ORGANIC

LETTERS

A New Synthetic Route to Phomoidride 2003

Vol. 5, No. 13
B and Its Derivatives 2235-2238

Yuki Hayashi, Tetsuji Itoh, and Tohru Fukuyama*

Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,

Bunkyo-ku, Tokyo 113-0033, Japan
fukuyama@[Link]

Received March 18, 2003 (Revised Manuscript Received May 19, 2003)

ABSTRACT

We have developed a new synthetic route to phomoidride B, which could also be applied to the synthesis of phomoidride B derivatives using
Pd-catalyzed coupling reaction of a thiolester with an organozinc reagent. In addition, direct construction of the maleic anhydride moiety has
been achieved by a Pd-catalyzed carbonylation reaction.

Phomoidride B (1)1 was isolated from the culture broth of completed the total synthesis.6 In our previous total synthesis
an unidentified fungus by a Pfizer group and shown to inhibit of phomoidride B, construction of the maleic anhydride
squalene synthase2 as well as Ras farnesyl transferase.3 moiety has been achieved by a unique formation of a
Because of its attractive biological properties and a unique, thiobutenoride and oxidation of a siloxythiophene. Herein,
complex structure, numerous synthetic approaches to 1 have we describe another method for constructing the maleic
been reported,4 and so far, four groups including ours5 have anhydride moiety using a Pd-catalyzed carbonylation which
was first reported by Shair and co-workers in their total
(1) (a) Dabrah, T. T.; Harwood, H. J., Jr.; Huang, L. H.; Jandovich, N. synthesis of 16d and a new synthetic route to 1 which could
D.; Kaneko, T.; Li. J.-C.; Lindsey, S.; Mosier, P. M.; Subashi, T. A.;
Therrien, M.; Watts, P. C. J. Antibiot. 1997, 50, 1. (b) Dabrah, T. T.; Kaneko, also be applied to the synthesis of phomoidride B derivatives
T.; Massefski, W., Jr.; Whipple, E. B. J. Am. Chem. Soc. 1997, 119, 1594. having various substituents at the upper side chain. The two
For reviews, see: (c) Hepworth, D. Chem. Ind. (London) 2000, 59. (d)
Starr, J. T.; Carreira, E. M. Angew. Chem., Int. Ed. 2000, 39, 1415. side chains of 1 are highly likely to affect its biological
(2) Abe, I.; Tomesch, S. W.; Prestwich, G. D. Nat. Prod. Rep. 1994, 11. activities. Therefore, the new derivatives of phomoidride B
279.
(3) For a review on Ras farnesyl transferase, see: Leonard, D. M. J.
Med. Chem. 1997, 40, 2971. Org. Lett. 2002, 4, 1447. (o) Matsushita, T.; Ashida, H.; Kimachi, T.;
(4) Recent synthetic studies: (a) Devaux, J.-F.; O’Neil, S. V.; Guillo, Takemoto, Y. Chem. Commun. 2002, 814. (p) Armstrong, A.; Critchley,
N.; Paquatte, L. A. Collect. Czech. Chem. Commun. 2000, 65, 490. (b) T. J.; Gourdel-Matin. M.-E.; Kelsey, R. D.; Mortlock, A. A. J. Chem. Soc.,
Clive, D. L. J.; Sun, S.; Gagliardini, V.; Sano, M. K. Tetrahedron Lett. Perkin Trans. 1 2002, 1344. (q) Armstrong, A.; Critchley, T. J.; Gourdel-
2000, 41, 6259. (c) Davies, H. M. L.; Calvo, R. L.; Townsend, R. J.; Ren, Martin, M.-E.; Kelsey, R. D.; Mortlock, A. A. Tetrahedron Lett. 2002, 43,
P.; Churchill, R. M. J. Org. Chem. 2000, 65, 4261. (d) Bio, M. M.; Leigton, 6027. (r) Spiegel, D. A.; Njardarson, J. T.; Wood, J. L. Tetrahedron 2002,
J. L. Org. Lett. 2000, 2, 2905. (e) Yoshimitsu, T.; Yanagisawa, S.; Nagaoka, 58, 6545. (s) Bio, M. M.; Leighton. J. L. J. Org. Chem. 2003, 68, 1693.
H. Org. Lett. 2000, 2, 3751. (f) Davies, H. M. L.; Ren, P. Tetrahedron (5) Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122,
Lett. 2000, 41, 9021. (g) Njardarson, J. T.; Wood, J. L. Org. Lett. 2001, 3, 7825.
2431. (h) Njardarson, J. T.; McDonald, I. M.; Spiegel, D. A.; Inoue, M.; (6) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.; Yoon,
Wood, J. L. Org. Lett. 2001, 3, 2435. (i) Ohmori, N. Chem. Commun. 2001, W. H.; He, Y.; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669. (b)
1552. (j) Baldwin, J. E.; Adlington, R. M.; Roussi, F.; Bulger, P. G.; Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He, Y.; Yoon,
Marquez, R.; Mayweg, A. V. W. Tetrahedron 2001, 57, 7409. (k) Banwell, W. H.; Choi, H.-S.; Angew. Chem., Int. Ed. 1999, 38, 1676. (c) Nicolaou,
M. G.; McRae, K. J.; Willis, A. C. J. Chem. Soc., Perkin Trans. 1 2001, K. C.; Jung, J.-K.; Yoon, W. H.; He, Y.; Zhong, Y.-L.; Baran, P. S. Angew.
2194. (l) Isakovic, L.; Ashenhurst, J. A.; Gleason, J. L. Org. Lett. 2001, 3, Chem., Int. Ed. 2000, 39, 1829. (d) Chuo, C.; Layton, M. E.; Sheehan, S.
4189. (m) Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755. (n) M.; Shair, M. D. J. Am. Chem. Soc. 2000, 122, 7424. (e) Tan, Q.;
Sulikowski, G. A.; Agnelli, F.; Spencer, P.; Koomen, J. M.; Russell, D. H. Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39, 4509.

