Synthetic study of polyoxypeptin: Stereoselective synthesis of the acyl side-chain segment

Article abstract of DOI:10.1016/S0040-4039(00)01282-X

The first synthesis of the acyl side-chain segment of polyoxypeptin, a potent inducer of apoptosis in human pancreatic carcinoma AsPC-1, was accomplished. The key feature of the present synthesis is the stereospecific palladium-catalyzed hydrogenolysis of

Full text of DOI:10.1016/S0040-4039(00)01282-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7499–7502
Synthetic study of polyoxypeptin: stereoselective synthesis of
the acyl side-chain segment
Yasuo Noguchi,† Tatsuhiro Yamada, Hiromi Uchiro and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya-Funagawara-machi, Shinjuku-ku,
Tokyo 162-0826, Japan
Received 21 June 2000; revised 17 July 2000; accepted 24 July 2000
Abstract
The first synthesis of the acyl side-chain segment of polyoxypeptin, a potent inducer of apoptosis in
human pancreatic carcinoma AsPC-1, was accomplished. The key feature of the present synthesis is the
stereospecific palladium-catalyzed hydrogenolysis of (Z)-alkenyloxirane to anti-hydroxyalkenoate by an
improved method. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: polyoxypeptin; Pd-catalyzed hydrogenolysis; alkenyl oxirane.
Polyoxypeptin (1) was isolated by Umezawa et al. as a potent inducer of apoptosis from a
culture broth of Streptomyces sp. in 1998.1 Polyoxypeptin has attracted a great deal of attention
because it strongly induced apoptosis in human pancreatic carcinoma AsPC-1 with an IC50 of
80 ng/mL in 24 h.1 The structure of polyoxypeptin was unambiguously established by X-ray
crystallographic analysis to be a new 19-membered cyclic hexadepsipeptide2 containing a novel
acyl side-chain3,4 and a hitherto unknown amino acid, (2S,3R)-3-hydroxy-3-methylproline.
Therefore, polyoxypeptin is considered to be an interesting target molecule from a synthetic
point of view5 as well as from medicinal interest. We have investigated the total synthesis of
polyoxypeptin, and we wish to report here the first synthesis of the acyl side-chain segment 2 (as
a methyl ester) based on the Pd-catalyzed hydrogenolysis of 4,5-epoxy-2-alkenoate described in
the preceding paper (Scheme 1).
Our retrosynthetic analysis of the acyl side-chain 2 is shown in Scheme 2. The a-hydroxy-b-
ketoester moiety (C-1–C-3) including a quaternary center at C-2 might be most conveniently
prepared by an asymmetric dihydroxylation of trisubstituted olefin 3 which, in turn, could be
derived from unsaturated ester 4 by the conventional Wittig approach. Stereospecific Pd-cata-
lyzed hydrogenolysis6 of (Z)-epoxyalkenoate 5 into the requisite anti-isomer 4 is now possible by
the modified Pd-catalyzed hydrogenolysis employing Ph3P in DMF as described in the preceding
paper. Finally, 5 could be obtained from allylic alcohol 6 by an asymmetric epoxidation and
(Z)-selective Horner–Emmons reaction.
* Corresponding author. Tel: +81-3-3260-8848; fax: +81-3-3260-8848; e-mail: kobayash@ps.kagu.sut.ac.jp
† Visiting scientist from Sankyo Co., Ltd.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01282-X

