A new synthetic route to phomoidride B and its derivatives

Article abstract of DOI:10.1021/ol034471c

(Matrix presented) 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 con

Full text of DOI:10.1021/ol034471c

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2235-2238
A New Synthetic Route to Phomoidride
B and Its Derivatives
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@mol.f.u-tokyo.ac.jp
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
an unidentified fungus by a Pfizer group and shown to inhibit
squalene synthase2 as well as Ras farnesyl transferase.3
Because of its attractive biological properties and a unique,
complex structure, numerous synthetic approaches to 1 have
been reported,4 and so far, four groups including ours5 have
completed the total synthesis.6 In our previous total synthesis
of phomoidride B, construction of the maleic anhydride
moiety has been achieved by a unique formation of a
thiobutenoride and oxidation of a siloxythiophene. Herein,
we describe another method for constructing the maleic
anhydride moiety using a Pd-catalyzed carbonylation which
was first reported by Shair and co-workers in their total
synthesis of 16d and a new synthetic route to 1 which could
also be applied to the synthesis of phomoidride B derivatives
having various substituents at the upper side chain. The two
side chains of 1 are highly likely to affect its biological
activities. Therefore, the new derivatives of phomoidride B
(1) (a) Dabrah, T. T.; Harwood, H. J., Jr.; Huang, L. H.; Jandovich, N.
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,
T.; Massefski, W., Jr.; Whipple, E. B. J. Am. Chem. Soc. 1997, 119, 1594.
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.
(2) Abe, I.; Tomesch, S. W.; Prestwich, G. D. Nat. Prod. Rep. 1994, 11.
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.;
Takemoto, Y. Chem. Commun. 2002, 814. (p) Armstrong, A.; Critchley,
T. J.; Gourdel-Matin. M.-E.; Kelsey, R. D.; Mortlock, A. A. J. Chem. Soc.,
Perkin Trans. 1 2002, 1344. (q) Armstrong, A.; Critchley, T. J.; Gourdel-
Martin, M.-E.; Kelsey, R. D.; Mortlock, A. A. Tetrahedron Lett. 2002, 43,
6027. (r) Spiegel, D. A.; Njardarson, J. T.; Wood, J. L. Tetrahedron 2002,
58, 6545. (s) Bio, M. M.; Leighton. J. L. J. Org. Chem. 2003, 68, 1693.
(5) Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122,
7825.
(6) (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. (c) Nicolaou,
K. C.; Jung, J.-K.; Yoon, W. H.; He, Y.; Zhong, Y.-L.; Baran, P. S. Angew.
Chem., Int. Ed. 2000, 39, 1829. (d) Chuo, C.; Layton, M. E.; Sheehan, S.
M.; Shair, M. D. J. Am. Chem. Soc. 2000, 122, 7424. (e) Tan, Q.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39, 4509.
(4) Recent synthetic studies: (a) Devaux, J.-F.; O’Neil, S. V.; Guillo,
N.; Paquatte, L. A. Collect. Czech. Chem. Commun. 2000, 65, 490. (b)
Clive, D. L. J.; Sun, S.; Gagliardini, V.; Sano, M. K. Tetrahedron Lett.
2000, 41, 6259. (c) Davies, H. M. L.; Calvo, R. L.; Townsend, R. J.; Ren,
P.; Churchill, R. M. J. Org. Chem. 2000, 65, 4261. (d) Bio, M. M.; Leigton,
J. L. Org. Lett. 2000, 2, 2905. (e) Yoshimitsu, T.; Yanagisawa, S.; Nagaoka,
H. Org. Lett. 2000, 2, 3751. (f) Davies, H. M. L.; Ren, P. Tetrahedron
Lett. 2000, 41, 9021. (g) Njardarson, J. T.; Wood, J. L. Org. Lett. 2001, 3,
2431. (h) Njardarson, J. T.; McDonald, I. M.; Spiegel, D. A.; Inoue, M.;
Wood, J. L. Org. Lett. 2001, 3, 2435. (i) Ohmori, N. Chem. Commun. 2001,
1552. (j) Baldwin, J. E.; Adlington, R. M.; Roussi, F.; Bulger, P. G.;
Marquez, R.; Mayweg, A. V. W. Tetrahedron 2001, 57, 7409. (k) Banwell,
M. G.; McRae, K. J.; Willis, A. C. J. Chem. Soc., Perkin Trans. 1 2001,
2194. (l) Isakovic, L.; Ashenhurst, J. A.; Gleason, J. L. Org. Lett. 2001, 3,
4189. (m) Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755. (n)
Sulikowski, G. A.; Agnelli, F.; Spencer, P.; Koomen, J. M.; Russell, D. H.
10.1021/ol034471c CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/05/2003

