A trans-vinylogous ester anion equivalent and its application to the synthesis of (+)-brefeldin A

Article abstract of DOI:10.1016/S0040-4039(00)02278-4

A new trans-vinylogous ester anion equivalent which reacts with a variety of carbonyl systems has been developed. In addition, the concise total synthesis of (+)-brefeldin A utilizing facile acylation of this new variant of vinylogous acyl anion equivalent has been accomplished.

Full text of DOI:10.1016/S0040-4039(00)02278-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1691–1694
A trans-vinylogous ester anion equivalent and its application to
the synthesis of (+)-brefeldin A
Young-Ger Suh,a,* Seung-Yong Seo,a Jae-Kyung Jung,a Ok-Hui Parka and Ra-Ok Jeonb
aCollege of Pharmacy, Seoul National University, San 56-1, Shinrim-Dong, Kwanak-Gu, Seoul 151-742, South Korea
bCollege of Pharmacy, Sookmyung Women’s University, Seoul 140-742, South Korea
Received 23 October 2000; revised 7 December 2000; accepted 8 December 2000
Abstract—A new trans-vinylogous ester anion equivalent which reacts with a variety of carbonyl systems has been developed. In
addition, the concise total synthesis of (+)-brefeldin A utilizing facile acylation of this new variant of vinylogous acyl anion
equivalent has been accomplished. © 2001 Elsevier Science Ltd. All rights reserved.
The vinylogous acyl anion has continuously attracted
considerable attention from the organic and medicinal
chemists due to its wide range of synthetic utilities.1
However, its synthetic application has been limited by
poor nucleophilicity, instability as well as difficulty in
regiocontrol of anion generation.
Our initial studies on the reaction of 2b were carried
out by intensive examination of the reaction conditions
for the halogen–metal exchange of halovinyl OBO
orthoesters which were prepared by the modified Watt’s
procedure.5 The iodo substituent of the vinyl OBO
orthoester 2a turned out to be crucial for the efficient
generation of the requisite trans-vinyl anion 2b since
bromo or chloro-substituted vinyl substrate afforded
cis-halovinyl anion by deprotonation rather than halo-
gen–metal exchange.1,4 In particular, the reverse addi-
tion of the iodoolefin 2a to t-BuLi in ether provided the
best results by the desired halogen–metal exchange.
Table 1 summarizes the result for the reaction of the
lithium anion 2b with a series of carbonyl compounds.
As anticipated, the aldehyde and ketone (entry 1–5)
underwent facile addition reaction to afford the allylic
alcohols in good or moderate yields. In the case of
lactones (entry 6 and 7), the addition products were
obtained in modest yields and the extended reaction
time at −78°C and an excess amount of 2b was neces-
sary in order to ensure higher yield. It is noticeable that
Weinreb amide (entry 8) is superior to lactone (entry 7)
for acylation of the vinyl anion 2b in terms of overall
yield.
Recently, we have investigated the versatile methods for
g-keto and g-hydroxy acrylate by direct introduction of
trans-acrylic acid to a variety of carbonyl systems as
part of a program directed toward the total synthesis of
(+)-brefeldin A.2 For this efficient transformation, the
trans-vinyl anion 2b, generated by halogen–metal
exchange of the corresponding (E)-1-(2-iodovinyl)-4-
methyl-2,6,7-trioxabicyclo[2.2.2]octane (2a, iodovinyl
OBO orthoester3) was considered as the best equivalent
of the requisite trans-vinylogous ester anion (1) in terms
of conciseness and diversity. To the best of our know-
ledge, the trans-vinylogous ester anion equivalent and
its synthetic utilization has not been reported yet
although the b-alkoxy directed cis-vinyl anions have
mainly been reported1,4 (Fig. 1).
We herein report a novel trans-vinylogous ester anion
equivalent (2b) as a variant of vinylogous acyl anion
and its reaction with a variety of carbonyl systems. In
addition, the total synthesis of (+)-brefeldin A achieved
by employing this methodology as a key reaction is also
reported.
O
O
CO2R
Li
X
O
1
2a
X = I
2b X = Li
Keywords: trans-vinylogous ester anion equivalent; brefeldin A; total
synthesis.
Figure 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02278-4

