Synthesis of aspergillide A from a synthetic intermediate of aspergillide B

Article abstract of DOI:10.1016/j.tetlet.2009.12.032

The first synthesis of aspergillide A, a cytotoxin produced by a marine-derived fungus, has been achieved from a synthetic intermediate of aspergillide B by using a proline-mediated epimerization of a 2,6-trans-substituted tetrahydropyran-2-acetaldehyde intermediate into the corresponding cis-isomer via a retro-oxy-Michael/oxy-Michael sequence as the key transformation.

Full text of DOI:10.1016/j.tetlet.2009.12.032

Tetrahedron Letters 51 (2010) 875–877
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Tetrahedron Letters
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Synthesis of aspergillide A from a synthetic intermediate of aspergillide B
*
Tomohiro Nagasawa, Shigefumi Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of aspergillide A, a cytotoxin produced by a marine-derived fungus, has been achieved
from a synthetic intermediate of aspergillide B by using a proline-mediated epimerization of a 2,6-trans-
substituted tetrahydropyran-2-acetaldehyde intermediate into the corresponding cis-isomer via a retro-
oxy-Michael/oxy-Michael sequence as the key transformation.
Received 13 November 2009
Revised 7 December 2009
Accepted 8 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aspergillide
Cytotoxic
Macrolide
Epimerization
In the course of screening for bioactive substances from marine-
derived fungi, Kusumi and co-workers isolated three cytotoxic
compounds, aspergillides A–C, from a bromine-modified 1/2PD
(potato-dextrose) culture medium of Aspergillus ostianus strain
01F313, and proposed their structures to be 14-membered macro-
lides I, II, and III, respectively, based on spectroscopic analyses
including NOESY experiments and the modified Mosher method
(Fig. 1).1 The proposed structure of aspergillide C (III) was con-
firmed by our total synthesis,2 while the stereochemical assign-
ment of aspergillides A and B was found to be incorrect through
the total synthesis of I and II by Hande and Uenishi.3 They revealed
that the physical and spectral data of their synthetic compound I
were identical to those reported by Kusumi and co-workers for
aspergillide B, and the data of synthetic II did not match those re-
ported either for aspergillide A or for aspergillide B. These results
enabled them to conclude that the genuine structure of aspergil-
lide B must be 2 (Fig. 2), and the real structure of aspergillide A
should be reinvestigated. Ooi and co-workers answered the ques-
tion regarding the structure of aspergillide A by means of X-ray
crystallographic analysis of its m-bromobenzaoate derivative,
which clarified that aspergillide A was the C3 epimer of aspergil-
lide B (compound 1, Fig. 2) possessing a 3,7-cis relationship as well
as 3R absolute configuration.4
O
O
H
O
O
H
O
O
H
O
O
O
H
H
H
HO
HO
HO
I
II
III
(aspergillide A)
(aspergillide B)
aspergillide C
Figure 1. Originally proposed structures of aspergillides A (I), B (II), and C (III).
of III7 have been published. However, no report concerning the
synthesis of aspergillide A (1) has appeared to date. We describe
herein the first synthesis of aspergillide A via a proline-mediated
isomerization of a 2,6-trans-substituted tetrahydropyran-2-acetal-
dehyde intermediate into the corresponding cis-isomer.
Since aspergillide A (1) and aspergillide B (2) are epimeric to
each other at the alkoxy-bearing C3 position b to the lactone car-
bonyl, we envisaged that they might be interconvertible via a ret-
ro-oxy-Michael/oxy-Michael equilibrium sequence. Concerned
about the possible formation of a
intramolecular attack of the C4 hydroxyl to the carbonyl group
c-lactone from 2 through the
Prompted by the unique molecular architecture of aspergillides
A (1), B (2), and C (III), the latter two of which possess a very rare
2,6-trans-substituted tetrahydro- and dihydropyran structural
unit, respectively, embedded in a 14-membered macrolide struc-
ture,5 three additional syntheses of 26 and an additional synthesis
O
O
H
O
O
H
O
O
H
H
3
7
R
S
HO
HO
1
2
aspergillide A
aspergillide B
* Corresponding author. Tel./fax: +81 22 717 8783.
E-mail address: skuwahar@biochem.tohoku.ac.jp (S. Kuwahara).
Figure 2. Revised stereochemistries of aspergillides A and B.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.032

