Total synthesis of (+)-brefeldin A

Article abstract of DOI:10.1021/jo0110855

The total synthesis of (+)-brefeldin A has been accomplished via 15 linear steps in a 7.9% overall yield from the known Weinreb amide 6. The key parts of this approach include the stereoselective construction of the cis-disubstituted hydroxycyclopentane skeleton and the direct introduction of the C1-C3 acrylate moiety using a new variant of a trans-vinylogous acyl anion equivalent.

Full text of DOI:10.1021/jo0110855

J . Org. Chem. 2002, 67, 4127-4137
4127
Tota l Syn th esis of (+)-Br efeld in A
Young-Ger Suh,*,† J ae-Kyung J ung,† Seung-Yong Seo,† Kyung-Hoon Min,† Dong-Yun Shin,†
Yong-Sil Lee,† Seok-Ho Kim,† and Hyun-J u Park‡
College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu,
Seoul 151-742, Korea, and College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea
ygsuh@plaza.snu.ac.kr
Received November 19, 2001
The total synthesis of (+)-brefeldin A has been accomplished via 15 linear steps in a 7.9% overall
yield from the known Weinreb amide 6. The key parts of this approach include the stereoselective
construction of the cis-disubstituted hydroxycyclopentane skeleton and the direct introduction of
the C1-C3 acrylate moiety using a new variant of a trans-vinylogous acyl anion equivalent.
In tr od u ction
(+)-Brefeldin A (1) has been, since its isolation1 and
structural elucidation2 many years ago, one of the most
attractive targets for synthetic chemists due to its wide
range of biological activities and well-functionalized
macrolide structure. Its biological mode of action has been
disclosed by a number of important discoveries.3 Espe-
cially, brefeldin A is known as a disassembler of the Golgi
apparatus, because brefeldin A can block protein trans-
port from the rough endoplasmic reticulum (ER) to the
Golgi complex and cause a redistribution of the cis,
medial, and trans Golgi proteins into the ER in mam-
malian cells.4 In addition, the ability of brefeldin A to
induce DNA fragmentation associated with apoptosis in
cancer cells has stimulated a great deal of recent interest
in its preclinical development as an anticancer agent.5,6
Since Corey’s first total synthesis of 1 in 1976,7 a number
of synthetic routes to this macrolide antibiotic have been
explored.8 In particular, the exciting biological activities
of brefeldin A, combined with the impracticality of the
previously developed syntheses led us to take on the
challenge of the total synthesis of 1.
In planning our approach, we hoped to develop a
versatile, practical, and stereocontrolled route that would
minimize protecting group manipulations and adapt a
platform that leads to a variety of analogues of 1. This
paper fully describes our synthetic studies9 toward (+)-
brefeldin A
Resu lts a n d Discu ssion
Syn th etic P la n . Our retrosynthetic strategy toward
1 is illustrated in Figure 1. (+)-Brefeldin A (1) could be
prepared from the seco acid 2 through the regioselective
macrolactonization and stereoselective reduction of the
C4 (refer to the numbering system of brefeldin A) ketone
at the final stage. It might be expected that, to effect the
proposed selective macrolactonization, the C15 hydroxy
group must be differentiated from the remaining C7
hydroxy group. However, we recognized that such mac-
rolactonization could take place preferentially at the C15
hydroxy group under controlled conditions. Therefore, we
* To whom correspondence should be addressed. Phone: +82-2-880-
7875. Fax: +82-2-888-0649.
† Seoul National University.
‡ Sungkyunkwan University.
(1) Singleton, V. L.; Bohonos, N.; Ullstrupp, A. J . Nature 1958, 181,
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Ishikawa, K.; Nakai, T. Synlett 1995, 901. (b) Kim, D.; Lim, J . I.
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10.1021/jo0110855 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/16/2002

4128 J . Org. Chem., Vol. 67, No. 12, 2002
Suh et al.
Sch em e 1a
a
Reagents and conditions: (a) H2, 10% Pd/C, EtOH; (b) DIBAL,
CH2Cl2, -78 °C, 98% for two steps; (c) TsCl, Et3N, 4-DMAP,
CH2Cl2; (d) lithium acetylide-EDA complex, DMSO, 81% for two
steps.
afforded the alkyne 7 as a part of the lower side chain in
an 81% two-step yield.
Syn th esis of th e Cycliza tion P r ecu r sor . The allylic
benzoate 5, bearing the butyrolactone moiety as a Pd(0)-
catalyzed cyclization precursor, was synthesized as out-
lined in Scheme 2.
Starting from the known Weinreb amide 6,10 treatment
with the lithium anion of 7 in THF at -78 °C provided
the ynone intermediate in an 81% yield.14 The initial
partial reduction of the ynone by hydrogenation in the
presence of Pd/BaSO4 resulted in a disappointingly low
yield of the desired enone 11. However, partial hydroge-
nation of the ynone intermediate was efficiently effected
using the Lindlar catalyst (Pd/CaCO3, quinoline, H2,
MeOH), which afforded the enone 11 in a 95% yield. The
allylic alcohol 12 was also efficiently synthesized as the
only stereoisomer in a 95% yield by stereoselective
reduction with LAH in the presence of LiI, according to
Suzuki’s protocol.11 In particular, the 1,3-syn diol func-
tionality was conveniently installed in a highly diaste-
reoselective fashion by this excellent method. At this
stage, the selective removal of the acetonide protecting
group was problematic due to the presence of the acid-
sensitive C15 TBS group (eq 1). The initial deprotection,
using an acid catalyst such as FeCl3-Si2O15 or B-
bromocatecholborane,16 afforded the triol 17 in 83 and
94% yields, respectively. However, these reactions on a
large scale consistently failed to provide mainly the triol
17.
F igu r e 1. Retrosynthetic analysis of (+)-brefeldin A.
decided to leave the C7 and C15 hydroxy groups undif-
ferentiated for synthetic efficiency. The acrylate moiety
of the seco acid 2 is directly introduced by the reaction
of a three-carbon synthon such as the trans-vinylogous
acyl anion 49c with the bicyclic lactone 3. The bicyclic
lactone 3, corresponding to the hydroxycyclopentane
skeleton of brefeldin A, is efficiently constructed by the
highly stereoselective palladium-catalyzed cyclization of
the allylic benzoate 5 we developed9a,9b as the key step.
The stereochemistry of C9 as well as the olefin geometry
of C10-C11 would also be established during this
process. The Weinreb amide 610 was considered to be the
best starting material, which could be conveniently
transformed into the cyclization precursor 5. This trans-
formation involves the coupling of 6 and 7, Suzuki’s
reduction11 for the installation of the C9 stereocenter, and
the formation of the butyrolactone moiety. This strategy
would provide the relevant timing of the necessary
operations and also minimize protecting group manipula-
tions.
Syn th esis of th e C10-C16 F r a gm en t. Our synthesis
was commenced by the preparation of the requisite 7,12
as shown in Scheme 1. The known R,â-unsaturated ester
813 was initially hydrogenated, and the resulting satu-
rated ester was reduced with DIBAL to give the corre-
sponding alcohol 9 in a 98% yield. Tosylation of the
alcohol 9, followed by the addition of lithium acetylide,
This problem was fortunately solved by the acetal
exchange conditions.10,17 The exposure of the acetonide
12 to camphorsulfonic acid (CSA) and the dimethylacetal
(10) (a) Tavares, F.; Lawson, J . P.; Meyers, A. I. J . Am. Chem. Soc.
1996, 118, 3303. (b) Piscopio, A. D.; Minowa, N.; Chakraborty, T. K.;
Koide, K.; Bertinato, P.; Nicolaou, K. C. J . Chem. Soc., Chem. Commun.
1993, 617.
(11) J ournet, M.; Cai, D.; DiMichele, L. M.; Larsen, R. D. Tetrahe-
dron Lett. 1998, 39, 6427.
(12) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, H. Tetrahedron Lett.
1988, 29, 5419.
(14) Annunziata, R.; Cinquini, M.; Cozzi, F.; Dondio, G.; Raimond,
L. Tetrahedron 1987, 43, 2369.
(15) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J . Org. Chem.
1986, 51, 404.
(13) (a) Drian, C. L.; Green, A. E. J . Am. Chem. Soc. 1982, 104, 5473.
(b) Nokami, J .; Ohkura, M.; Dan-oh, Y.; Sakamoto, Y. Tetrahedron Lett.
1991, 32, 2409.
(16) (a) Boeckman, R. K., J r.; Potenza, J . C. Tetrahedron Lett. 1985,
26, 1411. (b) Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. Tetrahedron
Lett. 1997, 38, 1271.

Total Synthesis of (+)-Brefeldin A
J . Org. Chem., Vol. 67, No. 12, 2002 4129
Sch em e 2a
a
Reagents and conditions: (a) 7, n-BuLi, ThF, -78 °C, 81%; (b) Lindlar catalyst, quinoline, H2, MeOH, 95%; (c) LAH, LiI, Et2O, -78
°C, 95%; (d) (MeO)2CHC6H4(p-OMe), CSA, CH2Cl2, 84%; (e) TsCl, Et3N, 4-DMAP, CH2Cl2, 99%; (f) PhO2SCH2CO2Me, NaH, DMF, 100 °C,
72%; (g) DDQ, CH2Cl2/H2O (18/1); (h) DBU, Ch3CN, 71% for two steps.