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Y.-G. Suh et al. / Tetrahedron Letters 42 (2001) 1691–1694
Table 1. Reaction of vinylogous acrylate anion equivalent 2b with carbonyl compounds
O
O
t-BuLi, ether
O
O
-78oC, 30min
then E+
E
O
I
O
2a
3
Reaction
Carbonyl
compounds
Entry
1
Products
Yield(%)b
76
conditionsa
O
H
O
O
3a
3b
3c
A
Ph
O
OH
O
H
O
O
(4-OMe)Ph
2
3
61
71
A
A
O
OH
MeO
O
O
O
H
O
O
OH
Ph
O
O
3d
3e
4
5
65
78
A
A
O
OH
O
O
O
O
OH
OH
O
O
O
O
3g
3h
6
7
B
61
O
O
O
O
O
Bc
46(72d)
HO
O
O
H
O
H
Me
N
O
O
O
OMe
O
3f
8
B
O
62
O
O
O
O
a Condition A : 3 equivalents of
bIsolated
2a were used; Condition B : 4 equivalents of 2a were used.
yields. The temperature of -78oC was maintained. d Yield based on recovered starting material.
c
due to the steric and geometric advantage. Finally,
The facile coupling reaction of the anion 2b as a
vinylogous acyl anion equivalent with bicyclic lactone
was successfully applied to the total synthesis of (+)-
brefeldin A6 (Scheme 1). Addition of 2b to the bicyclic
lactone 52b, followed by DBU treatment of the resulting
vinyl ketone for epimerization provided the enone inter-
mediate 77 as a single diastereomer in 51% yield. Alter-
natively, reaction of 2b with the Weinreb amide 6 which
was in situ generated by amidation of 5 with magne-
sium anion of N,O-dimethylhydroxylamine8 afforded
the enone 7 after DBU treatment. Exposure of the
enone 7 to 1N HCl and then hydrolysis of the resulting
hydroxy ester with LiOH afforded the dihydroxy acid 8
as an advanced precursor for macrolactonization.
Macrolactonization of the hydroxy acid 8 was con-
ducted according to the Yamaguchi procedure9 in the
presence of the free C7-hydroxy group. The preferred
macrolactonization of the C15-hydroxy group is likely
stereoselective reduction10 of the ketone 9 with NaBH4
afforded (+)-brefeldin A. The synthetic brefeldin A was
identical in all aspects with authentic brefeldin A.11
In conclusion, an efficient method for g-keto and g-
hydroxy acrylate by the direct introduction of trans-
acrylate moiety to the various carbonyl compounds has
been developed. Moreover, the concise total synthesis
of (+)-brefeldin A from the known bicyclic intermediate
5 has been accomplished by an application of the facile
acylation of a new variant of trans-vinylogous ester
anion equivalent.
Representative procedure
To a solution of t-BuLi (1.2 mmol, 6 equiv.) in pentane
at −78°C under argon was added a solution of

