BnO R BnO R
130 131
O
HO CO2H
f
O R = nC10H21
HO R
132 HO R

(-)-(4R,5R)-1
n
Scheme 21. Reagents. a: AcCl (5 equiv), MeOH, 5 min, 0ºC (88%); b: i. Pb(OAc) 4 , CH 2Cl2 , 3 h, rt, ii. [ C 1 0 H 2 1 PPh 3 ]Br, BuLi, THF, 12 h, 0ºC to rt (65 –
75%); c: TFA, THF-H 2 O (4:1), 6 h, 65ºC (85 – 95%); d: i. Pb(OAc) 4 , CH 2 Cl2, 3 h, rt, ii. Ph3P=CHCO 2Bn, THF, rt (70 – 80%); e: H 2 , 10% Pd/C, EtOH, 12 h,
rt; f: TsOH, Tol, 1 h, 70ºC (92 – 95%).
OTBS
O CO2Et
a b
CO2Et
O CO2Et
CO2Et
133 TBSO
134
TBSO OH TBSO
CO2Et c CHO d
EtO2C EtO2C
TBSO OH TBSO
135 136
EtO2C
O
f
O R = nC10H21
OTBS HO
R
TBSO R

(-)-(4R,5R)-1
137
Scheme 22. Reagents. a: i. HS-CH 2CH 2-SH, BF3OEt2, 10 min, rt (91%), ii. TBS-Cl, imidazole, THF, 24 h, rt (90%); b: OsO4 (cat), NMO, acetone, 4 h, rt
(83%); c: NaIO4, NaOH, EtOH-H2O, 45 min, rt (87%); d: [nC10H 21 PPh3]Br,BuLi, THF, 25 min, -78ºC (73%); e: i. H2 (60 psi), Pd/C(10%), EtOH, 1 h, rt (95%);
ii. TBAF, THF, 3 h, rt (74%).

an attempted CM reaction was observed, probably due to the pres-
ence of the electron-rich aryl ether. Therefore, this was oxidatively
cleaved prior to CM with undecene, which gave rise to 125. This
was hydrogenated to (+)-(4S,5S)-1.
Singh and co-workers [68] have described a general approach
towards the synthesis of -hydroxy-
-butyrolactones starting from
the mannitol derivative 127 (Scheme 21) [69]. The chiral centres of
the final -hydroxy-
-butyrolactones were the original C3 and C4
carbons of D-mannitol, which were preserved throughout the proc-
ess.
Selective hydrolysis of one of the acetal moieties of 127 gave
diol 128, which was subjected to oxidative cleavage to give an in-
termediate aldehyde. Wittig reaction produced 129, which upon
acetal hydrolysis, oxidative cleavage of the diol moiety in 130 and a
second Wittig reaction afforded 131. Hydrogenation took place
with simultaneous C=C saturation and debenzylation to give 132,
which upon acidic treatment lactonized to (-)-(4R,5R)-1.
Maycock and co-workers have carried out the synthesis of (-)-
muricatacin [70] using as starting material the chiral dienoate 133,
which was accessible from D-mannitol or from L-tartaric acid [71,
72] (Scheme 22). The strategy depended upon the desymmetriza-
tion of 134 by dihydroxylation and elaboration of the hydroxy alkyl
side chain.
The diene 134 was monodihydroxylated according to a previ-
ously reported procedure [71]. On the other hand, mono- or bis-
dihydroxylation of the dienoate 133, having the isopropylidene
protecting group, gave surprisingly low diastereoselectivities. The
conformation of the molecule having the isopropylidene system
Naturally Occurring  -Hydroxy-
-Lactones
O O
O O
O O a b
H
O BnO
HO
DAG
OCHO
c CHO d e
R R
OBn
140a
Scheme 23. Reagents. a: i. BnCl (98%), ii. AcOH, iii. NaIO4 (99%); b: i. [n C11H 23PPh3]Br, BuLi, THF, 12 h, rt (80%), ii. H2, Pd/C, EtOAc, 10 h, rt (91%); c: i.
BnCl, NaH, THF, 5 h, rt, ii. 2N HCl, DME, 48 h, rt, iii. NaIO4 , MeOH, 1 h, rt; d: (EtO2)P(O)CH 2CO 2Et, NaH, THF, 2 h, rt (67%); e: i. H2 , Pd/C, EtOAc, 24 h,
rt (71%); ii. TFA-H2O (4:1), 3 h, rt (50% from 141).
must be constrained by the five membered ring in such a manner
that both faces of the
-system are sufficiently exposed and hence
the undesired diastereomer was also formed. On the other hand, it
has been possible to carry out bis-dihydroxylations and to obtain
almost exclusively one isomer using unconstrained (non-cyclic)
diTBS and dibenzyl ethers. The diastereoselectivity of the dihy-
droxylation was attributed to the conformation of the molecule
which involves mutual protection of both carbon-carbon double
bonds. This conformation was rationalised in terms of the steric
interactions between the ether groups causing them to attain a con-
formation in which these bulky groups are as far apart as possible.
Diol 135 was oxidatively cleaved to afford the aldehyde 136.
Wittig olefination of 136 introduced the future twelve-carbon ali-
phatic side chain of muricatacin. Hydrogenation of both C=C
bonds, and desilylation of the protected alcohols followed by spon-
taneous cyclization led to (-)-(4R,5R)-1. The authors pointed out
that, since both enantiomers of 133 were available from the corre-
sponding tartaric acids, this method provided a formal access to
both enantiomers of muricatacin.
Starting from D-glucose, Kang and co-workers [73] have re-
ported a synthesis of (-)-muricatacin (Scheme 23).
First, diacetone-D-glucose was transformed into aldehyde 138
[74]. This was converted into the 3-hydroxyfuranose 139 by a Wit-
tig reaction followed by hydrogenation. Benzylation, acetal depro-
tection and oxidative cleavage of the resulting diol afforded alde-
hyde 140a. Wittig reaction, hydrogenation and acidic induced lac-
tonization afforded (-)-(4R,5R)-1.
This method has been extended by Yoon and co-workers [15]
for the synthesis of the other muricatacin enantiomer as well as both
enantiomeric epi-muricatacins (Scheme 24). In this approach, com-
pound 139 was used as precursor of the syn and anti enantiomers of
aldehydes 140b-d, which have been homologated to the final tar-
gets using as common steps those used previously (Scheme 23) for
the transformation of 140a into (-)-(4R,5R)-1. Following this ap-
proach, the stereochemistry of carbons C3 and C4 of the glucose
derivative 139 became carbons C4 and C5 of the final targets, with
retention or inversion of the configuration depending on each
stereoisomer.
The synthesis of (+)-(4S,5S)-1 required the inversion of the con-
figuration at both carbons C3 and C4 of the glucose derivative 139
(Scheme 24). Firstly, inversion of C4 was accomplished via a de-
hydration-hydroboration-oxidation sequence, which allowed for the
Current Organic Chemistry, 2010, Vol. 14, No. 1 31
OHC O R O
O O
HO
138 139
OCHO
HO
CO2Et
O
O
OBn R
141 (-)-(4R,5R)-1
R = nC12H25
synthesis of 143. Secondly, inversion of C3 was carried out by an
oxidation-reduction sequence, which allowed for the synthesis of
145. Both operations were carried out in complete stereoselective
fashion, with no other diastereomers being isolated in either step.
Protection of the free OH group in 145 as the benzyl derivative,
acidic removal of the isopropylidene group, and oxidative cleavage
gave the (2R,3S)-O-protected-2,3-dihydroxyaldehyde 140b.
The synthesis of the epi-isomers required the inversion of only
one of the chiral carbons, either C3 or C4, of the starting material.
Compound 140c was used as precursor of (+)-(4S,5R)-1. The syn-
thesis of 140c required inversion of the configuration of C3. This
was accomplished by an oxidation-reduction sequence, which af-
forded 147 as the sole isolated product. As before, benzyl-
protection of the hydroxy group in 147, acidic removal of the iso-
propylidene group and oxidative cleavage of the resulting he-
miacetal gave rise to 140c. On the other hand, the synthesis of
140d, precursor of (+)-(4R,5S)-1, required inversion of the configu-
ration of C4. This was accomplished from 139 by the dehydration –
hydroboration – oxidation sequence previously developed for the
synthesis of 140b.
Starting from inexpensive D-xylose and using conventional
reagents, Popsavin and co-workers planned a stereospecific formal
synthesis of both muricatacin enantiomers. This was possible mak-
ing profit of the latent symmetry plane present in the chiral precur-
sor and using Wittig reactions for the chain elongation of either C1
or C5 (Fig. 7).
The formal syntheses of the muricatacins [75,76] was based on
the preparation of the advanced intermediate aldehydo--lactones
96 and ent-96, which had been previously used as starting materials
for the synthesis of these targets [53, 13]. Following this approach,
stereocentres C2 and C3 of D-xylose became carbons C4 and C5 of
(+)-muricatacin without the need of inversion.
Compound 149 was readily prepared from D-xylose via 148
(Scheme 25) [77, 78]. Hydrolytic removal of the cyclohexylidene
protective group gave the corresponding lactol 150. Wittig olefina-
tion of 150 took place stereoselectively to afford the E-unsaturated
ester 151 as the only isolable product. Although the C=C double
bond was to be reduced in the subsequent step of the synthesis, the
Wittig step was particularly challenging and required the develop-
ment of particular reaction conditions to ensure a good E-
selectivity. Should any Z-,-unsaturated ester be formed, a drop in
yield was experienced because of intramolecular oxa-Michael addi-
tion to form a bicyclic lactone. Catalytic hydrogenation of 151
32 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