Ta ble 1. Ster eoselective Cycliza tion of Allylic Ben zoa te
of anisaldehyde led to the concomitant deprotection of
acetonide and the formation of benzylidene acetal, thus
5 (Equ a tion 2)
furnishing the hydroxydioxane 13 in a good yield. Tosyl-
ation of 13 followed by benzenesulfonyl acetate displace-
ment of the tosylate 14 provided the alkylated dioxane
15. Finally, oxidative cleavage of benzylidene 15 and
subsequent lactonization of 16 afforded the allylic ben-
zoate 5 as the cyclization precursor. DDQ treatment18 of
15 initially liberated a 10:1 diastereomeric mixture of
hydroxyesters 16a and 16b. However, DBU-promoted
lactonization of the isomeric mixtures afforded the de-
sired butyrolactone 5 as the only product in a 71% yield
for the two steps. The isomer 16a seems to undergo an
initial intramolecular acyl transfer and then lactoniza-
tion. With the cyclization precursor 5 in hand, the crucial
cyclization resulting in perfect chirality transfer was tried
next.
yield
(%)
ratio
entry
reaction conditionsa
(18:19)b
1
2
3
Pd(dppe)2, BSA, CH2Cl2, reflux
Pd(dppe)2, DBU, THF, reflux
Pd(PPh3)4, DBU, THF, reflux
73
81
88
9:1
7:1
>99:<1
a
b
Reactions were performed at a 0.05 M concentration. Ratio
was determined by 300 MHz 1H NMR.
confirmed by the observed coupling constants of their
olefinic hydrogens (15.3 and 10.5 Hz, respectively). The
formation of the (Z)-isomer 19 is likely due to the direct
cyclization of a part of the syn,anti-π-allyl palladium
complex19 initially derived from the (Z)-allylic benzoate
5. The use of a stronger base such as DBU provided lower
selectivity (entry 2). In light of the result20 that the
reaction rate for Pd(PPh3)4 is slower than that for Pd-
(dppe)2, we attempted the cyclization of 5 in the presence
of Pd(PPh3)4/DBU. To our delight, the cyclization of 5
under these conditions afforded the bicyclic lactone 18
in an excellent yield, with no detection of the (Z)-isomer
19. This result would arise from the greater steric effect
of Pd(PPh3)4 compared to that of Pd(dppe)2, which
provides the preferred syn,syn-π-allyl palladium complex
T2 in the transition state (Figure 2). Having successfully
addressed the synthesis of the bicyclic lactone 18, we
investigated the direct introduction of the requisite
acrylate moiety to the bicyclic lactone intermediate 18.
Syn th etic Ap p r oa ch by th e Th r ee-Ca r bon Ho-
m ologa tion . The sulfonyl group was initially removed
by the treatment of 18 with 6% Na-Hg in the presence
of B(OH)3,21 as shown in Scheme 3. The use of B(OH)3 is
Cycliza tion of th e Allylic Ben zoa te. The cyclization
of the allylic benzoate 5 was carried out according to a
procedure that was previously established in our labora-
tory.9a
The cyclization of 5 in the presence of 5 mol %
Pd(dppe)2 and N,O-bis(trimethylsilyl)acetamide (BSA) in
dichloromethane proceeded smoothly to afford the bicyclic
lactone 18 along with a small amount of the unexpected
stereoisomer 19, as shown in Table 1 (entry 1). The trans-
and cis-olefin geometries of 18 and 19, respectively, were
(19) For accounts of the extensive primary literature and Pd-
mediated allylic alkylation, see: (a) Tsuji, T. Palladium Reagents and
Catalysts. Innovations in Organic Chemistry; Wiley: Chichester, UK,
1997. (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(c) Frost, C. G.; Howarth, J .; Williams, J . M. J . Tetrahedron: Asym-
metry 1992, 3, 1089.
(20) Nystrom, J .-E.; Backvall, J .-E. J . Org. Chem. 1983, 48, 3947.
(21) Unpublished results. The details for the desulfonylation pro-
cedure under extremely mild conditions will be reported soon. Professor
Trost also reported the same conditions for the reductive elimination.
See: Trost, B. M.; Calkins, T. L.; Bochet, C. G. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2632.
(17) Meyers, A. I.; Lawson, J . P.; Walker, D. G.; Linderman, R. J .
J . Org. Chem. 1986, 51, 5111.
(18) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetraheron 1986, 42, 3021.

4130 J . Org. Chem., Vol. 67, No. 12, 2002
Suh et al.
Sch em e 4a
F igu r e 2. Transition state of Pd(0)-catalyzed cyclization.
Sch em e 3a
a
Reagents and conditions: (a) CSA, MeOH, 97%; (b) 26, methyl
3-iodoacrylate, toluene, reflux, 73%; (c) n-BuLi, THF, from -78
°C to room temperature, 77%; (d) t-BuLi, THF, from -78 °C to
room temperature, 81%.
After TBS deprotection, the alcohol 23 was transesteri-
fied with â-iodo acrylate with the assistance of Otera’s
distannoxane catalyst 26 (Scheme 4).25 Treatment of the
trans-iodo acrylate 24 with n-BuLi or t-BuLi (2 equiv)
did not provide the desired alkylation product 25a .
Instead, only the dehalogenated product 25b, obtained
by halogen-metal exchange followed by protonation of
the resulting vinyl anion, was observed. This failure
prompted us to develop a novel method for the direct
introduction of the acrylate moiety to a variety of carbo-
nyl functions including lactone.
a
Reagents and conditions: (a) 6% Na-Hg, B(OH)3, MeOH, 87%;
(b) 21, n-BuLi or LDA, THF; (c) 22, n-BuLi or LDA, DMPU or
HMPA, THF.
Revised Appr oach Usin g a Tr an s-Vin ylogou s Acyl
An ion . Consideration of the weak nucleophilicity of the
three-carbon synthon, due to the electron-withdrawing
effect of the carboxyl functionality, led us to adapt the
2,6,7-trioxabicyclo[2.2.2]octane system (OBO ortho es-
ters)26 as an equivalent of the carboxyl group.
quite crucial for the selective desulfonylation without ring
opening of the bicyclic lactone.
At this point, the synthetic plan called for the alkyla-
tion of the lactone 3 with an appropriately functionalized
three-carbon synthon.22 To this end, we first attempted
to utilize a propiolic acid or ester as a nucleophile
(Scheme 3). However, the lithium anions of methyl and
ethyl propiolate23 (21) were too weakly nucleophilic to add
the lactone 3 at a low temperature, despite the high
degree of structural strain of the bicyclic lactone 3. The
alkylation at higher temperatures only resulted in de-
composition of the reactants. In addition, the propiolic
acid (22) dianion was not sufficiently nucleophilic to
alkylate the bicyclic lactone 3 under a variety of condi-
tions.24
F igu r e 3. Trans-vinylogous acyl anion equivalent.
In addition, the OBO ortho esters were expected to
serve as an excellent carboxyl equivalent, since they are
resistant to attacks by strong nucleophiles and readily
hydrolyzed under mild conditions.27 Accordingly, we
selected the trans-vinyl anion 28b, generated by halogen-
metal exchange of the corresponding (E)-1-(2-iodovinyl)-
4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (28a ), as the
best equivalent of the requisite trans-vinylogous ester
Thus, an intramolecular acylation of the acrylate anion
generated by halogen-metal exchange was investigated.
(22) For the indirect introduction of an acrylate moiety in the
synthesis of brefeldin A, see; (a) Gais, H.-J .; Lied, T. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 145. (b) Kitahara, T.; Mori, K. Tetrahedron
1984, 40, 2935.
(23) The lithium anion of propiolate was found to decompose at
temperatures above -78 °C. See: (a) Midland, M. M.; Tramontano,
A.; Cable, J . R. J . Org. Chem. 1980, 45, 28. (b) Evans, D. A.; Fitch, D.
M.; Smith, T. E.; Cee, V. J . J . Am. Chem. Soc. 2000, 122, 10033. (c)
Corey, E. J .; Kim, C. U.; Chen, R. H. K.; Takeda, M. J . Am. Chem.
Soc. 1972, 94, 4397.
(24) (a) Carlson, R. M.; Oyler, A. R.; Peterson, J . R. J . Org. Chem.
1975, 40, 1610. (b) Carlson, R. M.; Oyler, A. R. Tetrahedron Lett. 1974,
2615.
(25) (a) Otera, J .; Yano, T.; Kawabata, A.; Nozaki, H. Tetraherdon
Lett. 1986, 27, 2383. (b) Otera, J . Chem. Rev. 1993, 93, 1449. (c) Otera,
J .; Dan-oh, N.; Nozaki, H. J . Org. Chem. 1991, 56, 5307. (d) Schreiber,
S. L.; Meyers, H. V. J . Am. Chem. Soc. 1988, 93, 1449.
(26) Corey E. J .; Raju, N. Tetrahedron Lett. 1983, 24, 5571.
(27) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.

Total Synthesis of (+)-Brefeldin A
J . Org. Chem., Vol. 67, No. 12, 2002 4131
Sch em e 5a
Ta ble 2. Rea ction of Tr a n s-Vin ylogou s Ester An ion
Equ iva len t 28b w ith Ca r bon yl Com p ou n d s
a
Reagents and conditions: (a) 57% HI, H2O, 85 °C, 90%; (b)
3-methyl-3-hydroxymethyloxetane, DCC, 4-DMAP, CH2Cl2, room
temperature, 95%; (c) BF3‚OEt2, CH2Cl2, -15 °C, 73%.
anion 27,28,29 as illustrated in Figure 3. To the best of
our knowledge, the trans-vinylogous ester anion equiva-
lent and its synthetic utilization have not been reported
yet,9c although the â-alkoxy-directed cis-vinyl anions have
been reported.29
The iodovinyl OBO ortho ester 28a was conveniently
prepared from propiolic acid (22) via a three-step se-
quence. Regioselective hydroiodination30 of propiolic acid
(22) with 57% HI, esterfication of the resulting iodo-
acrylic acid 29 with 3-methyl-3-hydroxymethyloxetane,
and then BF3‚OEt2-assisted rearrangement26 of the re-
sulting ester 30 afforded 28a (Scheme 5).
With the iodovinyl OBO ortho ester 28a in hand, we
carried out a survey of the regioselective halogen-metal
exchange reaction under varying reaction conditions of
base, solvent, and temperature. As expected, the iodo
substituent of the vinyl OBO ortho ester 28a turned out
to be crucial for the efficient generation of the requisite
trans-vinyl anion 28b, since the bromo-substituted vinyl
substrate afforded only the cis-halovinyl anion by depro-
tonation, rather than halogen-metal exchange.28,29 In
particular, the reverse addition of the iodoolefin 28a to
t-BuLi in ether provided the best results by the desired
halogen-metal exchange.9c
a
Condition A: 2 equiv of 28a was used. Condition B: 4 equiv
of 28a were used. Isolated yields. c Temperature was maintained
at -78 °C. Yield based on recovered starting material.
b
d
Sch em e 6a
Table 2 summarizes the results for the reaction of the
lithium anion 28b with a series of carbonyl compounds.
