A new total synthesis of (+)-brefeldin C

Article abstract of DOI:10.1055/s-2004-835669

A new synthesis of (+)-brefeldin C featuring a Bolm desymmetrisation reaction, a B-alkyl Suzuki-Miyaura cross-coupling and a Carreira alkynylation reaction as the key steps is reported.

Full text of DOI:10.1055/s-2004-835669

LETTER
139
A New Total Synthesis of (+)-Brefeldin C
New
T
ota
l
Syn
y
thesisof (+
)
l
-Brefe
l
v
dinC ie Archambaud, Karine Aphecetche-Julienne, André Guingant*
Laboratoire de Synthèse Organique, UMR CNRS 6513, FR CNRS 2465, Faculté des Sciences et des Techniques,
2 rue de la Houssinière, BP 92208 - 44322 Nantes Cedex 03, France
Fax +33(2)51125402; E-mail: guingant@chimie.univ-nantes.fr
Received 2 September 2004
As depicted in Scheme 2 and Scheme 3, union of frag-
ments 1 and 2 was envisaged via a palladium-mediated B-
alkyl Suzuki–Miyaura cross-coupling reaction.5 We
planned to synthesise fragment 1 (5) from acid-ester 6, the
synthesis of which was already reported6 through a de-
symmetrisation process of meso anhydride 7, whereas the
synthesis of fragment 2 was envisaged via opening of
commercially available (S)-2-methyl-oxirane with an
organometallic species. After functional group transfor-
mation (ester to aldehyde), application of the recently
developed Carreira protocol7 for the enantioselective syn-
thesis of propargylic alcohols was envisioned for the
attachment of fragment 3 with concomitant control of the
absolute configuration at C4.
Abstract: A new synthesis of (+)-brefeldin C featuring a Bolm de-
symmetrisation reaction, a B-alkyl Suzuki–Miyaura cross-coupling
and a Carreira alkynylation reaction as the key steps is reported.
Key words: brefeldin C, Bolm desymmetrisation reaction, B-alkyl
Suzuki–Miyaura cross-coupling, Carreira alkynylation reaction,
total synthesis
Brefeldin A (BFA) 1 (Scheme 1) is a naturally occurring
16-membered macrolide antibiotic first isolated1 from
Penicillium decumbens and subsequently identified as a
metabolite from several other ascomycetes sources.2 BFA
exhibits a diversity of biological activities, which include
antiviral and antitumor effects.3 BFA is also an important
tool for cell biologists due to its dramatic effects on the
structure and functioning of intracellular organelles,
particularly the Golgi apparatus.4 Therefore, BFA, and its
direct biosynthetic precursor brefeldin C (BFC), offer
promising opportunities for the development of structural
analogs useful for biological evaluation and study of intra-
cellular vesicular trafficking.
Our synthesis of fragment 1 (Scheme 4) thus commenced
with the desymmetrisation reaction of anhydride 7 avail-
able in multi-gram quantities from b-keto ester 8 through
a three-step sequence of known reactions (59% overall
yield).8 Applying the Bolm protocol6 to 7 afforded acid-
ester 6 in 99% yield and with 94% ee, in complete agree-
ment with the reported data. To establish the future C5
chiral centre of BFC with proper stereochemistry, acid-
ester 6 was cleanly epimerised to 9 upon treatment with
potassium tert-butoxide in THF (92% yield). Chemo-
selective acid to aldehyde transformation was best accom-
plished in a two-step sequence (BH3 overreduction to an
alcohol, followed by oxidation under Swern conditions) to
provide aldehyde-ester 10 in 58% overall yield. To com-
plete the synthesis of 5 (fragment 1), aldehyde 10 was
subjected to the conditions of the Takai reaction (excess
chromium chloride in a 1:6 THF–dioxane mixture for 72
h)9 to afford the vinylic iodide 5 in 75% isolated yield and
in excellent selectivity (E:Z isomer ratio = 97:3).
Herein, we report a new synthesis of natural (+)-BFC
featuring the construction and union of three principal
fragments resulting from the sequential disconnection of
the C1-O s-bond as well as the C3-C4 and C11-C12 s-
bonds of the macrocyclic lactone as outlined in Scheme 2.
OH
H
O
1: Brefeldin A (BFA) ; R = OH
R
O
Me
2: Brefeldin C (BFC) ; R = H
H
Scheme 1 Structures of naturally occurring brefeldins A and C.
OH
O
H
H
OAc
2
fragment 3
1
O
4
OMe
3
15
Me
O
OPMB
H
11
I
12
H
H
R2B
fragment 1
Me
2 Brefeldin C
fragment 2
Scheme 2 The key disconnections.
SYNLETT 2005, No. 1, pp 0139–0143
0
5.
0
1.
2
0
0
5
Advanced online publication: 12.11.2004
DOI: 10.1055/s-2004-835669; Art ID: D26604ST
© Georg Thieme Verlag Stuttgart · New York

