Total synthesis of stevastelin B, a novel immunosuppressant

Article abstract of DOI:10.1055/s-2001-13382

Total synthesis of stevastelin B is described. Evans asymmetric aldol methodology and Roush asymmetric allylation were used to construct four consecutive stereo-centers on the octadecanoic acid moiety of stevastelin B. Subsequent coupling with a dipeptide

Full text of DOI:10.1055/s-2001-13382

694
LETTER
Total Synthesis of Stevastelin B, a Novel Immunosuppressant
Naoki Kohyama, Yukio Yamamoto*
Graduate School of Human and Environmental Studies, Kyoto University, Sakyo-ku, Yoshida, Kyoto 606-8501, Japan
Fax +81-75-753-2999; E-mail: yuyamamo@ip.media.kyoto-u.ac.jp
Received 5 March 2001
Abstract: Total synthesis of stevastelin B is described. Evans
asymmetric aldol methodology and Roush asymmetric allylation
were used to construct four consecutive stereo-centers on the octa-
decanoic acid moiety of stevastelin B. Subsequent coupling with a
dipeptide and macrolactamization gave stevastelin B. The flexibili-
ty of this route could allow the synthesis of many analogues for bi-
ological tests, which cannot be obtained from natural sources.
C13H27
O
OH HN
O
O
O
O
AcO
NH
N
H
Key words: total synthesis, stevastelin B, immunosuppressant,
OH
asymmetric aldol reaction, asymmetric allylation
1; Stevastelin B
Stevastelins are novel depsipeptides, isolated from a cul-
ture broth of penicillium sp. NK374186 as immunosup-
pressants in 1994.1 Among stevastelins, stevastelin B is
the most abundant. Stevastelin B (1) contains four compo-
nents, namely valine, threonine, O-acetyl-serine and 3,5-
dihydroxy-2,4-dimethyloctadecanoic acid. The absolute
structure of stevastelin B was determined in 1996.2 Stev-
astelin B shows the inhibitory activity not only against T
cell activation but also B cell.1 Together with its low tox-
icity, stevastelins may be useful tools for investigation of
T cell and B cell activation mechanisms and have applica-
tions as immunosuppressants.1,3
Evans aldol methodology
Roush asymmtric allylation
C13H27
O
O
OH
C13H27CHO
BnO
NHBoc
Scheme 1
oxidized to acid 8 by ozonolysis and subsequent NaClO2-
NaH2PO4 oxidation.
Total synthesis of stevastelin B has not been reported yet,
although it has a very interesting structure and biological
activity. So we decided to make stevastelin B our target of
total synthesis. The synthetic plans are shown in Scheme
1. For the appropriate construction of four consecutive
stereo-centers in synthetic intermediate 3, which was a
crucial point in this total synthesis, we decided to use
Evans asymmetric aldol methodology4 and Roush asym-
metric allylation.5
Acid 8 was reduced to triol 128 which had been derived
from stevastelin B itself (Scheme 3). The 1H NMR spectra
and the specific rotation of 12 thus obtained were identical
with the reported data.2b Moreover, benzyl ether 13, pre-
pared by the same method for 3, was converted to ace-
tonide 14 to confirm the syn-stereochemistry of two
hydroxyl groups, independently. The gem-methyl groups
of 14 were observed at 19.55 and 30.11 ppm, respectively
(in 13C NMR). The 13C NMR spectra of syn-1,3-diol ace-
tonides are reported to show an axial methyl group at 19
ppm and an equatorial methyl group at 30 ppm, while the
two methyl groups of anti-1,3-diol acetonides appear at
24 ppm.9 Therefore, the relative stereochemistry of this
1,3-diol was unambiguously determined as syn (Scheme
4).