OCHO
HO
CHO
O R
O
R OBn
(+)-(4S,5S)-1 140b

OCHO O
R O
HO CHO
O R
O O
R OBn HO

140d 145
(-)-(4R,5S)-1

e d

O O O
R O b R O c R O

O O O
HO O
142 143 144

O O O
R O c R O d R O

O O O
HO O HO
139 146 147
R= nC H
12 25
e

OCHO
HO CHO
O R
O
R OBn
(+)-(4S,5R)-1 140c

Scheme 24. Reagents. a: i. Tf 2 O, py, CH 2Cl2 , -10ºC, ii. DBU, Et2 O, rt (76%); b: i. Sia 2BH, THF, 0ºC to rt, ii. H 2 O 2 , aq NaOH, rt (50%); c: (COCl)2 , DMSO,
Et3 N, 2 h, -60ºC to rt (82% from 139); d: NaBH 4 , MeOH, rt (96%, from 146, 76% from 143); e: i. BnCl, NaH, THF, 5 h, rt, ii. 9.6 N HCl-TFA, DME, 48 h,
rt, iii. NaIO 4 , MeOH, 1 h, rt (47% 140b, 55% 140c, 58% 140d).

In a related fashion, compound 159 was prepared from 157, in

turn obtained from D-xylose (Scheme 26). Hydrolytic removal of
H OH OR
O the acetal protecting group gave lactol 160. E-Selective Wittig ole-
O
fination produced 161, which upon reduction of the double bond
O OH CHO
96 afforded ester 162. Treatment with sodium methoxide promoted
OH OH simultaneous debenzoylation and cyclization to 163, which upon
OR oxidative cleavage of the diol moiety gave 96b. However, the elon-
O gation of the chain of the aldehydo-
-lactone 96b by a Witti g
D-Xylose O
CHO procedure took place only with low yields, possibly due to the
latent plane of symmetry
ent-96 electrophilic nature of the lactone moiety. Therefore, an alterna-
a, R = TBS; b, R = Bn
tive procedure was sought, which was based in the use of diol
Fig. (7).
66. Reduction of crude aldehyde 96b gave the expected primary
alcohol 164 along with an equal amount of ester 165. Except for
yielded the corresponding saturated ester 152, which upon acidic characterization purposes, the mixture was not separated, but was
treatment was lactonized to 153. Debenzylation furnished diol 154, further treated with aqueous acid to complete the lactonization of
which was transformed into the acetonide 155. Silylation followed 165 to 164. Catalytic hydrogenolysis of 164 furnished the known
by acetal hydrolysis and oxidative fission of the diol moiety in 156 diol 66, which had previously been used in the synthesis of (+)-
afforded the aldehydolactone 96a, precursor of (+)-muricatacin muricatacin [13].
[53].
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 33

HO HO BxO
O OH O O
i O b O

HO OH HO O BxO O
DBxylysn 148 149
BxO
BxO OBx O
O
j OH l n
OMn

BxO OH OH OH
150 151
BxO OBx O BxO OBx OH OH
f o
OMn
OH OH OH O OH O
152 153 154
O O
OH OH OTBh OTBh
h i j
O OHc
O O OH O O
155 O 156 O 96a O

HO
O
O
g
)++B)4S,5S+B1
Scheme 25. Reagents. a: i. cyclohexanone, H 2SO 4 (cat), Et2 O, 24 h, rt (21%), ii. AcOH-H 2 O (1:1), 20 – 30 min, 100ºC (75%); b: BnCl, KOH, DMSO, 1 h,
60ºC (75%); c: 70% aq AcOH, 8 h,
(71%); d: Ph 3P=CHCO 2 Me, DMF, 24 h, 60 - 70ºC (74%); e: H 2 , PtO 2 .EtOH, 24 h, rt (62%); f: TFA - H 2 O (2:1), 3 h, rt
(98%); g: H 2 , 5% Pd/C, 20 h, rt (91%); h: Me 2C(OMe) 2 , TsOH, DMF, 3.5 h, rt (31.5%); i: i. TBS-Cl, imidazole, DMF, 24 h, rt (81%); ii. AcOH - H 2 O (7:3),
3 h, 50ºC (91%); j: 0.65 M aq NaIO 4 , silica gel, CH 2Cl2 , 0.5 h, rt (97%).
HO BzO BzO
O O O
O a O b O

HO O HO O BnO O
157 158 159

BzO
BzO OBn O
O
c OH d e
OMe

BnO OH OH OH
160 161
BzO OBn O OH OBn OBn
f g
OMe OHC
OH OH OH O O
162 i 163 96b
O O

OBn OBn
h HO HO CO2Me
+
O OH
164 165
O
j

OH
HO HO
O
O
O R
66 O (+)-(4S,5S)-1

Scheme 26. Reagents. a: BzCl, py, CH2Cl2, 69 h, -22ºC and 24 h, rt (84%); b: BnBr, NaH, DMF, 0ºC to rt and 2.5 h, rt (64%); c: AcOH - H2O (7:3), 5.5 h,

