An efficient strategy for the synthesis of 5-hydroxyalkylbutan-4-olides from D-mannitol: Total synthesis of (-)-muricatacin

Article abstract of DOI:10.1016/S0040-4039(02)00375-1

A general approach towards the synthesis of 5-hydroxyalkylbutan-4-olides from D-mannitol has been described. The approach has successfully been used for the total synthesis of (-)-muricatacin, an anti-tumor natural product.

Full text of DOI:10.1016/S0040-4039(02)00375-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2773–2775
An efficient strategy for the synthesis of
5-hydroxyalkylbutan-4-olides from
D
-mannitol:
total synthesis of (−)-muricatacin
M. Chandrasekhar, Kusum L. Chandra and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Received 2 January 2001; revised 11 February 2002; accepted 21 February 2002
Abstract—A general approach towards the synthesis of 5-hydroxyalkylbutan-4-olides from
D-mannitol has been described. The
approach has successfully been used for the total synthesis of (−)-muricatacin, an anti-tumor natural product. © 2002 Elsevier
Science Ltd. All rights reserved.
Chiral hydroxylactones occupy an important position
as bio-active molecules and useful synthetic intermedi-
ates in total synthesis. One such group of hydroxylac-
tones comprises the 5-hydroxyalkylbutan-4-olides 1.
These are widely found in nature and show diverse
biological properties. Some of these compounds are
known to have insect antifeedant activity1 and are
cytotoxic to human tumor cells.2 The short chain
homologues are important flavor constituents in wine,
sherry, and tobacco smoke.3 These are also found in
microbial metabolite cultures of Erwinia quernica4 and
Streptomyces griseus.5 Many of these butanolides are
often used as synthons in the synthesis of complex and
biologically important natural products.6 These have
been used as precursors to HIV-1 protease inhibitors.7
One such molecule that has attracted much attention
since its isolation was (−)-muricatacin 1d. It was iso-
lated from the seeds of Anona muricata L.
(annonaceae),8 commonly known as sour soup or guan-
abana, and is grown commercially as a fruit crop
throughout the tropical regions of the world. This plant
as well as others in the family of annonaceae are a
source of many annonaceous acetogenins that are
known to have anti-tumor properties.2 Both enan-
tiomers of 1d are found in nature. The isolated material
is a mixture of the two, the (−)-(R,R)-enantiomer 1d
being predominant (ee of ca. 25% based on optical
rotation). It has been shown to be cytotoxic towards
human tumor cells. Biological studies revealed that the
length of the side chain is very crucial. Decreasing the
length of the alkyl side chain led to decreased activity
but increasing the chain length did not show any
increase in activity. Both (+)- and (−)-muricatacin
(threo) have the same activity. The biological activity of
muricatacin and other related compounds has
prompted many syntheses of this type of molecule.9–11
Most of the syntheses are target oriented. In this paper
we describe a general approach, which can be used for
synthesizing (−)-muricatacin and related natural
products.
While working on the total synthesis of (−)-
boronolide12 and hexadecanolide, a pheromone,13 we
realized that 5-hydroxyalkylbutan-4-olide 1 type natu-
OH
OH
OH
HO
OBn
OBn
R
O
O
R
O
O
O
OH
OH OH
OBn O
OBn
O
2
1
4
3
a: R = CH3; b: R = C4H9; c: R = C5H11
d: R = C12H25; e: R = CH2CH2Ph
Scheme 1.
* Corresponding author. E-mail: vinodks@iitk.ac.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00375-1