Evans asymmetric aldol reaction followed by hydrolysis
and esterification gave methyl ester 4 (Scheme 2). MTPA
ester derived from methyl ester 4 was used to determine
the enantiomeric purity. By 19F NMR, methyl ester 4
proved to be >99% ee. Reduction of 4 with LiBH4 gave a
diol,6 whose primary alcohol was selectively protected
with a TBS group to give alcohol 5. Coupling of 5 with
Boc-Ser(Bn)-OH followed by deprotection of the TBS
group under acidic conditions gave alcohol 6. Alcohol 6
was oxidized to the corresponding aldehyde by TPAP,7
which was converted to homoallyl alcohol 3 by Roush
asymmetric allylation using (R,R)-boronate 7. The diaste-
reomers, which might be yielded by the asymmetric ally-
lation, were not found at all. This boronate 7 can construct
the 3,4-anti configuration, regardless of the configuration
of aldehydes.5 In fact, the desired stereochemistry was
correctly constructed as described below. Olefin 3 was
Coupling of acid 8 with dipeptide 9 gave 10. Removal of
the benzyl groups in 10 by hydrogenation with Pd/C gave
11. After removal of the Boc group in 11, macrolactam-
ization under several conditions was examined, but the
desired macrocyclic product was not obtained. The free
serine hydroxyl group seemed to affect the cyclization re-
action. When we changed the position in which the Val-
Thr dipeptide was introduced, hydroxyl group of serine
Synlett 2001, No. 5, 694–696 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Stevastelin B, a Novel Immunosuppressant
695
O
O
C13H27
O
OH
C13H27
OTBS
a, b, c
C13H27
OMe
f, g
d, e
N
O
O
OH
OH
O
BnO
NHBoc
4
5
6
CO2Pri
CO2Pri
O
B
h, i
O
7
C13H27
O
C
13H27
COOH
j, k
l
O
OH
O
O
OH
BnO
BnO
NHBoc
NHBoc
8
3
OH
OR
C13H27
O
O
H
C13H27
O
N
OH HN
N
H
O
O
O
OH
O
O
O
O
HO
NH
RO
N
H
NHBoc
OH
10; R= Bn
11; R= H
Pd/ C, H2 (quant.)
Scheme 2 Reagents and conditions: a) n-Bu2BOTf, Et3N, C13H27CHO; b) H2O2, LiOH; c) CH2N2, 89% for 3 steps; d) LiBH4, MeOH, 99%;
e) TBSCl, Et3N, DMAP, 86%; f) Boc-Ser(Bn)-OH, DCC, HOBt, quant.; g) 3 N HClaq./ THF, 92%; h) TPAP, NMO, 70%; i) 7, -78 °C, 82%;
j) O3, Ph3P, -78 °C, 85%; k) NaClO2, NaH2PO4, 2-Methyl-2-butene, THF/ t-BuOH/ H2O, quant.; l) H-Val-Thr-OBn (9), DCC, HOBt, 55%
was successfully protected until the completion of macro-
lactamization.
LAH
C13H27
OH
8
Removal of the Boc group in homoallyl alcohol 3 fol-
lowed by coupling with dipeptide 15 gave 16 (Scheme 5).
Olefin 16 was oxidized to acid 17 by ozonolysis and
NaClO2-NaH2PO4 oxidation. Esterification of 17 with
pentafluorophenol and DCC gave active ester 18. Remov-
al of the Boc group followed by macrolactamization in the
presence of large excess of triethylamine gave the desired
macrocyclic benzyl ether 19.10 Hydrogenation of 19 with
Pd(OH)2/C followed by selective acetylation of the prima-
ry hydroxyl group in the serine residue gave stevastelin B
(1).11 The 1H and 13C NMR spectra were coincident with
those of the natural compound.
THF
88%
OH OH
12
Scheme 3
Li
C13H27
C13H27
liq. NH3
96%
OBn OH
13
OH OH
(MeO)2CMe2
p-TsOH
88%
Thus, the total synthesis of stevastelin B has been
achieved (18 steps, overall yield 3% from tetradecanal)
and the present synthetic strategy of stevastelin B allows
systematic syntheses of not only other natural stevastelins
but also other unnatural analogues which may show activ-
ities of biological interest. The total synthesis of stevaste-
lin B3, our next target, is now under course.
CH3
C
13H27
C13H27
30.11ppm
CH3
O
O
H
s-C4H9
O
O
H
H
CH3
19.55ppm
14
References and Notes
Scheme 4
(1) Morino, T.; Masuda, A.; Yamada, M.; Nishimoto, M.;
Nishikiori, T.; Saito, S.; Shimada, N. J. Antibiotics 1994, 47,
1341- 1343.