(85%); d: Ph 3P=CHCO 2 Me, DMF, 3.5 h, 60-70ºC (84%); e: H 2 , PtO 2 , EtOH, 16 h, rt (75%); f: NaOMe, MeOH, 1.5 h, rt (82%); g: aq NaIO 4 , silica gel,
CH 2Cl2, 1 h, rt (89%); h: NaBH 4 , MeOH, 1.5 h, 0ºC to rt; i: TFA, 2 h (73%), j: H 2 , Pd/C, EtOAc, 19 h, rt (69%).
34 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

BzO HO
O O
O a O b

HO O BnO O
158 166

OHC O O
O c MeO2C O

BnO O BnO O
167 168

O OBn O
d MeO2C OH e H
OMe
BnO OH O OCHO
169 170

OBn OH
f g HO HO
OHC O
O
O O
R
O O (-)-(4R,5R)-1
ent-96b ent-66

Scheme 27. Reagents. a: i. BnBr, NaH, DMF, 2.5 h, 0ºC to rt, ii. NaOMe, MeOH, 2 h, rt (89%); b: DCC, anh. H3PO4, py, DMSO, 3.5 h, rt (83%); c:
Ph3P=CHCO2 Me, CH 2Cl2, 2 h, rt (97%); d: i. H 2, PtO2 , EtOH, 19 h, rt (92%), ii. AcOH-H2O (1:1), 1.5 h,
(64%); e: aq NaIO 4 , silica gel, CH 2Cl2 , 1.5 h, rt
(98%); f: TFA-H 2 O (2:1), 2 h, rt (77% from 169); g: i. NaBH 4 , MeOH, 2.5 h, 0ºC to rt, ii. TFA, 1 h, iii. H 2 , Pd/C, 19 h (71%).

In order to prepare (-)-muricatacin by this method, aldehyde
ent-96b was required (Scheme 27). This was synthesized from
158, again preserving the C3 and C4 stereocentres of the starting
material, which this time became respectively C5 and C4 of the
target. Compound 158 was converted to the primary alcohol 166
through a simple one-pot procedure, which involved 3-O-
benzylation of 158 followed by 5-O-debenzoylation. Oxidation of
the primary hydroxyl group in 166 gave the unstable aldehyde 167,
which was further converted to the expected unsaturated esters 168
(2:1 Z-/E- mixture) by a Wittig reaction. Catalytic hydrogenation of
168 followed by hydrolytic removal of the cyclohexylidene protec-
tive group afforded lactol 169. Oxidative cleavage of purified diol
169 afforded the formate 170, which upon aqueous acidic treatment
yielded the aldehydolactone ent-96b, with the absolute configura-
tion of both stereocenters corresponding to (-)-(4R,5R)-1. This was
transformed into the diol ent-66 by a one-pot procedure comprised
of reduction to the primary alcohol, hydrogenolytic removal of the
benzyl ether protecting group under acidic conditions.
Last, several chiral auxiliary based strategies have been devel-
oped towards the synthesis of muricatacins.
Uang and co-workers have developed an asymmetric synthesis
of (-)-muricatacin using (+)-(1R)-camphor as chiral auxiliary [79].
Chiral oxathiolanone 171 (Scheme 28) was prepared from the con-
densation of thioglycolic acid and (+)-(1R)- camphor [80]. Com-
pound 171 was used as a chiral acetate equivalent. Thus, enoliza-
tion followed by alkylation with an allylic iodide gave 172 in mod-
erate yield and diastereoselectivity.
Treatment of 172 with an equivalent amount of osmium tetrox-
ide promoted first the oxidation of the sulfur to sulfone stage. The
sulfonyl group-directed stereoselective cis-dihydroxylation of the
C=C bond to give an intermediate osmate, which upon acid pro-
moted translactonization and sulfur dioxide extrusion gave (-)-
(4R,5R)-1 as the product, with recovery of the chiral auxiliary. On
the other hand, mCPBA oxidation of the C=C bond in 172 took
place via the sulfone in a non-directing fashion from the convex
face of the molecule. Acid induced ring opening followed by
translactonization and SO2 extrusion led to (-)-(4R,5S)-1.
Solladié and co-workers have reported the sulfoxide-directed
reduction of -keto--hydroxysulfoxides, easily made from -
hydroxyesters and the lithium anion of either (R)- or (S)-methyl-p-
tolylsulfoxide, to anti-1,2-diols (DIBAL) or syn-1,2-diols (DIBAL-
H, ZnBr2, zinc chelate formation between the carbonyl and sulfox-
ide oxygens) [81]. Alternatively, the same type of compounds can
be obtained by the reduction of -hydroxy--ketosulfoxides (syn
from the reduction with DIBAL-H and anti from the reduction with
DIBAL-H in the presence of ZnI2) [82]. Therefore, according to
Solladié´s methodology, the sulfoxide group can be efficiently used
twice to control the stereoselective reduction of carbonyl group in
both the - and -positions. Finally, the CH2-SOTol moiety may be
transformed into CH2OH by means of a Pummerer rearrangement
followed by reduction of an intermediate aldehyde, thus providing
access to syn and anti 1,2,3-triols. However, the method failed in
the case of long chain -hydroxy--ketosulfoxides, probably due to
enolization of the ketone moiety upon reduction. Solladié and co-
workers have provided a solution to this problem by using alkenyl
ketones instead of alkyl ketones, and have applied it to the synthesis
of (-)-muricatacin and (-)-epi-muricatacin [83] (Scheme 29).
Reaction of diethyl oxalate with the anion with (+)-(R)-methyl-
p-tolyl sulfoxide anion gave the -ketosulfoxide (R)-173. Reduction
of (R)-173 with DIBAL-H provided the 1,3-hydroxy sulfoxide
(R,S)-174 (92% de) showing that there was no significant effect of
the vicinal ester function, and providing C4 of the targets with the
correct absolute stereochemistry. Silylation followed by reaction
with methylphosphonate anion allowed for the synthesis of the new
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 35

a b
O
O O O S
S S O O
O O O
171 Os O
O O
172 R R
c -SO2

R
O
O
OH
O (-)-(4R,5R)-1
R
S
O
O O
OH H R
(-)-(4R,5S)-1
H
O
n
Scheme 28. Reagents. a: i. LDA, THF, 30 min, -78ºC, ii. C12H 25-CH=CH-CH2I, THF, 1 h, -78ºC (7 : 1,  : , 47%); b: OsO 4 (1 equiv), H 2O2, 24 h, 25ºC
(29%); c: mCPBA (3.2 equiv), CH2Cl2, 10 h, -10ºC to 25ºC (58%).
O O O OH O
EtO a EtO S : b EtO S :
OEt pTol pTol
O O 173 O 174
TBSO O
c MeO
S :
MeO P pTol
O O
175
TBSO O
d
R S :
e pTol
TBSO O
OH
R S : 177a
pTol
g O
O
176
S :
R pTol
f
O
TBSO O O
R S :
pTol 178a
OH h
177b OH
R
g O
S : O
O
R pTol