As anticipated, the aldehyde and the ketone (entries 1-5)
underwent facile addition reactions to afford the allylic
alcohols (31a -e) in good yields. In the case of the lactones
(entries 6 and 7), an extended reaction time at -78 °C
and an excess amount of 28b were necessary in order to
ensure a higher yield and to avoid over-addition leading
to the tertiary alcohol. It is notable that the Weinreb
amide31 (entry 8) is superior to the lactone (entry 7) for
acylation of the vinyl anion 28b in terms of the yield and
the reaction time.
Ap p lica t ion of a Tr a n s-Vin ylogou s Acyl An ion
Equ iva len t. On the basis of the above results, we first
reacted the lithium anion 28b with the bicyclic lactone
3 as shown in Scheme 6. The formation of the lithium
anion 28b (4 equiv) with t-BuLi (8 equiv) at -78 °C,
followed by the addition of the bicyclic lactone 3 (1 equiv),
afforded the enone 32 in a 51% yield as a 1:3 diastere-
a
Reagents and conditions: (a) 28a , t-BuLi, ether, -78 °C, 30
min, then 3, -78 °C, 51%; (b) DBU, CH2Cl2, reflux, 99%.
omeric mixture of 32a and 32b, along with 23% of the
recovered lactone 3. The trans-enone 32b was presum-
ably produced by epimerization of 32a due to the strongly
basic reaction conditions. Moreover, direct DBU treat-
ment of the diastereomeric mixture afforded the desired
enone 32b in a quantitative yield.
Although the alkylation of 3 with 28b was successful,
the long reaction time at -78 °C and the moderate yield
prompted us to investigate an alternative method for
coupling 3 and 28b. Thus, according to the Merck
procedure,32 a preliminary experiment was performed on
the lactone 339a as a model compound. Transamidation
of the lactone 33 under standard conditions (MeNH-
(OMe)‚HCl, iPrMgCl, THF, 0 °C), followed by the addition
of the resulting amide to the lithium anion 28b, provided
the hydroxy enone 34 in an excellent yield (eq 3).
Encouraged by these results, we attempted the same
reaction with the bicyclic lactone 3. Alkylation of 3 with
(28) For a recent review, see: Chinchilla, R.; Na´jera, C. Chem. Rev.
2000, 100, 1891.
(29) For the halogen-metal exchange reaction in the related
systems, see: (a) Richardson, S. K.; J eganathan, A.; Watt, D. S.
Tetrahedron Lett. 1987, 28, 2335. (b) Meyers, A. I.; Spohn, R. F. J .
Org. Chem. 1985, 50, 4872.
(30) (a) Zoller, T.; Uguen, D. Tetrahedron Lett. 1998, 39, 6719. (b)
Abarbri, M.; Parrain, J .-L.; Cintrat, J .-C.; Duchene, A. Synthesis. 1996,
82.
(32) Williams, J . M.; J obson, R. B.; Yasuda, N.; Marchesini, G.;
(31) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
Dolling, Ulf-H.; Grabowski, J . J . Tetrahedron Lett. 1995, 36, 5461.

4132 J . Org. Chem., Vol. 67, No. 12, 2002
Suh et al.
entropic effects might favor cyclization onto the desired
C15 hydroxy group, rather than the C7 hydroxy group.
As we anticipated, facile macrolactonization occurred
selectively at the C15 hydroxy group under the standard
Yamaguchi condition33 in the presence of the C7 hydroxy
group to provide the desired 13-membered macrolactone
36 in a 51% yield.34 The participation of the preferred
C15 hydroxy group in the macrolactonization is likely due
to the steric and geometric advantages. For the comple-
tion of the synthesis, stereoselective reduction of the C4
ketone remained. In previous studies on the reduction
of related brefeldin A systems, it has been reported that
NaBH4 or K-Selectride reduction of the advanced inter-
mediate 36 possessing the C7-hydroxyl group produces
mainly 4-epi brefeldin A (37),35 as outlined in eq 4.
However, the reduction of 36 with NaBH4 in MeOH at
-78 °C surprisingly furnished brefeldin A (1) as the sole
product. Moreover, the synthetic brefeldin A was identi-
cal in all aspects to authentic brefeldin A.36 Indepen-
dently, Hori and co-workers have also recently reported
the same result.6b
28b and then epimerization of the resulting cis-enone 32a
afforded the trans-enone 32b in an 81% overall yield from
3. It is notable that this facile alkylation process needs
only 3 h for its completion (Scheme 7).
Com p letion of th e Tota l Syn th esis of (+)-Br efel-
d in A. After successful coupling of the anion 28b with
the bicyclic lactone 3, the total synthesis of (+)-brefeldin
A, shown in Scheme 8, proceeded in a straightforward
fashion. Concurrent deprotection of the OBO ortho ester
and the C15 TBS group of the enone 32b with 1 N HCl
gave the initial trihydroxy ester intermediate, which was
directly subjected to hydrolysis (LiOH-H2O, THF/H2O)
to afford the seco acid 2 in an 85% yield.
Sch em e 7a
St u d ies on t h e R ed u ct ion of t h e C4 Ca r b on yl
Gr ou p . Thus, we investigated this interesting result in
a
Reagents and conditions: (a) MeNH(OMe)‚HCl, iPrMgCl,
THF, from -20 °C to room temperature; (b) 28a , t-BuLi, ether,
-78 °C, 30 min, then 35, from -78 °C to room temperature, 81%
from 3; (c) DBU, CH2Cl2, reflux, 99%.
more detail by the preparation of the intermediate 36
from the natural (+)-brefeldin A, followed by NaBH4
reduction. As outlined in Scheme 9, the natural (+)-
brefeldin A was converted to the known intermediate 38
by selective MEM protection of the C7 hydroxy group and
PDC oxidation of the C4 hydroxy group. The intermediate
38 was again deprotected by the reported procedure
(TiCl4, CH2Cl2, 0 °C),35a which consistently provided a
mixture of two inseparable isomers in the range from 1:2
to 1:5. Accordingly, the mixture was directly reduced with
NaBH4 in MeOH to afford a mixture of (+)-brefeldin A
(1) and the (Z)-isomer 40 of brefeldin A, which were
separated by flash column chromatography. The (Z)-
isomer 40 seems to be formed by way of the (Z)-isomer
39,37 which is produced during MEM deprotection of 38,
along with the (E)-isomer 36, by TiCl4 treatment. Obvi-
Sch em e 8a
(33) Inanaga, J .; Hirata, K.; Saeki, H.; Kastuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
(34) For the regioselective macrolactonization of diol acid, see: (a)
Hayward, M. M.; Roth, R. M.; Duffy, K. J .; Dalko, P. I.; Stevens, K. L.;
Guo, J .; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 192. (b) Parerson,
I.; Cowden, C. J .; Woodrow, M. D. Tetrahedron Lett. 1998, 39, 6037
(35) (a) Corey, E. J .; Wollenberg, R. H. Tetrahedron Lett. 1976, 4701.
(b) Bartlett, P. A.; Green, F. R. J . Am. Chem. Soc. 1978, 100, 4858.
(36) Authentic brefeldin A was purchased from Fluka Co.
(37) Photoinduced isomerizations of R,â-unsaturated carbonyl com-
pound have been reported. See: (a) Smith, A. B.; Lupo, A. T.; Ohba,
M.; Chen, K. J . Am. Chem. Soc. 1989, 111, 6648. (b) Ghosh, A. K.;
Wang, Y. J . Am. Chem. Soc. 2000, 122, 11027.
a
Reagents and conditions: (a) aq, 1 N HCl, H2O/THF (1/1), then
LiOH, 85%; (b) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, room
temperature, 2 h, then 4-DMAP, toluene, reflux, 24 h, 51%; (c)
NaBH4, -78 °C, 95%.
The selective macrolactonization of the diol acid 2 was
attempted in the hope that the conformational and

Total Synthesis of (+)-Brefeldin A
J . Org. Chem., Vol. 67, No. 12, 2002 4133
Sch em e 9a
filtered through a pad of Celite and washed with Et2O. The
filtrate was concentrated (<30 °C bath temperature) and dried
on a vacuum pump to give 27 g of crude ester as a colorless
oil, which was directly used for the next step: 1H NMR (CDCl3,
300 MHz) δ 4.08 (q, 2H, J ) 7.1 Hz), 3.74-3.86 (m, 1H), 2.24-
2.41 (m, 2H), 1.62-1.71 (m, 2H), 1.20 (t, 3H, J ) 7.1 Hz), 1.08
(d, 3H, J ) 6.0 Hz), 0.83 (s, 9H), 0.00 (s, 6H).
(ii) DIBAL Red u ction . To a solution of the above ester
(27.0 g, 0.104 mol) in CH2Cl2 (100 mL) at -78 °C was added
DIBAL (41.0 mL, 0.228 mol) dropwise over 30 min. After the
mixture was stirred for 1 h at -40 °C, the reaction was
quenched by slow addition of MeOH. A 15% aqueous Rochelle
solution was added, and the mixture was stirred at ambient
temperature for 2 h. After separation of the organic layers,
the aqueous phase was extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash
column chromatography (20% EtOAc/hexanes) to afford 22.1
g (98% for two steps) of alcohol 9 as a colorless oil: 1H NMR
(CDCl3, 300 MHz) δ 3.77-3.86 (m, 1H), 3.48-3.61 (m, 2H),
2.32 (bs, 1H), 1.51-1.61 (m, 2H), 1.08 (d, 3H, J ) 6.0 Hz),
0.83 (s, 9H), 0.00 (s, 6H); IR (neat) 3360 cm-1
.
