Total synthesis of (+)-brefeldin a

Article abstract of DOI:10.1021/ol800137f

(+)-Brefeldin A was synthesized through an efficient route, which features (1) construction of the five-membered ring from a Crimmins aldol via tandem Li-I exchange and carbanion-mediated cyclization with concurrent removal of the chiral auxiliary, (2) introduction of the lower side chain (C10 to C16) via a Rh-catalyzed Michael addition of a vinyl boronic acid, (3) stereoselective reduction of the C7 ketone with Sml_2, and (4) a 2-methyl-6- nitrobenzoic anhydride-mediated (Shiina) lactonization.

Full text of DOI:10.1021/ol800137f

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1533-1536
Total Synthesis of (+)-Brefeldin A
Yikang Wu* and Jian Gao
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
yikangwu@mail.sioc.ac.cn
Received January 20, 2008
ABSTRACT
(+
)-Brefeldin A was synthesized through an efficient route, which features (1) construction of the five-membered ring from a Crimmins aldol
via tandem Li I exchange and carbanion-mediated cyclization with concurrent removal of the chiral auxiliary, (2) introduction of the lower side
−
chain (C10 to C16) via a Rh-catalyzed Michael addition of a vinyl boronic acid, (3) stereoselective reduction of the C7 ketone with SmI2, and
(4) a 2-methyl-6-nitrobenzoic anhydride-mediated (Shiina) lactonization.
(+)-Brefeldin A (BFA, 1) is one of the naturally occurring
compounds of lasting interest over the decades. Since its first
isolation1 in 1958, BFA has been a target of study for
numerous chemists and bio-scientists. In particular, in the
field of total synthesis more than 30 successful approaches
have been documented during the past 30 years.2 Apart from
the natural compound itself, derivatives and analogues of
BFA are also receiving more and more attention.3
In 2004 we reported an aldol approach to 1 and its
7-epimer.2i,j The same strategy has also been applied to the
synthesis of the 15-demethyl analogues.3i While that approach
is efficient in constructing the key C4/C5 stereogenic centers,
the route to the key intermediate enone 2 and the lower side
chain was rather lengthy. Establishment of the C7 stereogenic
center was also unsatisfactory. Efforts to circumvent these
drawbacks led to a much more efficient synthesis of 1, which
is presented here below.
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10.1021/ol800137f CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/14/2008