140
S. Archambaud et al.
LETTER
Enantioselective
Carreira reaction
lactone bond formation
OH
H
OH
4
2
H
O
1
4
OH
3
5
9
3
O
OPMB
Me
15
Me
O
11
12
11
H
12
H
H
Brefeldin C 2
3
B-alkyl Suzuki -
Miyaura cross-coupling
O
O
O
H
H
H
H
H
OMe
11
OMe
O
OMe
OPMB
Me
I
12
H
H
OH
Takai reaction
4
5
6
O
O
H
CO2Et
O
Bolm desymmetrisation
process
H
O
7
8
Scheme 3 Strategic pathway to brefeldin C.
O
O
position to attempt their union to give 4. Towards this end,
alkene 11 was first subjected to hydroboration conditions
(9-BBN-H, followed by addition of a base) to form the B-
alkyl-9-BBN intermediate 13 (fragment 2). To this inter-
mediate was then added vinylic iodide 5 in conjunction
with a Pd(0) catalyst system.5 After numerous investiga-
tions of the influence of both the catalyst and the base it
was found that [Pd(dppf)Cl2·CH2Cl2] (0.1 equivalent) and
Cs2CO3 (2 equivalents) were the reagents of choice. Un-
der these conditions the cross-coupling proceeded in 6
hours at 30–35 °C in THF–DMF to give 4 in excellent
isolated yield (90%) along with minimum formation of
homo-coupling product (ca. 4% observed in the crude
material).
O
H
H
H
OMe
O
OMe
O
ref. 6
a
O
H
H
H
O
OH
OH
9
7
6
O
H
O
H
H
OMe
O
c
OMe
b
I
H
H
10
5
Having successfully addressed the connection of frag-
ments 1 and 2, the next task at hand was to operate a func-
tional group interconversion (ester 4 to aldehyde 14) and
to install the remaining side chain (fragment 3) with con-
trol of the absolute configuration of the stereogenic centre
at C4 (BFC numbering). In the event, the requisite alde-
hyde 14 was readily prepared from ester 4 following a
reduction–oxidation sequence (75% for two steps,
Scheme 6). At this stage, examination of molecular mod-
els suggested that the C5 and C9 stereogenic centres
would be of little utility to control the challenging C4
stereocentre. A strategy based on reagent control was thus
judged more adapted to install the C4 hydroxyl group with
the requisite absolute configuration. Following this idea,
Scheme 4 Reagents and conditions: a) tert-BuOK (1.5 equiv), THF,
0 °C to r.t., 1 h then HCl (6 N), 92%; b) BH3·SMe2 (3 equiv), THF,
–20 °C to r.t., 12 h, 60%; c) (COCl)2 (1.1 equiv), DMSO (2.2 equiv),
CH2Cl2, –60 °C, 15 min then DIEA (5 equiv), –60 °C to r.t., 96%;
d) CrCl2 (5 equiv), CHI3 (2 equiv), THF–dioxane (1:6), 25 °C, 72 h,
75%.
The synthesis of alkene 11 (precursor of fragment 2,
Scheme 5) was achieved in two simple steps featuring
epoxide-opening of (S)-2-methyl-oxirane with vinylmag-
nesium bromide in the presence of CuCl(COD)10 to give
12, followed by protection of the secondary hydroxyl
group as a p-methoxybenzyl ether (PMB). With the requi-
site fragment 1 and alkene 11 in hand, we were now in a
Synlett 2005, No. 1, 139–143 © Thieme Stuttgart · New York