Scheme 1. Retrosynthetic Analysis
Scheme 3a
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
with a variety of organozinc reagents by means of a Pd-
catalyzed reaction developed in our laboratory.7 Since this
coupling reaction proceeds under very mild conditions,
a Reagents and conditions: (a) LiSEt, THF, 0 °C, 75%; (b)
Ba(OH)2‚8H2O, MeOH; (c) ClCO2Me, Et3N, CH3CN; aq NaHCO3;
(d) (COCl)2, cat. DMF, CH2Cl2; CH2N2, Et2O, -20 °C, 41% (three
steps); (e) PhCO2Ag, t-BuOH, 50 °C, 36%.
Scheme 2a
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
To carry out a one-carbon homologation of the â-side methyl
ester at C-14, selective conversion to the corresponding
a Reagents and conditions: (a) Cs2CO3, CH3CN, 50 °C, 73%;
(b) Bu2BOTf, -78 °C; Et3N, -78 to 0 °C; 8, CH2Cl2, 0 °C, 71%;
(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 4a
Scheme 5a
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, K2CO3, DMF; (b)
NaH; p-O2NC6H4NTf2, THF, 71% (four steps from thiolester 10);
(c) cat. Pd(PPh3)4, HCO2H, Et3N, CH2Cl2; (d) (COCl)2, cat. DMF,
CH2Cl2; CH2N2, Et2O, -20 °C, 64% (two steps); (e) PhCO2Ag,
Et3N, t-BuOH, 50 °C, 86%; (f) m-CPBA, CH2Cl2, -20 °C; (g)
TFAA, i-Pr2NEt, Et2O, 92% (two steps); (h) cat. Pd(OAc)2, P(2-
furyl)3, i-Pr2NEt, H2O, CO (1 atm), DMF, 90 °C, 10 min; H+.
of the carbene into the C-12 position and successive
decomposition of the resulting â-keto ester moiety might be
responsible for the poor result.
Fortunately, we found that this homologation reaction
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
the proton at C-12, which was situated at the concave side
of the bicyclic system, was quite difficult when a large base
such as LHMDS was used. Deprotonation proceeded smoothly
using a small base like sodium hydride. Subsequent treatment
monocarboxylic acid was required. Hydrolysis of 10 with
barium hydroxide proceeded selectively at the thiolester and
the â-side methyl ester to give dicarboxylic acid 11. The
successful differentiation of the two methyl esters might be
attributable to the steric hindrance of the ethylthio group at
C-26 near the R-side methyl ester. Successive treatment of
11 with methyl chloroformate,10 triethylamine, and aqueous
sodium bicarbonate caused selective esterification of the
carboxylic acid at C-12, yielding the desired monocarboxylic
acid 12 as the sole product. Conversion of 12 to the
diazoketone and the subsequent Wolff rearrangement pro-
vided homologated tert-butyl ester 13 in disappointingly low
yield (36%). We reasoned that the unexpected C-H insertion
11
with p-O2NC6H4NTf2 gave the enol triflate 14 without
incident. After removal of the allyl group, the resulting
carboxylic acid was subjected to Arndt-Eistert reaction to
afford the corresponding tert-butyl ester 15 in good yield
(86%). We next attempted construction of the maleic
anhydride moiety. Despite attempts under a variety of
conditions, Pd-catalyzed carbonylation of 15 was unsuccess-
ful presumably due to the steric hindrance by the ethylthio
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,
103, 2127. (b) Evans, D. A.; Ripin, D. H. B.; Johnson, J. S.; Shaughnessy,
E. A. Angew. Chem., Int. Ed. Engl. 1997, 36, 2119.
(11) (a) This reagent seems to be as highly reactive as Comins’ reagent11b
and is particularly effective for construction of enol triflates from the â-keto
ester: Fukuyama, T. et al. Unpublished results. (b) Comins, D. L.; Dehghani,
A. D.; Foti, C. J.; Joseph, S. P. Org. Synth. 1997, 74, 77.
(10) Kim, S.; Kim, Y. C.; Lee, J. I. Tetrahedron Lett. 1983, 24, 3365.
Org. Lett., Vol. 5, No. 13, 2003
2237

