J. Am. Chem. Soc. 2001, 123, 3369-3370
3369
Scheme 1
A New Strategy for the Stereoselective Introduction
of Steroid Side Chain via r-Alkoxy Vinyl Cuprates:
Total Synthesis of a Highly Potent Antitumor
Natural Product OSW-11
Wensheng Yu and Zhendong Jin*
DiVision of Medicinal and Natural Products Chemistry
College of Pharmacy, The UniVersity of Iowa
Iowa City, Iowa 52242
Scheme 2
ReceiVed NoVember 28, 2000
Introduction of a steroid side chain into tetracyclic steroid
starting materials has been one of the most important aspects in
steroid synthesis, and it has been the subject of many investiga-
tions.2,31,4-Addition of an acyl anion equivalent to 17(20)-en-
16-one steroids is an attractive strategy to install a steroid side
chain. Although this strategy was recognized by Kessar,4 its
application in the synthesis of steroids is still in its infancy.5 The
reason for limited application of this strategy is that hard acyl
anion equivalents often prefer 1,2-addition over 1,4-addition,
whereas soft acyl anion equivalents afford an equilibrium between
17(20)-en-16-one steroids and 1,4-addition products.6
Scheme 3a
Recently, we reported a new methodology for the general
preparation of R-alkoxy vinyl anions.7 We also demonstrated that
R-alkoxy vinyl cuprates can undergo facile 1,4-addition to R,â-
unsaturated ketones.7 On the basis of these results, a new
convergent strategy for the introduction of the steroid side chain
was designed (Scheme 1). TMSCl-activated8 stereoselective 1,4-
addition of the R-alkoxy vinyl cuprate to steroid 17(20)-en-16-
one should afford the silyl enol ether, which can further undergo
oxidation, alkylation, or condensation at C-17. We were particu-
larly interested in the oxidation reaction because it allows the
stereoselective introduction of a hydroxy group to C-17, avoiding
the use of osmium tetroxide, which is commonly employed to
introduce the 16,17-diol.9,12
a a. (i) n-BuLi, -20-0 °C, 20 min; (ii) iso-butyl triflate, -30-25 °C,
12 h, 85%; b. TMSBr, MeOH, CH2Cl2, -40-25 °C, 15 min, 99%; c. (i)
t-BuLi (2 equiv), ether, -78 °C, 30 min; (ii) CuCN, LiCl, THF, -78 °C,
15 min.
other well-known anticancer agents in clinical use, including
mitomycin C, adriamycin, cisplatin, camptothecin, and taxol.
OSW-1 (1), the main constituent of Ornithogalum saundersiae
bulbs, is highly cytostatic in the NCI 60-cell in vitro screen, with
a mean IC50 of 0.78 nM.11 Due to these extraordinary antitumor
activities, OSW-1 is an attractive synthetic target.12 Fuchs reported
the first synthesis of the protected aglycone of OSW-1 in 1998.12a
By employing the same approach, Yu, Hui, and their co-workers
reported the first total synthesis of OSW-1 in 1999.12b In this
paper, we report a total synthesis of OSW-1(1) based on our
proposed new strategy.
The retrosynthetic analysis is outlined in Scheme 2. OSW-1
(1) was disconnected into the dissacharide 6 and the steroid
aglycone 7. 7 was envisaged to be prepared by the 1,4-addition
of the R-alkoxy vinyl cuprate 8 to 9 which was from commercially
available 5-androsten-3â-ol-17-one 10.
To demonstrate our new strategy, the total synthesis of a
naturally occurring saponin, OSW-1 (1), was investigated. OSW-1
(1) and its four natural analogues (2-5) are five highly potent
antitumor saponins that were recently isolated from the bulbs of
Ornithogalum saundersiae, a perennial grown in southern Africa.10
Scheme 3 outlines the synthesis of the requisite R-alkoxy vinyl
cuprate 8. The acetylenic ether 11 was prepared according to the
literature procedure.13 The R-bromo vinyl ether 13 was prepared
regio- and stereoselectively according to our procedures,7 which
was converted in situ to the high-order cuprate 8.14
Compound 15 was prepared from 10 according to literature
procedure (Scheme 4).15 Trost and co-workers have shown that
selenium dioxide-mediated allylic oxidation can regio- and
stereoselectively introduce a hydroxy group to the C-16 of the
steroid 17(20)-en-16-ones.15 However, in their examples the
double bond in the B ring was protected. It is noteworthy that
we were able to achieve complete chemo-, regio-, and stereose-
The IC50 values of these compounds against human promyelocytic
leukemia HL-60 cells range from between 0.1 and 0.3 nM.11 Their
anticancer activities are from 10 to 100 times more potent than
(1) Synthesis via R-halo vinyl ethers 2.
(2) Piatak, D. M.; Wicha, J.Chem. ReV. 1978, 78, 199 and references therein.
(3) Redpath, J.; Zeelen, F. J. Chem. Soc. ReV. 1983, 12, 75 and references
therein.
(4) (a) Kessar, S. V.; Gupta, Y. P.; Mahajan, R. K.; Rampal, A. L.
Tetrahedron 1968, 24, 893. (b) Kessar, S. V.; Gupta, Y. P.; Mahajan, R. K.;
Joshi, G. S.; Rampal, A. L. Tetrahedron 1968, 24, 899.
(5) 1,4-addition of the soft anion derived from 1-acetoxy-5-nitro-2-
methylpentane to 17(20)-en-16-one was very slow (one week). Furthermore,
a mixture of diastereoisomers at C-20 was obtained.
(6) Yu, W.; Jin, Z. Unpublished results.
(7) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2000, 122, 9840.
(10) Kubo, S.; Mimaki, Y.; Terao M.; Sashida, Y.; Nikaido, T.; Ohmoto,
T. Phytochemitstry 1992, 31, 3969.
(11) Mimaki, Y.; Kuroda, M.; Kameyama, A.; Sashida, Y.; Hirano, T.;
Oka, K.; Maekawa, R.; Wada, T.; Sugita, K.; Beutler, J. A. Bioorganic Med.
Chem. Lett. 1997, 7, 633.
(8) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019. (b)
Alexakisss, A.; Berlan, J.; Besace, Y. Tetrahedron Lett. 1986, 27, 1047.
(9) (a) Bernstein, S.; Lenhard, R. H.; Allen, W. S.; Heller, M.; Littell, R.;
Stolar, S. M.; Feldman, L. I.; Blank, R. H. J. Am. Chem. Soc. 1959, 81, 1689.
(b) Wendler, N. L.; Taub, D. J. Am. Chem. Soc. 1960, 82, 2836. (c) Bernstein,
S.; Littell, R. J. Org. Chem. 1959, 24, 429. (d) Brown, J. J.; Bernstein, S. J.
Org. Chem. 1961, 26, 5033.
(12) (a) Guo, C.; Fuchs, P. Tetrahedron Lett. 1998, 39, 1099. (b) Deng,
S.; Yu, B.; Lou, Y.; Hui, Y. J. Org. Chem. 1999, 64, 202. (c) Morzycki, J.
W.; Gryszkiewicz, A.; Jastrzebska, I. Tetrahedron Lett. 2000, 41, 3751.
(13) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987, 52,
2919.
(14) Lipshutz, B. H. Synthesis 1987, 87, 325 and references therein.
(15) Schmuff, N. R.; Trost, B. M. J. Org. Chem. 1983, 48, 1404.
10.1021/ja004098t CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/14/2001