10.1021/ol034471c CCC: $25.00 © 2003 American Chemical Society

Published on Web 06/05/2003
 Scheme 1. Retrosynthetic Analysis Scheme 3 a

prepared by the present route might help understand the

structure/activity relationships of the phomoidrides.
Our retrosynthetic analysis of 1 and its derivatives as
shown in Scheme 1 is based on the intermediacy of the
thiolester 2 as a key intermediate, which could be coupled
a Reagents and conditions: (a) LiSEt, THF, 0 °C, 75%; (b)
with a variety of organozinc reagents by means of a Pd-
catalyzed reaction developed in our laboratory.7 Since this Ba(OH)2‚8H2O, MeOH; (c) ClCO2Me, Et3N, CH3CN; aq NaHCO3;
(d) (COCl)2, cat. DMF, CH2Cl2; CH2N2, Et2O, -20 °C, 41% (three
coupling reaction proceeds under very mild conditions, steps); (e) PhCO2Ag, t-BuOH, 50 °C, 36%.

Scheme 2 a selective conversion of thiolester to the corresponding ketone

is possible in the presence of esters, aldehydes, and ethers.
Hence, we fully anticipated that preparation of a range of
ketones would be possible from such highly oxy-function-
alized compound 2 at the very last stage of the synthesis.
We envisioned that thiolester 2 would arise from the ketone
intermediate 3 via the formation of the γ-lactone-acetal. The
intermediate 3 in turn could be obtained from the bicyclic
compound 4 by a four-step sequence involving removal of
the Evans’ chiral auxiliary (Xp), one-carbon homologation
of the â-side methyl ester at C-14, conversion of the ethythio
group at C-26 to the ketone, and construction of the maleic
anhydride moiety.
The bicyclic compound 4 was synthesized according to
our procedure reported earlier (Scheme 2). Assembly of the
three fragments (1,3-diene unit 6, N-acryloyl-(S)-4-benzyl-
oxazolidinone 5, and enantiopure R,â-unsaturated aldehyde
8 which was prepared from L-malic acid8) was effected
successively by Michael reaction, Evans’ aldol reaction,9 and
the intramolecular Diels-Alder reaction to give 4 in good
yield.
The Evans’ chiral auxiliary was removed by treatment with
lithium ethylthiolate to afford the thiolester 10 (Scheme 3).9
a Reagents and conditions: (a) Cs2CO3, CH3CN, 50 °C, 73%; To carry out a one-carbon homologation of the â-side methyl
(b) Bu2BOTf, -78 °C; Et3N, -78 to 0 °C; 8, CH2Cl2, 0 °C, 71%; ester at C-14, selective conversion to the corresponding
(c) SO3‚Py, DMSO-i-Pr2NEt, 73%; (d) ZnCl2‚OEt2, Py, CH2Cl2,
88%. (7) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189.