Y.-G. Suh et al. / Tetrahedron Letters 42 (2001) 1691–1694
1693
O
OMe
N
H
OMe
N
OTBS
O
Me
O
Me
O
H
O
H
4
6
reference 2b
a
b, c
O
O
H
H
H
O
O
O
e
d, c
HO
OTBS
O
OTBS
5
7
O
OH
H
O
H
H
O
H
H
O
COOH
OH
7
O
O
HO
f
g
HO
HO
H
15
8
9
(+)-Brefeldin A
Scheme 1. Reaction conditions: (a) NH(OMe)Me·HCl, iPrMgCl, THF, −20°C to rt; (b) 2a, t-BuLi, ether, −78°C, 30 min, then
6, −78°C to rt, 81% from 5; (c) DBU, CH2Cl2, reflux, 99%; (d) 2a, t-BuLi, ether, −78°C, 30 min, then 5, −78°C, 51%; (e) 1N HCl,
H2O/THF (1/1), then LiOH, 85%; (f) 2,4,6-trichlobenzoyl chloride, Et3N, THF, rt, 2 h , then 4-DMAP, toluene, reflux, 24 h, 51%;
(g) NaBH4, MeOH, −78°C, 95%.
iodovinyl OBO orthoester 2a (169 mg, 0.60 mmol, 3
equiv.) in anhydrous ether (2 mL) using a cannula and
argon pressure for the transfer. After stirring for 30 min
at −78°C, a solution of benzaldehyde (20 mg, 0.20
mmol, 1 equiv.) in anhydrous ether (2 mL) was added
dropwise using a cannula. The reaction mixture was
warmed to room temperature and stirred for 3 h. The
mixture was quenched with H2O (1 mL) and then
diluted with ether (10 mL). The aqueous layer was
extracted with ether (10 mL×2) and the combined
extracts were washed with H2O and brine, dried over
Na2SO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatography
on silica gel using a mixture of ethyl acetate and hexane
(1 : 2) with 1% (v/v) triethylamine to afford 3a (40 mg,
76%).
References
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(+)-brefeldin A, see: Ducray, P.; Rousseau, B.;
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5. The iodovinyl OBO orthoester 2a was conveniently pre-
pared by regioselective hydroiodination of propiolic acid
(10) (Scheme 2) and the procedure reported in Ref. 4a.
Zoller, T.; Uguen, D. Tetrahedron Lett. 1998, 39, 6719.
6. For the indirect introduction of acrylate moiety in the
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Acknowledgements
This work was supported by grant (1999-2-215-001-3)
from the Basic Research Program of the KOSEF and in
part by 2000 BK21 project for Medicine, Dentistry and
Pharmacy.
I
O
I
O
c
O
b
a
CO2H
10
O
CO2H
I
O
O
11
12
2a
Scheme 2. Reaction conditions: (a) 57% HI, H2O, 85°C, 90%; (b) 3-methyl-3-hydroxymethyloxetane, DCC, DMAP, CH2Cl2, rt,
95%; (c) BF3·OEt2, CH2Cl2, −15°C, 73%.

1694
Y.-G. Suh et al. / Tetrahedron Letters 42 (2001) 1691–1694
7. Spectral data for 7: [h]1D1 −29.0° (c 0.14, CH2Cl2); 1H
1384, 1055, 615, 470, 407 cm−1; HRMS (EI) m/z calcd for
C27H46O6Si 494.3064, found 494.3064 (M+).
8. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini,
G.; Dolling, U.-H.; Grabowski, J. J. Tetrahedron Lett.
1995, 36, 5461.
9. Inanaga, J.; Hirata, K.; Saeki, H.; Kastuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
10. Zhu, J.-W.; Nagasawa, H.; Nagura, F.; Mohamad, S. B.;
Uto, Y.; Ohkura, K.; Hori, H. Bioorg. Med. Chem. 2000,
8, 455.
NMR (CDCl3, 500 MHz): l 0.00 (s, 6H), 0.80 (s, 3H),
0.84 (s, 9H), 1.07 (d, 3H, J=6.0 Hz), 1.24–1.47 (m, 6H),
1.84 (m, 1H), 1.90 (m, 2H), 1.98 (ddd, 1H, J=13.5, 9.0,
6.0 Hz), 2.20 (ddd, 1H, J=13.8, 8.4, 5.8 Hz), 2.70 (m,
1H), 3.14 (q, 1H, J=8.7 Hz), 3.72 (m, 1H), 3.92 (s, 6H),
4.34 (brs, 1H), 5.35 (m, 2H), 6.45 (d, 1H, J=16.0 Hz),
6.50 (d, 1H, J=16.0 Hz); 13C NMR (CDCl3, 100 MHz):
l −4.7, −4.4, 14.4, 18.1, 23.7, 25.4, 25.9, 30.6, 32.3, 39.1,
39.2, 42.4, 44.3, 53.7, 68.5, 72.8, 72.9, 105.8, 130.9, 131.3,
132.7, 137.5, 201.3; IR (neat) 3852, 3441, 2927, 1651,
11. The authentic brefeldin A was purchased from Fluka Co.
.
.