7500
Scheme 1.
Scheme 2.
Epoxyalkenoate 5, a substrate for Pd-catalyzed hydrogenolysis, was synthesized from a chiral
alcohol 7, readily prepared from
-(+)-isoleucine by a known procedure.7 Thus, alcohol 7 was
L
transformed into phosphonium bromide 8, and its corresponding phosphonium ylide was
treated with methyl chloroformate, followed by reaction with propionaldehyde to afford an
(E)-alkenoate 9 in 40% yield based on chloroformate. After DIBAL reduction of unsaturated
ester 9 (80% yield), the resulting allylic alcohol was subjected to Sharpless asymmetric
epoxidation8 using
-(−)-tartrate to give an epoxyalcohol 10 in 75% yield with a diastereomeric
D
excess of over 99%. Epoxyalcohol 10 was oxidized by Swern oxidation, and the resulting
aldehyde was reacted with (Z)-selective phosphonate9 to obtain a (Z)-epoxyalkenoate 5 in 81%
yield (two steps from 10) in stereochemically pure form (Scheme 3).
Scheme 3. Reagents and conditions: a: (i) 48% aq. HBr, H2SO4, reflux, 5 h, 73%. (ii) Ph3P, 85°C, 4 days, 93%. b: (i)
NaHMDS, THF, −78°C, 1.5 h. (ii) ClCO2Me (0.5 equiv.), −78°C to rt, 1 h. (iii) CH3CH2CHO, THF, rt, 5 days, 40%
(based on ClCO2Me). c: DIBAL, ether, 0°C, 1 h, 80%. d: TBHP, Ti(O-i-Pr)4, D-(−)-DET, MS4A, CH2Cl2, −23°C, 1.5
h, 75%. e: (i) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N, rt, 1 h. (ii) (CF3CH2O)2P(O)CH2CO2Me, KHMDS,
18-crown-6, THF, −78°C, 1 h, 81% (two steps)

7501
(Z)-Alkenyloxirane (5) was then subjected to hydrogenolysis employing the modified method
described in the preceding paper. Thus, 5 was treated with 5 mol% Pd2(dba)3·CHCl3, 5 mol%
Ph3P, HCO2H, and Et3N in DMF at room temperature for 3 h to obtain the desired anti-isomer
4 in 73% yield with high stereospecificity (anti:syn=96:4) (Scheme 4).
Scheme 4.
Transformation of 4 into the acyl side-chain segment 2 is summarized in Scheme 5. After
protection of the hydroxyl group of 4 with TBDPS chloride, an unsaturated ester was reduced
to a saturated alcohol 11 in high yield. The alcohol 11 was oxidized by Swern condition, and the
resulting aldehyde was reacted with phosphorane to afford an unsaturated ester 12 as a single
stereoisomer. Asymmetric dihydroxylation10 of 12 was next carried out using AD-mix-b in the
presence of MeSO2NH2 to obtain a diol 13. The stereoselectivity of the present dihydroxylation
was excellent, producing an almost single isomer.11 The secondary hydroxyl group was then
oxidized with SO3·Py, and finally deprotection of the silyl group with HF–CH3CN12 completed
1
the synthesis of the acyl side-chain segment 2.13 The structure of 2 was confirmed by H and 13C
NMR spectra which are in good accordance with those of natural polyoxypeptin.
Scheme 5. Reagents and conditions: a: (i) TBDPSCl, imidazole, CH2Cl2, rt, 2 days, 83%. (ii) H2, Pd–C, AcOEt, rt, 12
h, 98%. (iii) DIBAL, Et2O, 0°C, 1 h, 97%. b: (i) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N, rt, 1 h. (ii)
Ph3P=C(Me)CO2Me, benzene, reflux, 4 h, 68% (two steps). c: AD-mix-b, MeSO2NH2, t-BuOH–H2O, 0°C, 4 days,
54% (61% based on the recovered 12). d: (i) SO3·Py, Et3N, DMSO, rt, 3 h, 99%. (ii) HF, CH3CN, rt, 12 h, 60%
In conclusion we were able to achieve the first synthesis of the acyl side-chain segment of
polyoxypeptin. The stereochemistry at C-6 and C-7 was controlled by modified Shimizu–Tsuji
reaction using Ph3P in DMF, and the quaternary chiral center at C-2 was established by
Sharpless asymmetric dihydroxylation. It is noteworthy that all reactions proceeded with high to
excellent stereoselectivity. Preparation of other segments and the coupling toward the total
synthesis of polyoxypeptin are now in progress.

