Enantioselective formal synthesis of brefeldin A and analogues via anionic cyclization of an alkenyl epoxide

Article abstract of DOI:10.1055/s-2006-941575

Cyclopentene derivatives suitable as intermediates for syntheses of brefeldin A and analogues 6,7-dehydrobrefeldin C and norbrefeldin A were prepared by epoxynitrile cyclization of alkenyl epoxides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-941575

LETTER
1323
Enantioselective Formal Synthesis of Brefeldin A and Analogues via Anionic
Cyclization of an Alkenyl Epoxide
S
ynthesis of Br
e
i
feldin
n
AAnalogue
a
s
via
A
nionic Cyc
H
lization übscher, Günter Helmchen*
Organisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: G.Helmchen@oci.uni-heidelberg.de
Received 24 February 2006
Horner–Wadsworth–
Emmons olefination
Abstract: Cyclopentene derivatives suitable as intermediates for
syntheses of brefeldin A and analogues 6,7-dehydrobrefeldin C and
norbrefeldin A were prepared by epoxynitrile cyclization of alkenyl
epoxides.
macrolacto-
nization
OΣ
OH
H
H
H
H
O
Key words: cyclizations, antitumor agents, natural products, dia-
stereoselectivity, stereoselective synthesis
CHO
O
HO
HO
CHO
Julia–Kocienski
olefination
FGI
OH
Brefeldin A (1, Figure 1) was first isolated in 1958 from
Penicillium decumbens.1 Its absolute configuration was
determined by X-ray crystal structure analysis in 1971.2
The compound possesses many interesting biological
properties, including antifungal,3 antiviral,4 antitumor,5
nematocidal6 and antimitotic activity.7 Furthermore,
brefeldin A induces DNA fragmentation combined with
apoptosis in cancer cells.8 This property makes it an inter-
esting target for medicinal chemistry.
H
H
O
OΣ
OΣ
CN
CN
epoxynitrile cyclization
Scheme 1 Retrosynthetic analysis
al., we opted for an alkenyl epoxide precursor in order to
introduce a double bond into the five-membered ring,
hoping to make a variety of addition products, for exam-
ple diols, accessible. With respect to methods develop-
ment, it was of interest to explore ways of controlling the
mode of cyclization, i.e. achieving SN2 rather than SN2¢-
type substitution.
OH
H
1
O
15
4
5
7
O
HO
9
H
1
Figure 1 Brefeldin A (1)
Syntheses of the requisite epoxynitriles 6a and 6b are
described in Scheme 2. Wittig olefination of the known
aldehyde 214 with an ylide derived from the phosphonium
salt 3 gave the corresponding diene, which was treated
with TBAF·3H2O to furnish the dienol 4 in 86% yield over
two steps (ratio of Z- to E-isomer = 16:1).
The medicinal use of brefeldin A is limited by its poor bio-
availability after oral administration and its low solubility
in water.9 In order to provide compounds with improved
pharmacokinetic properties, a few derivatives have been
prepared by transformation of natural brefeldin A.10
1. Ph3P+(CH2)3CN Br– (3)
Remarkably, numerous total syntheses of brefeldin A
have been reported,11 however, to the best of our knowl-
edge no analogue has been prepared by total synthesis.
KHMDS (toluene), THF
E/Z 1:16, 91%
OH
OTBDPS
O
2. TBAF·3H2O, THF
94%
CN
2
It was our objective to develop a short and efficient syn-
thesis of a cyclopentane derivative as intermediate, which
would serve as basis for fast syntheses of brefeldin A (1)
and analogues in combinatorial manner (Scheme 1). An
epoxynitrile12 cyclization appeared particularly promising
in order to provide such an intermediate in multigram
amounts. Previously, Taber et al.13 have used an intramo-
lecular alkylation of an epoxide with an amide enolate as
key step of a synthesis of brefeldin A. Other than Taber et
4
Ti(Oi-Pr)4, (–)-DET
CH2Cl2, 4 Å MS
71%
O
O
OΣ
OH
ΣBr, NaH, TBAI
THF
CN
CN
6a, Σ = Bn, 84%
6b, Σ = PMB, 78%
5
Scheme 2 Synthesis of the epoxynitriles 6a and 6b
SYNLETT 2006, No. 9, pp 1323–1326
0
1.
0
6.