O 179a
O
i

178b R
O
h O
OH HO
R (-)-(4R,5R)-1
i R
O
O O O
HO
179b (-)-(4R,5S)-1
Scheme 29. Reagents. a: (+)-R-TolS(O)Me, LDA, THF, -78ºC; b: DIBAL-H, THF, 90 min, -78ºC (92% de, 85%); c: i. TBSCl, DBU, CH2Cl2 (98%), ii.
(MeO)2 P(O)Me, BuLi, THF (94%); d: nC10H 21CHO, Cs2CO 3, iPrOH 889%); e: DIBAL-H, ZnI2 (1 equiv), -78ºC (>95% de, 92%); f: DIBAL-H, Yb(OTf)3 (1
equiv), -78ºC (>95% de, 93%); g: i. TBAF, ii. Me 2C(OMe)2 (91%); h: i. Ac 2 O, ii. LiAlH4 (82%); i: i. Swern oxidation, ii. Ph3 P=CHCO 2Me, iii. H 2, Pd, iv. THF-
H2O, TsOH,
.
36 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

O O O OH O
a b
S : S :
N pTol pTol
N 181 182
180

pTol OH O
c + S : d
S O
Br pTol
OH Br OH
183

O
O O O
O O
e f O
S :
pTol CO2Me
Br Br Br
184 185 OH
186
O O

g O h O
R = nC12H25

R
O
OH
187
(-)-(4R,5R)-1

Scheme 30. Reagents. a: (+)-(R)-TolS(O)Me, LDA, THF, -15ºC to -30ºC (72%); b: DIBAL-H, THF, -78ºC (93%); c: NBS, H2O, Tol, rt (89%); Me2C(OMe)2,
CSA (cat), acetone, rt (92%); e: i. TFAA, TEA, CH2Cl2, 15 min, 0ºC, ii. NaHCO3, iii. Ph3P=CHCO2 Me, benzene, rt (1 : 1 mixture E / Z, 58%); f: i. H2, Pt/C,
EtOAc, rt (94%); i. CSA (cat), MeOH, rt (84%); g: Ag2O, CH3CN, rt (81%); nC12H25MgBr, Li2CuCl4, 36 h, -78ºC to rt (72%).

chiral ketophosponate 175. Emmons-Horner reaction afforded 176,
which was used as the final common intermediate for the synthesis
of (-)-(4R,5R)-1 and (-)-(4R,5S)-1.
Towards the first target, 176 was submitted to a diastereoselec-
tive syn reduction of the carbonyl group with DIBAL-H in the pres-
ence of ZnI2, which fixed the absolute stereochemistry of C5 of the
target (-)-muricatacin. On the other hand, towards (-)-(4R,5S)-1,
176 was reduced with anti diastereoselectivity using DIBAL-H
alone (80% de). Both yield and de in favour of the anti alcohol
increased in the presence of Yb(OTf)3 (1 equiv).
Both syntheses were terminated by desilylation and acetaliza-
tion to 178a and 178b, which upon Pummerer rearrangement, fol-
lowed by reduction of the resulting intermediate gave the primary
alcohols 179a and 179b. Finally, Swern oxidation, Wittig ho-
mologation, double-bond reduction, and acetonide cleavage and
lactonisation under acidic conditions gave (-)-(4R,5R)-1 and (-)-
(4R,5S)-1.
Raghavan and co-workers [84] have also used Solladié´s chiral
sulfoxide methodology for the synthesis of (-)-muricatacin (Scheme
30).
Their synthesis began with the preparation of
-ketosulfoxide
181 by condensation of the lithium anion of (R)-tolyl methyl sul-
foxide with 1-imidazolyl-2-propen-1-one 180. The authors noted
that the condensation of ethyl acrylate with the anion of tolyl
methyl sulfoxide afforded predominantly the conjugate addition
product and none of the ketosulfoxide 181. Diastereoselective re-
duction of the
-ketosulfoxide 181 with DIBAL-H afforded the
allyl alcohol 182, which was subsequently transformed into bromo-
hydrin 183 in a stereospecific fashion. The bromodiol 183 was then
transformed into the acetonide 184. This was subjected to Pum-
merer reaction affording an intermediate aldehyde which, without
purification, was used directly in a Wittig reaction to give an equi-
molar mixture of the cis- and trans-olefins 185. Without separation,
hydrogenation and acetal deprotection with concomitant cyclisation
of the resulting hydroxy ester afforded the bromolactone 186.
Treatment of 186 with Ag2O in acetonitrile afforded the epoxide
187. Ring-opening of the epoxide ring in 187 afforded (-)-
muricatacin.
5. ENANTIOSELECTIVE SYNTHESES OF MURICATAC-
INS
In 1992 Sharpless and co-workers reported that asymmetric di-
hydroxylation (AD) of ,-unsaturated esters 188 using their re-
cently introduced AD-mixes provided a very efficient and conven-
ient method for the direct preparation of optically active ,-
hydroxylactones (92-99% ee) [85]. In the catalytic AD reaction of
,-unsaturated esters, the resulting diols lactonized spontaneously
in a completely regioselective fashion to the -lactones. Both abso-
lute (R or S) and relative (syn) configurations of the stereocentres
are established in the AD step. This procedure was applied to the
synthesis of both (-)-(4R,5R)-1 (96% ee) and (+)-(4S,5S)-1 (95%
ee) (Scheme 31).
The enantiomeric excess of both products could be increased to
100% by crystallization. The starting ,-unsaturated ethyl ester
189a was prepared via a Johnson-Claisen rearrangement of alcohol
188, which in turn was synthesized either by the addition of dode-
cylmagnesium bromide to acrolein or by reaction of tridecanal with
vinylmagnesium bromide.
In an extension of Sharpless´ procedure, Konno and co-workers
[86] have prepared (-)-epi-muricatacin by treatment of (-)-(4R,5R)-
1 with p-nitrobenzoic acid under Mitsunobu reaction conditions,
which led to (-)-(4R,5S)-1 after hydrolysis.
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 37

CHO RCHO
a b

HO R
188

e OEt d R
R
O O
O O
HO HO
(-)-(4R,5R)-1 R (+)-(4S,5S)-1

189a

f g

R i OH h OH
O R = nC12H25
O OH
HO
(rac)-(4R,5S)-1
R OH R
rac-191 190

Scheme 31. Reagents. a: nC12H25 MgBr; b: CH2=CHBr (2 equiv) (96%); c: CH3C(OEt)3 , EtCO2 H (cat),
(92%) ; d : AD-mix-, MeSO 2NH2 , tBuOH – H2O,
0ºC (95% ee, 82%); e: AD-mix-, MeSO 2NH2, tBuOH – H2O, 0ºC (96% ee, 84%). f: i. Ph3 P, DEAD, pNO2-C6H 4-CO 2H, THF, 40ºC, ii. K2CO3 , MeOH (30%);
g: i. LiAlH4 , Et2O, 12 h, 0ºC to rt; h: OsO4 (1%), NMO, acetone - H2O (9:1), 18 h, rt; i: Cp*RuCl[Ph2 P(CH 2)2NH 2-2 -P,N] (1% mol), acetone, 1 – 2h, 30ºC
(>99%).
O

OTPS OMe (+)-(4S,5S)-1

a b
O O R
(-)-(4R,5R)-1
190
R
c 189b

TPSO
O
O
R = nC12H25
191
R
d

HO O OH
O
e O
O O
R

192 R (+)-(4S,5R)-1

Scheme 32. Reagents. a: i. DIBAL-H (93%); ii. TPS-Cl (84%); iii. [nC13H27 PPh3]Br, sBuLi, 1 h, 25ºC (84%); b: i. Jones oxidation, 12 h, 25ºC (89%), ii. CSA,
MeOH (97%); c: i. AD-mix- (92%), ii. CDI (97%); d: i. TBAF (91%), ii. NaIO4, RuCl3 (87%); e: DMF, 3 h, 153ºC (84% ee, 91%).