(4S)-4-[ter t-Bu tyl(d im eth yl)silyl]oxyp en tyl 4-Meth yl-
ben zen esu lfon a te (10). To a solution of the alcohol 9 (22.0
g, 0.101 mol) and Et3N (15.0 mL, 0.151 mol) in CH2Cl2 (100
mL) at 0 °C were added p-toluenesulfonyl chloride (18.0 g,
0.096 mol) and DMAP (1.20 g, 10.1 mmol). After stirring for 3
h at ambient temperature, the mixture was diluted with CH2-
Cl2 and saturated aqueous NH4Cl. The mixture was extracted
with CH2Cl2, and the combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (5% EtOAc/hexanes) to afford 34.0 g (91%) of tosylate
10 as a clear and colorless oil: 1H NMR (CDCl3, 300 MHz) δ
7.76 (d, 2H, J ) 6.0 Hz), 7.32 (d, 2H, J ) 6.0 Hz), 4.01 (t, 2H,
J ) 6.3 Hz), 3.67-3.77 (m, 1H), 2.43 (s, 3H), 1.55-1.80 (m,
2H), 1.31-1.42 (m, 2H), 1.06 (d, 3H, J ) 6.0 Hz), 0.83 (s, 9H),
0.00 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 144.6, 133.2, 129.7,
127.8, 70.8, 67.6, 35.1, 25.7, 25.1, 23.6, 21.5, 17.9, -4.4, -4.8;
a
i
Reagents and conditions: (a) MEMCl, Pr2NEt, CH2Cl2; (b)
PDC, 4 Å, MS, CH2Cl2; (c) TiCl4, CH2Cl2, 0 °C; (d) NaBH4, MeOH,
-78 °C.
ously, the major product proved to be the (Z)-isomer 40
by careful analysis of the spectral data. Particularly, the
1H NMR spectrum shows an 11.8 Hz coupling constant
for the cis olefinic hydrogens of the (Z)-isomer 40.
Con clu sion
In conclusion, we have achieved the enantioselective
total synthesis of (+)-brefeldin A in 15 linear steps with
a 7.9% overall yield. The key features of this synthetic
route involve the following: (1) the highly stereoselective
construction of the hydroxycyclopentane skeleton of (+)-
brefeldin A via Pd(0)-catalyzed allylic cyclization; (2) the
efficient preparation of the γ-keto acrylate by the direct
introduction of the trans-acrylate moiety to the lactone
carbonyl, utilizing a novel vinylogous acyl anion equiva-
lent; (3) the ring-size selective macrolactonization of the
diol acid; and (4) the stereoselective reduction of the C4
ketone of an advanced brefeldin A intermediate. These
studies provide a timely contribution to the development
of a practical synthetic approach to a variety of brefeldin
A analogues. With this practical synthesis of (+)-brefeldin
A now in hand, the intensive exploration of the promising
biological properties of this macrolide will be extended.
IR (neat) 2928, 1540, 1255 cm-1
.
(6S)-6-(ter t-Bu tyld im eth ylsilyl)oxy-1-h ep tyn e (7). To a
solution of the tosylate 10 (9.5 g, 25.5 mmol) in DMSO (20
mL) at ambient temperature was added lithium acetylide
ethylenediamine (3.13 g, 30.6 mol). After the mixture was
stirred for 2 h, the reaction was quenched by a slow addition
of saturated aqueous NH4Cl. The reaction mixture was
extracted with Et2O, and the combined organic layers were
washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (5% EtOAc/hexanes) to afford 5.12 g (89%) of heptyne 7
as a colorless oil: [R]17D +14.2 (c 3.7, CH2Cl2) [lit.38 [R]20D +14.5
1
(c 7.0, CH2Cl2)]; H NMR (CDCl3, 300 MHz) δ 3.72-3.81 (m,
1H), 2.11-2.17 (m, 2H), 1.89 (t, 1H, J ) 2.4 Hz), 1.42-1.64
(m, 4H), 1.08 (d, 3H, J ) 6.0 Hz), 0.83 (s, 9H), 0.00 (s, 6H); 13
C
NMR (CDCl3, 75 MHz) δ 84.6, 68.2, 68.1, 38.6, 25.9, 24.7, 23.7,
18.4, 18.1, -4.4, -4.8; IR (neat) 2857, 2116 cm-1
.
(Z,8S)-8-[1-(ter t-Bu t yl)-1,1-d im et h ylsilyl]oxy-1-[(4S)-
2,2-d im eth yl-1,3-d ioxola n -4-yl]-3-n on en -2-on e (11): (i)
Alk yla tion of th e Wein r eb Am id e 6. To a solution of the
silyloxyheptyne 7 (1.29 g, 5.75 mmol) in THF (10 mL) at -78
°C was slowly added n-BuLi (1.5 M solution in n-hexane, 3.80
mL, 5.70 mmol). After stirring for 10 min at -78 °C and for
20 min at -20 °C, the solution was added dropwise via cannula
to a solution of 6 (0.970 g, 4.78 mmol) in THF (10 mL) at -78
°C. After the mixture was stirred for 1 h, the reaction was
quenched by an addition of saturated aqueous NH4Cl. The
reaction mixture was extracted with Et2O, and the combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash
column chromatography (10% EtOAc/hexanes) to afford 1.43
Exp er im en ta l Section
Gen er a l P r oced u r e. Unless noted otherwise, all starting
materials were obtained from commercial suppliers and used
without further purification. Air- and moisture-sensitive reac-
tions were performed under an argon atmosphere. Flash
column chromatography was performed using silica gel 60
(230-400 mesh) with indicated solvents. Thin-layer chroma-
tography was performed using 0.25 mm silica gel F254 plates.
Optical rotations were measured using sodium light (D line
589.3 nm)
(4S)-4-[ter t-Bu tyl(d im eth yl)silyl]oxy-1-p en ta n ol (9): (i)
Hyd r ogen a tion . To a solution of 8 (27 g, 0.105 mol) in EtOH
(50 mL) was added 10% Pd/C (1.2 g), and the mixture was
stirred under an H2 atmosphere using a balloon at ambient
temperature. After stirring for 5 h, the reaction mixture was
g (81%) of ynone as a colorless oil: [R]17 +15.5 (c 5.35, CH2-
D
Cl2); 1H NMR (CDCl3, 300 MHz) δ 4.46-4.54 (m, 1H), 4.13
(38) Drian, C. L.; Greene, A. E. J . Am. Chem. Soc. 1982, 104, 5473.

4134 J . Org. Chem., Vol. 67, No. 12, 2002
Suh et al.
(dd, 1H, J ) 8.2, 5.8 Hz), 3.72-3.82 (m, 1H), 3.55 (dd, 1H, J
) 8.2, 6.3 Hz), 2.96 (dd, 1H, J ) 16.8, 6.3 Hz), 2.69 (dd, 1H, J
) 16.8, 7.1 Hz), 2.34 (t, 2H, J ) 6.8 Hz), 1.42-2.36 (m, 4H),
1.37 (s, 3H), 1.31 (s, 3H), 1.09 (d, 3H, J ) 6.0 Hz), 0.85 (s,
9H), 0.00 (s, 3H), -0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
184.6, 109.0, 95.2, 80.8, 71.4, 69.1, 67.8, 49.8, 38.5, 26.8, 25.8,
25.4, 23.8, 23.7, 19.0, 18.0, -4.4, -4.8; IR (neat) 2930, 2212,
1672 cm-1; HRMS (CI) calcd for C20H37O4Si1 (M+ + H)
369.2461, found 369.2458.
(neat) 3436, 2929 cm-1; HRMS (CI) calcd for C25H43O5Si1 (M+
+ H) 451.2880, found 451.2878.
(2S,4S,6R)-6-((Z,6S)-6-[1-(ter t-Bu tyl)-1,1-d im eth ylsilyl]-
oxy-1-h ep t en yl)-2-(4-m et h oxyp h en yl)-1,3-d ioxa n -4-yl]-
m eth yl-4-m eth yl-ben zen esu lfon a te (14). To a solution of
the alcohol 13 (450 mg, 0.998 mmol), Et3N (280 µL, 2.01 mmol),
and 4-DMAP (13.0 mg, 0.106 mmol) in CH2Cl2 (10 mL) at 0
°C was added p-toluenesulfonyl chloride (229 mg, 1.20 mmol).
The mixture was stirred for 30 min at 0 °C and warmed to
ambient temperature. After stirring for an additional 5 h, the
reaction mixture was extracted with EtOAc and the combined
organic layers were washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by flash column chromatography (15% EtOAc/hexanes) to
(ii) P a r t ia l Hyd r ogen a t ion . To a solution of the above
ynone (590 mg, 1.60 mmol) in MeOH (20 mL) was added 5%
Pd on CaCO3 (47.6 mg) and quinoline (120 µL, 1.02 mmol),
and the reaction mixture was stirred under an H2 atmosphere
using a balloon. After stirring for 2 h, the reaction mixture
was filtered through a pad of Celite, which was then rinsed
with Et2O. The filtrate was concentrated in vacuo, and the
resulting residue was purified by flash column chromatogra-
phy (10% EtOAc/hexanes) to afford 563 mg (95%) of enone 11
afford 589 mg (99%) of tosylate 14 as a colorless oil: [R]13
D
-18.3 (c 6.50, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.74 (dd,
2H, J ) 6.6, 1.7 Hz), 7.21-7.31 (m, 4H), 6.80 (d, 2H, J ) 6.8
Hz), 5.44 (s, 1H), 5.35-5.51 (m, 2H), 4.51-4.58 (m, 1H), 3.98-
4.11 (m, 3H), 3.75 (s, 3H), 3.69-3.75 (m, 1H), 2.38 (s, 3H),
2.01-2.08 (m, 2H), 1.31-1.54 (m, 6H), 1.07 (d, 3H, J ) 6.0
Hz), 0.85 (s, 9H), 0.00 (s, 3H), -0.01 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 159.8, 144.7, 133.2, 132.7, 130.4, 129.7, 128.8, 127.9,
127.4, 113.3, 100.4, 73.5, 72.5, 71.4, 68.3, 55.2, 39.2, 32.7, 27.9,
as a colorless oil: [R]16 +16.2 (c 6.80, CH2Cl2); 1H NMR
D
(CDCl3, 300 MHz) δ 6.11 (d, 1H, J ) 11.2 Hz), 6.05 (dd, 1H, J
) 11.2, 6.0 Hz), 4.40-4.48 (m, 1H), 4.17 (dd, 1H, J ) 8.2, 5.8
Hz), 3.71-3.77 (m, 1H), 3.52 (dd, 1H, J ) 8.2, 6.8 Hz), 2.92
(dd, 1H, J ) 16.8, 5.6 Hz), 2.59 (dd, 1H, J ) 16.8, 7.6 Hz),
2.54-2.59 (m, 2H), 1.34-1.54 (m, 4H), 1.37 (s, 3H), 1.32 (s,
3H), 1.07 (d, 3H, J ) 6.0 Hz), 0.84 (s, 9H), 0.00 (s, 6H); 13C
NMR (CDCl3, 75 MHz) δ 198.4, 149.6, 126.3, 108.5, 71.7, 69.4,
68.1, 48.2, 39.1, 29.3, 26.7, 25.8, 25.3, 25.1, 23.7, 18.0, -4.5,
-4.9; IR (neat) 2930, 1693, 1616 cm-1; HRMS (CI) calcd for
25.8, 25.6, 23.8, 21.5, 18.0, -4.4, -4.8; IR (neat) 2929 cm-1
;
LRMS (CI) m/z 603 (M+ - H).