2
0
0
6
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-941575; Art ID: G07206ST
© Georg Thieme Verlag Stuttgart · New York

1324
T. Hübscher, G. Helmchen
LETTER
The dienol 4 was epoxidized under Sharpless conditions15 in order to improve the formation of 8a. Addition of
to afford the epoxide 5 with enantiomeric purity of 97% Lewis acids for activation of the epoxide, for example
ee. The alcohol 5 was transformed into the benzyl ether 6a BF3·OEt2, led to very low yields (entry 4). In contrast,
and the p-methoxybenzyl ether 6b.
addition of DMPU to the solvent gave rise to enhanced
formation of the cyclopentene 8a (entry 5). As a conse-
quence, solvents more polar than THF were investigated.
With DMF or N,N-dimethylacetamide (DMA) mainly
cyclopentene 8a was formed (entries 6 and 7); only traces
of 9 were found, but a new side product appeared, the
diene 10, which could be easily removed by chromatogra-
phy on silica gel.18
The benzhydryl-protected cyclization precursor 6c was
prepared in 49% overall yield from the known epoxide 716
by Swern oxidation followed by a Wittig reaction pro-
ceeding with a Z/E ratio of 34:1 (Scheme 3).
1. (COCl)2, DMSO
Et3N, CH2Cl2
O
OCHPh2
O
61%
OCHPh2
Using reaction conditions according to entry 7 of Table 1,
the epoxynitriles 6b and 6c were cyclized to the cyclo-
pentenes 8b and 8c in 64% and 60% yield, respectively
(Scheme 5).
HO
2. 3, KHMDS
(toluene), THF
80%
CN
7
6c
Scheme 3 Synthesis of the benzhydryl-protected epoxynitrile 6c
OH
O
H
OΣ
The epoxynitrile cyclization was first examined with the
benzyl-protected precursor 6a, probing a variety of reac-
tion conditions (Scheme 4). The results displayed in
Table 1 demonstrate that the outcome is strongly depen-
dent on the solvent and the base.
OΣ
LHMDS
DMA
CN
CN
H
6a, Σ = Bn
8a, 66%
8b, 64%
8c, 60%
6b, Σ = PMB
6c, Σ = Ph2CH
OH
CN
+
OH
Scheme 5 Epoxynitrile cyclization of 6a–c
H
OBn
OBn
base
*
*
6a
+
solvent
With a good supply of 8a–c in hand, functionalization of
the cyclopentene moiety was addressed. In order to pro-
tect the OH group, alcohol 8a was treated with MEMCl to
give the ether 11 (Scheme 6). A first attempt of hydration
of the double bond of this compound by hydroboration–
oxidation resulted in mixtures of regio- and stereoisomers.
Fortunately, oxymercuration–demercuration furnished al-
cohol 12 as main product in 71% yield; in addition, the re-
gioisomer 13 (6%) and traces of starting material were
found, which were removed by column chromatography.
CN
OH
H
8a
9
NC
OBn
10
Scheme 4 Epoxynitrile cyclization of 6a
Table 1 Epoxynitrile Cyclization of 6a
Entry Base
Solvent
Yield of 8a Yield of 9 Yield of 10
(%)a
(%)a
59
38
39
12
27
7
(%)a
OMEM
H
OBn
1
KHMDS
THF
5
–
MEMCl, (i-Pr)2NEt
8a
CH2Cl2
97%
2
NaHMDS THF
8
–
CN
H
11
3
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
THF
THF
THF
DMF
DMA
19
–
–
1. Hg(OAc)2, THF–H2O
2. NaOH, NaBH4
4b
5c
6
–
52
47
66
5
OMEM
OMEM
HO
H
H
H
OBn
OBn
21
15
+
HO
7
2
CN
CN
H
a Yield of isolated product.
b With BF3·OEt2 as additive.
c With DMPU as additive.