One of the factors that contributed to the efficiency of the
present approach was an expeditious synthesis (Scheme 1)
of enone 2, which exploited a cyclization initiated by the
The resultant 5 was connected6a to the readily accessible6b
chiral auxiliary 6 to afford the acyl oxazolidinthione 7.
Subsequent treatment of 7 with the known2j enal 8 under
the Crimmins7 conditions afforded the enantiopure syn aldol
9 in 90% isolated yield. Other diastereomers, formed in less
than 3% yield altogether, were readily removed by chroma-
tography. The newly formed hydroxyl group in 9 was then
protected with TBSCl/2,6-lutidine/DMF, leading to the TBS
ether 10.
Scheme 1
The tandem lithium-iodine exchange-cyclization reaction
was first attempted using an equimolar amount of n-BuLi.
The exchange was expected to work well because vinyl
carbanions are more stable than alkyl carbanions in general.
However, the product in this case was rather complex,
containing several components apart from unreacted 10 and
the expected chiral auxiliary 6. Introduction of additional
n-BuLi (<0.3 mol equiv with respect to 10) did result in
complete disappearance of the starting 10. However, it also
led to an even more complex product mixture. Later, we
found in the literature that Negishi8 had used t-BuLi to realize
a smooth lithium-iodine exchange/ring closure from a
simple amide precursor. Although the situation in our case
appeared to be more complicated because of the presence
of a chiral auxiliary and the high risk of subsequent elimi-
nation of the â-silyloxy group, to our gratification used
t-BuLi instead of n-BuLi did indeed result in a great im-
provement. The number of components in the product mix-
ture was remarkably reduced. Through careful optimization
of the reaction conditions, we finally managed to obtain 11
in 75% yield.9
attack of an in situ formed vinyl lithium onto an internally
tethered carbonyl group with concurrent removal of the chiral
auxiliary. Successful execution of this plan called for facile
access to a vinyl halide building block of pure cis config-
uration. Consequently, quite a few known protocols4 were
examined, including decarboxylative elimination of R,â-
dibromocarboxylic acids under microwave conditions,4a
addition of catecholborane to a terminal alkyne followed by
halogenation,4b conversion of vinyl 1,1-dibromide into a cis
vinyl monobromide under the Bu3SnH/Pd(PPh3)4 conditions,4c
and Wittig reaction of Ph3PdCHI4d with an aldehyde.
However, none of them gave satisfactory results. The desired
product was either formed in low yields or it was contami-
nated with the undesired trans isomers. Finally, the problem
was solved using Oshima’s4e protocol. Thus, by treating the
commercially available alkynol 3 with DIBAL-H/InCl3/Et3B/
I2, very pure cis 4 was cleanly formed in 82% yield.4f
The alcohol 4 was oxidized into the known5a acid 5 by
Jones oxidation in 95% yield. Use of PDC5b or IBX/oxone5c
here was less satisfactory (82% and 62% yield, respectively).
Transposition of the carbonyl group in 11 was executed
following Carnell’s10 reduction-oxidation stratagem. The
ketone was first reduced to the alcohol under Luche11
conditions. The resultant 12 was then re-oxidized with PCC/
p-TsOH, giving enone 2 in 63% yield (from 11). PCC/SiO210d
or PCC/4 Å MS10e also afforded 2 in 60-65% yield.
However, IBX/DMSO10f oxidation did not lead to any 2 but
only 11.
Completion of a highly efficient route to enone 2 set the
stage for introduction of the lower side chain. In our first
(5) (a) Apparu, M.; Demenge, P.; Fagret, D.; Ghezzi, C.; Majid, S.;
Mathieu, J.-P.; Manuclaire, L.; Pasqualini, R.; Vidal, M. PCT Int. Appl.
WO 9600717 A1, Jan. 11, 1996, 56 pp.; Chem. Absrt. 1996, 124, 288981.
(b) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 5, 399-402. (c)
Thottumkara, A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett. 2005, 7, 2933-
2936.
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Wu, Y.-K.; Yang, Y.-Q.; Hu, Q. J. Org. Chem. 2004, 69, 3990-3992.
(7) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997,
119, 7883-7884.
(8) Sawada, H.; Webb, M.; Stoll, A. T.; Negishi, E. I. Tetrahedron Lett.
1986, 27, 775-778.
(9) A similar lithium-iodine exchange has been reported to be failed,
see: Morita, A.; Kuwahara, S. Org. Lett. 2006, 8, 1613-1616.
(10) (a) Carnell, A. J.; Casy, G.; Gorins, G.; Kompany-Saeid, A.;
McCague, R.; Olivo, H. F.; Roberts, S. M.; Willetts, A. J. J. Chem. Soc.,
Perkin Trans. 1 1994, 3431-3439. (b) Buchi, G.; Egger, B. J. Org. Chem.
1971, 36, 2021-2023. (c) Backstrom, P.; Okecha, S.; De Silva, N.;
Wijekoon, D.; Norin, T. Acta Chem. Scand. Ser. B 1982, 36, 31-36. (d)
Luzzio, F. A.; Moore, W. J. J. Org. Chem. 1993, 58, 2966-2971. (e) Mehta,
G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V. J. Am. Chem. Soc. 1986,
108, 3443-3452. (f) Shibuya, M.; Ito, S.; Takahashi, M.; Iwabuchi, Y.
Org. Lett. 2004, 6, 4303-4306.
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42, 3893-3896. (b) Brown, H. C.; Subrahmanam, C.; Hamaoka, T.;
Ravindran, N.; Bowman, D. H.; Misumi, S.; Unni, M. K.; Somayaji, V.;
Bhat, N. G. J. Org. Chem. 1989, 54, 6068-6075. (c) Uenishi, J.; Kawahama,
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X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040-6041. (e) Takami,
K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Org. Chem,
2003, 68, 6627-6631. (f) To our knowledge, a clear-cut stereoselective
synthesis of this compound has never been documneted so far. For a
synthesis of cis/trans mixture of 4, see: Nishida, A.; Shirato, F.; Nakagawa,
M. Tetrahedron: Asymmetry 2000, 11, 3789-3806.
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5459.
1534
Org. Lett., Vol. 10, No. 8, 2008