Meth yl 3-[(2R,4S,6R)-6-((Z,6S)-6-[1-(ter t-Bu tyl)-1,1-d i-
m eth ylsilyl]oxy-1-h ep ten yl)-2-(4-m eth oxyp h en yl)-1,3-d i-
oxa n -4-yl]-2-(p h en ylsu lfon yl)p r op a n oa te (15). To a sus-
pension of NaH (60% in mineral oil, 87.6 mg, 2.19 mmol) in
DMF (3 mL) at 0 °C was added dropwise a solution of methyl
benzenesulfonyl acetate (469 mg, 2.19 mmol) in DMF (8 mL).
After stirring for 30 min, a solution of the tosylate 14 (530
mg, 0.876 mmol) in DMF (10 mL) was added. The solution
was warmed to 100 °C and stirred for 7 h. The reaction was
quenched by an addition of saturated aqueous NH4Cl, and the
reaction mixture was diluted with EtOAc. The reaction
mixture was extracted with EtOAc and the combined organic
layers were washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash
column chromatography (20% EtOAc/hexanes) to afford 408
mg (72%) of 15 as a colorless oil: 1H NMR (CDCl3, 300 MHz)
δ 7.85 (d, 2H, J ) 7.8 Hz), 7.64-7.66 (m, 1H), 7.54 (dt, 2H, J
) 7.8, 1.5 Hz), 7.26-7.31 (m, 2H), 6.78-6.85 (m, 2H), 5.40,
5.42 (s, 1H), 5.37-5.54 (m, 2H), 4.52-4.61 (m, 1H), 4.33-4.38,
4.01-4.15 (m, 1H), 3.96-4.03, 3.78-3.83 (m, 1H), 3.77, 3.75
(s, 3H), 3.69-3.75 (m, 1H), 3.61, 3.37 (s, 3H), 2.17-2.39 (m,
2H), 2.00-2.13 (m, 2H), 1.21-1.55 (m, 6H), 1.10, 1.08 (d, 3H,
J ) 6.0 Hz), 0.86, 0.85 (s, 9H), 0.02 (s, 6H); IR (neat) 1746,
1615 cm-1; LRMS (EI) m/z 589 (M+ - tC4H9).
(1R,2Z,7S)-7-[1-(ter t-Bu tyl)-1,1-dim eth ylsilyl]oxy-1-[(2S)-
5-oxo-4-(p h en ylsu lfon yl)tetr a h yd r o-2-fu r a n yl]m eth yl-2-
octen yl 4-Meth oxyben zoa te (5): (i) Oxid a tive Clea va ge
of th e P MB Gr ou p . To a solution of 15 (242 mg, 0.374 mmol)
in CH2Cl2/water (18:1, 5 mL) at ambient temperature was
added DDQ (262 mg, 1.15 mmol). The reaction mixture was
stirred for 2 h and additional DDQ (281 mg, 1.24 mmol) was
added. After stirring for 24 h, the reaction mixture was diluted
with CH2Cl2, filtered through silica gel, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (40% EtOAc/hexanes) to afford 240 mg of a mixture of
16a and 16b (10:1) as a colorless oil. Major isomer 16b: 1H
NMR (CDCl3, 300 MHz) δ 7.80-7.90 (m, 4H), 7.62-7.66 (m,
1H), 7.52-7.56 (m, 2H), 6.64-6.90 (m, 2H), 5.29-5.45 (m, 2H),
5.11-5.19 (m, 1H), 4.52-4.58 (m, 1H), 4.05-4.14 (m, 1H), 3.84,
3.82 (s, 3H), 3.64-3.71 (m, 1H), 3.51, 3.23 (s, 3H), 2.35-2.60
(m, 2H), 1.74-2.21 (m, 4H), 1.19-1.47 (m, 4H), 1.05, 1.04 (d,
3H, J ) 6.0 Hz), 0.85, 0.84 (s, 9H), 0.00 (s, 6H)
C
20H39O4Si1 (M+ + H) 371.2618, found 371.2624.
(2R,3Z,8S)-8-[1-(ter t-Bu tyl)-1,1-dim eth ylsilyl]oxy-1-[(4S)-
2,2-d im eth yl-1,3-d ioxola n -4-yl]-3-n on en -2-ol (12). To a
solution of the enone 11 (200 mg, 0.54 mmol) in Et2O (10 mL)
at -40 °C was added LiI (723 mg, 5.40 mmol). After the
mixture was stirred for 10 min at -40 °C, LAH (100 mg, 2.64
mmol) was added in one portion at -78 °C. The reaction
mixture was stirred at -78 °C for 30 min before the reaction
was quenched by the addition of MeOH. A 15% aqueous
Rochelle solution and EtOAc were added, and the mixture was
stirred at ambient temperature for 1 h. Separation of the
layers was followed by extraction of the aqueous phase with
EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash chromatography (20% EtOAc/hexanes) to
afford 198 mg (99%) of allylic alcohol 12 as a colorless oil:
[R]13 +13.7 (c 9.75, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ
D
5.32-5.48 (m, 2H), 4.63 (dt, 1H, J ) 8.0, 4.4 Hz), 4.14-4.23
(m, 1H), 4.04 (dt, 1H, J ) 8.0, 6.0 Hz), 3.68-3.76 (m, 1H), 3.51
(t, 1H, J ) 7.5 Hz), 2.63 (bs, 1H), 2.00-2.07 (m, 2H), 1.28-
1.84 (m, 6H), 1.28 (s, 3H), 1.22 (s, 3H), 1.07 (d, 3H, J ) 6.0
Hz), 0.85 (s, 9H), 0.00 (s, 3H), -0.01 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 132.0, 131.7, 109.0, 74.5, 69.5, 68.3, 66.3, 40.7, 39.2,
27.6, 26.8, 25.8, 25.7, 23.7, 18.0, -4.5, -4.8; IR (neat) 3418,
2930 cm-1; HRMS (CI) calcd for C20H41O4Si1 (M+ + H)
373.2774, found 373.2764.
(2S,4S,6R)-6-((Z,6S)-6-[1-(ter t-Bu tyl)-1,1-d im eth ylsilyl]-
oxy-1-h ep t en yl)-2-(4-m et h oxyp h en yl)-1,3-d ioxa n -4-yl]-
m eth a n ol (13). To a solution of the allylic alcohol 12 (76 mg,
0.20 mmol) and CSA (4.7 mg, 0.02 mmol) in CH2Cl2 (3 mL) at
ambient temperature was added p-anisaldehyde dimethylac-
etal (104 µL, 0.61 mmol). After the mixture was stirred for 4
h, the reaction was quenched by an addition of saturated
aqueous NaHCO3 and the mixture extracted with CH2Cl2. The
combined organic layers were washed with H2O and brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (20% EtOAc/hex-
anes) to afford 77 mg (84%) of benzylidene alcohol 13 as a
1
colorless oil: [R]15 -40.5 (c 7.50, CH2Cl2); H NMR (CDCl3,
(ii) La cton iza tion of Hyd r oxy Ester s 16a a n d 16b. To
a solution of a mixture (240 mg) of 16a and 16b in CH3CN (5
mL) at ambient temperature was added DBU (65 µL, 0.43
mmol). After stirring for 18 h, the reaction mixture was
concentrated in vacuo. The residue was purified by flash
column chromatography (50% EtOAc/hexanes) to afford 152
mg (71% for two steps) of lactone 5 as a colorless oil: 1H NMR
(CDCl3, 300 MHz) δ 7.88-7.96 (m, 4H), 7.65-7.68 (m, 1H),
D
300 MHz) δ 7.39 (d, 2H, J ) 6.8 Hz), 6.84 (d, 2H, J ) 6.8 Hz),
5.54 (s, 1H), 5.40-5.52 (m, 2H), 4.58-4.65 (m, 1H), 3.95-4.01
(m, 1H), 3.75 (s, 3H), 3.61-3.75 (m, 3H), 2.03-2.10 (m, 2H),
1.32-1.67 (m, 6H), 1.07 (d, 3H, J ) 6.0 Hz), 0.84 (s, 9H), 0.00
(s, 3H), -0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 159.9,
132.9, 130.9, 129.3, 127.5, 113.5, 100.6, 76.9, 72.8, 68.4, 65.4,
55.1, 39.2, 32.5, 27.9, 25.8, 25.7, 23.8, 18.0, -4.5, -4.8; IR

Total Synthesis of (+)-Brefeldin A
J . Org. Chem., Vol. 67, No. 12, 2002 4135
7.53-7.59 (m, 2H), 6.87-6.91 (m, 2H), 5.85-5.92 (m, 1H),
5.58-5.69 (m, 1H), 5.38-5.45 (m, 1H), 4.70-4.77, 4.49-4.54
(m, 1H), 4.14-4.20, 4.00-4.04 (m, 1H), 3.83 (s, 3H), 3.70-
3.77 (m, 1H), 1.85-3.19 (m, 5H), 1.32-1.45 (m, 5H), 1.08, 1.05
(d, 3H, J ) 6.0 Hz), 0.83 (s, 9H), 0.00 (s, 6H); IR (neat) 2929,
1779, 1714 cm-1; LRMS (EI) 573 (M+ - tC4H9).
(EI) m/z 282 (M+); HRMS (EI) calcd for C8H11O3I (M+)
281.9753, found 281.9760.