12, 71%
13, 6%
OMEM
H
1. MEMCl, (i-Pr)2NEt
OBn
CH2Cl2
MEMO
With KHMDS in THF, 6a was mainly transformed into
the cyclopropane derivative 917 (Table 1, entry 1). By
changing the cation of the base to sodium and lithium
(entries 2 and 3), the content of cyclopentene 8a in-
creased, while 9 remained the major product. In further
experiments with LHMDS as base, additives were probed
2. DIBAL-H (hexane)
CH2Cl2
CHO
H
14, 66%
Scheme 6 Formal synthesis of brefeldin A – synthesis of the Taber–
Kajiwara aldehyde 14
Synlett 2006, No. 9, 1323–1326 © Thieme Stuttgart · New York

LETTER
Synthesis of Brefeldin A Analogues via Anionic Cyclization
1325
Finally, the newly introduced OH group of 12 was pro- from which the a,b-unsaturated ester 22 was obtained by
tected as MEM ether and the cyano group was trans- Horner–Wadsworth–Emmons olefination (overall yield
formed into a formyl group by treatment with an excess of 86%, ratio of E- and Z-isomer = 16:1). Ester 22 was selec-
DIBAL-H; aqueous work-up gave the aldehyde 14 in 66% tively deprotected by saponification and treatment with
yield from 12. The aldehyde has already been synthesized TBAF to give the hydroxy acid 23 in 88% yield. Macro-
by Taber et al.13 and Kajiwara et al.19 in their syntheses of lactonization of 23 was accomplished under Yamaguchi
brefeldin A. With our approach, the synthesis of the alde- conditions in 77% yield.23 Removal of the MEM protect-
hyde 14 could be achieved via a shorter route, i.e. in nine ing group proved less easy than reported for the MEM de-
13
steps and 15% overall yield.
rivative of brefeldin A. Reaction with TiCl4 gave 6,7-
dehydrobrefeldin C (15) in 63% yield, which could not be
improved. Noting that 15 is a fairly stable compound,
deprotection with concentrated aqueous HBr24 was tried,
which furnished 15 in 77% yield as crystalline solid (mp
141.5–143 °C).
Subsequent to the formal synthesis of brefeldin A, the
analogues 6,7-dehydrobrefeldin C (15) and norbrefeldin
A (16, Figure 2) were synthesized starting from nitrile 11
and aldehyde 14, respectively.
OMEM
OMEM
OH
OH
H
H
H
H
H
OBn
OBn
OTBDPS
18, KHMDS
O
O
O
O
HO
DME
–78 °C to r.t.
CHO
20
3
H
H
H
15
6,7-dehydrobrefeldin C
16
norbrefeldin A
21, 88%
OMEM
Figure 2 Analogues of brefeldin A
H
H
1. Li, naphthalene
THF, r.t. to –25 °C
CO2Et
OTBDPS
The lower side chains of 15 and 16 were introduced via
Julia–Kocienski olefination.11 The requisite sulfone 18
(Scheme 7) was prepared from the known chiral alcohol
17,20 which was transformed into 18 by Mitsunobu reac-
tion with 1-phenyl-5-mercaptotetrazole and subsequent
oxidation.21 The achiral lower side chain synthon 19 was
obtained in essentially the same manner from 1,5-dihy-
droxypentane.
2. Swern oxidation
3. (EtO)2P(O)CH2CO2Et
NaH, THF, r.t. to –78 °C
22
86%, E/Z 16:1
OMEM
H
1. 1 N NaOHaq
THF–MeOH, 60 °C
,
CO H
OH
2
2. TBAF, THF, r.t.
H
23
88% (E), 5% (Z)
N
OTBDPS
OTBDPS
N
a, b
N
( )
3
( )
3
OH
OH
S
N
94%
1. a) 2,4,6-trichlorobenzoyl-
chloride, Et3N, THF, r.t.
b) DMAP, toluene, 110 °C
OH
O
O
Ph
H
H
18
17
O
N
O
N
N
2. concd HBraq, THF, r.t.
a, b, c
66%
( )
3
( )
HO
TBDMSO
S
N
3
O
O
15, 77%
Ph
19
Scheme 8 Synthesis of 6,7-dehydrobrefeldin C (15)
Scheme 7 Synthesis of the lower side chain synthons. Reagents and
conditions: (a) 1-phenyl-5-mercaptotetrazole, PPh3, DIAD, THF,
0 °C to r.t.; (b) (NH4)6Mo7O24·4H2O, H2O2, EtOH, r.t.; (c) TBDMSCl,
imidazole, DMAP, CH2Cl2, 0 °C to r.t.
The synthesis of norbrefeldin A (16) was carried out from
aldehyde 14 and side chain synthon 19 in the same way as
that of 15 (Scheme 9). The target was obtained in eight
steps and 27% overall yield, as a crystalline compound
(mp 187.5–189.0 °C).