Synlett 2001, No. 5, 694–696 ISSN 0936-5214 © Thieme Stuttgart · New York

696
N. Kohyama, Y. Yamamoto
LETTER
C13H27
C13H27
C13H27
COOH
a
b, c
O
O
OH
O
O
OH
O
O
OH
O
O
H
N
H
N
BnO
BnO
BnO
N
H
NHBoc
N
H
NHBoc
NHR
O
O
OH
OH
3; R= Boc
CF3COOH/ CH2Cl2
R= H
16
17
d
C13H27
O
C13H27
COOC6F5
f, g
e
OH HN
O
O
OH
Stevastelin B
O
O
O
O
H
N
O
BnO
BnO
NH
N
H
NHBoc
N
H
O
OH
OH
18; R= Boc
19
CF3COOH/ CH2Cl2
R= H
Scheme 5 Reagents and conditions: a) Boc-Val-Thr-OH (15), DCC, HOBt, quant.; b) O3, Ph3P, -78 °C, 87%; c) NaClO2, NaH2PO4, 2-
Methyl-2-butene, THF/ t-BuOH/ H2O, 62%; d) C6F5OH, DCC, 66%; e) high dilution, Et3N (20 equiv), 47% for 2 steps; f) Pd(OH)2/ C, H2,
56%; g) Ac2O, pyridine, 81%.
(2) a) Morino, T.; Shimada, K.; Masuda, A.; Yamashita, N.;
Nishimoto, M.; Nishikiori, T.; Saito, S. J. Antibiotics 1996,
49, 565- 568. b) Shimada, K.; Morino, T.; Masuda, A.; Sato,
M.; Kitagawa, M.; Saito, S. J. Antibiotics 1996, 49, 569- 574.
(3) Hamaguchi, T,; Masuda, A.; Morino, T.; Osada, H. Chem.
Biol. 1997, 4, 279- 286.
(4) a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127- 2129. b) Evans, D. A.; Nelson, J. V.; Vogel,
E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099- 3111.
(5) a) Roush, W. R.; Ando, K.; Powers, D.B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339- 6348. b)
Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc.
1990, 112, 6348- 6359. c) Scheidt, K. A.; Tasaka, A.;
Bannister, T. D.; Wendt, M. D.; Roush, W. R. Angew. Chem.
Int. Ed. 1999, 38, 1652- 1655.
(6) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000- 4005.
(7) a) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13-
19. b) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A.
D. J. Chem. Soc., Chem. Commun. 1987, 1625- 1627.
(8) Triol 12: [ ]D21 +16.6 (c 1.0, CHCl3); 1H NMR H (270 MHz,
CDCl3): 4.38 (1H, br s), 3.85-3.61 (5H, m), 3.37 (1H, br s),
2.85 (1H, br s), 1.89 (1H, m), 1.29-1.23 (24H, m), 0.91 (3H, t,
J = 7.1), 0.87 (3H, d, J = 6.6), 0.75 (3H, d, J = 6.9); 13C NMR
C (68 MHz, CDCl3): 83.6, 77.8, 69.3, 37.9, 37.4, 35.6, 32.0,
29.7, 29.7, 29.4, 26.1, 22.8, 14.2, 13.3, 4.2; HRMS (FAB)
calcd for C20H43O3 (M+H)+ 331.3212, found 331.3205.
(9) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945- 948.
CHHCHOCO), 1.50 (1H, m, CHHCHOCO), 1.32 [3H, d,
J = 7.3, CH(OH)MeCHCONH], 1.28-1.21 [18H, m, (CH2)9],
1.17 [3H, d, J = 6.1, MeCH(OH)CH], 1.08 [3H, d, J = 6.7,
CHOCHMeCH(OH)], 0.98 (3H, d, J = 6.7, MeCHMe), 0.88
(3H, t, J = 7.0, CH2Me), 0.84 (3H, d, J = 6.7, MeCHMe);13C
NMR C (126 MHz, CDCl3): 175.4, 171.8, 171.1, 169.6,
137.0, 128.5, 128.0, 127.7, 80.4, 74.9, 73.5, 69.2, 66.6, 60.1,
56.5, 53.6, 49.8, 41.1, 31.9, 31.4, 30.9, 29.7, 29.6, 29.5, 29.4,
29.3, 25.6, 22.7, 19.5, 17.9, 16.1, 14.1, 12.5, 9.6; IR
(CHCl3): 3300, 2926, 2855, 2361, 1827, 1734, 1647, 1558,
1541, 1458, 1420, 1364, 1215, 1117, 1055, 984, 935, 872,
756, 696, 669; HRMS (FAB) calcd for C39H66N3O8 (M+H)+
704.4849, found 704.4825.