1-[(E)-2-Iodoeth en yl]-4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]-
octa n e (28a ). To a solution of the ester 30 (550 mg, 2.0 mmol)
in CH2Cl2 (5 mL) at -15 °C was added boron trifluoride
etherate (60 µL, 0.50 mmol). After the mixture was stirred for
24 h at the same temperature, the reaction was quenched by
an addition of triethylamine (60 µL, 0.60 mmol). The reaction
mixture was diluted with Et2O, filtered through a pad of Celite,
and concentrated in vacuo. The residue was purified by flash
column chromatography (20% EtOAc/hexanes with 2% Et3N)
to afford 480 mg (87%) of OBO ortho ester 28a as a white
5-((E,6S)-6-[1-(ter t-Bu tyl)-1,1-d im eth ylsilyl]oxy-1-h ep -
t en yl)-4-(p h en ylsu lfon yl)-2-oxa b icyclo[2.2.1]h ep t a n -3-
on e (18). To a solution of the allylic benzoate 5 (70 mg, 0.11
mmol) and DBU (26 µL, 0.17 mmol) in THF (5 mL) heated at
reflux was added a solution of Pd(PPh3)4 (6.4 mg, 5.5 µmol) in
THF (1 mL). After stirring for 3 h, the reaction mixture was
cooled to ambient temperature and concentrated in vacuo. The
residue was purified by flash column chromatography (25%
EtOAc/hexanes) to afford 46.7 mg (88%) of bicyclic lactone 18
1
solid: mp 97 °C; H NMR (CDCl3, 300 MHz) δ 6.81 (d, 1H, J
) 14.6 Hz), 6.43 (d, 1H, J ) 14.6 Hz), 3.89 (s, 6H), 0.76 (s,
3H); 13C NMR (CDCl3, 75M Hz) δ 140.1, 106.5, 84.5, 72.9, 30.5,
14.4; IR (neat) 2936, 2874, 1625, 1469, 1396, 1348, 1315, 1176,
1046, 996, 883, 772, 656 cm-1; LRMS (EI) m/z 282 (M+); HRMS
(EI) calcd for C8H11O3I (M+) 281.9753, found 281.9759.
Sta n d a r d P r oced u r e for a n Ad d ition of th e tr a n s-
Vin yl An ion 28b to a Ca r bon yl Com p ou n d : (E)-3-(4-
Meth yl-2,6,7-tr ioxa bicyclo[2.2.2]oct-1-yl)-1-p h en yl-2-p r o-
p en -1-ol (31a ). To a solution of t-BuLi (1.7 M solution in
pentane, 0.63 mL, 1.1 mmol) at -78 °C was added a solution
of the iodovinyl OBO ortho ester 28a (150 mg, 0.53 mmol) in
anhydrous ether (2 mL). After the mixture was stirred for 30
min at the same temperature, a solution of benzaldehyde (28
mg, 0.26 mmol) in anhydrous ether (1 mL) was added dropwise
using a cannula. The reaction mixture was warmed to room
temperature and stirred for 3 h. The reaction was quenched
with water, and then the mixture was diluted with Et2O. The
reaction mixture was extracted with Et2O, and the combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash
column chromatography (30% EtOAc/hexanes with 1% (v/v)
triethylamine) to afford 73 mg (81%) of 31a as a white solid:
1H NMR (400 MHz, CD3OD) δ 7.25-7.35 (m, 5H), 6.17 (dd,
1H, J ) 15.6, 5.8 Hz), 5.65 (dd, 1H, J ) 15.6, 1.4 Hz), 3.93 (s,
6H), 0.81 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 142.7, 136.4,
127.9, 127.1, 126.1, 125.0, 106.0, 72.9, 72.4, 29.9, 12.9; IR (neat)
3437 cm-1; LRMS (EI) m/z 262 (M+), 233, 161; HRMS (EI) calcd
for C15H18O4 262.1205, found 262.1205.
as a colorless oil: [R]11 -35.2 (c 1.45, CH2Cl2); 1H NMR
D
(CDCl3, 300 MHz) δ 8.04 (d, 2H, J ) 7.2 Hz), 7.61 (t, 1H, J )
7.2 Hz), 7.50 (t, 2H, J ) 7.2 Hz), 5.45 (dt, 1H, J ) 15.3, 6.6
Hz), 5.01 (dd, 1H, J ) 15.3, 9.0 Hz), 4.81 (bs, 1H), 3.64-3.74
(m, 1H), 3.40-3.53 (m, 1H), 2.54 (dt, 1H, J ) 10.2, 2.7 Hz),
2.42 (ddd, 1H, J ) 13.4, 10.7, 2.0 Hz), 2.27 (d, 1H, J ) 10.2
Hz), 1.71-1.82 (m, 3H), 1.15-1.39 (m, 4H), 1.05 (d, 3H, J )
6.0 Hz), 0.85 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3, 75 MHz)
δ 167.8, 136.9, 135.4, 130.5, 128.7, 126.0, 77.5, 74.9, 68.4, 43.7,
41.4, 39.1, 38.2, 32.2, 25.9, 24.8, 23.7, 18.2, -4.4, -4.7; IR
(neat) 1788 cm-1; HRMS (EI) calcd for C21H29O5S1Si1 (M+
tC4H9) 421.1505, found 421.1505.
-
5-((E,6S)-6-[1-(ter t-Bu tyl)-1,1-d im eth ylsilyl]oxy-1-h ep -
ten yl)-2-oxa bicyclo[2.2.1]h ep ta n -3-on e (3). To a solution
of the bicyclic lactone 18 (10 mg, 0.021 mmol) and boric acid
(13 mg, 0.21 mmol) in MeOH (1 mL) was added 6% Na/Hg (48
mg, 0.13 mmol) in one portion. After stirring for 1 h, the
reaction was quenched by an addition of saturated aqueous
NH4Cl. The reaction mixture was extracted with EtOAc, and
the combined organic layers were washed with saturated
aqueous NaHCO3, H2O, and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash
column chromatography (25% EtOAc/hexanes) to afford 6.1 mg
(87%) of lactone 3 as a colorless oil: [R]11 -19.4 (c 0.22, CH2-
D
1
Cl2); H NMR (CDCl3, 300 MHz) δ 5.52 (dt, 1H, J ) 15.0, 6.6
Hz), 5.25 (dd, 1H, J ) 15.0, 8.5 Hz), 4.82 (bs, 1H), 3.69-3.75
(m, 1H), 2.83-2.92 (m, 1H), 2.78 (d, 1H, J ) 2.4 Hz), 2.19 (ddd,
1H, J ) 10.5, 4.0, 2.4 Hz), 2.09 (ddd, 1H, J ) 13.4, 10.2, 2.0
Hz), 1.90-1.98 (m, 2H), 1.68 (d, 1H, J ) 10.5 Hz), 1.59 (ddd,
1H, J ) 13.4, 4.8, 2.4 Hz), 1.21-1.41 (m, 4H), 1.06 (d, 3H, J )
6.0 Hz), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3, 75 MHz)
δ 176.3, 133.2, 129.3, 80.6, 68.4, 48.3, 40.8, 39.6, 39.1, 35.1,
(E)-1-(4-Meth oxyph en yl)-3-(4-m eth yl-2,6,7-tr ioxabicyclo-
[2.2.2]oct-1-yl)-2-p r op en -1-ol (31b): 1H NMR (300 MHz,
CD3OD) δ 7.23 (d, 2H, J ) 9.5 Hz), 6.86 (d, 2H, J ) 9.5 Hz),
6.14 (dd, 1H, J ) 15.6, 5.9 Hz), 5.61 (d, 1H, J ) 15.6 Hz), 5.07
(d, 1H, J ) 5.9 Hz), 4.85 (d, 1H, J ) 3.0 Hz), 3.90 (s, 6H), 3.75
(s, 3H), 0.77 (d, 3H, J ) 3.0 Hz); 13C NMR (75 MHz, CD3OD)
δ 159.2, 136.6, 134.7, 127.5, 124.8, 113.4, 106.0, 72.5, 72.4, 54.3,
29.9, 12.9; IR (neat) 3440 cm-1; LRMS (EI) m/z 292 (M+);
HRMS (EI) calcd for C16H20O5 292.1311, found 292.1311.
(E)-4-Meth yl-1-(4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]oct-
1-yl)-1-p en ten -3-ol (31c). Compound 31c was decomposed to
the corresponding diol ester in CDCl3: 1H NMR (300 MHz,
CDCl3) δ 7.00 (dd, 1H, J ) 15.6, 4.9 Hz), 6.07 (dd, 1H, J )
15.6, 1.7 Hz), 4.24 (s, 2H), 3.53 (m, 5H), 2.25 (bs, 3H), 1.80
(m, 1H), 0.93 (d, 3H, J ) 6.8 Hz), 0.92 (d, 3H, J ) 6.8 Hz),
0.84 (s, 3H)
(E)-4-(4-Meth yl-2,6,7-tr ioxabicyclo[2.2.2]oct-1-yl)-2-ph e-
n ylbu t-3-en -2-ol (31d ): 1H NMR (300 MHz, CD3OD) δ 7.40-
7.44 (m, 2H), 7.17-7.31 (m, 3H), 6.28 (dd, 1H, J ) 15.8, 1.0
Hz), 5.57 (d, 1H, J ) 15.6 Hz), 3.91 (s, 6H), 3.29-3.31 (m, 1H),
1.56 (s, 3H), 0.79 (d, 3H, J ) 1.2 Hz); 13C NMR (75 MHz, CD3-
OD) δ 146.4, 140.8, 127.6, 126.4, 125.0, 122.8, 106.2, 73.0, 72.4,
29.9, 28.2, 12.9; IR (neat) 3455 cm-1; HRMS (EI) calcd for
C16H20O4 276.1362, found 276.1369.
(E)-1-[2-(4-Met h yl-2,6,7-t r ioxa b icyclo[2.2.2]oct -1-yl)-
vin yl]-cycloh ep ta n ol (31e): 1H NMR (400 MHz, CD3OD) δ
6.16 (d, 1H, J ) 15.7 Hz), 5.54 (d, 1H, J ) 15.7 Hz), 3.95 (s,
6H), 1.67-1.39 (m, 12H), 0.83 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 142.1, 121.3, 106.3, 74.2, 72.4, 40.4, 29.8, 29.3, 21.7,
12.9; IR (neat) 3463 cm-1; LRMS (EI) m/z 268 (M+); HRMS
(EI) calcd for C15H24O4 268.1675, found 268.1680.
