Synthesis of the proposed structure of feigrisolide C

Article abstract of DOI:10.1021/ol0500160

(Chemical Equation Presented) Possible structures of feigrisolide C were synthesized via ring-closing olefin metathesis reaction of a diester derivative prepared from 8-epinonactic acid, but physical characteristics of the synthetic samples did not match with those of the natural sample of feigrisolide C.

Full text of DOI:10.1021/ol0500160

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1085-1087
Synthesis of the Proposed Structure of
Feigrisolide C
Woo Han Kim, Jae Hoon Jung, Lee Taek Sung, Sang Min Lim, and Eun Lee*
Department of Chemistry, College of Natural Sciences, Seoul National UniVersity,
Seoul 151-747, Korea
eunlee@snu.ac.kr
Received January 4, 2005
ABSTRACT
Possible structures of feigrisolide C were synthesized via ring-closing olefin metathesis reaction of a diester derivative prepared from 8-epi-
nonactic acid, but physical characteristics of the synthetic samples did not match with those of the natural sample of feigrisolide C.
Feigrisolide C (1) is a 15-membered macrodiolide isolated
from the culture broth of Streptomyces griseus (strain GT
Scheme 1. Retrosynthetic Analysis
051022).1 It is a medium inhibitor of 3R-hydroxysteroid
dehydrogenase and exhibits 50% inhibition of Coxsackie
virus B3 at 25 µg/mL. It was also claimed to be a metabolite
of Streptomyces sp. 6167 of marine origin.2
Ring-closing olefin metathesis reaction of the diene
intermediate A was envisaged as a key step in the synthesis
of feigrisolide C (1). The diester A was to be prepared from
(+)-methyl 8-epi-nonactate (2), the unsaturated carboxylic
acid B, and the allylic alcohol C (Scheme 1). Radical
cyclization reaction of a â-alkoxymethacrylate intermediate
D3 would supply the key intermediate 2.
Methyl (S)-(+)-3-hydroxybutyrate (3) was reacted with
the lithium enolate of tert-butyl acetate to yield the â-keto
ester product, which was converted into the benzylidene
acetal ester 4 via stereoselective syn reduction and acetal-
ization.4 The mixed hydride reduction of 4 proceeded
tions led to the formation of the â-alkoxymethacrylate
moiety, and the intermediate 7 was obtained after iodide
substitution. Low-temperature radical cyclization reaction of
regioselectively to produce 5-benzyloxyhexane-1,3-diol, and
tosylation of the primary hydroxyl group provided the
secondary alcohol 5. The reaction of 5 with excess methyl
7 in the presence of tributylstannane and triethylborane led
3,3-dimethoxy-2-methylpropionate (6) under acidic condi-
to the stereoselective formation (14:1) of the threo product5
in good yield (92%), which was transformed into 2 after
benzyl deprotection via hydrogenolysis (Scheme 2).
The (Z)-boron enolate of the chiral imide 8 reacted with
acrolein to produce the syn-aldol imide 9.6 Mitsunobu
(1) Tang, Y.-Q.; Sattler, I.; Thiericke, R.; Grabley, S. J. Antibiot. 2000,
53, 934-943.
(2) Sobolevskaya, M. P.; Fotso, S.; Havash, U.; Denisenko, V. A.;
Helmke, E.; Prokofeva, N. G.; Kuznetsova, T. A.; Laatsch, H.; Elyakov,
G. B. Chem. Nat. Comp. 2004, 40, 282-285.
10.1021/ol0500160 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/17/2005

