Asymmetric total synthesis of pseurotin A

Article abstract of DOI:10.1021/ol034630s

(Matrix presented) The asymmetric total syntheses of pseurotin A and 8-O-demethylpseurotin A have been accomplished. Key reactions are a NaH-promoted intramolecular cyclization of an alkynylamide to form a γ-lactam, an aldol reaction of a benzylidene-subs

Full text of DOI:10.1021/ol034630s

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2287-2290
Asymmetric Total Synthesis of
Pseurotin A
,†
Yujiro Hayashi,* Mitsuru Shoji,† Shinpei Yamaguchi,† Takasuke Mukaiyama,†
Junichiro Yamaguchi,† Hideaki Kakeya,‡ and Hiroyuki Osada‡
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan, and Antibiotics Laboratory,
DiscoVery Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
hayashi@ci.kagu.tus.ac.jp
Received April 11, 2003
ABSTRACT
The asymmetric total syntheses of pseurotin A and 8-O-demethylpseurotin A have been accomplished. Key reactions are a NaH-promoted
intramolecular cyclization of an alkynylamide to form a γ-lactam, an aldol reaction of a benzylidene-substituted ketone, and the late-stage
introduction of the benzoyl group by a selective oxidation of a benzylidene moiety with dimethyldioxirane (DMD).
The pseurotins are a small family of secondary microbial
metabolites isolated from a culture broth of Pseudeurotium
oValis (strain S2269/F) in 1976 by P. Bloch and C. Tamm
et al.1 Pseurotin A was reported to inhibit chitin synthase
by Sterner et al. in 19932 and also found to induce cell
differentiation of PC12 cells by Komagata et al. in 1995.3
Structurally, it contains a novel, highly substituted, and
oxygenated 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skel-
eton with five chiral centers (Figure 1). The structure of
pseurotin A, including its absolute stereochemistry, has been
unambiguously determined by a single-crystal X-ray analysis
of its 12,13-dibromo derivative.4 Recently, azaspirene, pos-
sessing the same core structure, has been isolated from the
fungus Neosartorya sp. by Kakeya and Osada et al. and
found to inhibit the endothelial migration induced by vascular
endothelial growth factor.5 Because of the unprecedented,
densely functionalized core structure of the pseurotins and
azaspirene, their total synthesis poses a significant challenge,
and several synthetic endeavors aimed at the total synthesis
of pseurotin A have been reported.6 We have completed the
first total synthesis of a member of this class of compounds,
that of azaspirene, in which a Sharpless asymmetric dihy-
droxylation, a MgBr2-mediated, highly diastereoselective
Mukaiyama aldol reaction, and a NaH-mediated, intramo-
lecular addition of an amide to an alkyne are employed as
key steps.7 Just recently, Tadano et al. have orally presented
syntheses of pseurotin A and of 8-O-demethylpseurotin A2
from D-glucose.8 At the same time, as described in this paper,
our group has also accomplished total syntheses of both
pseurotin A and 8-O-demethylpseurotin A from the key
intermediate in our synthesis of azaspirene.
† Tokyo University of Science.
‡ RIKEN.
(1) (a) Bloch, P.; Tamm, C.; Bollinger, P.; Petcher, T. J.; Weber, H. P.
HelV. Chim. Acta, 1976, 59, 133. (b) Bloch, P.; Tamm, C. HelV. Chim.
Acta, 1981, 64, 304. (c) Breitenstein, W.; Chexal, K. K.; Mohr, P.; Tamm,
C. HelV. Chim. Acta, 1981, 64, 379.
(5) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.; Osada,
H. Org. Lett. 2002, 4, 2845.
(6) (a) Dolder, M.; Shao, X.; Tamm, C. HelV. Chim. Acta, 1990, 73, 63.
(b) Shao, X.; Dolder, M.; Tamm, C. HelV. Chim. Acta, 1990, 73, 483. (c)
Su, Z.; Tamm, C. HelV. Chim. Acta, 1995, 78, 1278. (d) Su, Z.; Tamm, C.
Tetrahedron 1995, 51, 11177. (e) Aoki, S.; Ohi, T.; Shimizu, K.; Shiraki,
R.; Takao, K.; Tadano, K. Heterocycles 2002, 58, 57.
(7) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.;
Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am. Chem.
Soc. 2002, 124, 12078.
(2) Wenke, J.; Anke, H.; Sterner, O. Biosci. Biotech. Biochem. 1993,
57, 961.
(3) Komagata, D.; Fujita, S.; Yamashita, N.; Saito, S.; Morino, T. J.
Antibiot. 1996, 49, 958.
(4) Weber, H. P.; Petcher, T. J.; Bloch, P.; Tamm, C. HelV. Chim. Acta,
1976, 59, 137.
10.1021/ol034630s CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/30/2003

