Toward chemical libraries of annonaceous acetogenins. Total synthesis of trilobacin

Full text of DOI:10.1021/jo961286m

7640
J . Org. Chem. 1996, 61, 7640-7641
assisted Kennedy oxidative-cyclization with rhenium
oxide,10 and the Mitsunobu inversion of alcohols.11 Here,
we combine these principles with the advantages of
convergent synthesis. We start with two fragments, each
containing two stereogenic centers; one is a phosphonium
salt and the other is an aldehyde. Referring to the
structure of 1, the phosphonium salt contains stereogenic
centers 23 and 24, and the aldehyde contains centers 15
and 16.
Tow a r d Ch em ica l Libr a r ies of An n on a ceou s
Acetogen in s. Tota l Syn th esis of Tr iloba cin
Subhash C. Sinha,*,† Anjana Sinha,†
Ahmad Yazbak,‡ and Ehud Keinan*,†,‡
The Scripps Research Institute, Department of Molecular
Biology and the Skaggs Institute for Chemical Biology,
10550 North Torrey Pines Road, La J olla, California 92037,
and Department of Chemistry, Technion-Israel Institute of
Technology, Technion City, Haifa 32000, Israel
The phosphonium salts 4a -d (Scheme 1A) and alde-
hydes 7a -d (Scheme 1B) were prepared using the AD
reaction with alkenes 2 and 5, respectively. For example,
reaction of 2 with AD-mix-â produced the (R,R) lactone
3a in 96% ee (>99.5% ee after recrystallization). The
latter was converted to either (R,R) phosphonium salt,
4a , or, using the Mitsunobu inversion, to the (4R,5S)
diastereomer, 4b. The two other enantiomers, 4c,d , were
prepared from 2 in 94% ee (>99.5% ee after recrystalli-
zation) using AD-mix-R. All stereoisomeric aldehydes,
7a -d , were similarly prepared in very high ee (Scheme
1B).
Coupling of all four Wittig reagents 4a -d with the four
aldehydes 7a -d can produce 16 stereoisomeric Z-alkenes.
This strategy is demonstrated here by the synthesis of
four of such alkenes, 8a -d (Scheme 2). Oxidative
cyclization with Re2O7/lutidine affords the corresponding
trans-substituted tetrahydrofurans 9a -d . Conversion of
9a to the corresponding mesylate followed by acid-
catalyzed acetonide-cleavage and ring closure produces
tricyclic lactone 10. Alternatively, Mitsunobu inversion
of the free alcohol’s configuration within 9a , prior to its
activation and ring-closure, gives rise to lactone 11.
Similarly, isomers 12 and 13 were obtained from 9b,
isomers 14 and 15 from 9c, and isomers 16 and 17 from
9d .12,13 Since products 14-17 are epimers of 10-13 at
the free hydroxyl position, their interconversion is pos-
sible by the Mitsunobu reaction. We have confirmed this
idea by an alternative synthesis of diastereomers 14 and
15 from 10 and 11, respectively.
Received J uly 9, 1996
To date, more than 230 different acetogenins have been
isolated from 26 plants of the Annonaceae.1 Taking into
consideration that the number of plants within this
family exceeds 2300, one may conclude that isolation and
full characterization of the entire naturally occurring
repertoire of the Annonaceous acetogenins will require
a formidable effort. Many of these compounds have
shown remarkable cytotoxic, antitumor, antimalarial,
immunosuppressive, pesticidal, and antifeedant activi-
ties.2 For example, studies with human solid-tumor cell
lines show that trilobacin, 1 is over 1 billion times more
potent cytotoxic agents than adriamycin.3 The urgent
need for a comprehensive biological screening of such
compounds led us to design synthetic approaches that
will generate large chemical libraries of isomeric aceto-
genins.4,5
A dominant structural feature that appears in more
than 40% of the Annonaceous acetogenins, particularly
in those showing the highest antitumor activity, is a
linear 10-carbon skeleton (i.e., carbons 15-24 in 1) that
comprises two adjacent tetrahydrofuran rings flanked by
two hydroxyl groups. Having six stereogenic carbinol
centers, this unit alone may appear in the form of as
many as 64 stereoisomers. To date, only four different
diastereomers of this fragment have been identified in
naturally occurring bis-THF acetogenins. Here, we
present an efficient methodology to produce 32 such
stereoisomers. We demonstrate this approach by the
actual synthesis of eight diastereomers, 10-17, and by
the use of one of them in the first total synthesis of 1.
