Asymmetric synthesis of (-)-acaterin

Article abstract of DOI:10.1016/S0040-4039(03)01412-6

The asymmetric synthesis of (-)-acaterin, an inhibitor of acyl-CoA cholesterol acyl transferase has been achieved starting from the commercially available starting materials, octan-1-ol and methyl (R)-lactate. The key steps are a Sharpless asymmetric dihydroxylation and a Wittig olefination.

Full text of DOI:10.1016/S0040-4039(03)01412-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6149–6151
Asymmetric synthesis of (−)-acaterinꢀ
Subba Rao V. Kandula and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 28 April 2003; revised 29 May 2003; accepted 5 June 2003
Abstract—The asymmetric synthesis of (−)-acaterin, an inhibitor of acyl-CoA cholesterol acyl transferase has been achieved
starting from the commercially available starting materials, octan-1-ol and methyl (R)-lactate. The key steps are a Sharpless
asymmetric dihydroxylation and a Wittig olefination.
© 2003 Elsevier Ltd. All rights reserved.
Acyl-CoA cholesterol acyl transferase (ACAT) plays an
important role in cholesterol ester accumulation in
atherogenesis1 and in cholesterol absorption from the
intestines.2 Inhibitors of ACAT activity are expected to
be effective for the treatment of atherosclerosis and
hypercholesterolemia. Acaterin (Fig. 1) is one of the
ACAT inhibitors isolated from a culture broth of Pseu-
domonas sp. A92 by Endo and co-workers.3 Acaterin
has a butenolide skeleton with an alkyl chain at the C-2
position, which is related to Annonaceous acetogenins,4
and has remarkable antitumor activity.3 While Kita-
hara and co-workers5 established the absolute stereo-
chemistry after the synthesis of all the diastereomers of
acaterin, the biosynthesis of acaterin was investigated
by Fujimoto.6 Synthetic strategies based on the Baylis–
Hillman reaction have recently been reported for this
molecule simultaneously by two different research
groups.7 As part of our research program aimed at
developing enantioselective synthesis of naturally occur-
ring lactones8 and amino alcohols,9 we became inter-
ested in developing a simple and feasible route to
acaterin. In this paper we report a concise synthesis of
(−)-acaterin employing the Sharpless asymmetric dihy-
droxylation procedure and a Wittig olefination as key
steps.
product 5 in 93% yield. The dihydroxylation of olefin 5
with osmium tetroxide and potassium ferricyanide as
co-oxidant in the presence of (DHQD)2PHAL as chiral
Figure 1.
The synthesis of (−)-acaterin started from commercially
available octan-1-ol 4 as illustrated in Scheme 1. Com-
pound 4 was oxidized to the aldehyde and subsequently
treated with (methoxycarbonylmethylene)triphenyl-
phosphorane in THF under reflux to give the Wittig
Scheme 1. Reagents and conditions: (a) (i) P2O5, DMSO,
CH2Cl2, Et3N, 0°C, 4 h, 96%; (ii) Ph3PꢀCHCOOMe, THF,
reflux, 12 h, 93%; (b) (DHQD)2PHAL, OsO4, CH3SO2NH2,
K3Fe(CN)6, K2CO3, t-BuOH:H2O (1:1), 24 h, 0°C, 98%; (c)
HBr/AcOH, dry MeOH, 40°C, 24 h, 83%; (d) TBDMSCl,
imidazole, DMAP (cat.), CH2Cl2, 36 h, 92%; (e) PPh3,
CH3CN, reflux, 12 h, 66%.
ꢀ NCL communication No. 6644.
* Corresponding author. Tel.: +91-20-5893300 ext. 2050; fax: +91-20-
5893614; e-mail: tripathi@dalton.ncl.res.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01412-6