Scheme 2. Synthesis of (+)-Methyl 8-epi-Nonactate (2)
Scheme 4. Synthesis of the Macrodiolide 1
reaction of 9 with benzoic acid and subsequent basic hy-
drolysis7 led to the anti-aldol benzoate acid 10. For prepara-
tion of the allylic alcohol fragment, methyl (R)-3-hydroxy-
pentanoate (11)8 was converted into the BOM-protected diol
12, which was further transformed into a 1:1 mixture of the
allylic alcohols 13 and 14 via oxidation and reaction with
vinyl Grignard reagent9 (Scheme 3).
Scheme 3. Preparation of B and C Fragments
The first-generation Grubbs catalyst did not work in this
case, and the benzoate protection for the allylic alcohol
moiety in 17 was important, as neither the corresponding
TBS-ether nor the free alcohol produced the proper mac-
rodiolides.12 It is also to be noted that the trans isomer 19
(3) For selected examples of radical cyclizations of â-alkoxyacrylates
and related compounds, see: (a) Lee, E.; Jeong, E. J.; Kang, E. J.; Sung,
L. T.; Hong, S. K. J. Am. Chem. Soc. 2001, 123, 10131-10132. (b) Lee,
E.; Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min, S. J.; Son, S. H.;
Lim, S. M.; Jang, W. S. Angew. Chem., Int. Ed. 2002, 41, 176-178. (c)
Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Joo, J. M. J.
Am. Chem. Soc. 2002, 124, 384-385. (d) Jeong, E. J.; Kang, E. J.; Sung,
L. T.; Hong, S. K.; Lee, E. J. Am. Chem. Soc. 2002, 124, 14655-14662.
(e) Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Kwak,
H. S.; Park, J. H.; Lee, E.; Hong, C. Y.; Jeong, S.; Jeon, K.; Park, J. H. J.
Org. Chem. 2003, 68, 8080-8087. (f) Keum, G.; Kang, S. B.; Kim, Y.;
Lee, E. Org. Lett. 2004, 6, 1895-1897.
(4) This is an improved version of the previous synthesis. See: Lee, E.;
Sung, L. T.; Hong, S. K. Bull. Kor. Chem. Soc. 2002, 23, 1189-1190.
(5) Lee, E.; Choi, S. J. Org. Lett. 1999, 1, 1127-1128.
(6) For an example of acrolein aldol reactions, see: Sunazuka, T.; Hirose,
T.; Shirahata, T.; Harigaya, Y,; Hayashi, M.; Komiyama, K.; Omura, S. J.
Am. Chem. Soc. 2000, 122, 2122-2123.
(7) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141-6144.
The TBS-protected 8-epi-nonactic acid 15 was prepared
from the methyl ester 2 via a two-step sequence. Yamaguchi
esterification reaction10 of the carboxylic acid 15 and the
allylic alcohol 13 proceeded efficiently, and TBS deprotec-
tion of the product ester led to the hydroxy ester 16. A second
Yamaguchi reaction of the acid 10 and the alcohol 16
provided the pivotal diester intermediate 17. The crucial ring-
closing metathesis reaction of 17 proceeded in the presence
of the Grubbs catalyst 1811 to give the unsaturated macrodi-
olide 19 in 80% yield (Scheme 4).
(8) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856-
5858.
(9) Structure determination of 13 and 14 was carried out by NMR analysis
of the (O)-acetyl (S)-mandelates: for example, the methyl triplet signal of
the derivative from 13 was found at δ 0.74 and the corresponding signal of
the derivative from 14 was found at δ 0.93.
(10) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
(11) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(12) For similar results, see: Paquette, L. A.; Efremov, I. J. Am. Chem.
Soc. 2001, 123, 4492-4501.
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Org. Lett., Vol. 7, No. 6, 2005

was the sole product. Benzoate deprotection of 19 and
subsequent hydrogenation then led to the macrodiolide 1.
The spectroscopic data of 1 did not match with those of
feigrisolide C, and it was clear that the macrodiolide 1 did
not represent the true structure of feigrisolide C. Careful
examination of the original paper revealed that the authors
had originally intended to propose the 3′-epimer 20 as the
structure of feigrisolide C13 (Figure 1).
Scheme 5. Synthesis of the 3′-Epimer 20
Figure 1. Possible structures of feigrisolide C.
For synthesis of 20, the syn-aldol benzoate acid 21 was
prepared from 9 in two steps. Esterification reaction of 21
and 16 was carried out uneventfully to provide the diester
22. Ring-closing metathesis reaction of 22 was less efficient
than in the case of 17, but eventually, the reaction provided
a moderate yield of the macrodiolide 23.14 Usual basic
deprotection and subsequent hydrogenation led to the
epimeric structure 20 (Scheme 5).
Unfortunately, comparison of the spectroscopic data of 20
with those of the natural product revealed that the structure
20 did not represent the true structure of feigrisolide C.
Identification of the real structure of feigrisolide C requires
further investigation, but the present studies present more
examples of the ring-closing metathesis reaction in the
preparation of relatively strained macrodiolide systems.
Acknowledgment. Authors thank Center for Marine
Natural Products and Drug Discovery (Seoul National Uni-
versity and the Ministry of Maritime Affairs and Fisheries,
Republic of Korea) for a MarineBio 21 grant (2004) and
Center for Bioactive Molecular Hybrids (Yonsei University
and KOSEF) for a research grant (2004). Brain Korea 21
graduate fellowship grants to W. H. Kim, L. T. Sung, and
S. M. Lim are gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures, H NMR and 13C NMR spectra of 1, 20, and
feigrisolide C, and 13C NMR spectra of the intermediates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) This was confirmed by private communication with Dr. I.
Sattler. We also thank Dr. Sattler for spectroscopic data and a sample of
feigrisolide C.
(14) In this case, a small amount of the cis isomer was also produced.
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