(E)-7-Hydr oxy-1-(4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]oct-
1-yl)-h ep t-1-en -3-on e (31f): 1H NMR (300 MHz, CD3OD) δ
6.44 (d, 1H, J ) 15.8 Hz), 6.40 (d, 1H, J ) 15.8 Hz), 3.97 (s,
32.4, 25.9, 25.4, 23.8, 18.1, -4.4, -4.7; IR (neat) 1789 cm-1
;
HRMS (EI) calcd for C15H25O3Si1 (M+ - tC4H9) 281.1573, found
281.1573.
(Z)-3-Iod o-p r op en oic Acid (29). To a solution of the
propiolic acid 22 (6.2 g, 88 mmol) in water (13 mL) was added
57% HI (17.6 mL). The mixture was stirred for 24 h at 85 °C
and then cooled to ambient temperature. The reaction mixture
was diluted with 1 N aqueous HCl and Et2O and extracted
with Et2O. The combined organic layers were washed with 10%
sodium thiosulfate and brine, dried over MgSO4, and concen-
trated in vacuo. Recrystallization of the residue from hot
hexanes afforded 15.8 g (91%) of acid 29 as a white solid. The
acid 29 thus obtained displayed NMR spectra and mp identical
to literature data:30 mp 65-67 °C; 1H NMR (CDCl3, 300 MHz)
δ 7.64 (d, 1H, J ) 9.0 Hz), 6.96 (d, 1H, J ) 9.0 Hz).
(3-Meth yl-3-oxeta n yl)m eth yl (Z)-3-Iod o-2-p r op en oa te
(30). To a solution of the acid 29 (5.2 g, 26 mmol) in CH2Cl2
(30 mL) at ambient temperature was added oxetane 31 (2.8 g,
27 mmol), DMAP (1.0 g, 8.0 mmol), and then DCC (5.8 g, 28
mmol). After stirring for 1 h, the reaction mixture was diluted
with n-hexane, filtered through a pad of Celite, and concen-
trated in vacuo. The residue was purified by flash column
chromatography (33% EtOAc/hexanes) to afford 6.9 g (95%)
of ester 30 as a white solid: mp 144 °C; 1H NMR (CDCl3, 300
MHz) δ 7.88 (d, 1H, J ) 14.9 Hz), 6.86 (d, 1H, J ) 14.9 Hz),
4.46 (d, 2H, J ) 13.9 Hz), 4.34 (d, 2H, J ) 6.1 Hz), 4.17 (s,
2H), 1.28 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 164.3, 129.5,
95.4, 79.3, 68.8, 38.8, 21.1; IR (neat) 3439, 1725 cm-1; LRMS

4136 J . Org. Chem., Vol. 67, No. 12, 2002
Suh et al.
6H), 3.54 (t, 2H, J ) 6.3 Hz), 2.65 (t, 2H, J ) 6.8 Hz), 1.69-
1.81 (m, 4H), 0.81 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 203.5,
140.0, 133.0, 107.8, 74.8, 63.4, 41.9, 33.7, 32.4, 22.1, 15.0; IR
(neat) 3443, 1682, 1652 cm-1; LRMS (EI) m/z 56 (M+); HRMS
(EI) calcd for C13H20O5 256.1311, found 256.1323.
The residue was purified by flash column chromatography
(30% EtOAc/hexanes with 1% (v/v) triethylamine) to afford 28
mg (99%) of trans-enone 32b as a colorless oil.
P r ep a r a tion of th e Dih yd r oxy Acid 2. To a solution of
32b (15 mg, 0.03 mmol) in a mixture of THF and water (1:1,
1 mL) was added 1 N HCl (0.1 mL). The reaction mixture was
stirred for 2 h, and lithium hydroxide monohydrate (8 mg, 0.19
mmol) was added. After stirring for an additional 2 h, the
reaction mixture was acidified with 1 N HCl (pH < 3) and
extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in
vacuo. Purification via flash column chromatography of the
residue with a mixture of benzene, THF, and formic acid (15:
5:1) afforded 7.5 mg (85%) of dihydroxy acid 2 as a colorless
oil: [R]11D -31.3 (c 0.15, CH2Cl2); 1H NMR (CD3OD, 500 MHz)
δ 7.04 (d, 1H, J ) 15.9 Hz), 6.62 (d, 1H, J ) 15.9 Hz), 5.49
(dd, 1H, J ) 15.2, 8.4 Hz), 5.40 (dt, 1H, J ) 15.2, 6.4 Hz), 4.26
(m, 1H), 3.68 (m, 1H), 3.27 (q, 1H, J ) 8.8 Hz), 2.64 (quintet,
1H, J ) 8.6 Hz), 2.22 (m, 1H), 1.98-2.06 (m, 3H), 1.85 (m,
1H), 1.36-1.51 (m, 6H), 1.12 (d, 3H, J ) 6.2 Hz); 13C NMR
(CDCl3, 75 MHz) 201.7, 167.1, 139.2, 133.0, 131.4, 130.8, 71.5,
67.0, 53.9, 48.4, 45.2, 42.2, 38.2, 37.9, 32.0, 25.3, 22.0; IR (KBr)
3418, 1696 cm-1; LRMS (EI) m/z 278 (M+ - H2O).
(E)-1-[(1R,2S,4R)-4-Hyd r oxy-2-vin ylcyclop en t yl]-3-(4-
m e t h yl-2,6,7-t r ioxa b icyclo[2.2.2]oct -1-yl)-2-p r op e n -1-
on e (31g): 1H NMR (300 MHz, CD3OD) δ 6.57 (d, 1H, J )
15.9 Hz), 6.49 (d, 1H, J ) 15.9 Hz), 5.76 (ddd, 1H, J ) 17.3,
10.2, 7.8 Hz), 5.02 (d, 1H, J ) 15.6 Hz), 4.98 (d, 1H, J ) 7.6
Hz), 4.31 (bs, 1H), 3.96 (s, 6H), 3.03 (m, 2H), 2.65 (d, 1H, J )
6.8 Hz), 2.15-1.84 (m, 3H), 1.61 (m, 1H), 0.83 (s, 3H).
(E)-1-[(4S)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-4-(4-m eth yl-
2,6,7-tr ioxa bicyclo[2.2.2]oct-1-yl)-3-bu ten -2-on e (31h ): 1H
NMR (300 MHz, CDCl3) δ 6.42 (s, 2H), 4.42 (m, 1H), 4.12 (dd,
1H, J ) 8.3, 6.6 Hz), 3.92 (s, 6H), 3.46 (dd, 1H, J ) 8.3, 6.6
Hz), 3.03 (dd, 1H, J ) 17.3, 8.0 Hz), 2.65 (dd, 1H, J ) 17.3,
8.0 Hz), 1.03 (s, 3H), 0.80 (s, 3H).
P r ep a r a tion of th e En on e 32b: (i) Alk yla tion of th e
La cton e 3. To a solution of t-BuLi (1.7 M solution in pentane,
700 µL, 1.18 mmol) in Et2O (1 mL) at -78 °C was added a
solution of the iodovinyl OBO ortho ester 28a (167 mg, 0.59
mmol) in Et2O (1 mL). After the mixture was stirred for 30
min at the same temperature, a solution of the bicyclic lactone
3 (40 mg, 0.12 mmol) in Et2O (1 mL) was added dropwise. The
mixture was stirred for 12 h at -78 °C, and the reaction was
quenched with water. The reaction mixture was extracted with
Et2O, and the combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (30%
EtOAc/hexanes with 1% (v/v) triethylamine) to afford 30 mg
(51%) of enone 32 as a colorless oil. Careful analysis of 1H NMR
spectrum revealed a 3:1 32a :32b diastereomeric mixture.
(ii) Ep im er iza tion of th e Dia ster eom er ic Mixtu r e of
32a a n d 32b. To a solution of the above mixture (30 mg, 0.061
mmol) in CH2Cl2 (2 mL) was added DBU (5 mg, 0.03 mmol).
After heating at reflux for 2 h, the reaction mixture was cooled
and concentrated in vacuo. The residue was purified by flash
column chromatography (30% EtOAc/hexanes with 1% (v/v)
triethylamine) to afford 30 mg (99%) of trans-enone 32b as a
P r ep a r a tion of th e 4-Oxo-br efeld in 36. To a solution of
the dihydroxy acid 2 (5.0 mg, 0.017 mmol) in THF (0.5 mL)
was added triethylamine (12 µL, 0.080 mmol) and trichlo-
robenzoyl chloride (3.2 µL, 0.020 mmol). The reaction mixture
was stirred for 2 h and diluted with anhydrous toluene (10
mL). The toluene solution was added dropwise (3 mL/h) to a
toluene solution (2 mL) of 4-DMAP (12 mg, 0.10 mmol) heated
at reflux. After continued heating for 24 h, the reaction
mixture was diluted with EtOAc, washed with aqueous HCl
and 5% NaHCO3, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (25% EtOAc/hexanes) to afford 2.3 mg (51%) of macro-
lactone 36 as a colorless oil: [R]25 -39.3 (c 0.35, CH2Cl2); 1H
D
NMR (CDCl3, 300 MHz) δ 7.71 (d, 1H, J ) 15.8 Hz), 6.38 (d,
1H, J ) 15.8 Hz), 5.79 (ddd, 1H, J ) 14.9, 10.7, 4.1 Hz), 5.49
(dd, 1H, J ) 14.9, 10.7 Hz), 4.59 (m, 1H), 4.26 (bs, 1H), 2.92
(dd, 1H, J ) 18.4, 9.0 Hz), 2.54 (m, 1H), 1.72-2.25 (m, 8H),
1.56 (m, 2H), 1.24 (d, 3H, J ) 9.0 Hz), 1.18 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 200.6, 166.4, 140.2, 135.9, 128.3, 73.7, 72.2,
56.2, 45.4, 42.6, 35.6, 34.2, 32.2, 25.6, 20.2; IR (neat) 3733,
3647, 3441, 1716, 1697 cm-1; LRMS (EI) m/z 278 (M+); HRMS
(EI) calcd for C16H22O4 278.1518, found 278.1515.
colorless oil: [R]11 -29.0 (c 0.14, CH3OH); 1H NMR (CD3OD,
D
300 MHz) δ 6.51 (dd, 1H, J ) 15.8, 1.2 Hz), 6.43 (dd, 1H, J )
15.8, 1.2 Hz), 5.36 (m, 2H), 4.33 (bs, 1H), 3.93 (s, 6H), 3.71
(m, 1H), 3.14 (q, 1H, J ) 8.3 Hz), 2.71 (m, 1H), 2.20 (ddd, 1H,
J ) 13.9, 9.0, 6.1 Hz), 1.83-2.03 (m, 4H), 1.21-1.49 (m, 4H),
1.06 (dd, 3H, J ) 6.1, 1.0 Hz), 0.84 (s, 9H), 0.80 (s, 3H), 0.00
(s, 6H); 13C NMR (CDCl3, 100 MHz) δ 201.3, 137.5, 132.7,
131.3, 130.9, 105.8, 72.9, 72.8, 68.5, 53.7, 44.3, 42.4, 39.2, 39.1,
32.3, 30.6, 25.9, 25.4, 23.7, 18.1, 14.4, -4.5, -4.7; IR (neat)
3441, 1651 cm-1; HRMS (EI) calcd for C27H46O6Si1 494.3064,
found 494.3064.