2774
M. Chandrasekhar et al. / Tetrahedron Letters 43 (2002) 2773–2775
ral products can also be synthesized easily from
D
-man-
prepared from phosphonium salts with different alkyl
groups to provide olefin 11. The acetonide group of 11
was cleaved, as above. The diol 12, thus obtained, was
converted into the olefinic compound 13 using Wittig
chemistry. Conversion of 13 into target compounds
such as 1b, 1c, 1d, and 1e was carried out as for 1a. In
this way, we were able to synthesize several hydroxy-
alkyl g-lactones in ꢀ45% overall yield (Scheme 3).
nitol. The retrosynthetic analysis for our approach is
shown in Scheme 1. The g-lactone unit can be con-
structed from the corresponding hydroxy acid, which
can originate from the acetonide 2. The appropriate
alkyl group can be added to the aldehyde of 3.
The synthesis commences with the diacetonide benzyl
ether 5,14 which was subjected to selective hydrolysis
using acetyl chloride in MeOH at 0°C to give diol 6 in
88% yield. The diol 6 was subjected to oxidative cleav-
age using lead tetraacetate (LTA) in CH2Cl2 and the
crude aldehyde was reduced with NaBH4 to provide
alcohol 7. The alcohol was then tosylated, and the
crude tosylate was reduced with NaBH4 in DMSO to
give 8 whose acetonide group was cleaved using tri-
fluoroacetic acid in THF–water mixture (4:1). The diol
9, thus obtained, was cleaved to give an aldehyde using
LTA as above. This aldehyde, without any purification,
was subjected to a Wittig olefination reaction with
(benzyloxycarbonylmethylene)triphenylphosphorane to
give the a,b-unsaturated ester 10, which was converted
into the target compound 1a by hydrogenation over
Pd/C followed by treatment of the resulting crude
hydroxy acid with p-TsOH (Scheme 2).
In order to show more versatility in our approach, we
studied the synthesis of analogues having extra
hydroxyl groups. This was accomplished from the
known diol 14,12 which was subjected to oxidative
cleavage with LTA, and the aldehyde so obtained was
allowed to react with an ylide prepared from (ethoxy-
carbonylmethylene)triphenylphosphorane to provide
the a,b-unsaturated ester 15 as a mixture of cis and
trans isomers (ratio 70:30). This mixture, on treatment
with CuCl2·2H2O15 gave a lactone after cleaving the
acetonide group. It is to be mentioned here that only
the cis isomer lactonized and the trans isomer remained
unchanged. The unsaturated lactone 16 was hydro-
genated to provide the saturated lactone 17 which could
be an important precursor in synthesis (Scheme 4).
In conclusion, we have developed a simple and flexible
strategy for the synthesis of hydroxyalkylbutan-4-olides
We extended this approach to compounds with differ-
ent alkyl groups in the side chain. For alkyl groups
other than Me, the scheme was modified. The aldehyde,
obtained from the diol 6, was treated with ylides,
from
D-mannitol. Using the above strategy, a total
synthesis of (−)-muricatacin 1d16 was accomplished.
OBn
O
OBn
c
OBn
O
O
b
a
O
O
O
OH
OH
O
OBn OH
OBn
OBn
O
7
6
5
OBn
f
OH OBn
e
OBn
O
d
BnO2C
1a
HO
O
OBn
10
OBn
OBn
9
8
Scheme 2. Reagents and conditions: (a) AcCl (5 equiv.), MeOH, 0°C, 5 min (88% yield); (b) (i) Pb(OAc)4, CH2Cl2, rt, 3 h; (ii)
NaBH4, EtOH, 0°C, 2 h (96% yield); (c) (i) TsCl, Et3N, CH2Cl2, 14 h; (ii) NaBH4, DMSO, 160°C, 7 min (73% yield); (d) TFA,
THF–H2O (4:1), 65°C, 6 h (86% yield); (e) (i) Pb(OAc)4, CH2Cl2, rt, 3 h; (ii) BnO2CCH2P+Ph3Br−, n-BuLi, THF, 0°C–rt, 12 h
(74% yield); (f) (i) H2, 10% Pd/C, EtOH, rt, 12 h; (ii) p-TSA, toluene, 70°C, 1 h (95% yield).
OH OBn
OBn
O
c
b
a
HO
O
6
R'
R'
OBn
OBn
12
11
OBn
d
BnO2C
b: R' = C2H5; c: R' = C3H7
d: R' = C10H21; e: R' = C6H5
1
R'
OBn
13
Scheme 3. Reagents and conditions: (a) (i) Pb(OAc)4, CH2Cl2, rt, 3 h; (ii) R%CH2P+Ph3Br−, n-BuLi, THF, 0°C–rt, 12 h (65–75%
yield); (b) TFA, THF–H2O (4:1), 65°C, 6 h (85–95% yield); (c) (i) Pb(OAc)4, CH2Cl2, rt, 3 h; (ii) BnO2CCH2P+Ph3Br-, n-BuLi,
THF, 0°C–rt, 12 h (70–80% yield); (d) (i) H2, 10% Pd/C, EtOH, rt, 12 h; (ii) p-TSA, toluene, 70°C, 1 h (92–95% yield).

