Total synthesis of (-)-CP-263,114 (phomoidride B) [8]

Full text of DOI:10.1021/ja001664b

J. Am. Chem. Soc. 2000, 122, 7825-7826
Scheme 1. Retrosynthetic Analysis
7825
Total Synthesis of (-)-CP-263,114 (Phomoidride B)
Nobuaki Waizumi, Tetsuji Itoh, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo, CREST
The Japan Science and Technology Corporation (JST)
7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
ReceiVed May 15, 2000
CP-263,114 (phomoidride B, 1) was recently isolated from the
culture broth of an unidentified fungus by a Pfizer group and
shown to inhibit squalene synthase as well as Ras farnesyl
transferase.1 In addition to these interesting biological activities,
CP-263,114 has a unique, densely functionalized polycyclic
skeleton that consists of a bridgehead double bond, a γ-lactone-
acetal, and a maleic anhydride moiety. These structural features
and interesting bioactivities have attracted much interest from
synthetic chemists. While a number of synthetic studies including
ours2 have been reported to date,3 the only total synthesis of
racemic 1 has recently been disclosed by Nicolaou.4 However,
the absolute configuration of 1 remains unknown.5 Herein we
report an enantioselective total synthesis of 1 and reveal its
absolute configuration.
fragments A, B, and an acryloyl derivative. Fragment A would
be derived from an appropriate chiral building block. To achieve
a facile Diels-Alder reaction, a reliable procedure for stereose-
lective construction of an (E,E)-diene such as B must be
established to secure the coplanarity of the diene. To this end,
we opted to carry out a conjugate addition to a reactive allenic
ester, in which nucleophilic attack is known to occur from the
less hindered side.7
Conjugate addition of the alkenylcopper 48 to the allenic ester
3, prepared from 28 by brief treatment with DBU, in the presence
of TMSCl and HMPA9 afforded the desired 1,3-diene 5 as the
predominant product. After introduction of a second carbomethoxy
group to 5, Michael addition of the resultant malonate to
N-acryloyl-(S)-4-benzyloxazolidinone10 was performed to give 6
without appreciable isomerization of the double bonds. A boron-
mediated diastereoselective aldol reaction11 of 6 with aldehyde
7,8 which was prepared from (S)-epichlorohydrin,12 yielded the
adduct as a single diastereomer. The aldol product was then
oxidized under Parikh-Doering conditions13 to furnish enone 8.
Upon treatment with zinc chloride-ether complex in the presence
of a small amount of pyridine,14 8 underwent a smooth intramo-
lecular Diels-Alder reaction to give predominantly the desired
bicyclic compound 9. The relative configuration of 9 was
determined by NOE studies.15 This impressive stereoselectivity
seems to be dictated by the stereochemistry at C-12 position. A
similar type of diastereoselection has been reported in the
literature.16 However, this could be the first case where the adduct
possesses a bridgehead olefin.
Our retrosynthetic analysis of CP-263,114 features an intramo-
lecular Diels-Alder reaction which is particularly well-suited for
the preparation of strained bicyclic carbocycles (Scheme 1).6 The
precursor for the Diels-Alder reaction could be divided into three
(1) (a) Dabrah, T. T.; Harwood, H. J., Jr.; Huang, L. H.; Jankovich, N. D.;
Kaneko, T.; Li. J.-C.; Lindsey, S.; Moshier, P. M.; Subashi, T. A.; Therrien,
M.; Watts, P. C. J. Antibiot. 1997, 50, 1. (b) Dabrah, T. T.; Kaneko, T.;
Massefski, W., Jr.; Whipple, E. B. J. Am. Chem. Soc. 1997, 119, 1594. (c)
Hepworth, D. Chem. Ind. (London) 2000, 2, 59.
(2) Waizumi, N.; Itoh, T.; Fukuyama, T. Tetrahedron Lett. 1998, 39, 6015.
(3) (a) Nicolaou, K. C.; Ha¨rter, M. W.; Boulton, L.; Jandeleit, B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1194. (b) Nicolaou, K. C.; Postema, M. H.
