Total synthesis of (-)-stevastelin B

Article abstract of DOI:10.1039/b202298b

The total synthesis and an unambiguous structure confirmation of stevastelin B 1, a novel 15-membered cyclic depsipeptide, are described; the fatty acid moiety in 1, prepared stereoselectively from L-quebrachitol was converted into the amino carboxylic acid, whose macrolactamization by Shioiri's procedure effectively constructed the cyclic structure of 1.

Full text of DOI:10.1039/b202298b

Total synthesis of (–)-stevastelin B†
Kazuo Kurosawa, Toshihiko Nagase and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan. E-mail: chida@applc.keio.ac.jp; Fax: 81 45 566 1573; Tel: 81 45 566 1573
Received (in Cambridge, UK) 6th March 2002, Accepted 7th May 2002
First published as an Advance Article on the web 16th May 2002
The total synthesis and an unambiguous structure confirma-
tion of stevastelin B 1, a novel 15-membered cyclic depsipep-
tide, are described; the fatty acid moiety in 1, prepared
of 11 were identical to those reported for the authentic
compound derived from natural stevastelin B by degra-
dation.3b
stereoselectively from
L-quebrachitol was converted into the
Treatment of 11 with 2-methoxypropene in the presence of
CSA at rt afforded acetonide 12 in 76% yield (Scheme 2). To
introduce a tripeptide, acylation of 12 with Boc-Val-Thr-
Ser(Bzl)‡ under various reaction conditions were attempted.
However, none of the acylated product was obtained even under
Yamaguchi’s conditions.12 Recognition of the poor reactivity of
the hydroxy group in 12, probably due to the steric hindrance,
led us to explore the stepwise introduction of the peptide
moiety. Although condensation of 12 with Cbz-Ser(Bzl) in the
presence of DCC and DMAP gave no coupling product, it was
found that the reaction under Yamaguchi’s conditions success-
fully afforded the acylated products. Unfortunately, partial
racemization of the serine moiety during the condensation
process had occurred, and compound 13 and its 2A-epimer were
obtained as an inseparable mixture in a ratio of ca. 6+1
amino carboxylic acid, whose macrolactamization by
Shioiri’s procedure effectively constructed the cyclic struc-
ture of 1.
Stevastelin B 1, a member of stevastelin family, is a novel cyclic
depsipeptide isolated from a culture broth penicillium, and
reported to show a potent immunosuppressive activity.1,2 The
structural study by spectral, degradation and synthetic methods
established that stevastelin B consists of (2S,3S,4S,5R)-3,5-di-
hydroxy-2,4-dimethylstearic acid,
L
-serine,
L
-threonine and -
L
valine, and has a 15-membered cyclic structure.3 Its interesting
mode of action, repression of both T cells and B cells,1 as well
as its unique structure has attracted synthetic attention, and total
synthesis,4 synthetic approach,5 and preparation and biological
assessment of simple analogues6 of 1 have been reported to
date. Here we report an alternative total synthesis of 1, which
fully confirmed the proposed absolute structure of the natural
product.
1
(determined with 300 MHz H NMR) in 73% yield. Hydro-
genolysis of a mixture of 13 and its epimer in the presence of
10% Pd–C ethylenediamine complex13 selectively deprotected
the N-Cbz group to give an amine, which, without isolation, was
coupled with Boc-Val-Thr 14‡ by the action of ethyl-
For a synthesis of the fatty acid moiety with four contiguous
chiral centers in 1, we chose
active cyclitol obtained in large quantity from the serum of the
rubber tree, as the starting material.7 The known 1
L
-quebrachitol 2, an optically
3-(3-dimethylaminopropyl)carbodiimide
hydrochloride
(WSC4HCl) and 1-hydroxybenzotriazole (HOBt) to provide 15
and its diastereomer in 95% yield. At this stage, diastereomers
were cleanly separated by silica gel chromatography, and
D-
(1,2,3,4,5/6)-1,2-anhydro-3,4-O-isopropylidene-5-methyl-6-O-
methylcyclohexane-1,2,3,4,6-pentol8 3, prepared from 2 in 7
steps in 33% overall yield, was treated with Me3Al to give the
trans-diaxial ring opening product 4 in 77% yield (Scheme 1).
PCC oxidation of 4 provided ketone 5. From our earlier
observations, it was highly anticipated that Baeyer–Villiger
reaction of 5, possessing a methyl and an oxygen substituents on
a- and aA-carbons respectively, proceeds in highly regiose-
lective manner.9 Indeed, treatment of 5 with mCPBA afforded
the expected product, 7-membered lactone 6 as the sole isomer
in 81% yield from 4. Reduction of 6 with LiAlH4, followed by
conventional acetylation gave 7 (98%), which was converted
into O-mesylate derivative 8 in 67% yield. Base treatment of 8
cleanly afforded epoxide 9 (96%), which was then reacted with
didodecylmagnesium in the presence of CuCN10 to provide 10
in 87% yield. Deprotection of the O-methyl group in 10 with
trimethylsilyl iodide11 afforded the precursor of the fatty acid
moiety 11 in 85% yield. The spectroscopic data and [a]D value
Scheme 1 Piv = -COCMe3, Ms = -SO2Me. Reagents and conditions: i see
ref 8; ii Me3Al, CH2Cl2–hexane (2+1), rt; iii PCC-Al2O3, CH2Cl2, rt; iv
mCPBA, KHCO3, (CH2Cl)2, rt; v LiAlH4, THF, rt, then Ac2O, pyridine, rt;
vi MeONa, MeOH, rt; vii PivCl, DMAP, pyridine, rt, then MsCl, pyridine,
rt; viii (n-C12H25)2Mg, CuCN (10 mol%), Et2O, rt; ix TMSI, CH2Cl2, rt.
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b2/b202298b/
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CHEM. COMMUN., 2002, 1280–1281
This journal is © The Royal Society of Chemistry 2002

