Total synthesis of (+)-brefeldin c utilizing aza-Claisen rearrangement

Article abstract of DOI:10.1055/s-0030-1260762

The total synthesis of (+)-brefeldin C was accomplished. An asymmetric aza-Claisen rearrangement developed by our laboratory was employed to construct the C-4 and C-5 stereogenic centers of (+)-brefeldin C as a key step. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260762

LETTER
1459
Total Synthesis of (+)-Brefeldin C Utilizing Aza-Claisen Rearrangement
T
otal
S
ynthesis of (+)-
a
Brefeldin
C
koto Inai, Takeshi Nishii, Shingo Mukoujima, Tomoyuki Esumi, Hiroto Kaku, Keiko Tominaga,
Hiroaki Abe, Mitsuyo Horikawa, Tetsuto Tsunoda*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
Fax +81(88)6553051; E-mail: tsunoda@ph.bunri-u.ac.jp
Received 8 March 2011
be carried out at a later stage of the synthesis. The seco-
acid 5 could be prepared from aldehyde 6 and known phe-
nyl tetrazole sulfone 7 by a Julia–Kocienski reaction.7 So,
amide 9 could be targeted as the key intermediate, which
would be converted to 6 via lactol 8. From our previous
results,1,2 it was expected that the asymmetric aza-Claisen
rearrangement of 10 could construct the two consecutive
stereogenic centers of 5 via the rearranged product 9.8
Abstract: The total synthesis of (+)-brefeldin C was accomplished.
An asymmetric aza-Claisen rearrangement developed by our labo-
ratory was employed to construct the C-4 and C-5 stereogenic cen-
ters of (+)-brefeldin C as a key step.
Key words: aza-Claisen rearrangement, amide enolate, asymmet-
ric synthesis, brefeldin C, natural product synthesis
The aza-Claisen rearrangement of amide enolates 1 devel-
oped by us afforded amides 2, [3,3]-sigmatropic products,
with excellent stereoselectivities (syn/anti > 98:2, RS/
SR = 10:1; Scheme 1).1 The reaction could be applied to
substrates containing heteroatom on the rearranging
framework (X = alkyl, OH, NH, Y = alkyl, OR) and has a
potential for broad use in the stereocontrolled construc-
tion of carbon skeletons occurring in natural products
such as (–)-isoiridomyrmecin,2a (+)-a-skytanthine,2b anti-
mycin A3b2c,d and halipeptin A–D.2e–g
OH
H
O
O
4
15
7
5
R
9
H
(+)-brefeldin C (3) R = H
(+)-brefeldin A (4) R = OH
Figure 1 Structures of (+)-brefeldin C and A
OR
OR
H
H
O
H
O
OH
OR
OH
3
N
Ph
OLi
aza-Claisen
HN
Ph
CHO
S
6
R
H
rearrangement
5
Y
Y
O
H
X
1
SO2PT
OTBS
X
X = Alk, OH, OR, NH2
Y = Alk, OR
2
7
Scheme 1 Aza-Claisen rearrangement
OH
OH
OH
H
H
H
O
O
OH
In order to demonstrate its applicability to the synthesis of
natural products, we chose (+)-brefeldin C (3, Figure 1)
isolated from Penicillium brefeldianum by Nozoe and his
co-workers as a synthetic target.3 (+)-Brefeldin C (3) is a
biosynthetic precursor of (+)-brefeldin A (1), which pos-
sesses unique biological activities such as disassembly of
the Golgi apparatus.4 (+)-Brefeldin C (3) has a 13-mem-
bered macrolide with a trans-fused five-membered ring
system bearing four stereogenic centers and two trans-
olefins and also shows biological activity.5 Therefore,
several total syntheses of 3 have been reported since
Schreiber’s first total synthesis.6 Herein we report the to-
tal synthesis of 3 utilizing the aza-Claisen rearrangement
as a key step.