Our previously described synthetic approach to the bis-
THF acetogenins4,6 is based on selective placement of the
oxygen functions onto a naked, unsaturated carbon
skeleton.7,8 This was achieved using the Sharpless
asymmetric dihydroxylation (AD) reaction,9 the ligand-
Altogether, by using two diastereomeric Wittig re-
agents 4a ,b and two diastereomeric aldehydes 7a ,b we
have synthesized eight diastereomers of the desired
tricyclic skeleton, 10-17. Consequently, combinatorial
coupling of all four Wittig reagents 4a -d with all four
aldehydes, 7a -d , should create a library of 32 out of 64
possible stereoisomeric skeletons.
The recently corrected structure of trilobacin, 1,3b
exhibits two very unusual features: an erythro junction
between the two adjacent THF rings and a cis stereo-
chemistry in the B ring. This structure suggests that
our synthetic lactone 11 is the appropriate precursor of
1. Thus, lactone 11 was converted to the primary Wittig
salt 20 (Scheme 3). Treatment of the latter with BuLi
* To whom correspondence should be addressed.
† The Scripps Research Institute.
‡ Technion-Israel Institute of Technology.
(1) (a) Rupprecht, J . K.; Hui, Y.-H.; McLaughlin, J . L. J . Nat. Prod.
1990, 53, 237. (b) Fang, X.-P.; Rieser, M. J .; Gu, Z.-M.; Zhao, G.-X.;
McLaughlin, J . L. Phytochem. Anal. 1993, 4, 27. (c) Figade´re, B. Acc.
Chem. Res. 1995, 28, 359. (d) Koert, U. Synthesis 1995, 115. (e) Hoppe,
R.; Scharf, H.-D. Synthesis 1995, 1447. (f) Zeng, L.; Zhang, Y.;
McLaughlin, J . L. Tetrahedron Lett. 1996, 37, 5449.
(2) Gu, Z.-M.; Zhao, G.-X.; Oberlies, N. H.; Zeng, L.; McLaughlin, J .
L. In Recent Advances in Phytochemistry; Arnason, J . T., Mata, R.,
Romeo, J . T., Eds.; Plenum Press: New York, 1995; Vol. 29, pp 249-
310.
(3) (a) Zhao, G.-X.; Hui, Y.-H.; Rupprecht, J . K.; McLaughlin J . L.;
Wood, K. V. J . Nat. Prod. 1992, 55, 347. (b) Zhao, G.-X.; Gu, Z.-M.;
Zeng, L.; Chao, J .-F.; Kozlowski, J . F. Wood, K.V.; McLaughlin J . L.
Tetrahedron 1995, 51, 7149.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(10) (a) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 3729.
(b) Tang, S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5299. (c) Tang,
S.; Kennedy, R. M. Tetrahedron Lett. 1992, 33, 5303. (d) Boyce, R. S.;
Kennedy, R. M. Tetrahedron Lett. 1994, 35, 5133. (e) McDonald, F.
E.; Towne, T. B. J . Org. Chem. 1995, 60, 5750.
(4) Sinha, S. C.; Sinha-Bagchi, A.; Yazbak, A.; Keinan, E. Tetrahe-
dron Lett. 1995, 36, 9257.
(5) For other synthetic approaches to bis-THF annonaceous aceto-
genins see: Hoye, T. R.; Ye, Z. J . Am. Chem. Soc. 1996, 118, 1801 and
references cited therein.
(6) Sinha, S. C; Sinha-Bagchi, A.; Keinan, E. J . Am. Chem. Soc.
1995, 117, 1447.
(7) Sinha, S. C; Keinan, E. J . Am. Chem. Soc. 1993, 115, 4891.
(8) (a) Sinha, S. C; Keinan, E. J . Org. Chem. 1994, 59, 949. (b) Sinha,
S. C; Sinha-Bagchi, A.; Keinan, E. J . Org. Chem. 1993, 58, 7789.
(11) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Martin, S. F.; Dodge,
J . A. Tetrahedron Lett. 1991, 32, 3017.