(11) Stevastelin B (1): [ ]D25 -18.1 (c 1.0, CHCl3) (The rotation of
the natural compound is not reported.); 1H NMR H (500
MHz, CDCl3): 7.73 (1H, d, J = 7.9, NH), 7.34 (1H, d, J = 7.9,
NH), 6.74 (1H, d, J = 6.7, NH), 5.01 (1H, m, CHOCO), 4.55
(1H, m, MeCHMe), 4.54 (1H, dd, J = 7.9, 3.7, COCHNH),
4.35 (1H, m, MeCHOH), 4.25 (1H, t, J = 6.7, COCHNH),
4.11 [1H, dd, J = 8.6, 3.7, MeCHCH(OH)], 3.95 (1H, dd,
J = 11.6, 4.3, CHCHHOAc), 3.88 (1H, dd, J = 11.6, 4.3,
CHCHHOAc), 3.32 (1H, m, COCHNH), 2.13 (1H, m,
MeCHCONH), 2.04 (3H, s, MeCO), 1.97 [1H, m,
MeCHCH(OH)], 1.37 (3H, d, J = 7.3, MeCHMe), 1.35-1.21
[24H, m, (CH2)12], 1.18 [(1H, d, MeCH(OH)CH], 1.10
(3H, d, J = 7.3, MeCHMe), 1.00-0.98 [6H, m,
MeCHCH(OH)CHMe], 0.88 (3H, t, J = 6.7, CH2Me);
13C NMR C (126 MHz, CDCl3): 172.3, 172.0, 171.9, 170.7,
169.7, 80.7, 75.0, 66.7, 62.4, 60.1, 57.7, 55.4, 49.7, 40.9, 31.9,
31.3, 30.4, 29.7, 29.6, 29.5, 29.4, 29.3, 29.3, 25.6, 22.7, 19.3,
18.6, 18.4, 14.1, 12.5, 9.6; IR (CHCl3): 3308, 3088, 2926,
2855, 2361, 1828, 1734, 1641, 1541, 1458, 1379, 1200, 1128,
1080, 986, 939, 870, 756, 667; HRMS (FAB) calcd for
C34H62N3O9 (M+H)+ 656.4486, found 656.4497.
(10) Benzyl ether 19: [ ]D25 -11.3 (c 1.2, CHCl3); 1H NMR H (500
MHz, CDCl3): 8.10 (1H, d, J = 7.3, NH), 7.49 (1H, d, J = 7.9,
NH), 7.35-7.27 (5H, m, Ph), 4.99 (1H, m, CHOCO), 4.62 (1H,
m, MeCHMe), 4.50 (2H, s, PhCH2), 4.44 (1H, dd, J = 7.6, 2.8,
COCHNH), 4.33 (1H, m, MeCHOH), 4.00 [1H, dd, J = 8.9,
4.0, MeCHCH(OH)CHMe], 3.88 (1H, dd, J = 9.2, 3.7,
CHCHHOBn), 3.68 (1H, dd, J = 9.2, 3.7, CHCHHOBn), 3.28
(1H, m, BnOCH2CH), 3.23 (1H, m, Me2CHCH), 2.27 (1H, m,
MeCHCO), 1.94 [1H, m, MeCHCH(OH)], 1.60 (1H, m,
Article Identifier:
1437-2096,E;2001,0,05,0694,0696,ftx,en;Y04501ST.pdf
Synlett 2001, No. 5, 694–696 ISSN 0936-5214 © Thieme Stuttgart · New York