D.; Miller, N. D.; Yang, G. Angew. Chem., Int. Ed. Engl. 1997, 36, 2821. (c)
Davies, H. M. L.; Calvo, R.; Ahmed, G. Tetrahedron Lett. 1997, 38, 1737.
(d) Sgarbi, P. W. M.; Clive, D. L. J. Chem. Commun. 1997, 2157. (e)
Armstrong, A.; Critchley, T. J.; Mortlock, A. A. Synlett 1998, 552. (f) Kwon,
O.; Su, D.-S.; Meng, D.; Deng, W.; D’Amico, D. C.; Danishefsky, S. J. Angew.
Chem., Int. Ed.. 1998, 37, 1877. (g) Kwon, O.; Su, D.-S.; Meng, D.; Deng,
W.; D’Amico, D. C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37,
1880. (h) Chen, C.; Layton, M. E.; Shair, M. D. J. Am. Chem. Soc. 1998,
120, 10784. (i) Bio, M. M.; Leighton, J. L. J. Am. Chem. Soc. 1999, 121,
890. (j) Nicolaou, K. C.; Baran, P. S.; Jautelat, R.; He, Y.; Fong, K. C.; Choi,
H.-S.; Yoon, W. H.; Zhong, Y.-L. Angew. Chem., Int. Ed. 1999, 38, 549. (k)
Clive, D. L. J.; Sun, S.; He, X.; Zhang, J.; Gagliardini, V. Tetrahedron Lett.
1999, 40, 4605. (l) Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron
Lett. 1999, 40, 5215. (m) Meng, D.; Tan, Q.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1999, 38, 3197. (n) Sulikowski, G. A.; Agnelli, F.; Corbett, R. M. J.
Org. Chem. 2000, 65, 337. (o) For reviews: see ref 1c and Diederichsen, U.
Nachr. Chem. Technol. Lab. 1999, 47, 1423; Starr, J. T.; Carreira, E. M.
Angew. Chem., Int. Ed. 2000, 39, 1415.
(4) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W.
H.; He, Y.; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669. (b) Nicolaou,
K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He, Y.; Yoon, W. H.; Choi,
H.-S. Angew. Chem., Int. Ed. 1999, 38, 1676.
(5) We have recently learned that Professor Nicolaou’s group has deter-
mined the absolute configuration of 1 which is consistent with our own
conclusion. Nicolaou, K. C.; Jung, J.-K.; Yoon, W. H.; He, Y.; Zhong, Y.-L.;
Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 1829.
(6) Gwaltney, S. L., II; Sakata, S. T.; Shea, K. J. J. Org. Chem. 1996, 61,
7438 and references therein.
Construction of the maleic anhydride moiety on 9 presented
formidable challenges. We could eventually solve the problem
in the following manner. The Evans’ chiral auxiliary was removed
by lithium thiolate generated from allyl thioglycolate to give thiol
ester 10. Upon treatment with DBU, 10 underwent intramolecular
aldol-type cyclization to provide 11 as a single diastereomer. After
Pd-catalyzed deprotection of the allyl group, dehydration and
concomitant decarboxylation were carried out by heating the
resultant carboxylic acid in a mixture of acetic anhydride and
pyridine at 100 °C to furnish directly the thiobutenolide 12. This
(7) Bertrand, M.; Gil, G.; Viala, J. Tetrahedron Lett. 1977, 18, 1785.
(8) A detailed procedure for the preparation of this compound is described
in Supporting Information.
(9) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetrahedron
Lett. 1986, 27, 4029.
(10) Ho, G.-J.; Mathre, D. J.; J. Org. Chem. 1995, 60, 2271.
(11) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(12) In preliminary studies we found that the aldehyde 7b, which was
derived from L-malic acid (S-configuration), formed a matched pair with 6.
(13) Parikh, J. R.; Do¨ering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505.
(14) In the absence of pyridine, an acid-catalyzed double bond isomerization
occurred to give a small amount of the unreactive 1,3-diene isomer.
(15) NOEs between H-9 and H-12, H-12 and H-16, H-17 and H-26,
respectively, were observed.