generation2j synthesis of BFA and many of previous ones,
this was accomplished via a Michael addition of an in situ
formed organolithium cuprate species. Although the best
yield of that approach exceeded 90%, the operation was
cumbersome and the outcome varied from run to run. Failure
to meet the requirement for strict exclusion of oxygen/
moisture and the precise stoichiometry of the reagents often
led to formation of only undesired side products. Besides,
waste of 2 equiv of the optically active lower side chain there
was another shortcoming. During the present endeavor we
found, in the literature, that similar Michael additions could
also be achieved12 using boronic acids and an appropriate
Rh catalyst. Although the methodology was tested only on
relatively simple compounds (to our knowledge), the impres-
sive yields, the need for only a slight excess of the boronic
acids, and its operational simplicity encouraged us to examine
it on our substrate.
Scheme 3
The requisite lower side chain 18 was synthesized by
incorporating different literature steps, as shown in Scheme
2. The alcohol 15 was assembled from the commercially
with the simple substrates in the literature, the anticipated
ketone 19 was obtained cleanly. Although the yield is only
slightly higher than that in the previous lithium cuprate-
mediated protocol, the present approach is much simpler and
consumes less of the lower side chain.
It is noteworthy that although the rhodium catalyst is quite
stable to air and moisture, it appears rather sensitive to
catechol. Compound 18, when contaminated by traces of
catechol (which is difficult to completely remove by routine
workup or/and chromatography), did not undergo the Michael
addition at all.
Scheme 2
Reduction of C7 in 19 was a challenge that remained from
our previous2j work; where the best R/â-OH ratio achieved
after screening a range of different reagents/conditions was
3:2 (by Corey-Bakshi-Shibata16 reduction). In the hope of
finding better conditions in the present endeavor, we
examined three other reducing agents (Table 1), which are
less common compared with those tested earlier.
available alkyne 13 and epoxide 14 as reported13 by Nokami.
However, in the subsequent zip reaction (migration of
the triple bond) Lesot’s14 Li/t-BuOK/H2N(CH2)3NH2 con-
ditions gave significantly higher yields than Nokami’s13
KH/H2N(CH2)2NH2 (89% vs 68%). Protection of the hy-
droxyl group in 16 with BnBr afforded the known2j 17.
Finally, treatment of 17 with catecholborane followed by
alkaline hydrolysis yielded the desired boronic acid 18.15
Addition of the boronic acid 18 to enone 2 was performed
under the Csaky’s12b conditions (Scheme 3). Despite the
presence of additional labile functionalities in 2 compared
Table 1. Reduction of the C7 Carbonyl Group in Ketone 19
under Different Conditions (cf. Scheme 3 for the Structures)
entry
conditions
R/â (total yielda)
1
2
3
4
SmI2/i-PrOH/0 °C/24 h
5:1b (89%)
Sm/cat. I2/i-PrOH/0 °C/30 h
t-BuLi/DIBAL-H/-78 °C/1 h
n-BuLi/DIBAL-H/-78 °C/1 h
5:1c (77%)
â-OH only (95%)
1:5c (100%)
a Based on isolated products. b Calculated from isolated isomers. c Cal-
culated from H NMR of the crude mixture.
1
(12) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229-4231. (b) de la Herran, G.; Mba, M.; Murcia, C.; Plumet, J.; Csaky,
A. G. Org. Lett. 2005, 7, 1669-1671.
(13) Nokami, J.; Ohkura, M.; Dan-oh, Y.; Sakamoto, Y. Tetrahedron
Lett. 1991, 32, 2409-2412 (with only specific rotation reported).
(14) Parenty, A.; Campagne, J.-M.; Aroulanda, C.; Lesot, P. Org. Lett.
2002, 4, 1663-1666 (the antipode of 16).
(15) It should be noted that the olefinic carbon directly bonded to boron
in 18 appears in 13C NMR as an almost unrecognizable lump (caused by
11B) at around δ 122 as revealed by the HMQC experiment. The difficulty
in detecting this signal presumably misled some investigators to report only
one of the two olefinic carbones or to take the extra line (stemming from
the trimer gradually formed on standing) for another olefinic carbon in
similar cases, see, e.g.: (a) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003,
68, 6031-6034. (b) Fairlamb, I. J. S.; Marrison, L. R.; Dickinson, J. M.;
Lua, F.-J.; Schmidt, J. P. Bioorg. Med. Chem. 2004, 12, 4285-4299. Cf.
also the description in the Supporting Information section.
Interestingly, although the number of reagents examined
in this work is much smaller than that in the previous2i,j study,
the results turned out to be much better. The SmI2/i-PrOH17
(Entry 1) gave a very pleasing R/â ratio of 5:1, while the
(16) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551-5553. (b) For a review, see: Singh, V. K. Synthesis 1992, 605-
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Org. Lett., Vol. 10, No. 8, 2008
1535