2236 Org. Lett., Vol. 5, No. 13, 2003

 Scheme 4 a Scheme 5 a

a Reagents and conditions: (a) 80% aq AcOH, 70 °C, 34% (two

steps from 16); (b) Jones oxidn; (c) (COCl)2, cat. DMF, CH2Cl2;
EtSH, imidazole, CH2Cl2, 63% (two steps); (d) cat. PdCl2(PPh3)4,
RZnI-THF solution; pump up; toluene, 0.5-1 h, 78% (20), 65%
(21); (e) HCO2H, quant.

a Reagents and conditions: (a) allyl bromide, K CO , DMF; (b)

2 3
NaH; p-O2NC6H4NTf2, THF, 71% (four steps from thiolester 10); of the carbene into the C-12 position and successive
(c) cat. Pd(PPh3)4, HCO2H, Et3N, CH2Cl2; (d) (COCl)2, cat. DMF,
decomposition of the resulting â-keto ester moiety might be
CH2Cl2; CH2N2, Et2O, -20 °C, 64% (two steps); (e) PhCO2Ag,
Et3N, t-BuOH, 50 °C, 86%; (f) m-CPBA, CH2Cl2, -20 °C; (g) responsible for the poor result.
TFAA, i-Pr2NEt, Et2O, 92% (two steps); (h) cat. Pd(OAc)2, P(2- Fortunately, we found that this homologation reaction
furyl)3, i-Pr2NEt, H2O, CO (1 atm), DMF, 90 °C, 10 min; H+. could be improved by introducing a double bond between
C-11 and C-12. Thus, the free carboxylic acid of 12 was
protected as the allyl ester (Scheme 4). While extraction of
monocarboxylic acid was required. Hydrolysis of 10 with the proton at C-12, which was situated at the concave side
barium hydroxide proceeded selectively at the thiolester and of the bicyclic system, was quite difficult when a large base
the â-side methyl ester to give dicarboxylic acid 11. The such as LHMDS was used. Deprotonation proceeded smoothly
successful differentiation of the two methyl esters might be using a small base like sodium hydride. Subsequent treatment
attributable to the steric hindrance of the ethylthio group at with p-O2NC6H4NTf211 gave the enol triflate 14 without
C-26 near the R-side methyl ester. Successive treatment of incident. After removal of the allyl group, the resulting
11 with methyl chloroformate,10 triethylamine, and aqueous carboxylic acid was subjected to Arndt-Eistert reaction to
sodium bicarbonate caused selective esterification of the afford the corresponding tert-butyl ester 15 in good yield
carboxylic acid at C-12, yielding the desired monocarboxylic (86%). We next attempted construction of the maleic
acid 12 as the sole product. Conversion of 12 to the anhydride moiety. Despite attempts under a variety of
diazoketone and the subsequent Wolff rearrangement pro- conditions, Pd-catalyzed carbonylation of 15 was unsuccess-
vided homologated tert-butyl ester 13 in disappointingly low ful presumably due to the steric hindrance by the ethylthio
yield (36%). We reasoned that the unexpected C-H insertion group. To decrease the steric effect, 15 was converted to
the ketone 16 by Pummerer reaction. Gratifyingly, carbo-
(8) A detailed procedure for the preparation of aldehyde 8 is described
in the Supporting Information.
(9) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, (11) (a) This reagent seems to be as highly reactive as Comins’ reagent11b
103, 2127. (b) Evans, D. A.; Ripin, D. H. B.; Johnson, J. S.; Shaughnessy, and is particularly effective for construction of enol triflates from the â-keto
E. A. Angew. Chem., Int. Ed. Engl. 1997, 36, 2119. ester: Fukuyama, T. et al. Unpublished results. (b) Comins, D. L.; Dehghani,
(10) Kim, S.; Kim, Y. C.; Lee, J. I. Tetrahedron Lett. 1983, 24, 3365. A. D.; Foti, C. J.; Joseph, S. P. Org. Synth. 1997, 74, 77.