7502
References
1. (a) Umezawa, K.; Nakazawa, K.; Uemura, T.; Ikeda, Y.; Kondo, S.; Naganawa, H.; Kinoshita, N.; Hashizume,
H.; Hamada, M.; Takeuchi, T.; Ohba, S. Tetrahedron Lett. 1998, 39, 1389–1392. (b) Umezawa, K.; Nakazawa,
K.; Ikeda, Y.; Naganawa, H.; Kondo, S. J. Org. Chem. 1999, 64, 3034–3038.
2. See for examples: (a) A83586C: Smitka, T. A.; Deeter, J. B.; Hunt, A. H.; Mertz, F. P.; Ellis, R. M.; Boeck, L.
D.; Yao, R. C. J. Antibiot. 1988, 41, 726–733. (b) L-156,602: Hensens, O. D.; Borris, R. P.; Koupal, L. R.;
Caldwell, C. G.; Currie, S. A.; Haidri, A. A.; Homnick, C. F.; Honeycutt, S. S.; Lindenmayer, S. M.; Schwartz,
C. D.; Weissberger, B. A.; Woodruff, H. B.; Zink, D. L.; Zitano, L.; Fieldhouse, J. M.; Rollins, T.; Springer, M.
S.; Springer, J. P. J. Antibiot. 1991, 44, 249–254. (c) Azinothricin: Maehr, H.; Liu, C.-M.; Palleroni, N. J.;
Smallheer, J.; Todaro, L.; Williams, T. H.; Blount, J. F. J. Antibiot. 1986, 39, 17–25. (d) Variapeptin: Nakagawa,
M.; Hayakawa, Y.; Furihata, K.; Seto, H. J. Antibiot. 1990, 43, 477–484.
3. The C-7 substituent is methyl instead of ethyl in L-156,6022b and variapeptin.2d
4. See for the synthesis of the acyl side chain of L-156,602: Caldwell, C. G.; Rupprecht, K. M.; Bondy, S. S.; Davis,
A. A. J. Org. Chem. 1990, 55, 2355–2361.
5. (a) A83586C: Hale, K. J.; Cai, J. Chem. Commun. 1997, 2319–2320. (b) L-156,602: Durette, P. L.; Baker, F.;
Barker, P. L.; Boger, J.; Bondy, S. S.; Hammond, M. L.; Lanza, T. J.; Pessolano, A. A.; Caldwell, C. G.
Tetrahedron Lett. 1990, 31, 1237–1240.
6. (a) Shimizu, I.; Oshima, M.; Nisar, M.; Tsuji, J. Chem. Lett. 1986, 1775–1776. (b) Oshima, M.; Yamazaki, H.;
Shimizu, I.; Nisar, M.; Tsuji, J. J. Am. Chem. Soc. 1989, 111, 6280–6287.
7. Schurig, V.; Leyrer, U.; Wistuba, D. J. Org. Chem. 1986, 51, 242–245.
8. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976.
9. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
10. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.;
Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768–2771.
11. A similar asymmetric dihydroxylation approach was presented by Professor Y. Hamada et al. (Chiba University)
at Annual Meeting of Pharmaceutical Society of Japan (March, 2000, Gifu).
12. When desilylation was carried out using Bu4NF in THF instead of HF–CH3CN, retro-Claisen fragmentation
occurred to give a substituted d-lactone.
13. Mp 69–71°C. [h]2D3 +55° (c 0.36, CHCl3). H NMR (CDCl3, 400 MHz): l 0.79 (t, J=7.3 Hz, 3H), 0.81 (d, J=6.4
1
Hz, 3H), 0.86 (t, J=7.3 Hz, 3H), 0.97–1.07 (m, 2H), 1.14–1.30 (m, 4H), 1.33–1.41 (m, 2H), 1.42 (s, 3H), 1.62–1.70
(m, 2H), 1.75–1.79 (m, 1H), 1.84 (ddt, J=13.1, 4.3 and 2.7 Hz, 1H), 3.06 (s, 1H), 3.45 (dt, J=9.5 and 2.4 Hz,
1H), 3.81 (s, 3H), 4.23 (d, J=2.7 Hz, 1H). 13C NMR (CDCl3, 100 MHz): l 176.63, 98.60, 78.93, 76.34, 52.77,
38.28, 36.87, 31.09, 30.95, 26.54, 25.36, 24.13, 19.50, 18.62, 11.57, 9.53. FAB-MS (pos.); m/z 325 (M+Na)+.
FAB-MS (neg.); m/z 301 (M−H)−. FAB-HRMS (pos.) calcd for C16H30NaO5 (M+Na)+ 325.1984, found 325.1990.
.