Ikariya and co-workers [87] have reduced 189a to the corre-
sponding primary alcohol 190, which upon dihydroxylation af-
forded triol rac-191. Oxidative lactonization of the 1,4-diol moiety
in rac-191 was possible by using a ruthenium catalyst-KOtBu com-
bination to afford rac-(4R,5S)-muricatacin.
Alternatively [88], the methyl ester 189b has been prepared by
Couladouros and co-workers from starting with a DIBAL-H reduc-
tion of butyrolactone. Silylation followed by Wittig-Schlosser ole-
fination of the corresponding aldehyde gave 190 (E:Z = 8.5 : 1.5).
Treatment of this alkene mixture under Jones oxidation conditions
38 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

OH
Br R a R b R c

193 194
OH
195
R R
[Ru]+ OH
C O O
R [Ru]+ O
OH OH

OH (-)-(4R,5R)-1

Scheme 33. Reagents. a: ethynylmagnesiumbromide, CuCl (10%), THF, 14 h, 50ºC (80%); b: AD-mix- (94% ee, 90%); c: (cod)RuCpCl (10%), trifuryl-
phosphine (15%), Bu4NBr (30%), N-hydroxysuccinimide (3 equiv), NaHCO3 (2 equiv), DMF-H2 O (7:1).

OH O O
a b c
R R R
H H
196 197 198
OH OH

R R R
d e

MeO2C O O
199
O O
200 (-)-(4R,5R)-1
f

OH OH OH
R R R
e g
O O O

O O O
ent-200 (+)-(4S,5S)-1 (+)-(4S,5R)-1

R = nC11H23

Scheme 34. Reagents. a: 1,3,5-trichloro[1,3,5]triazin-2,4,6-trione, TEMPO (1%), Et2O, -50ºC (95%); b: i. Ph3 P=CHCO2 Et, ii. DIBAL-H, THF, 30 min, -78ºC
(90%), iii. MnO2, CH2 Cl2 , 24 h, rt (98%); c: (F3CCH2O) 2(O)CH 2CO 2Me, KOtBu, 18-crown-6, THF, 2.5 h, -78ºC (93%); d: AD-mix-, tBuOH-H2O (1:1), 18 h,
0ºC (>95% ee, 86%); e: H2 (1 atm), Pd/C, MeOH, 24 h (98%); f: AD-mix-
, tBuOH-H2O (1:1), 18 h, 0ºC; g: i. Ph3 P, DEAD, pNO2-C 6H4-CO2H, THF, 2 h, rt
(92%), ii. K 2CO3 , MeOH, 10 min, rt (85%).

gave rise to desilylation followed by oxidation to an intermediate
carboxylic acid, which upon esterification afforded 189b (Scheme
32).
In addition to the synthesis of the threo isomers, these authors
also reported the synthesis of (+)-epi-muricatacin from intermediate
190. Thus, bis-hydroxylation with AD-mix- followed by reaction
with CDI afforded the protected diol 191, which upon desilylation
and oxidation of the primary OH group afforded the carboxylic acid
192. This was finally lactonized by heating in DMF, giving rise to
(+)-epi-(4S,5R)-1.
In a synthesis of (-)-muricatacin developed by Trost and co-
workers, a 1-propyne subunit has been used as surrogate of the
propionate moiety in 189a. This was made possible by a new ruthe-
nium-catalyzed cycloisomerization-oxidation of homopropargyl
alcohols, which constitutes useful access to a variety of -
butyrolactones [89] (Scheme 33).
For the synthesis of (-)-muricatacin, the known allylic bromide
193 [90] was coupled with ethynylmagnesium bromide under
Cu(I)-catalysis to afford 194. Sharpless AD of the C=C bond in 194
took place with 94% ee. A ruthenium vinylidenecarbene, readily
formed from the terminal alkyne and a ruthenium catalyst under
mild conditions, experienced an intramolecular nucleophilic addi-
tion giving rise to a ruthenium oxacarbene. Oxidation (N-
hydroxyxuccinimide) of the latter released the lactone (-)-(4R,5R)-
1, regenerating the catalytically active species.
The asymmetric dihydroxylation of dienoates has been used by
O´Doherty and co-workers for the synthesis of both muricatacin
enantiomers [91] (Scheme 34).
The synthesis required the preparation of the (2Z,4E)-dienoate
199 as starting material for the AD reaction. This was accomplished
(>20:1, Z,E to E,E) by a Still-Gennari olefination [92] of enal 198.
Compound 198 was in turn synthesized from the commercially
available alcohol 196 via oxidation followed by homologation of
aldehyde 197 to 198 by an established Wittig olefination/DIBAL-H
reduction/allylic oxidation sequence. This method allowed for the
preparation of multigram quantities of the (2Z,4E)-dienoate 199.
Reaction of the (2Z,4E)-dienoate 199 under typical Sharpless AD-
mix- conditions afforded lactone 200 (>95% ee), which was hy-
drogenated to furnish (-)-(4R,5R)-1. Similar operations but using
instead Sharpless AD-mix-
gave rise to (+)-(4S,5S)-1 (92% ee). A
Mitsunobu inversion on the latter allowed for the synthesis of (+)-
epi-muricatacin.
On the other hand, treatment of the (E)-4,6-heptadienoate 201
with Sharpless AD-mix- reagent [93] provided an approximately
1:1 ratio of products resulting from dihydroxylation of the E and
terminal alkenes, although the undesired diol 202 could be recycled
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 39

MeO2C
+ O
HO O
OH OH
204
203
a OH
+ c
OH
MeO2C MeO2C
Br Br
201
O
202 O
b OPMB
205

R
e
O O
O O
OH OPMB
(-)-(4R,5R)-1 206

Scheme 35. Reagents. a: AD-mix-
, MeSONH2 , tBuOH-H2O (47%, combined yield of 203 and 204); b: I2, Ph3P, imidazole, CH2Cl2 (71%); c: i.
PMBOC(NH)CCl3, TfOH (cat), Et2O, 18 h, rt (100%), ii. PyHBr 3, CH2Cl2 , 12 h, 0ºC (100%); d: DBU, DMF, 85 h, 80ºC (72%); e: i. (E)-1-iododec-1-ene,
(Ph3P) 2PdCl2 (10%), CuI, Et3N, benzene, 18 h, rt, ii. H2, Pd/C(10%), MeOH, 26 h (>98% ee, 97%).