LETTER
New Total Synthesis of (+)-Brefeldin C
141
OH
OPMB
a
b
O
H
H
H
MgBr
+
Me
Me
Me
12
11
O
H
H
c
d
OPMB
H
OMe
OPMB
H
B
Me
Me
13
4
Scheme 5 Reagents and conditions: a) (2S)-2-methyl-oxirane, THF, –78 °C, then CuCl(COD) (0.1 equiv), vinylmagnesium bromide (1.5
equiv), –78 °C to r.t., 15 h; b) NaH (3 equiv), DMF, 12, PMBCl (2 equiv) in THF (DMF–THF 5:1), 0 °C to r.t., 15 h, 94% (2 steps); c) 11 (1
equiv), THF, 9-BBN (2 equiv), 30 °C, 3 h; d) 3 M aq Cs2CO3 (1.5 equiv), 5 (0.76 equiv) in DMF (DMF–THF 1:1), [Pd(dppf)Cl2·CH2Cl2] (0.076
equiv), 30 °C, 6 h, 90%.
our attention was attracted by the Carreira’s protocol, N-methylephedrine, the reaction proceeded reluctantly to
which makes use of in situ generated zinc alkynylides as- give a mixture of propargylic alcohols in low yield and
sociated with a chiral amine as nucleophilic species to with an almost total lack of diastereoselectivity. Thus, it
generate chiral propargylic alcohols from aldehydes with does appear that, as originally forecasted, the stereo-
a high degree of enantioselectivity. A further motivation chemistry of the catalyst is the dominating stereocontrol
for this strategy came from the fact that a propargylic ac- element of the reaction.
etate structure may be transformed into an (E)-a,b-unsat-
With propargylic alcohol 15a now in hand, the next objec-
tive was its transformation into (E)-a,b-unsaturated acid
19. This was accomplished in four efficient steps as illus-
urated aldehyde,11 the oxidation of which would furnish
an (E)-a,b-unsaturated acid unit ultimately required for
the macrolactonisation step (Scheme 3). To test the viabil-
trated in Scheme 7. Thus, after silylation of the hydroxyl
ity of the projected alkynylation route, aldehyde 14 was
group at C4, the resulting TBDPS ether was treated with
a palladium source in acetic acid to give allylic gem-di-
acetate 17, which, without purification, was exposed to
the action of triethylamine in methanol to give aldehyde
18. Key acid 19 was finally accessed by oxidation of 18
with sodium chlorite in tert-BuOH. The synthesis of (+)-
BFC was now well within reach, with only macrocyclisa-
tion and deprotection of alcohol functionalities as re-
exposed to propargylic acetate in the presence of zinc tri-
flate, triethylamine and (–)-N-methylephedrine under the
reported conditions. The required propargylic alcohol 15a
was then isolated in excellent chemical yield and with a
good diastereoselectivity (95:5).12 As shown in Scheme 6,
switching (–)-N-methylephedrine to its (+)-enantiomer af-
forded epimeric alcohol at C4 with a somewhat lower
diastereoselectivity whereas, in the presence of racemic
quired steps. Towards this end, PMB cleavage was first
O
O
H
H
H
OMe
OPMB
H
OPMB
5
a,b
9
H
H
Me
Me
H
14
4
additive
selectivity
OH
15a/15b
H
OAc
4
OPMB
c
5
95/5
8/92
52/48
(–)- N-methylephedrine
(+)- N-methylephedrine
( )- N-methylephedrine
9
H
Me
H
15a α-OH
15b β-OH
Scheme 6 Reagents and conditions: a) LiAlH4, Et2O, 0–25 °C, 3 h, 85%; b) (COCl)2 (1.1 equiv), DMSO (2.2 equiv), CH2Cl2, –60 °C, 15
min then DIEA (5 equiv), –60 °C to r.t., 89%; c) Zn(OTf)2 (4.2 equiv), (–)-N-methylephedrine (3.2 equiv), Et3N (3.2 equiv), toluene, 23 °C, 2
h then propargylic acetate (3.2 equiv), 23 °C, 15 min then 14 (1 equiv), 23 °C, 24 h, 93%.
Synlett 2005, No. 1, 139–143 © Thieme Stuttgart · New York