(12) Compounds 10, 13, 14, and 17 can be obtained by tandem
oxidative cyclization with the appropriate stereoisomer of 5-hydroxy-
tricosa-8,12-dien-1,4-olide. Significantly higher yields were obtained
with a modified perrhenate reagent CF3CO2ReO3/(CF3CO)2O rather
than with Re2O7/H5IO6 (ref 6).
(13) Chemical purity of all compounds was verified by TLC, 1H
NMR, 13C NMR, and HRMS. For physical data of 10-17 see the
supporting information.
S0022-3263(96)01286-8 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 22, 1996 7641
Sch em e 1. Syn th esis of All P ossible Ster eoisom er ic Sta r tin g Bu ild in g Block sa
a
Key: (a) (i) AD-mix-â, methanesulfonamide, t-BuOH, H2O, 0 °C, 24 h, (ii) aqueous KOH, MeOH then 3 N HCl, (iii) TsOH, CH2Cl2, rt,
1 h; (b) (i) LAH, Et2O-THF, 0 °C to reflux, 2 h; (ii) TsOH, acetone, C6H6 azeotropic distillation, 24 h, (iii) PPh3, I2, imidazole, toluene, rt,
3 h, (iv) PPh3, NaHCO3, CH3CN, reflux, 4 h; (c) p-nitrobenzoic acid, PPh3, DEAD, C6H6, 16 h; (d) (i) tert-butyldiphenylchlorosilane (BPSCl),
imidazole, DMF, rt, 16 h; (ii) Pd-C (10%), MeOH, propionic acid, H2, 24 h, (iii) PCC, Celite, CH2Cl2, 2 h; (e) (i) aqueous KOH, EtOH,
reflux, 16 h, then 3 N HCl, (ii) TsOH, CH2Cl2, 1 h; (f) (i) AD-mix-R, methanesulfonamide, t-BuOH, H2O, 0 °C, 24 h, (ii) aqueous KOH,
MeOH then 3 N HCl, (iii) TsOH, CH2Cl2, rt, 1 h.
Sch em e 2. Syn th esis of Eigh t Rep r esen ta tive Bis-THF Ster eoisom er sa
a
Key: (a) (i) KN(SiMe3)2, THF, -78 °C, 2 h, then aldehyde 7a or 7b in THF-HMPA, -78 °C to rt, 16 h; (b) (i) TBAF, THF, rt, 2 h, (ii)
Re2O7, lutidine, CH2Cl2, 4 h; (c) dimethoxypropane, acetone, TsOH, 1 h; (d) (i) MsCl, CH2Cl2, -20 to 0 °C, 1 h, (ii) TsOH, MeOH-H2O,
rt, 16 h, (iii) pyridine, 100 °C, 2 h; (e) (i) p-nitrobenzoic acid, PPh3, DEAD, C6H6, 16 h, (ii) aqueous KOH, EtOH, reflux, 16 h, then 3 N
HCl, (iii) TsOH, CH2Cl2, 1 h.
Sch em e 3. F in a l Step s of Tr iloba cin Syn th esisa
Key: (a) (i) LAH, Et2O-THF, 0 °C to reflux, 2 h; (ii) BMSCl, diisopropylethylamine, DMAP, CH2Cl2, rt, 12 h, then MOMCl, 12 h; (b)
TBAF, THF, 0 °C to rt, 1 h; (c) PPh3, I2, imidazole, CH2Cl2, rt, 1 h; (d) PPh3, NaHCO3, CH3CN, 45 °C, 24 h; (e) n-BuLi, THF, 0 °C, 0.5 h,
then aldehyde 21 in THF 0 °C to rt, 1 h; (f) (i) Rh(PPh3)3Cl (10%) C6H6, EtOH, H2, rt, 2 h, (ii) acetyl chloride, MeOH, ether, reflux, 6 h.
and then with aldehyde 214 followed by hydrogenation
and deprotection afforded 1, which was found to be
identical (1H NMR, [R]D, IR, MS) to the naturally occur-
ring trilobacin.
Ack n ow led gm en t. We thank the US-Israel Bina-
tional Science Foundation, the Israel Cancer Research
Fund, and PharMore Therapeutics Ltd. for financial
support.
In conclusion, the convergent synthetic strategy out-
lined here provides a useful entry to a 32-member
chemical library of stereoisomeric bis-THF acetogenins.
This approach is demonstrated here by the first total
synthesis of trilobacin.
Su p p or tin g In for m a tion Ava ila ble: Physical data of 10-
17 (2 pages).
J O961286M