Scheme 2 Bzl = -CH2Ph, Cbz = -C(O)OCH2Ph. Reagents and conditions: i 2-methoxypropene, CSA, CH2Cl2, rt; ii mixed acid anhydride (prepared from
N-benzyloxycarbonyl-O-benzyl- -serine and 2,4,6-trichlorobenzoylchloride, Et3N, THF), DMAP, toluene–THF, rt; iii H2, 10% Pd–C ethylenediamine
L
complex, MeOH, rt, then 14, WSC4HCl, HOBt, DMF, rt; iv AcOH–H2O (7+3), rt; v TEMPO, KBr, NaOCl, NaHCO3, H2O–CH2Cl2 (1+15), 0 °C, then
NaClO2, HOSO2NH2, NaH2PO4, t-BuOH–H2O (4+1), rt; vi TFA, CH2Cl2, 0 °C; vii DEPC, Et3N, DMF (0.01 mol dm23 solution), rt; viii H2, 20% Pd(OH)2-C,
MeOH, rt; ix Ac2O, pyridine, 0 °C.
H, d, J 7.4), 1.40–1.78 (2 H, m), 1.84 (1 H, m), 2.06 (3 H, s), 2.13 and 2.66
compound 15 was isolated in pure form in 55% overall yield
(each 1 H, 2 m), 2.91 and 3.39 (each 1 H, 2br s), 3.64 (1 H, m), 3.97 (1 H,
dd, J 6.9 and 6.9), 4.21, 4.44 and 4.48 (each 1 H, 3 m), 4.49 (1 H, dd, J 5.5
and 11.3), 4.65 (1 H, dd, J 7.2 and 11.3), 4.86 (1 H, m), 6.71, 7.20 and 7.51
to give aldehyde, which was further oxidized by sodium chlorite
(each 1 H, 3br s); HRMS (FAB) m/z 656.4477, calcd for C34H62N3O9 (M +
to afford carboxylic acid 17. Treatment of 17 with TFA
H) 656.4486.
from 12. Acid hydrolysis of 15 gave triol 16 (94% yield). The
primary alcohol in 16 was selectively oxidized with TEMPO14
provided amino carboxylic acid 18. The crucial step, macro-
lactamization of 18, was successfully carried out under Shioiri’s
protocol15 [(diethyl phosphorocyanidate (DEPC) in DMF (0.01
mol dm23)] to give macrocycle 19 in 41% yield from 16.
Removal of the O-benzyl group in 19 by hydrogenolysis
afforded triol 20, which was treated with acetic anhydride in
pyridine at 0 °C to furnish stevastelin B 1 in 67% yield from 19.
The direct comparison of synthetic 1 with natural stevastelin
B,§ kindly provided by Nippon Kayaku Co., Ltd., revealed that
the synthetic compound is unambiguously identical with the
natural product, confirming the proposed whole structure of
stevastelin B.¶
¶ 1H and 13C NMR spectral data of natural stevastelin B had been originally
reported as DMSO-d6 solutions [ref.3(a)], whereas those of Yamamoto’s
synthetic sample were presented as CDCl3 solutions (ref. 4). 1H and 13C
NMR spectra of our synthetic 1 were fully identical with those of the natural
product in both CDCl3 and DMSO-d6; however, our data in CDCl3 were not
consistent with the data reported by Yamamoto. The [a]D value of
25
Yamamoto {[a]D 218.1 (c 1.0, CHCl3)} (ref. 4) is also somewhat
different from ours and that of the natural product.
1 T. Morino, A. Masuda, M. Yamada, M. Nishimoto, T. Nishikiori, S.
Saito and N. Shimada, J. Antibiot., 1994, 47, 1341.
2 T. Morino, K.-i. Shimada, A. Masuda, M. Nishimoto and S. Saito, J.
Antibiot., 1996, 49, 1049.
3 (a) T. Morino, K.-i. Shimada, A. Masuda, N. Yamashita, M. Nishimoto,
T. Nishikiori and S. Saito, J. Antibiot., 1996, 49, 564; (b) K.-i. Shimada,
T. Morino, A. Masuda, M. Sato, M. Kitagawa and S. Saito, J. Antibiot.,
1996, 49, 569.
We thank Drs T. Morino and T. Aoyama (Pharmaceutical