142
S. Archambaud et al.
LETTER
OTBDPS
OTBDPS
H
H
H
H
H
H
OAc
OAc
OPMB
OPMB
H
a
b
15a
OAc
H
Me
Me
16
17
OTBDPS
OTBDPS
H
CO2H OPMB
CHO
OPMB
c
d
H
H
Me
Me
H
18
19
OTBDPS
OTBDPS
H
H
H
O
CO2H OH
e
H
f
O
H
Me
Me
H
21
20
g
(+) -BFC
2
Scheme 7 Reagents and conditions: a) 15a (1 equiv), DMF, imidazole (2.5 equiv), TBDPSCl (1.2 equiv), 0 °C to r.t., 12 h, 96%; b) Pd(PPh3)4
(0.05 equiv), PPh3 (0.6 equiv), toluene, HOAc (1.5 equiv), r.t., 20 min then 16 (1 equiv), 110 °C, 1 h, 51% (+33% of 18); c) 17, MeOH, Et3N
(3.25 equiv), r.t., 12 h, 80%; d) 18, 2-methyl-2-butene (120 equiv), tert-BuOH, 0 °C then NaO2Cl (1.5 equiv), NaH2PO4·2H2O (1.5 equiv), H2O
(tert-BuOH–H2O 1.25:1), r.t., 24 h, 98%; e) 19, CH2Cl2–H2O (20:1), DDQ (1.5 equiv), r.t., 12 h, 78%; f) 20, THF, Et3N (1.4 equiv), 2,4,6-
trichlorobenzyl chloride (1.12 equiv), r.t., 8 h then toluene (toluene–THF 10:1), addition to DMAP (6.8 equiv) in toluene, reflux, 16 h, 79%; g)
21, THF, n-Bu4NF (1.5 equiv), r.t., 6 h, 78%.
accomplished with DDQ in CH2Cl2 at ambient tempera-
ture to give the hydroxy acid 20, which was next cyclised
via its Yamaguchi mixed anhydride13 to afford the desired
macrocyclic lactone 21 isolated in 79% yield after chro-
matography. Finally, deprotection of the silyl ether with
TBAF in THF completed the assembly of (+)-brefeldin C
(Scheme 7). The spectroscopic (1H NMR, 13C NMR,
HRMS) and physical properties (melting point, optical ro-
tation) were identical in all respects with those of natural
BFC. Moreover, an X-ray crystallographic study14 unam-
biguously confirmed the structure and stereochemistry of
the synthetic BFC, revealing its virtually identical solid-
state conformation with that of BFA.
Acknowledgment
This work was supported by grants from the CNRS and INSERM
(‘Physique et Chimie du Vivant’ and ‘Molécules et Cibles Théra-
peutiques’). We are indebted to D. Brégeon for preliminary experi-
ments, to M.-J. Bertrand for technical assistance and to Pr. J.
Lebreton (Université de Nantes) and Dr J. Cherfils (LEBS, CNRS,
Gif sur Yvette) for useful discussions.
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In conclusion, a convergent and highly stereocontrolled
total synthesis of (+)-brefeldin C was accomplished be-
ginning with the desymmetrisation of anhydride 7. The
palladium-mediated Suzuki cross-coupling and the Car-
reira alkynylation reaction were the keystones of the strat-
egy for the stereoselective union of fragments 2 and 3 to
the chiral acid-ester 6. Overall, this synthesis required a
total of 16 steps in its longest linear sequence with an
overall yield of ca. 4.6%. We are currently developing an
analogous, modular strategy for the synthesis of a small
library of BFA and BFC analogues.
Synlett 2005, No. 1, 139–143 © Thieme Stuttgart · New York

LETTER
New Total Synthesis of (+)-Brefeldin C
143
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Synlett 2005, No. 1, 139–143 © Thieme Stuttgart · New York