6150
S. R. V. Kandula, P. Kumar / Tetrahedron Letters 44 (2003) 6149–6151
Acknowledgements
ligand under the Sharpless asymmetric dihydroxylation
conditions10 gave the diol 6 in excellent yield, [h]2D5
+11.23 (c 1, CHCl3) [lit.11 [h]D25 +10.1 (c 1.42, CHCl3)].
Regioselective conversion of the diol 6 to bromohydrin
7 was achieved employing the protocol developed by
Sharpless.12 Thus, treatment of 6 with hydrogen bro-
mide in acetic acid gave 713 in 83% yield. Subsequently,
the hydroxyl group was protected as a silyl ether using
tert-butyldimethylsilyl chloride and imidazole in the
presence of a catalytic amount of DMAP to afford 8 in
92% yield which on treatment with triphenylphosphine
in acetonitrile under reflux conditions furnished the
phosphonium salt 9 in good yield.
Subba Rao thanks CSIR, New Delhi for financial
assistance. We are grateful to Dr. M. K. Gurjar for his
support and encouragement.
References
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2. Heilder, J. G. In Pharmacological Control of Hyperlipi-
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423–438.
Scheme 2 summarizes the preparation of fragment 13
from the commercially available methyl (R)-lactate.
Hydroxyl protection of 10 as the THP ether was fol-
lowed by reduction of the ester to the corresponding
alcohol 12 in good yield. The subsequent PCC oxida-
tion resulted in the formation of the aldehyde 13, which
was used in the next reaction without any further
purification.
3. Naganuma, S.; Sakai, K.; Endo, A. J. Antibiot. 1992, 45,
1216–1221.
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5. Ishigami, K.; Kitahara, T. Tetrahedron 1995, 51, 6431–
6442.
The final step involved the coupling of phosphonium
salt 9 with aldehyde 13 and subsequent cyclization. To
this end, the Wittig olefination between 9 and 13 was
carried out in the presence of LiHMDS at −78°C to
give the olefin 1414 in 73% yield. Subsequent cyclization
using a catalytic amount of p-TsOH in methanol fur-
nished (−)-acaterin in 68% yield, [h]2D5 −21.33 (c 0.3,
CHCl3) [lit.5 [h]D25 −19.7 (c 0.61, CHCl3)] (Scheme 3).
The physical and spectroscopic data of 1 were in full
agreement with the literature data.5
6. Sekiyama, Y.; Fujimoto, Y.; Hasumi, K.; Endo, A. J.
Org. Chem. 2001, 66, 5649–5654.
7. (a) Vijay Anad, R.; Baktharaman, S.; Singh, V. K. Tetra-
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8. (a) Pais, G. C. G.; Fernandes, R. A.; Kumar, P. Tetra-
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Kumar, P. Tetrahedron: Asymmetry 1999, 10, 4349–4356;
(c) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2002,
2921–2923.
9. (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000,
3447–3449; (b) Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2000, 41, 10309–10312; (c) Kandula, S. R. V.;
Kumar, P. Tetrahedron Lett. 2003, 44, 1957–1958; (d)
Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2002, 43, 4425–4426; (e) Fernandes, R. A.; Kumar,
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10. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed.
1996, 35, 448–481; (b) Torri, S.; Liu, P.; Bhuvaneswari,
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In conclusion, we have developed a new synthetic route
to (−)-acaterin employing Sharpless asymmetric dihy-
droxylation and Wittig olefination as key steps. A short
reaction sequence and high yielding steps to (−)-aca-
terin renders our strategy a good alternative to the
known methods. Currently, studies are in progress for
the synthesis of other isomers of acaterin including
4-dehydroacaterin, using an intermolecular Refor-
matsky reaction as the key step.
11. Gurjar, M. K.; Sylesh Kumar, V.; Venkateswara Rao, B.
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Scheme 2. Reagents and conditions: (a) DHP, p-TsOH (cat.),
dry CH2Cl2, 96%; (b) LiAlH4, dry THF, 0°C–rt, 12 h, 92%;
(c) PCC, anhydrous CH3COONa, Celite, 4 h.
13. Compound 7: [h]2D5 +36.14, mp 41–41.5°C, IR (CHCl3):
3604, 3019, 2928, 2400, 1735, 1658, 1215, 756, 669; 1H
NMR (200 MHz): 0.85 (t, J=6.3 Hz, 3H), 1.26–1.42 (m,
10H), 1.81–1.92 (2H, m), 3.01 (bs, 1H), 3.77 (s, 3H),
4.09–4.13 (d, J=8 Hz, 1H), 3.97 (m, 1H); 13C NMR (50
MHz): 13.81, 22.41, 25.02, 28.96, 29.14, 31.57, 33.22,
47.89, 52.74, 72.11, 169.70; MS: m/z 279 (M+−2), 263,
197, 183, 168, 152, 140, 123, 111, 95, 81. Anal. calcd for
C11H21O3Br (281.18) C, 46.98; H, 7.52; Br, 28.41. Found
C, 47.07; H, 7.65; Br, 28.14%.
Scheme 3. Reagents and conditions: (a) LiHMDS, dry THF,
−78°C, 30 min then 13, 10 h, 73%; (b) cat. p-TsOH, MeOH,
overnight, 68%.

S. R. V. Kandula, P. Kumar / Tetrahedron Letters 44 (2003) 6149–6151
6151
1H), 6.83–6.84 (d, J=8.74 Hz, 1H); 13C NMR (125
MHz): −3.79, −4.72, 13.80, 17.94, 18.91, 22.40, 25.26,
28.95, 28.93, 29.25, 30.15, 31.57, 36.42, 41.09, 60.73,
62.14, 97.39, 115.19, 128.19, 173.19, 156.37; GC–MS: m/z
456 (M+). Anal. calcd for C25H48O5Si (456.73) C, 65.74;
H, 10.59. Found C, 65.52; H, 10.21%.
14. Compound 14: [h]2D5 −12.67, IR (neat): 1723, 1666; 1H
NMR (500 MHz): 0.03 (s, 3H), 0.08 (s, 3H), 0.86–0.89 (t,
J=6.3 Hz, 3H), 1.28–1.31 (m, 10H), 1.27 (s, 9H), 1.41–
1.46 (two doublets, J=6 Hz, 3H), 1.52–1.56 (m, 2H),
1.59–1.87 (m, 6H), 3.74 (s, 3H), 4.24–4.26 (t, J=11.2 Hz,
2H), 4.32–4.44 (m, 1H), 4.70–4.71, (m, 1H), 4.95–4.97 (m,