N
HN
O
Ph
Ph
10
9
8
Scheme 2 Retrosynthetic analysis of (+)-brefeldin C (3)
For the synthesis of the bicyclic lactone 16 (Scheme 3),
tosyl amide 13 was chosen as a starting material that was
easily prepared by the Mitsunobu reaction (TMAD/Bu3P)
of known alcohol 119 with chiral auxiliary 12 made from
(R)-phenethylamine.10 After the removal of the tosyl
group under the Birch reaction conditions,11 the desired
amine was acylated with 2-acetoxyacetyl chloride in pyri-
dine–CH2Cl2 and hydrolyzed with LiOH·H2O in a mixture
of MeOH and H2O to afford the precursor 10 for the rear-
rangement in excellent yield. As the aza-Claisen rear-
rangement of 2-hydroxyacetamide had already been
carried out using 2.5 equivalents of LHMDS and had pro-
ceeded in excellent yield without any protection of the hy-
droxy group,1 precursor 10 was treated directly under the
Our retrosynthetic analysis of 3 is illustrated in Scheme 2.
The construction of the 13-membered lactone ring could
SYNLETT 2011, No. 10, pp 1459–1461
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260762; Art ID: U02411ST
© Georg Thieme Verlag Stuttgart · New York

1460
M. Inai et al.
LETTER
same conditions with LHMDS (2.5 equiv) at –78 °C and
then heated at 65 °C for 36 hours to give rearranged amide
(SR)-9a as a major product along with (RS)-9b and a trace
of silylated 14 with the TMS group. The mixture of amide
9a/9b and its silyl ether 14a/14b was treated with TBAF
in THF to give the separable mixture of 9a and 9b, and the
ratio of 9a/9b was determined by HPLC analysis to be
85:15. After separation by SiO2 column chromatography,
the pure amide (SR)-9a was converted to lactone 16 by the
hydroboration of the exo-olefin with catecholborane fol-
lowed by acidic cyclization with p-toluenesulfonic acid.
OH
OH
H
H
H
H
O
LiAlH4
OH
Ph3P=CHCOOEt
THF, 0 °C
92%
toluene, 80 °C
77%
O
O
16
8
OH
1) TBSCl, Et3N, CH2Cl2, 85%
2) TIPSOTf, DIPEA, CH2Cl2, quant.
H
4
COOEt
COOEt
3) 1 M aq HCl, EtOH, 92%
OH
H
17
1) DMP
OTIPS
OTIPS
H
CH2Cl2, 0 °C
H
Ts
Ts
N
TMAD, Bu3P
benzene
92%
HN
4
4
COOEt
+
9
OH
2) DBU
OH
Ph
CHO
Ph
CH2Cl2, 0 °C
96%
11
12
13
H
H
19
18
1) Na, NH3–THF, –78 °C
2) AcOCH2COCl
pyridine, CH2Cl2
73% (3 steps)
Scheme 4 Synthesis of key intermediate 20
OH
LHMDS (2.5 equiv)
toluene, –78 °C;
O
Kocienski reaction in 91% yield.7 The selective cleavage
of the TBS group under acidic conditions followed by hy-
drolysis with 1 M aqueous NaOH gave the seco-acid 21.
The macrocyclization of 21 was achieved using the
Yamaguchi method in 89% yield.13 Finally, removal of
the TIPS group with TBAF furnished (+)-brefeldin C (3).
All spectroscopic data {[a]D, 1H NMR, 13C NMR, IR, and
HRMS}14 for the synthetic (+)-brefeldin C (3) agreed with
those reported previously in the literature.6d
65 °C, 36 h
3) LiOH⋅H2O
MeOH–H2O, 0 °C, 98%
N
10
Ph
OR
OR
H
S
H
R
O
O
1) separation
R
S
+
2) catecholborane;
H2O2, NaOH
THF
HN
Ph
HN
Ph
85%
14a R = TMS
9a R = H
TBAF
THF
14b R = TMS
9b R = H
TBAF
THF
OTIPS
H
9a/9b = 85:15 (total 85%, 2 steps)
SO2PT
OTBS
KHMDS, 19
COOEt
OTBS
OH
S
OH
O
DME
–78 °C to r.t.