O O
a Br b OMe
H N
Br
207 208

O OMe R O OMe
c d
N N

209 210
O O
e O f O
R R

OH OH
211 (-)-(4R,5R)-1
R = nC12H25

Scheme 36. Reagents. a: CBr 4, Ph3 P, CH2Cl2, 30 min, 0ºC (94%); b: i. BuLi (2 equiv), THF, -78ºC to -20ºC, ii. ClCONMe(OMe) (85%); c: H 2 (1 atm), Lind-
lar´s catalyst, EtOAc-quinoline (9:1), 2.5 h, 0ºC (82%); d: nC11H 23CH=CH2, Grubbs-Hoveyda catalyst, CH2Cl2, 18 h, rt (58%); e: OsO4 (2%), (DHQ)2 PHAL (4
%), MeSO2NH 2 (1 equiv), K3 Fe(CH)6 (3 equiv), K2CO 3 (3 equiv), tBuOH-H 2O (>95% ee, 83%); f: H2 (1 atm), Pd/C, EtOAc (100%).

to 201 in a single step by treatment under conditions for alcohol
iodination (Scheme 35).
Lactone 204 has been used by Nishiyama and co-workers [94]
for the synthesis of (-)-muricatacin using their elimination reaction
of 2,3-dibromoalkoxy derivatives leading to propargylic ethers by
utilizing DBU as the base [95], a reaction assisted by the electron-
withdrawing ability of the O-functional groups at the C1 position of
the 2,3-dibromoalkoxy derivatives. PMB-protection of 204 fol-
lowed by bromination of the double bond and elimination with a
slight excess of DBU afforded alkyne 206. The Sonogashira cou-
pling of 206 with (E)-1-iododec-1-ene, followed by hydrogenolysis,
simultaneously to saturate the triple bond and to remove the pro-
tecting group, provided (-)-(4R,5R)-1 in high optical purity.
Cossy and co-workers have developed a synthesis of (-)-
muricatacin [96] by a combination of chemoselective AD and
cross-metatheses (CM) reactions starting from (2Z,4E)-dienamide
209 (Scheme 36).
The starting material was prepared in a three-step procedure
starting by a Fuchs-Corey reaction of crotonaldehyde to afford the
dibromodiene 207. This was transformed into the acetylenic amide
208 in one pot via the acetylide intermediate which was generated
in situ by treatment of 207 with n-BuLi, followed by capture with
ClCON(OMe)Me. Compound 209 was produced after a selective
catalytic cis-hydrogenation of the triple bond, and was then sub-
jected to a CM reaction with n-tetradecene in the presence of the
Grubbs–Hoveyda catalyst to synthesize the Weinreb amide 210.
40 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

O O
a b c R
O
HO R O
HO R HO R OH
188
212a 212b
(+)-(4S,5S)-1

R
O
O
OH
(+)-(4S,5R)-1

Scheme 37. Reagents. a: D-(-)-Diisopropyl tartrate, Ti(OiPr)4 , tBuOOH, CH 2Cl2 , -20ºC (47.5%); b: i. DEAD, Ph3 P, ClCH 2CO2 H, benzene, rt, ii. NaOMe (1%),
MeOH (90%); c: i. LiCH2 CO2Li, THF, 18 h,
, ii. TsOH (cat.), benzene, 1 h,
((+)-(4S,5S)-1, 98% ee, 65%; (+)-(4S,5R)-1, >98% ee, 60%)

HO a HO R b HO R c

213 O
214
OtBu
O
I R R
d e R
O
O
O O OH
215 216 (-)-(4R,5R)-1

Scheme 38. Reagents. a: i. LiNH2, NH3(l)-Et2O, 2h, -33ºC, ii. nC12H25Br, 1h, -33ºC, DMSO, 18 h, rt (71%), iii. H2 , 5% Pd/CaCO 3, MeOH, 6 h, rt (91%); b: L-
(+)-diethyl tartrate, Ti(OiPr) 4, tBuOOH, 4A molecular sieves, 1 week, -12ºC (84% ee, 76%,); c: i. TsCl, Et3N, DMAP (cat.), CH2 Cl2 , 5 h, rt, ii. NaI, acetone, 2
d (91%); d: i. CH3CO2tBu, Li(CyNiPr), THF, 1 h, -78ºC ii. Addition of 21, HMPA, -78ºC to rt (81%); e: camphorsulphonic acid, CH2Cl2, 15 h, 0ºC (84% ee,
70%).

Treatment of 210 with a modified AD-mix- mixture effected a
chemoselective and enantioselective dihydroxylation of the ,-
double bond to afford the diol which cyclized under the reaction
conditions, forming the five-membered lactone 211 (>95% ee) in
one pot. Finally, hydrogenation of 211 furnished (-)-(4R,5R)-1.
2,3-Epoxyalcohols, obtained in enantiomerically enriched form
by asymmetric epoxidation (AE) of allylic alcohols, have also been
used as starting materials in various syntheses of muricatacins.
Bessodes and co-workers [97] used the ring-opening of the ep-
oxide moiety of the secondary 1-oxiranylalcohols 212a and 212b as
key step for their synthesis of (+)-epi-muricatacin and (+)-
muricatacin, respectively (Scheme 37). Under kinetic resolution
conditions with D-(-)-diisopropyl tartrate, epoxidation of the allylic
alcohol 188, obtained by Grignard reaction of dodecylmagnesium
bromide with acrolein, led to the (2S,3R)-epoxy alcohol 212a. This
step fixed the configuration of C4 in the final products.
Ring-opening of the epoxide in 212a by reaction with the lith-
ium enolate of lithium acetate took place with simultaneous lactoni-
zation to afford (+)-(4S,5R)-1.
In order to achieve the (5S)-configuration of (+)-(4S,5S)-1, an
inversion of the alcohol centre was required. This was carried out
by reaction of 212a with chloroacetic acid using a Mitsunobu reac-
tion followed by deacylation to give 212b. Following the same
operations as before, (+)-(4S,5S)-1 was produced.
In a different approach towards (-)-muricatacin, Makabe and
co-workers [98] located the aliphatic chain of muricatacin as sub-
stituent of the epoxide ring (Scheme 38) of the starting material.
Thus, they prepared compound 214 and manipulated first the pri-
mary OH group, leaving the ring-opening of the epoxide for the end
of the synthesis.
Alkylation of 2-propyn-1-ol with dodecylbromide followed by
hydrogenation of the resulting 2-pentadecyn-1-ol over Lindlar cata-
lyst gave rise to 213. Asymmetric epoxidation of 213 with L-(+)-
diethyl tartrate afforded epoxyalcohol (2S,3R)-214, establishing the
future C5 configuration of the final target. Compound 214 was
transformed into iodide 215 by tosylation and reaction with NaI in a
one-pot procedure. Alkylation of the lithium enolate of tbutyl ace-
tate with 215 furnished ester 216, which was transformed into (-)-
(4R,5R)-1 by cleavage of the tbutyl ester using camphorsulphonic
acid with simultaneous stereospecific (inversion of configuration)
intramolecular acid-catalyzed nucleophilic ring-opening of the ep-
oxide (84% ee). Optically pure (-)-(4R,5R)-1 was obtained after two
crystallizations (hexane – Et2O).
The regio- and stereospecific Lewis acid mediated ring-opening
of vinylepoxides to -hydroxy allyl ethers developed by Miosk-
owski and co-workers [99] has been used for the synthesis of (-)-
muricatacin [58] (Scheme 39).
Compound 214 was oxidized to corresponding epoxyaldehyde,
which was subjected to a Wittig olefination to give the ,-
unsaturated ester 217. The key step of the synthesis consisted in the
ring-opening of 217 with only one molar equivalent of 3,4-
dimethoxybenzylalcohol (DMPMOH), which was successfully
carried out using BF3.OEt2 as Lewis acid, allowing for the regio and
stereoselective preparation of alcohol 218. The free OH group was
benzylated, and the DMPM-group was selectively oxidatively de-
protected leading to the allylic alcohol 219. Finally, hydrogenation
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 41

OH
O O
a b CO2Et
OH R
R R CO2Et
214 217 ODMPM

OH 218
OBn
c CO2Et d R
R
O
OH
219 O
(-)-(4R,5R)-1

Scheme 39. Reagents. a: i. Py.SO3, Et3N, CH2Cl2:DMSO (5:1), ii. (EtO)2 P(O)CH2CO 2Et, NaH, THF (91%); b: DMPOH, BF3 OEt2, CH2Cl2 (52%); c: i. BnBr,
NaH, DMF, ii. DDQ, CH2Cl2-H 2O (65%); d: i. Ni(OAc)2, NaBH4 , EtOH, ii. TsOH, benzene (60%), iii. H 2, Pd/C, EtOH (96%).