(16) Evans, D. A.; Ripin, D. H. B.; Johnson, J. S.; Shaughnessy, E. A.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2119 and references therein.
10.1021/ja001664b CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/29/2000

7826 J. Am. Chem. Soc., Vol. 122, No. 32, 2000
Scheme 2. Total Synthesis of (-)-CP-263,114a
Communications to the Editor
a Reagents and yields: (a) cat. DBU, THF, 0 °C; then 4, TMSCl, HMPA, Me2S-THF, -78 °C to room temperature, 80%; (b) LHMDS, THF;
ClCO2Me, -78 °C, 84%; (c) N-acryloyl-(S)-4-benzyloxazolidinone, cat. Cs2CO3, CH3CN, 50 °C, 82%; (d) Bu2BOTf, Et3N, CH2Cl2; 7a, 0 °C, 1 h, 80%;
(e) SO3‚Py, DMSO-i-Pr2NEt, 1 h, 75%; (f) ZnCl2‚OEt2, Py, CH2Cl2,1 h; (g) allyl thioglycolate, LHMDS, ether, 0 °C, 3 h, 53% (2 steps); (h) DBU, THF,
rt, 1.5 h, 93%; (i) cat. Pd(OAc)2, PPh3, pyrrolidine, CH3CN, rt, 15 min; (j) Py, Ac2O, 100 °C, 1 h, 87% (2 steps); (k) TBSCl, DBU, CH2Cl2; (l) NIS,
CH2Cl2, rt, 79% (2 steps); (m) AgNO3, DMSO, 50 °C, 1 h, 74%; (n) LiOH‚H2O, MeOH, rt, 1 h; Ba(OH)2‚8H2O, rt, 1 h; (o) (COCl)2, CH2Cl2, rt;
CH2N2, ether, -15 °C, 10 min; (p) PhCO2Ag, t-BuOH, 50 °C, 1 h, 54% (3 steps); (q) mCPBA, CH2Cl2, -20 °C, 5 min; (r) TFAA, i-Pr2NEt, toluene,
0 °C, 1 h; (s) 80% aq AcOH, 70 °C, 13 h, 51% (3 steps); (t) Jones oxidn, 0 °C, 20 min; (u) HCO2H, rt, 1 h, 96% (2 steps).
process involves the formation of a somewhat unstable â-lactone
intermediate. The thiobutenolide 12 thus formed was silylated to
give 2-silyloxythiophene, which was subsequently oxidized with
NIS to give 5-iodothiobutenolide. Upon heating with silver nitrate
in DMSO, thiomaleic anhydride 13 was obtained in high yield.
Successive treatment of 13 with lithium hydroxide and barium
hydroxide in a one-pot process caused selective hydrolyses of
the thiomaleic anhydride and the less hindered methyl ester, giving
monocarboxylic acid 14 after acidic workup. The conventional
Arndt-Eistert protocol was used to convert 14 into the homolo-
gated ester 15. Careful oxidation of the sulfide in 15 with mCPBA
followed by treatment with trifluoroacetic anhydride and i-Pr2-
NEt gave the desired ketone after aqueous workup. Hydrolysis
of the acetonide with 80% aqueous acetic acid induced the
concomitant cyclization to afford γ-lactone-acetal 16. Finally,
Jones oxidation of the secondary alcohol followed by deprotection
of the tert-butyl ester with formic acid gave (-)-CP-263,114. The
synthetic 1 was identical in all respects with natural CP-263,114
[1H NMR, 13C NMR and [R]27 -10° (c ) 0.25, CH2Cl2) (lit.
D
[R]D -11° (c ) 0.5, CH2Cl2))]. Since the specific rotation of the
synthetic 1 is same as that of the natural 1, we conclude that the
absolute configuration of CP-263,114 is the one depicted in
Scheme 2.
Acknowledgment. This work was supported in part by the Ministry
of Education, Sports and Culture, Japan. We thank Dr. Takushi Kaneko
of Pfizer for kindly providing samples of the natural products. We also
thank Professor David Evans of Harvard University for valuable
discussions.
Supporting Information Available: Experimental details and spec-
troscopic data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA001664B