Org. Lett., Vol. 5, No. 13, 2003 2237

nylation of 16 was in turn successful upon treatment with a coupling reaction proceeds more slowly in THF than in
catalytic amount of Pd(OAc)2, P(furyl)3, and i-Pr2NEt under toluene.14 Indeed, when THF was removed under reduced
an atmosphere of CO (1 atm) in DMF containing water at pressure before adding toluene, the reaction proceeded
90 °C, giving the desired maleic anhydride 3 in a quantitative smoothly to give the desired ketone 20 in 78% yield without
yield after acidic workup. On the other hand, use of methanol affecting the other delicate functional groups. Finally,
instead of water resulted in the formation of dimethyl deprotection of the tert-butyl ester with formic acid gave
maleate, which could not be converted to the maleic phomoidride B (1). Similarly, the ethyl ketone analogue (22)
anhydride 3. While Shair and co-workers reported earlier a was synthesized.
construction of the maleic anhydride moiety by Pd-mediated In conclusion, we have successfully developed a new
carbonylation, it required rather drastic reaction conditions synthetic route featuring Pd-catalyzed carbonylation reaction
(5.0 equiv of Pd(OAc)2, 12.5 equiv of P(OMe)3, and CO and Pd-catalyzed coupling reaction of thiolester with organo-
(500 psi) in THF-CH3CN).6d Nicolaou and co-workers have zinc reagents, which could be applied to the synthesis of
attempted the similar Pd-mediated transformation without phomoidride B and its derivatives. Because the introduction
success.12 of the upper side chains are performed at the last stage of
At the last stage of the total synthesis, 3 was converted to the synthesis, it is easy to prepare a variety of the side-chain
the key intermediate thiolester 19 (Scheme 5). When 3 was analogues of phomoidride B. Hopefully, the present synthetic
heated with 80% aqueous acetic acid, removal of the route would help understand the structure/activity relation-
acetonide and the cyclization occurred concomitantly to ships of phomoidrides.
provide the γ-lactone-acetal 17. The resulting primary alcohol
Acknowledgment. We thank Professor Hidetoshi Tokuya-
of 17 was oxidized with Jones reagent to give the carboxylic
ma (University of Tokyo) for helpful discussions. This work
acid 18. Conversion of 18 to the acid chloride followed by
was financially supported in part by CREST, JST, and the
treatment with ethanethiol furnished the thiolester 19.13 With
Ministry of Education, Culture, Sports, Science and Technol-
the thiolester in hand, the critical Pd-catalyzed coupling
ogy, Japan. T.I. thanks JSPS for a generous predoctoral
reaction was next attempted. Initial attempts at coupling 19
fellowship. We thank Dr. Takushi Kaneko of Pfizer for
with (E)-3-pentenylzinc iodide (1.0 M THF solution) in
kindly providing samples of the natural products.
toluene were unsuccessful, recovering only the starting
material. The model studies revealed that the Pd-catalyzed Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
(12) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi, charge via the Internet at [Link]
H.-S. J. Am. Chem. Soc. 2002, 124, 2190.
(13) It was difficult to condense 18 with ethanethiol using DCC, BOPCl, OL034471C
or WSCD or via mixed anhydride due to the extreme steric hindrance around
the carboxylic acid. (14) Fukuyama, T. et al. Unpublished results.

2238 Org. Lett., Vol. 5, No. 13, 2003