nylation of 16 was in turn successful upon treatment with a
catalytic amount of Pd(OAc)2, P(furyl)3, and i-Pr2NEt under
an atmosphere of CO (1 atm) in DMF containing water at
90 °C, giving the desired maleic anhydride 3 in a quantitative
yield after acidic workup. On the other hand, use of methanol
instead of water resulted in the formation of dimethyl
maleate, which could not be converted to the maleic
anhydride 3. While Shair and co-workers reported earlier a
construction of the maleic anhydride moiety by Pd-mediated
carbonylation, it required rather drastic reaction conditions
(5.0 equiv of Pd(OAc)2, 12.5 equiv of P(OMe)3, and CO
(500 psi) in THF-CH3CN).6d Nicolaou and co-workers have
attempted the similar Pd-mediated transformation without
success.12
At the last stage of the total synthesis, 3 was converted to
the key intermediate thiolester 19 (Scheme 5). When 3 was
heated with 80% aqueous acetic acid, removal of the
acetonide and the cyclization occurred concomitantly to
provide the γ-lactone-acetal 17. The resulting primary alcohol
of 17 was oxidized with Jones reagent to give the carboxylic
acid 18. Conversion of 18 to the acid chloride followed by
treatment with ethanethiol furnished the thiolester 19.13 With
the thiolester in hand, the critical Pd-catalyzed coupling
reaction was next attempted. Initial attempts at coupling 19
with (E)-3-pentenylzinc iodide (1.0 M THF solution) in
toluene were unsuccessful, recovering only the starting
material. The model studies revealed that the Pd-catalyzed
coupling reaction proceeds more slowly in THF than in
toluene.14 Indeed, when THF was removed under reduced
pressure before adding toluene, the reaction proceeded
smoothly to give the desired ketone 20 in 78% yield without
affecting the other delicate functional groups. Finally,
deprotection of the tert-butyl ester with formic acid gave
phomoidride B (1). Similarly, the ethyl ketone analogue (22)
was synthesized.
In conclusion, we have successfully developed a new
synthetic route featuring Pd-catalyzed carbonylation reaction
and Pd-catalyzed coupling reaction of thiolester with organo-
zinc reagents, which could be applied to the synthesis of
phomoidride B and its derivatives. Because the introduction
of the upper side chains are performed at the last stage of
the synthesis, it is easy to prepare a variety of the side-chain
analogues of phomoidride B. Hopefully, the present synthetic
route would help understand the structure/activity relation-
ships of phomoidrides.
Acknowledgment. We thank Professor Hidetoshi Tokuya-
ma (University of Tokyo) for helpful discussions. This work
was financially supported in part by CREST, JST, and the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. T.I. thanks JSPS for a generous predoctoral
fellowship. We thank Dr. Takushi Kaneko of Pfizer for
kindly providing samples of the natural products.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; Choi,
H.-S. J. Am. Chem. Soc. 2002, 124, 2190.
(13) It was difficult to condense 18 with ethanethiol using DCC, BOPCl,
or WSCD or via mixed anhydride due to the extreme steric hindrance around
the carboxylic acid.
OL034471C
(14) Fukuyama, T. et al. Unpublished results.
2238
Org. Lett., Vol. 5, No. 13, 2003