I OH
I- O I-
R OH R OH R OH
C3-attack I C2-attack
OH I
A B

OH
OH
I-
R I
C1-attack R
OH O
II C

Scheme 40.
OH
O
a b c
RCHO R OH OH R I
R
220 221 OH
222
OH
d
R R = nC12H25

(-)-(4R,5R)-1 O

Scheme 41. Reagents. a: i. (EtO)2P(O)CH2CO 2Et, LiOH, THF, 2 h,
(90%); ii. DIBAL-H, Toluene, 1h, rt (91%); b: (-)-D-Diethyl tartrate, TBHP, Ti(OiPr)4,
3A molecular sieves, CH2Cl2 , 3 h, -20ºC; c: LiI, DME, 7 h, 70ºC (70%); d: i. CH2(CO 2Et)2, NaOEt, EtOH, 1 h,
, ii. H2 SO4 , H2 O, 18 h,
(50%).

of the double bond, acidic induced lactonization and debenzylation
gave rise to (-)-(4R,5R)-1.
In a related approach, Bonini, Rigi and co-workers have made
use of a 1-iodo-2,3-diol as key intermediate for the synthesis of (-)-
muricatacin [100]. A previous report [101] had shown that 1-iodo-
2,3-diols (II) could be obtained by rearrangement of 2,3-
epoxyalcohols (I) by the use of LiI in DME at 60ºC, a reaction
which takes place with complete chemo-, regio-, and stereoselectiv-
ity (Scheme 40).
In the reaction conditions, the formation of both iodohydrins (A
or B) in equilibrium with the starting 2,3-epoxyalcohol I and the
terminal epoxide C was possible. The rate of the reaction of C with
the nucleophile (I-) on the primary epoxide carbon was expected to
be much faster than that of compound I. Thus I- may react irre-
versibly with epoxide C affording the iodohydrin II. Starting from
the trans-2,3-epoxy alcohols the corresponding 1-iodo 2,3-syn-diols
were obtained, while from the cis epoxy alcohols the 1-iodo 2,3-
anti-diols could be obtained.
The synthesis of (-)-muricatacin by this procedure required the
preparation of the trans-1-oxiranylmethanol 221 [100] (Scheme
41). This was accomplished from tridecanal by standard homologa-
tion and reduction to the allylic alcohol 220. The subsequent AE
was then followed by the rearrangement of the chiral 2,3-epoxy
alcohol 221 (ee > 97%) with LiI in DME. The final coupling of the
iodohydrin 222 with the sodium enolate of diethyl malonate, fol-
lowed by hydrolysis and decarboxylation, afforded natural (-)-
muricatacin in a five-step sequence.
The photo-induced rearrangement of ,-epoxy diazomethyl
ketones in an alcoholic solvent developed by Zwanenburg and co-
workers constitutes a convenient synthetic route to 4-hydroxy-2-
alkene esters (Scheme 42) [102]. The chiral integrity of the
stereogenic center at the -carbon atom of the epoxide function is
retained in the product and therefore 4-hydroxy-2-alkene esters
with defined stereochemistry at the C4 carbon atom can be pre-
pared. Hydrogenation of the 4-hydroxy-2-alkene esters gives -
hydroxy carboxylic esters, which readily ring-close to yield enan-
tiopure -lactones.
42 Current Organic Chemistry, 2010, Vol. 14, No. 1 Murcia et al.

Sharpless
R1 OH R1 * OH
epoxidation *
O

h

R1 CO2R2 R1 *
* *
R1 * O R2OH N2
O O
OH O
Scheme 42.
O
a b
R OH R OH
OH 220 221

OTBS O O
e O d O
N2
R CO2Et R R OH
225 224 223

OTBS OTBS OTBS

g h
R R R N2
O O
OH OH O
226 227 228

OTBS
nC H R j CO2Et
R= 12 25
O R
O
HO OH
(-)-(4R,5R)-1 229

Scheme 43. Reagents. a: i. nC12H25Br, LiNH2 , NH3(l) (80%), ii. LiAlH4 , THF-Et2O (8:7) (93%); b: D-(-)-DET, Ti(OiPr) 4, molecular sieves, TBHP, -20ºC (91%
ee, 85%); c: i. DMSO, ClCOCOCl, iPr 2NEt, -78ºC (88%), ii. NaClO 2, NaH2 PO4 (90%); d: ClCO 2iBu, Et3N, CH 2N2 (60%); e: i. h, EtOH, ii. TBSCl (55%); f:
DIBAL-H (81%); g: L-(+)-DET, Ti(OiPr) 4, molecular sieves, TBHP, -20ºC (>95% de, 92%,); h: i. RuO4, ii. ClCO2iBu, Et3N, CH2N 2 (52%); i: h, EtOH
(50%); j: i. Ni(OAc)2, NaBH 4, ii. TsOH, iii. TBAF (38%).

The sequential application of this methodology has been used
for the synthesis of (-)-muricatacin (Scheme 43) [103]. This se-
quence of reactions had the attractive feature that the stereochemis-
try of the respective stereogenic centers in the ultimate product
could be controlled at will simply by choosing the right chiral in-
ducer in both sequential Sharpless epoxidations.
The required starting allylic alcohol 220 was readily obtained
by C-alkylation of propargyl alcohol followed by LiAlH4 reduction
of the triple bond to double bond. Sharpless asymmetric epoxida-
tion of 220 using D-(-)-diethyl tartrate as chiral inducer resulted in
epoxy alcohol (2R,3R)-221.
Swern oxidation of 221 followed by oxidation with sodium
chlorite afforded acid 223. Diazomethyl ketone 224 was prepared
by a standard series of operations. Irradiation of this diazo com-
pound in ethanol gave the 4-hydroxy-2-alkene ester, which was
silylated to derivative 225. The ester thus obtained was reduced
with DIBAL-H to give the allylic alcohol 226. The second Shar-
pless epoxidation was carried out using L-(+)-diethyl tartrate as
chiral inducer, resulting in epoxy alcohol 227. The stereochemistry
of this step was governed by the reagent and was not influenced by
the presence of the initially introduced stereogenic centre. Oxida-
tion with ruthenium tetroxide, conversion into epoxy diazomethyl
ketone and irradiation in ethanol afforded ester 229. Reduction of
the double bond, acid-catalyzed lactonization and deprotection of
the alcohol gave rise to (-)-(4R,5R)-1.
Towards the synthesis of (-)-epi-muricatacin, the same series of
reactions was carried out but starting from (2S,3S)-221 (99% ee,
75% yield) which was obtained by Sharpless AE of the same pre-
cursor 220 but using L-(+)-diethyl tartrate.
The diastereoselective addition of enantioenriched (Z)-
-
silyloxy allylic stannanes to aldehydes has been used as a key trans-
formation for the synthesis of both enantiomers of the muricatacins
[104] (Scheme 44). This approach was based on the high syn
stereoselectivity and stereospecificity with respect to the stannane
moiety previously reported for related SE2´ additions to other alde-
hydes [105]. The R or S configuration of C4 in the final muricatacin
was controlled by the absolute stereochemistry of the stereogenic
centre of the allylic stannane, whereas the configuration of C5 was
Naturally Occurring  -Hydroxy-
-Lactones Current Organic Chemistry, 2010, Vol. 14, No. 1 43