M. Chandrasekhar et al. / Tetrahedron Letters 43 (2002) 2773–2775
2775
O
HO
O
b
EtOOC
C4H9
OBn
a
HO
C4H9
OBn
O
O
15
14
O
O
OH
OH
C4H9
c
C4H9
OH
OBn
O
17
O
16
Scheme 4. Reagents and conditions: (a) (i) Pb(OAc)4, CH2Cl2, rt, 3 h; (ii) EtO2CCHꢀPPh3, MeOH, rt, 12 h (75% yield); (b)
CuCl2·2H2O, MeCN, rt, 12 h (65% yield); (c) H2, 10% Pd/C, EtOH, rt, 12 h.
Acknowledgements
32, 3795; (e) Ghosh, A. K.; McKee, S. P.; Thompson, W.
J. J. Org. Chem. 1991, 56, 6500; (f) Poss, M. A.; Reid, J.
A. Tetrahedron Lett. 1992, 33, 1411; (g) Askin, D.; Wal-
lace, M. A.; Vacca, J. P.; Reamer, R. A.; Volante, R. P.;
Shinkai, I. J. Org. Chem. 1992, 57, 2771.
V.K.S. would like to thank DST (Government of India)
for a Swarnajayanti Fellowship (1998). We also thank
CSIR, New Delhi for a Junior Research Fellowship to
K.L.C.
8. Rieser, M. J.; Kozlowski, J. F.; Wood, K. V.; McLaugh-
lin, J. L. Tetrahedron Lett. 1991, 32, 1137.
9. For syntheses of muricatacin from optically active start-
ing materials, see: (a) Figadere, B.; Harmange, J.-C.;
Laurens, A.; Cave, A. Tetrahedron Lett. 1991, 32, 7539;
(b) Pelletier, C. G.; Saniere, M.; Charvet, I.; Merrer, Y.
L.; Depezay, J.-C. Tetrahedron Lett. 1994, 35, 115; (c)
Somfai, P. J. Chem. Soc., Perkin Trans. 1 1995, 817; (d)
Saniere, M.; Charvet, I.; Merrer, Y. L.; Depezay, J.-C.
Tetrahedron 1995, 51, 1653; (e) Yoon, S.-H.; Moon,
H.-S.; Hwang, S.-K.; Choi, S. R.; Kang, S.-K. Bioorg.
Med. Chem. 1998, 6, 1043.
References
1. Numata, A.; Hokimoto, K.; Takemura, T.; Katsuno, T.;
Yamamoto, K. Chem. Pharm. Bull. 1984, 32, 2815.
2. Cave, A.; Chaboche, C.; Figadere, B.; Harmange, J. C.;
Laurens, A.; Peyrat, J. F.; Pichon, M.; Szlosek, M.;
Cotte-Lafitte, J.; Quero, A. M. Eur. J. Med. Chem. 1997,
32, 617.
3. (a) Muller, C. J.; Maggiora, L.; Kepner, R. E.; Webb, A.
D. J. Agric. Food Chem. 1969, 17, 1373; (b) Muller, C. J.;
Kepner, R. E.; Webb, A. D. Am. J. Enol. Viticult. 1973,
24, 5; (c) Schumacher, J. N.; Green, C. R.; Best, F. W.;
Newell, M. P. J. Agric. Food Chem. 1977, 25, 310.
4. Wright, A. E.; Matthias, M.; Midland, S.; Munnecke, D.
E.; Sims, J. J. Tetrahedron Lett. 1989, 30, 5699.
5. Grafe, U.; Reinhardt, G.; Schade, W.; Krebs, D.; Eritt,
I.; Fleck, W. F.; Heinrich, E.; Radics, L. J. Antibiot.
1982, 35, 609.
6. (a) Matsumoto, T.; Ichihara, A.; Ito, N. Tetrahedron
1969, 25, 5889; (b) Iwaki, S.; Marumo, S.; Saito, T.;
Yamada, M.; Katagiri, K. J. Am. Chem. Soc. 1974, 96,
7842; (c) Pearson, W. H.; Hembre, E. J. J. Org. Chem.
1996, 61, 7217; (d) Ha, J. D.; Cha, J. K. J. Am. Chem.
Soc. 1999, 121, 10012; (e) Avedissian, H.; Sinha, S. C.;
Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan,
E. J. Org. Chem. 2000, 65, 6035.
7. (a) Nishi, T.; Kataoka, M.; Morisawa, Y. Chem. Lett.
1989, 1193; (b) Gante, J.; Kahlenberg, H. Chem.-Ztg.
1991, 115, 215; (c) Chakraborty, T. K.; Gangakhedkar,
K. K. Tetrahedron Lett. 1991, 32, 1897; (d) Harding, K.
E.; Coleman, M. T.; Liu, L. T. Tetrahedron Lett. 1991,
10. For a synthesis of muricatacin by kinetic resolution, see:
Saiah, M.; Bessodes, M.; Antonakis, K. Tetrahedron Lett.
1993, 34, 1597.
11. For syntheses of muricatacin using enantioselective meth-
ods, see: (a) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K.
B.; Sinha, S. C.; Sinha, A.-B.; Keinan, E. Tetrahedron
Lett. 1992, 33, 6407; (b) Marshall, J. A.; Welmaker, G. S.
J. Org. Chem. 1994, 59, 4122; (c) van Aar, M. P. M.;
Thijs, L.; Zwanenburg, B. Tetrahedron 1995, 51, 11223;
(d) Solladie, G.; Hanquet, G.; Izzo, I.; Crumbie, R.
Tetrahedron Lett. 1999, 40, 3071.
12. Chandrasekhar, M.; Raina, S.; Singh, V. K. Tetrahedron
Lett. 2000, 41, 4969.
13. Raina, S.; Singh, V. K. Tetrahedron 1996, 52, 4479.
14. (a) Kierstead, R. W.; Faraone, A.; Mennona, F.; Mullin,
J.; Guthrie, R. W.; Crowley, H.; Simko, B. J. Med.
Chem. 1983, 26, 1561; (b) Jurczak, J.; Bauer, T.;
Chimielewski, M. Carbohydr. Res. 1987, 164, 493.
15. Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh,
V. K. Tetrahedron Lett. 1998, 39, 3091.
16. The specific rotation of (−)-1d: [h]2D5 −23.5 (c 0.43, CHCl3)
{lit.8 [h]2D5 −23.3 (c 1.8, CHCl3).