Group, Nippon Kayaku Co., Ltd., Tokyo, Japan) for a gift of
natural stevastelin B.
4 N. Kohyama and Y. Yamamoto, Synlett, 2001, 694.
5 T. K. Chakraborty, S. Ghosh and S. Dutta, Tetrahedron Lett., 2001, 42,
5085.
6 T. Hamaguchi, A. Masuda, T. Morino and H. Osada, Chem. Biol., 1997,
4, 279.
7 N. Chida and S. Ogawa, Chem. Commun., 1997, 807.
8 N. Chida, M. Yoshinaga, T. Tobe and S. Ogawa, Chem. Commun.,
1997, 1043; N. Chida, K. Yamada and S. Ogawa, J. Chem. Soc., Perkin
Trans. 1, 1993, 1957.
9 N. Chida, T. Tobe and S. Ogawa, Tetrahedron Lett., 1994, 35, 7249.
10 B. H. Lipshutz and S. Sengupta, Org. React., 1992, 41, 135; N. Chida,
N. Sakata, K. Murai, T. Tobe, T. Nagase and S. Ogawa, Bull. Chem. Soc.
Jpn., 1998, 71, 259.
11 H. Sakurai, A. Shirahata, K. Sakai and A. Hosomi, Synthesis, 1979,
740.
12 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi, Bull.
Chem. Soc. Jpn., 1979, 52, 1989.
13 H. Sajiki, K. Hattori and K. Hirota, J. Org. Chem., 1998, 63, 7990.
14 T. Inokuchi, S. Matsumoto, T. Nishiyama and S. Torii, J. Org. Chem.,
1990, 55, 462.
15 T. Shioiri, Y. Yokoyama, Y. Kasai and S. Yamada, Tetrahedron, 1976,
32, 2211; S. Yamada, Y. Kasai and T. Shioiri, Tetrahedron Lett., 1973,
1595; S. Takuma, Y. Hamada and T. Shioiri, Chem. Pharm. Bull., 1982,
30, 3147.
Notes and references
‡ These peptides were prepared by condensation (WSC4HCl, HOBt, DMF)
of appropriate protected amino acids which were purchased from Peptide
Institute, Inc. (Osaka, Japan).
17
§ Natural 1: [a]D 248 (c 0.1, CHCl3) (measured in our laboratory).
21
Synthetic 1: [a]D 251 (c 0.25, CHCl3); dH (300 MHz, DMSO-d6) 0.73 (3
H, d, J 7.1, 4-Me), 0.82 (3 H, d, J 6.1, val-Me), 0.85 (3 H, t, J 6.3, 18-H3),
0.88 (3 H, d, J 6.6, val-Me), 1.00 (3 H, d, J 6.1, thr-Me), 1.13 (3 H, d, J 7.6,
2-Me), 1.23 (22 H, m, 7–17-CH2), 1.43 and 1.53 (each 1 H, 2 m, 6-H2), 1.72
(1 H, m, 4-H), 1.98 (3 H, s, OAc), 2.10 (1 H, m, val-bH), 2.19 (1 H, m, 2-H),
3.61 (1 H, m, 3-H), 3.94 (1 H, dd J 7.1 and 10.7, ser-bH), 3.98 (1 H, dd, J
10.3 and 11.0, val-aH), 4.18 (1 H, m, thr-bH), 4.27 (1 H, bd J 9.1, thr-aH),
4.40 (1 H, dd, J 6.6 and 10.7, ser-bH), 4.73 (1 H, ddd J 6.6, 7.1 and 8.1, ser-
aH), 4.90 (1 H, d, J 4.4, thr-OH), 4.92 (1 H, m, 5-H), 5.52 (1 H, d, J 5.1,
3-OH), 7.81 (1 H, d, J 8.1, ser-NH), 7.93 (1 H, d, J 10.3, val-NH) and 8.32
(1 H, d, J 9.1, thr-NH); dC (75 MHz, DMSO-d6) 6.5 (4-CH3), 13.9 (18-C),
16.4 (2-CH3), 19.0 (val-CH3), 19.4 (val-CH3), 20.5 (thr-CH3), 20.6
(COCH3), 22.1 (17-C), 25.4 (7-C), 28.69, 28.73, 28.9, 28.99, 29.04, 29.8
and 31.3 (8–16-C and val-bC), 31.7 (6-C), 40.0 (4-C), 46.3 (2-C), 49.9 (ser-
aC), 57.7 (thr-aC), 61.2 (val-aC), 62.4 (ser-bC), 66.8 (thr-bC), 75.3 (3-C),
78.8 (5-C), 169.4 (ser-CO), 170.1 (OCOCH3), 170.4 (thr-CO), 171.3 (val-
CO) and 174.9 (1-C); dH (300 MHz, CDCl3) 0.88 (3 H, t, J 6.3), 1.03 (3 H,
d, J 6.3), 1.05 (6 H, d, J 6.6), 1.14 (3 H, d, J 6.3), 1.25 (22 H, m), 1.31 (3
CHEM. COMMUN., 2002, 1280–1281
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