876
T. Nagasawa, S. Kuwahara / Tetrahedron Letters 51 (2010) 875–877
PMBO
RO
OHC
PMBO
OHC
O
O
O
O
epimerization
R1O
a
d
e
1
6
O
O
O
O
O
a) DBU, PhMe
or
b) KOt-Bu, THF
3
7
3
7
TBSO
TBSO
R2O
TBSO
TBSO
13: R = PMB
14: R = H
12
3
4
9: R1 = R2 = H
f
b
c
10: R1 = R2 = TBS
(ref. 6c)
11: R1 = H, R2 = TBS
Scheme 1. Attempted epimerization of TBS-protected aspergillide B (3) to TBS-
protected aspergillide A (4).
OTBS
O
O
O
O
O
O
h
g
during the attempt to directly epimerize 2 into 1, we chose the
TBS-protected form of 2 (compound 3, Scheme 1), the penultimate
intermediate in Uenishi’s and our syntheses of aspergillide B,3,6c as
the substrate for the epimerization. Thus, the 3,7-trans isomer 3
was first subjected to DBU in toluene in the hope of obtaining
the corresponding 3,7-cis isomer 4, the TBS ether of 1. The basic
treatment, however, did not afford the desired product 4 even at
elevated temperatures, resulting only in the recovery of the start-
ing material 3. The use of KOt-Bu as a stronger base also brought
no fruitful outcome, giving only the starting material at room tem-
perature or a complex mixture at 45 °C.8
Faced with the difficulty to epimerize the 3,7-trans macrolactone
3 into the corresponding cis-isomer 4, we next planned to prepare
3,7-cis-substituted seco acid 5 beforehand and then macrolactonize
it into 4 (Scheme 2). As a possible precursor of 5, we chose 3,7-trans-
substituted lactone 6 since it was known to be obtainable very
efficiently from 7 and 8 in our previous synthesis of aspergillide B
(2),2,6c and the requisite stereochemical inversion at the C3 position
of 6 on its way to 5 was expected to be possible from literature prece-
dents by conducting an appropriate epimerization reaction on a
suitable intermediate before macrolactonization.9
The elaboration of 6 to 1 commenced with the reductive open-
ing of the lactone ring of 6 with LiAlH4 to give diol 9. Protection of
the two hydroxyl groups of 9 to bis-TBS ether 10 was followed by
selective removal of the protecting group at the primary hydroxyl,
affording 11 in 86% yield for the three steps (Scheme 3). Oxidation
of the resulting alcohol with Dess–Martin’s periodinane proceeded
smoothly to furnish aldehyde 12, which set the stage for the key
transformation in the present synthesis, the epimerization at the
C3 position of the 3,7-trans-substituted intermediate 12 to the cor-
responding 3,7-cis isomer 13. The conversion of 12 into 13 was
realized very efficiently by the Massi–Dondoni protocol using pro-
line as the epimerization catalyst.10 Thus, the treatment of 12 with
5
O
O
O
RO
4: R = TBS
1: R = H
15
i
TBSO
Scheme 3. Conversion of 6 into aspergillide A (1). Reagents and conditions: (a)
LiAlH4, THF, 0 °C to rt, 1 h; (b) TBSOTf, Et3N, CH2Cl2, 0 °C to rt, 1 h; (c) CSA
(0.2 equiv), CH2Cl2/MeOH, 0 °C, 1 h (86%, three steps); (d) Dess–Martin’s period-
inane, NaHCO3, CH2Cl2, rt, 5 h (97%); (e) D-proline (0.3 equiv), MeOH, 0 °C, 1 h, then
60 °C, 3 h (81%); (f) DDQ, phosphate buffer (pH 7.0), CH2Cl2, rt, 8 h (80%); (g)
NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O, 0 °C, 7 h (97%); (h)
Cl3C6H2COCl, Et3N, THF, 0 °C to rt, 2 h, then DMAP, PhMe, 80 °C, 8 h (30%); (i)
TBAF, THF, rt, 2 h (76%).
sired 3,7-cis isomer 13.11 After deprotection of the PMB group of
13 by DDQ oxidation, the resulting product 14 was oxidized to
the seco acid 5 by the Pinnick oxidation. Unexpectedly, the macrol-
actonization of 5 into 4 was found to be problematic in contrast to
the case of the corresponding 3,7-trans seco acid, which under-
went smooth macrolactonization under the Yamaguchi lactoniza-
tion conditions and led, after deprotection, to aspergillide B (2) in
previous synthetic studies.3,6c On treatment of 5 with 2-methyl-
6-nitrobenzoic anhydride in the presence of DMAP in CH2Cl2 at
room temperature for 28 h (Shiina’s method),12 no desired product
4 was obtained, but instead dimeric macrodiolide 15 was isolated
in 22% yield. Gerlach’s modification of the Corey–Nicolaou macrol-
actonization (PySSPy, Ph3P, AgBF4, PhMe, 110 °C, 54 h)13 and mod-
ified Mukaiyama’s lactonization conditions (2-bromo-1-
ethylpyridinium tetrafluoroborate, Et3N, MeCN, 90 °C, 6 h)14 both
gave complex mixtures. The only successful result was obtained
when the seco acid 5 was subjected to Yamaguchi’s conditions
(Cl3C6H2COCl, Et3N, THF, then DMAP, PhMe, 81 °C, 8 h; substrate
concentration, 0.8 mM),15 which gave the desired product 4 in
30% yield along with 19% of the dimeric product 15.16,17 Unfortu-
nately, all attempts to improve the chemical yield of 4 by varying
the reaction conditions (mainly, reaction temperature, and concen-
tration) were unsuccessful and could not exceed the above-men-
tioned yield (30%). Finally, the TBS-protecting group of 4 was
removed with TBAF to give aspergillide A (1) as a crystalline solid
(mp 64.5–65.5 °C) after chromatographic purification. The specific
rotation and spectral data of 1 were in good agreement with those
reported in the literature.1,18
D-proline for 1 h at 0 °C and for an additional 3 h at 60 °C gave a
95:5 epimeric mixture of 13 and 12 in 81% yield favoring the de-
O
O
OH
HO2C
TBSO
1
O
O
3
7
TBSO
In conclusion, the first synthesis of aspergillide A (1) was accom-
plished from 6, an intermediate in our total synthesis of aspergillide
B, by using the proline-mediated epimerization of the 3,7-trans-
substituted cyclic intermediate 12 into the corresponding cis-iso-
mer 13 as the key step. Efforts to develop a more efficient synthetic
route to 1, including the improvement of the macrolactonization
step, are now underway and will be reported in due course.
4
5
CO2Me
PMBO
O
PMBO
7
O
(refs. 2,6c)
OTBS
O
Acknowledgments
O
8
6
We thank Ms. Yamada (Tohoku University) for measuring NMR
and MS spectra. This work was supported, in part, by a Grant-in-
Scheme 2. Synthetic plan for aspergillide A (1) from known compound 6.

T. Nagasawa, S. Kuwahara / Tetrahedron Letters 51 (2010) 875–877
877
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ꢀ
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