R1 H

R1 SnBu3
230
b c

OR2 OR2

R1 SnBu3 R1 SnBu3

(R)-231, R2 = H (S)-231, R2 = H
d d
(R)-232, R2 = TBS (S)-232, R2 = TBS

e e

Bu3Sn OTBS Bu3Sn OTBS

CO2Et
R1 R1 OHC
(R)-233 (S)-233 234

f f

OTBS OTBS
CO2Et CO2Et
R1 R1
OH OH

(S,S)-235 (R,R)-235

g g

R3 R3
O O
O O
OH OH
(+)-(4S,5S)-1 (-)-(4R,5R)-1
R1 = nC10H21, R3 = nC12H25

Scheme 44. Reagents. a: i. Bu3SnLi, ii, DIAD; b: (S)-BINAL-H, 8 h, -78ºC (>96% ee); c: (R)-BINAL-H, 8 h, -78ºC, d: TBSCl, imidazole, CH2Cl2, rt (45%
from 1); e: BF3.OEt2, CH2Cl2, 5 min, -78ºC (88% S-isomer, 95% R-isomer); f: i. BF3.OEt2, CH 2Cl2, 50 min, -78ºC,, ii. (E)-HOC-CH=CH-CO2 Et, 25 min, -
78ºC (syn:anti = 95:5; 95% ee, 77%); g: i. H2 /Pd-C(5%), EtOH, 2 h (88%), ii. 49% aq HF, THF-H2O (1:1), 6 h, rt (83%).

induced by the higly syn diastereoselectivity of the aldol step.
Therefore, the ability to prepare each enantiomer of the allylic stan-
nanes was required.
The synthesis of both (R)-233 and (S)-233 was carried out by
the enantioselective reduction of the acylstannane 230, readily pre-
pared from 2-tridecenal and Bu3SnLi followed by in situ oxidation
of the intermediate lithio alkoxide, with either (S)- or (R)-BINAL-
H, followed by OH-protection and 1,3-isomerization of the tributyl-
stannyl group (45-48% overall yield, 95% ee). Boron trifluoride
promoted addition of allylstannanes 233 to the aldehyde group of
(E)-ethyl 3-formyl-2-propenoate (234), which was obtained by
ozonolysis of the terminal C=C bond of ethyl sorbate, afforded
compounds 235 as 95:5 mixtures of the corresponding syn and anti
diastereomers with 95% ee. It is worth mentioning that the synthe-
sis of compounds 235 could also be carried out as a one-pot proce-
dure from silyloxy stannanes 232 in the presence of boron
trifluoride without isolation of isomers 233. Finally, catalytic hy-
drogenation of the C=C double bonds in 235 followed by HF-
promoted deprotection of the silyl group with simultaneous lactoni-
zation allowed for the obtention of each muricatacin enantiomer.
The authors noted that high syn stereoselectivities were ob-
tained when the stannanes were added to an unsaturated aldehyde
such as 234. On the other hand, reaction with the related saturated
aldehyde (3-formylpropenoate) resulted in lower syn:anti ratios.
This has been interpreted in terms of a possible through-space in-
teraction of the ester carbonyl with the intermediate BF3-complex
44 Current Organic Chemistry, 2010, Vol. 14, No. 1
a HO
OTMS
O O
R R
TMSOF
i
Scheme 45. Reagents. a: Ti(O Pr)4 - R-BINOL (1.2) (20%), CH 2Cl2, -20ºC (80% ee, 48%); b: H2 , Pd/C, toluene, 12 h, rt (87%).
of the aldehyde in the latter case. This interaction was prohibited by
the (E)-double bond in 234.
Figadère and co-workers have been the first to use (2-
[(trimethylsilyl)oxy]furan (TMSOF) in an enantioselective aldol
reaction [106, 107]. The addition of TMSOF in CH2Cl2 to aliphatic
aldehydes using a (R)-BINOL-Ti(OiPr)4 (2:1) Lewis acid catalyst at
-20ºC gave excellent results in terms of chemical yield and enanti-
oselectivity. The efficiency of their strategy was illustrated by the
synthesis of (+)-muricatacin in only two steps (Scheme 45).
Addition of TMSOF to tridecanal under the aforementioned
conditions followed by hydrogenation gave rise to (+)-(4S,5S)-1 in
48% yield and 80% ee. This was accompanied by the anti isomer
(+)-(4R,5S)-1 (60:40 syn:anti, 32% yield), which was separated
from the former by chromatography.
6. SUMMARY AND OUTLOOK
In this review we have surveyed the different synthetic strate-
gies thus far reported for the stereoselective synthesis of muricatac-
ins, naturally occurring -hydroxy-
-lactones related to acetogenins,
which display cytotoxic activity towards human tumoral cell lines.
These syntheses can be grouped into three main categories: i) those
which start from racemic materials and are based on resolution of
an advanced synthetic intermediate (syntheses based on resolution);
ii) those which make profit of the stereocentres already present in
easily available starting materials (chiral pool syntheses); and iii)
those in which the stereocentres of the targets are induced by using
chiral reagents (enantioselective approaches). Within each category,
the different synthetic procedures have been grouped by the key
chiral precursor or reagent used, and have been analyzed from the
older to the most recent ones, in an effort to highlight the advances
introduced by each new procedure that has been incorporated into
the literature with the passing of time. All these efforts have pro-
vided a wide variety of synthetic methods which differ in the avail-
ability of the starting materials, the number of steps of the synthesis
and their individual yields, and the enantiomeric purity of the final
targets. Noteworthy, most of them are suitable for the synthesis of
the targets in multigram quantities. In addition, some of the chiral
pool and enantioselective syntheses reported for the natural muri-
catacins (syn, both enantiomers) do also apply for the preparation of
the unnatural epi-muricatacins (anti), either by chosing epimeric
starting materials or by selective manipulation of the stereocentres
of the synthetic intermediates. Also, some of these procedures have
already been used for the preparation of muricatacin analogues
(e.g., Fig. 5) by simple variations in the reagents. Efforts to be ad-
dressed in the future are the development of new syntheses which
are shorter, high yielding, highly diastereo- and enantioselective
and versatile enough for the preparation of a wide variety of new
analogues of this type of molecules with improved biological activi-
ties.
ACKNOWLEDGEMENTS
This review has been written under coverage of projects UCM-
BSCH GR58/08-910815 and CTQ2006-15279-C03-01, which are
Murcia et al.
b HO
O O O
236
(-)-(4R,5R)-1
acknowledged for financial support. Dr. María Teresa Molina
(IQM, CSIC) is thanked for her valuable help with literature man-
agement. Prof. J. Plumet (UCM) is thanked for his valuable support
of this work.
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