Enantioconvergent Formal Synthesis of Brefeldin a via Sakai-Catalyzed Cyclization

Full text of DOI:10.1021/jo990507w

3800
J . Org. Chem. 1999, 64, 3800-3801
Toward this end, we have developed a synthesis of BFA
analogues that can either be linked to a solid support, for
affinity chromatography, or, that would incorporate photo-
activatable radioactive probes. We report here the synthesis
of the key intermediate 3a which could rapidly and ef-
ficiently lead to these derivatives, but also to 2 (Scheme 1).
The latter could lead, in few steps, to BFA as described by
Gais.2f
En a n tiocon ver gen t F or m a l Syn th esis of
Br efeld in A via Sa k a i-Ca ta lyzed Cycliza tion
Pierre Ducray, Bernard Rousseau,* and
Charles Mioskowski*
Service des Mole´cules Marque´es, CEA/ Saclay,
91191 Gif sur Yvette, France
We developed an enantioconvergent synthesis of optically
pure aldehyde 3a starting from racemic pentenal 5 (Scheme
1). A catalytic asymmetric intramolecular hydroacylation of
5 in the first step should lead to optically pure cyclopen-
tanones 4a and 4b in equal amounts.5 Indeed, the stereo-
chemistry of the newly created center should only depend
on the chirality of the catalyst. (S)-BINAP, as rhodium
ligand, should provide (3R) 4a and 4b. The hydroxyl group
on this stereogenic center could then be used as a directing
group in the asymmetric reduction of the ketone.2n A highly
diastereoselective reduction is expected. Finally, epimeriza-
tion should transform trans aldehyde 3b into key intermedi-
ate 3a .
Racemic pentenal 5 was obtained using a Heck reac-
tion6 between vinylic bromide 6 and cis-4,7-dihydro-1,3-
dioxepin (Scheme 2). All attempts to perform this reaction
asymmetrically were unsuccessful despite the report of
Shibasaki6b who described a similar arylation with 72% ee.
This result prompted us to develop the enantioconvergent
strategy reported herein. The hydrolysis of 7 with aqueous
HCl was followed by treatment with EtSH in a one-pot
reaction to afford 8. TBS protection of the hydroxyl group,
followed by cleavage of the thioacetal, provided 4-pentenal
5.7
Sakai cyclization using a catalytic amount (0.9%) of
cationic Rh[(S)-BINAP]+BF4- proceeded smoothly to afford
a 1:1 mixture of trans-(3R,4R)-cyclopentanone 4a and cis-
(3R,4S)-cyclopentanone 4b in high yield (90%) and with high
enantioenrichment (96% for each) (Scheme 3). An efficient
transformation into aldehyde 3a was then carried out
starting from the 4a + 4b epimeric mixture. The hydrogena-
tion of the benzyl ether was followed by the highly diaste-
reoselective reduction of the resulting ketone using sodium
triacetoxyborohydride.2n The primary hydroxyl group in 9a
and 9b was acetylated and the secondary hydroxyl group
protected with MEM chloride. After deacetylation, the
primary hydroxyl was protected as MTM ether.8 The TBS
protecting group was then removed, and the resulting
hydroxyl group was oxidized with PCC to furnish alde-
hydes 3a and 3b. Basic treatment converted the cis alde-
hyde 3b to the thermodynamically favored chiral synthon
3a .
Received March 23, 1999
Since the isolation of Brefeldin A (BFA) 1 in 1958,1 much
effort has been devoted to its study.2 Initially, interesting
biological activities including antitumor, antifungal, and
antiviral effects, as well as the unique bicyclic macrolactone
framework, stimulated synthetic efforts. Since the early
1990s, it has been found that BFA causes rapid redistribu-
tion of Golgi proteins into the endoplasmic reticulum, leaving
no definable Golgi apparatus, and blocks transport of
proteins into post-Golgi compartments in the cell.3 Under-
standing the mechanism through which BFA acts on the
Golgi should help explain how membrane organelles main-
tain their identity.4 To answer this fundamental question,
the identification of the biological target of BFA is necessary.
* To whom correspondence should be addressed. E-mail: bernard.
rousseau@cea.fr or mioskow@bioorga.u•strasbg.fr.
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10.1021/jo990507w CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/06/1999

Communications
J . Org. Chem., Vol. 64, No. 11, 1999 3801
Sch em e 1
Sch em e 2
Sch em e 4
acetylene 11 and oxidation of the reaction mixture with
alkaline hydrogen peroxide10 afforded primary alcohol 12
which, upon treatment with oxalyl chloride, furnished the
corresponding chloro compound. Debenzylation followed by
THP protection afforded 13.
Condensation of aldehyde 3a with trimethylsulfonium
methyl sulfate, under phase transfer conditions, gave the
desired epoxide 10 (Scheme 3).11 Reductive alkylation of 10
with the organolithium reagent12 derived from halide 1313
afforded, with concomitant regeneration of the hydroxyl
function, olefin 2. The stereoselectivity of this process is
better than that of classical olefination methods applied to
BFA syntheses (E/ Z ) 90/10).
Sch em e 3
A formal, catalytic, and enantioconvergent synthesis of
BFA is reported. Our approach utilizes, as the key steps,
an asymmetric Sakai cyclization and a reductive alkylation
of epoxide rendering this approach particularly attractive
despite the large number of total or partial syntheses of
(+) BFA described in the literature. This allows the con-
version of racemic 5 into an optically pure product using only
0.9% of a chiral catalyst. These two reactions were, for
the first time, applied to the total synthesis of a natural
product.
Ack n ow led gm en t. We warmly thank Drs. Franc¸ois
Ke´pe`s, Catherine J ackson, and Eric Doris for hepful
discussions. We also thank Ms Florence Pillon, Mrs Alain
Valleix, Franck Sobrio, and Dr. Patrick Berthault for
running important control experiments.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, characterization data, and 1H and 13C spectra for all
compounds including unnumbered intermediates. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O990507W
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