(+)-Br efeld in A (1). To a solution of 36 (2.3 mg, 0.008
mmol) in MeOH (0.5 mL) at -78 °C was added sodium
borohydride (1.2 mg, 0.031 mmol). After the mixture was
stirred for 1 h at the same temperature, the reaction was
quenched by an addition of saturated aqueous NH4Cl. The
reaction mixture was extracted with EtOAc, and the combined
organic layers were washed with brine, dried over Mg2SO4,
and concentrated in vacuo. The residue was purified by flash
column chromatography (EtOAc only) affording 2.2 mg (95%)
of 1 as a white solid. Recrystallization of the crude 1 from
EtOAc provided analytically pure (+)-brefeldin A: mp 203-
P r epar ation of 32b th r ou gh Wein r eb Am ide: (i) P r epa-
r a tion of th e Wein r eb Am id e 35. To a slurry of the bicyclic
lactone 3 (24 mg, 0.07 mmol) and N,O-dimethylhydroxyamine
hydrochloride (28 mg, 0.29 mmol) in THF (1 mL) at -20 °C
was added iPrMgCl (2.0 M solution in ether, 0.28 mL, 0.56
mmol) over 10 min. The mixture was warmed to room
temperature and stirred for 1 h.
(ii) Alk yla tion of th e Wein r eb Am id e 35. To a solution
of t-BuLi (1.7 M solution in pentane, 0.33 mL, 0.56 mmol) in
Et2O (0.5 mL) at -78 °C under argon was added a solution of
the iodovinyl OBO ortho ester 28a (80 mg, 0.28 mmol) in Et2O
(1 mL). After the mixture was stirred for 30 min at the same
temperature, the above Weinreb amide was added dropwise
using a cannula. After the mixture was stirred for 3 h, the
reaction was quenched with water. The reaction mixture was
extracted with Et2O, and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in
vacuo. Flash column chromatography (30% EtOAc/hexanes
with 1% (v/v) triethylamine) of the residue afforded 28 mg
(81%) of enone 32a as a colorless oil.
204 °C; [R]25 +92.5 (c 0.20, CH3OH); 1H NMR (CDCl3 + CD3-
D
OD) δ 7.32 (dd, 1H, J ) 15.6, 3.1 Hz), 5.80 (ddd, 1H, J ) 15.6,
1.5, 0.5 Hz), 5.63 (ddd, 1H, J ) 14.9, 10.0, 4.8 Hz), 5.20 (dd,
1H, J ) 14.9, 9.2 Hz), 4.76 (qdd, 1H, J ) 10.7, 6.2, 1.6 Hz),
4.19 (m, 1H), 3.96 (td, 1H, J ) 9.1, 2.0 Hz), 2.35-0.77 (m, 12H),
1.19 (d, 3H, J ) 6.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 152.8,
136.8, 129.7, 117.1, 75.3, 71.8, 71.3, 51.8, 44.2, 43.2, 41.0, 33.9,
31.7, 26.6, 20.8; IR (neat) 3733, 3646, 3362, 1715, 1645 cm-1
HRMS (EI) calcd for C16H24O4 280.1675, found 280.1663.
;
P r ep a r a tion of th e En on e (38): (i) MEM P r otection .
To a solution of (+)-brefeldin A (10 mg, 0.036 mmol) and iPr2-
NEt (20 µL, 0.11 mmol) in CH2Cl2 (2 mL) at 0 °C was added
MEMCl (10 µL, 0.088 mmol). After stirring for 12 h at ambient
temperature, the mixture was diluted with CH2Cl2 and
saturated aqueous NH4Cl. The mixture was extracted with
CH2Cl2, and the combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (50%
EtOAc/hexanes) to afford 10.3 mg (76%) of MEM ether as a
(iii) Ep im er iza tion of th e En on e 32a . To a solution of
32a (28 mg, 0.06 mmol) in CH2Cl2 (2 mL) was added 1,8-
diazabicyclo[5.4.0]undec-7-ene (5 mg, 0.03 mmol). The reaction
mixture was heated at reflux for 2 h and concentrated in vacuo.

Total Synthesis of (+)-Brefeldin A
J . Org. Chem., Vol. 67, No. 12, 2002 4137
clear and colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.32 (dd,
1H, J ) 15.6, 2.9 Hz), 7.29 (dd, 1H, J ) 15.6, 2.0 Hz), 5.67 (m,
1H), 5.22 (dd, 2H, J ) 15.0, 9.5 Hz), 4.86-4.76 (m, 1H), 4.71
(s, 2H), 4.16-4.06 (m, 2H), 3.74-3.53 (m, 3H), 3.38 (s, 3H),
2.30-2.14 (m, 3H), 2.02-1.69 (m, 7H), 1.23 (d, 3H, J ) 6.3
Hz), 0.88 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 173.7, 151.6,
136.4, 130.5, 117.6, 94.4, 77.6, 77.2, 75.9, 71.9, 66.9, 59.0, 52.0,
44.0, 40.7, 38.5, 34.1, 31.8, 26.7, 20.9; IR (KBr) 3444, 1713,
1644 cm-1; LRMS (EI) m/z 368 (M+).
(ii) Oxid a tion . To a solution of the above MEM ether (7.6
mg, 0.021 mmol) and 4 Å molecular sieves (3 mg) in CH2Cl2
(1.5 mL) at ambient temperature was added PDC (78 mg, 0.21
mmol). After stirring for 3 h at ambient temperature, the
mixture was diluted with Et2O, filtered through a pad of Celite,
and concentrated in vacuo. The residue was purified by flash
column chromatography (33% EtOAc/hexanes) to afford 7.0 mg
(98%) of enone 38 as a clear and colorless oil: 1H NMR (CDCl3,
300 MHz) δ 7.69 (d, 1H, J ) 15.8 Hz), 6.37 (d, 1H, J ) 15.8
Hz), 5.79 (ddd, 1H, J ) 4.1, 10.7, 14.9 Hz), 5.44 (dd, 1H, J )
10.7, 14.9 Hz), 4.65 (s, 2H), 4.59 (m, 1H), 4.08 (m, 1H), 3.63
(m, 2H), 3.48 (m, 2H), 3.32 (s, 3H), 2.81 (q, 1H, J ) 9.1 Hz),
2.50 (quintet, 1H, J ) 9.0 Hz), 2.24-1.68 (m, 7H), 1.26 (d, 3H,
J ) 6.0 Hz); IR (KBr) 1724, 1697, 1629 cm-1; LRMS (EI) m/z
366 (M+).
Dep r otection of 38. To a solution of the enone 38 (7.0 mg,
0.019 mmol) in CH2Cl2 (1.5 mL) at 0 °C was added TiCl4 (1.0
M solution in CH2Cl2, 57 µL, 0.057 mmol). After stirring for
30 min at 0 °C, the mixture was diluted with CH2Cl2 and
saturated aqueous NH4Cl. The mixture was extracted with
CH2Cl2, and the combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (50%
EtOAc/hexanes) to afford 5.0 mg (95%) of the inseparable
mixture of 36 and 39, which proved to be (1H NMR) a 72/28
mixture of (Z)-isomer 39 and (E)-isomer 36, as a clear and
colorless oil: (Z)-isomer; 1H NMR (CDCl3, 300 MHz) δ 6.29
(d, 1H, J ) 12.6 Hz), 6.04 (d, 1H, J ) 12.6 Hz), 5.35 (dd, 1H,
J ) 14.8, 10.5 Hz), 5.19 (m, 1H), 4.87 (m, 1H), 4.23 (m, 1H),
3.45 (q, 1H, J ) 7.8 Hz), 2.61 (m, 1H), 2.18-1.65 (m, 8H), 1.21
(d, 3H, J ) 9.0 Hz).
Red u ction of th e 4-Oxo-br efeld in A (36) a n d Its Isom er
(39). To a solution of the mixture of 36 and 39 (5 mg, 0.018
mmol) in MeOH (1.0 mL) at -78 °C was added sodium
borohydride (1.3 mg, 0.036 mmol). After the mixture was
stirred for 1 h at the same temperature, the reaction was
quenched by an addition of saturated aqueous NH4Cl. The
reaction mixture was extracted with EtOAc, and the combined
organic layers were washed with brine, dried over Mg2SO4,
and concentrated in vacuo. The residue was purified by flash
column chromatography (EtOAc only) to afford 3.4 mg (68%)
of (Z)-isomer 40 and 1.3 mg (27%) of (+)-brefeldin A (1) as a
white solid. (Z)-Isomer of brefeldin A (40): 1H NMR (CDCl3,
300 MHz) δ 6.15 (dd, 1H, J ) 11.8, 9.3 Hz), 5.63 (d, 1H, 11.1
Hz), 5.58 (m, 1H), 5.53 (m, 2H), 4.93 (m, 1H), 4.35 (m, 1H),
2.43-2.26 (m, 2H), 2.00-1.63 (m, 9H), 1.47 (m, 3H), 1.23 (d,
3H, J ) 7.2 Hz).
Ack n ow led gm en t. This research was supported by
Grant 01-PJ 1-PG3-21500-0051 from the Ministry of
Health & Welfare and Grant 1999-2-215-001-3 from the
Basic Research Program of the KOSEF.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of key synthetic intermediates. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0110855