91%
H
H
O
TsOH⋅H2O
H
7
R
20
HN
toluene, 80 °C
89%
O
H
H
OTIPS
OH Ph
1) 1 M HCl
H
H
16
THF, 90%
15
COOH
OH
2) 1 M NaOH
EtOH, quant.
Scheme 3 Synthesis of lactone 16
21
The reduction of lactone 16 with LiAlH4 in THF, followed
by the Wittig reaction of lactol 8 with ethyl (triphe-
nylphosphoranylidene)acetate in toluene at 80 °C afford-
ed a,b-unsaturated ester 17 (Scheme 4).
1) 2,4,6-Cl3C6H2COCl
Et3N, THF
2) DMAP, toluene (1 x 10–3 M)
reflux, 89%
OH
H
H
O
O
3) TBAF, THF, 0 °C, quant
The protection of the secondary hydroxy group at the C-4
position was carried out in a three-step sequence (silyla-
tion of the primary alcohol with a TBS group, silylation of
the secondary alcohol with a TIPS group, and then selec-
tive cleavage of the TBS group with 1 M aqueous HCl in
EtOH). Oxidation of 18 with Dess–Martin periodinane
(DMP)12 and subsequent epimerization of the C-9 posi-
tion with DBU in CH2Cl2 gave 19 in high yield (88% yield
in 2 steps).6b
(+)-brefeldin C (3)
Scheme 5 Total synthesis of (+)-brefeldin C (3)
Thus, we achieved the total synthesis of (+)-brefeldin C
(3) utilizing asymmetric aza-Claisen rearrangement as a
key step. Further synthetic studies of not only the (+)-
brefeldin A (4) and its analogues, but also other variants
of the analogues and investigation of their biological ac-
tivities are now in progress.
With the desired key intermediate 19 in hand, we focused
on the construction of the 13-membered macrolactone
ring and total synthesis of (+)-3 (Scheme 5). Aldehyde 19
was coupled with phenyl tetrazole sulfone 7 by a Julia–
Synlett 2011, No. 10, 1459–1461 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (+)-Brefeldin C
1461
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Acknowledgment
This work was supported partially by a Grant-in-Aid for Scientific
Research (C) from MEXT (the Ministry of Education, Culture,
Sports, Science and Technology of Japan). We are also thankful to
MEXT-Senryaku, 2008-2012.
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[a]D19 +119.8 (c 1.00, CHCl3) {lit.6d [a]D20 +121 (c 0.07,
MeOH)}. 1H NMR (600 MHz, CDCl3): d = 7.38 (dd,
J = 15.6, 3.0 Hz, 1 H), 5.91 (dd, J = 15.6, 1.92 Hz, 1 H), 5.73
(ddd, J = 15.1, 10.4, 4.7 Hz, 1 H), 5.19 (dd, J = 15.1, 9.6 Hz,
1 H), 4.86 (dqd, J = 10.8, 6.3, 1.9 Hz, 1 H), 4.10 (br d,
J = 9.6 Hz, 1 H), 2.25 (quin, J = 8.8 Hz, 1 H), 2.03–1.98 (m,
2 H), 1.89–1.81 (m, 3 H), 1.76–1.51 (m, 6 H), 1.41–1.35 (m,
1 H), 1.26 (d, J = 6.3 Hz, 3 H), 0.98–0.92 (m, 1 H). 13C NMR
(125 MHz, CDCl3): d = 166.3, 152.0, 136.3, 130.3, 117.3,
76.0, 71.7, 54.0, 46.9, 35.1, 34.1, 31.9, 31.8, 26.8, 25.2, 20.9.
IR (ATR): 3406, 2933, 1713 cm–1. MS (CI): m/z = 265 [M +
H]+, 247 (base peak), 201. HRMS (CI): m/z [M + H]+ calcd
for C16H25O3: 265.18036; found: 265.1789.
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Synlett 2011, No. 10, 1459–1461 © Thieme Stuttgart · New York