t-BuLi/DIBAL-H18 (Entry 3) led exclusively to the â isomer.
Thus, selective reduction of the C7 carbonyl group to either
isomer of the alcohol becomes much more feasible now.
The subsequent steps were performed similarly to those
in our previous2i,j work. The C7 hydroxyl group was masked
as a TBS ether (using a different reagent here). The Bn
groups were cleaved under the Liu19 conditions. The newly
released benzylic alcohol was selectively oxidized first with
MnO220 and then NaClO2/NaH2PO4/methyl-2-butene,21 pro-
viding the hydroxy acid 23 (Scheme 4).
1980. However, as in a recent23 related transformation,
Shiina’s24 MNBA (2-methyl-6-nitro-benzoic anhydride) was
found to be superior. In the present work we also tried
MNBA. The results were quite satisfactory. While the yield
of 24 was essentially the same as the best achieved under
the Yamaguchi conditions, the operation was remarkably
simpler, and the yield no longer varied drastically from run
to run.
Finally, the TBS protecting groups were removed with 2
N HCl to yield the end product (+)-BFA, 1.
In summary, a concise enantioselective total synthesis of
natural BFA has been completed. The potentially interesting
elements encapsulated include (1) a facile access to pure cis
vinyl iodo alkenol 4,25 (2) direct formation of an enone from
a Crimmins aldol via tandem lithium-iodine exchange and
intramolecular neucleophilic addition with concurrent re-
moval of the chiral auxiliary, (3) use of a boronic acid as
the lower side chain and the Michael addition mediated by
a rhodium catalyst, (4) stereoselective reduction of the C7
ketone in an extremely difficult situation, and (5) a macro-
lactonization using MNBA, which is more convenient than
the Yamaguchi protocol (the best choice up to now in all
BFA syntheses involving similar lactonization).
Scheme 4
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20372075, 20321202,
20672129, 20621062, 20772143) and the Chinese Academy
of Sciences (“Knowledge Innovation”, KJCX2.YW.H08) is
gratefully acknowledged. The editor and referees are thanked
for their kind help with improving the manuscript.
Yamaguchi22 lactonization has been the method of choice
for the ring-closure in all the relevant BFA syntheses since
Supporting Information Available: Experimental pro-
cedures, physical and spectroscopic data for all new com-
1
pounds, H and 13C NMR spectra of 2, 4, 7, 9, 10, 11, 16,
(18) (a) Bian, J.; Van Wingerden, M.; Ready, J. M. J. Am. Chem. Soc.
2006, 128, 7428-7429. (b) Kovacs, G.; Galambos, G.; Juvancz, Z. Synthesis
1977, 171-172.
17, 18, 19, 20, 20′, 21, 24, and 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
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OL800137F
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Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993. (b) In synthesis of BFA, the
yield of the ring-closure product(s) fluctuated considerably from run to run
(to our experience).
(23) Wu, Y.-K.; Yang, Y.-Q. J. Org. Chem. 2006, 71, 4296-4301.
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form than the corresponding trans isomers) may find diverse uses as
bifunctional building blocks in organic synthesis.
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Org. Lett., Vol. 10, No. 8, 2008