The synthesis of 6,7-dehydrobrefeldin C (15) was initiat-
ed by transforming the nitrile 11 by treatment with an ex-
cess of DIBAL-H into the aldehyde 20 (88% yield,
Scheme 8). The Julia–Kocienski coupling of 20 with the
sulfone 18 proceeded with essentially complete stereo-
control to give the E-olefin 21 in 88% yield. This was
selectively deprotected with an excess of lithium
naphthalenide22 to give the corresponding alcohol, which
was oxidized under Swern conditions to an aldehyde,
In conclusion, we have developed short syntheses of the
cyclopentene 8a and the Taber–Kajiwara aldehyde 14.
With these useful building blocks in hand, we were able
to synthesize the new brefeldin A analogues 6,7-dehydro-
brefeldin C (15) and norbrefeldin A (16). The biological
evaluation of these compounds and the synthesis of
further analogues is in progress.
Synlett 2006, No. 9, 1323–1326 © Thieme Stuttgart · New York

1326
T. Hübscher, G. Helmchen
LETTER
(11) Latest total synthesis: Trost, B. M.; Crawley, M. L. Chem.
Eur. J. 2004, 10, 2237; this article also contains an extensive
bibliography on previous total syntheses of brefeldin A.
(12) (a) Stork, G.; Cama, L. D.; Coulson, D. R. J. Am. Chem. Soc.
1974, 96, 5268. (b) Stork, G.; Cohen, J. F. J. Am. Chem. Soc.
1974, 96, 5270. (c) Levine, S. G.; Bonner, M. P.
Tetrahedron Lett. 1989, 4767. (d) Brefeldin C: Suzuki, T.;
Yang, X. H.; Matsuda, Y.; Tada, H.; Unno, K. Akita Igaku
1992, 19, 545.
OMEM
H
N
OBn
N
N
MEMO
TBDMSO
S
N
3
CHO
H
O
O
Ph
14
19
8 steps
(13) Taber, D. F.; Silverberg, L. J.; Robinson, E. D. J. Am. Chem.
Soc. 1991, 113, 6639.
OH
H
(14) Roush, W. R.; Straub, J. A.; Van Nieuwenhze, M. S. J. Org.
Chem. 1991, 56, 1636.
O
O
HO
(15) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765.
H
16, 27%
(16) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A. III;
Sharpless, K. B.; Walker, F. J. Tetrahedron 1990, 46, 245.
(17) The cyclopropane 9 was formed as a mixture of two
diastereomers. In the reaction according to entry 1 of
Table 1, the ratio of the diastereomers was 1.5:1 (1H NMR).
The configurations of these compounds were not
determined.
Scheme 9 Synthesis of norbrefeldin A (16)
Acknowledgment
We thank Profs. D. F. Taber, University of Delaware, and M. Kaji-
wara, Meiji College of Pharmacy, Tokyo, for spectral data of alde-
hyde 14, BASF AG for the donation of chemicals and the Fonds der
Chemischen Industrie for a Kekulé grant to T.H. The synthesis of
the p-methoxybenzyl-protected cyclopentene 8b was achieved by
Dennis Schmidt as part of an Advanced Laboratory Course.
(18) Typical Procedure.
A 1 M solution of LHMDS (13.0 mL, 13.0 mmol) in THF
was placed in a dry Schlenk tube under argon and the solvent
was removed in vacuo. The residue was dissolved in dry
DMA (120 mL) at r.t., and a solution of 6a (1.50 g, 6.17
mmol) in dry DMA (50 mL) was added dropwise via syringe
pump. The reaction mixture was stirred for 20–60 min,
cooled to 0 °C and then treated with sat. aq NH4Cl and Et2O.
The aqueous layer was separated, acidified with 1 N aq HCl
and extracted with Et2O. The organic layers were washed
with 1 N aq HCl, H2O and brine. The combined organic
layers were dried over Na2SO4, filtered and evaporated in
vacuo. The residue was subjected to flash chromatography
on silica gel (120 g, PE–EtOAc 4:1 → 1:1) to give 8a (1.01
g, 67%) as a yellow oil.
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Synlett 2006, No. 9, 1323–1326 © Thieme Stuttgart · New York