oxidation12 of the secondary alcohol afforded ethyl ketone
4 containing the fully functionalized γ-lactam moiety.
Scheme 2. Synthesis of γ-Lactam 4
Figure 1. Structures of pseurotin A and azaspirene.
Our retrosynthetic analysis is as follows: Pseurotin A
might be prepared by consecutive aldol and dehydration
reactions between side-chain aldehyde 36a and an ethyl ketone
containing the fully functionalized γ-lactam moiety 4, which
in turn could be synthesized from γ-lactam 5. It should be
possible to prepare γ-lactam 5 from our synthetic intermedi-
ate for azaspirene 67 by functional group transformation
(Scheme 1).
Scheme 1. First Retrosynthesis of Pseurotin A
With a practical route to ethyl ketone 4 in hand, its aldol
condensation with n-butanal, a model aldehyde, was inten-
sively investigated. Despite extensive experimentation on this
key aldol reaction, the desired aldol product could only be
obtained in low yield, with mostly decomposition of the
γ-lactam moiety occurring at the stage of enolate generation
(Scheme 3). The Mukaiyama aldol reaction cannot be
The synthesis of ethyl ketone 4 starts from methyl
pentenoate and follows our procedure for azaspirene up to
alcohol 8 (Scheme 2).7 The hydroxy group of 8 was protected
using benzyl bromide and NaH. Although attempts at the
direct conversion of ester 9 into amide 6 by literature
procedures proved to be fruitless due to steric hindrance
around the ester moiety, a two-step transformation worked
well; the hydrolysis of ester 9 to carboxylic acid 10,
conversion to the acid chloride, and treatment with ammonia
afforded amide 6 in 45% yield, with recovery of carboxylic
acid 10 in 34% yield. The relative stereochemistry of 6 has
been unambiguously determined by a single-crystal X-ray
analysis.9 Protection of amide 6 with the Boc group by KH
and Boc2O and oxidation of the alkyne with KMnO4 in
acetone-buffer solution10 gave a single isomer 12, the
stereochemistry of which has not been determined. Treatment
of 12 with MeI and Ag2O11 afforded the methyl ethers 5R
and 5â in 82% yield with the desired isomer predominating
(5R:5â ) 4:1). Removal of the acetonide and Corey-Kim
Scheme 3. Attempt of Aldol Reaction of 4
examined because silyl enol ethers of 4 cannot be prepared
even using Corey’s in situ trapping method.13 As we suppose
that the benzoyl substituent causes the instability of ketone
4 under the basic conditions of enolate formation, we turned
(8) Aoki, S.; Oi, T.; Shimizu, K.; Shiraki, R.; Takao, K.; Tadano, K.
Abstracts of Papers, 44th Symposium on the Chemistry of Natural Products,
Tokyo, Japan, 2002; p 73.
(9) Details of the crystallographic data, see ref 7.
(10) Srinivasan, N. S.; Lee, D. G. J. Org. Chem. 1979, 44, 1574.
(11) Greene, A. E.; Drian, C. L.; Crabbe, P. J. Am. Chem. Soc. 1980,
102, 7583.
(12) (a) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586. (b)
Corey, E. J.; Kim, C. U.; Misco, P. F. Organic Syntheses; Wiley: New
York, 1988; Collect. Vol. VI, p 200.
(13) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
2288
Org. Lett., Vol. 5, No. 13, 2003

ethyl ketone 14 having a triisopropylsilyl (TIPS) ether and
a benzylidene group, which is a key intermediate in our total
synthesis of azaspirene,7 was employed as the aldol donor.
Scheme 4. Synthesis of Benzylidene γ-Lactam 13
The lithium enolate of 147 reacted with side-chain aldehyde
3 (E:Z ) 4:1) prepared by the literature procedure,6a affording
the aldol product 15 in 54% yield (diastereomeric ratio )
2:1) with recovery of ketone 14 in 45% yield (Scheme 5).
Oxidation of aldols 15 with the Dess-Martin periodinane15
(DMP) in CH2Cl2 proceeded smoothly, providing 1,3-
1
our attention to other ketones containing a synthetic equiva-
lent of the benzoyl group.
diketone 16. H NMR suggests that the oxidized product
exists mostly in the 1,3-diketo form, rather than the keto-
enol form. On attempting to purify 16 by thin-layer-
chromatography (TLC), spiro compounds 17 and 18 were
formed via cyclization and dehydration reactions due to the
mild acidity of silica gel. Other acids such as p-TsOH‚H2O
and acetic acid were ineffective,16 because side reactions such
as hydration to benzylidene moiety and deprotection of
acetonide took place. The second TLC treatment converted
17 to 18 completely (68% yield from 15), with separation
from the contaminating side-chain (E)-isomer.
The unexpected experimental results described below
promoted us to select a ketone with a benzylidene substituent
as the aldol donor. In the previous transformation of 6 to
11, Boc-protected amide 11 was obtained in good yield on
treatment of amide 6 with KH in the presence of Boc2O.
Surprisingly, however, during the optimization of this step,
it was found that benzylidene γ-lactam 13 was obtained in
51% yield without formation of the desired Boc-protected
amide 11 when amide 6 was first treated with KH and then
with Boc2O. After screening the reaction conditions, we
found that the yields of (Z)- and (E)-γ-lactams 13 could be
increased to 86 and 9%, respectively, when amide 6 was
treated with NaH in DMF under ultrasound radiation
(Scheme 4).
The next task is selective oxidation of the benzylidene
moiety without affecting the other olefinic parts. It was found
that choice of oxidant and temperature are keys for the
success of this reaction. Dimethyldioxirane14a,17 (DMD) is
the best oxidant, and when 18 was treated with DMD at low
temperature (-60 °C) for 12 h in the presence of MS3A,
diol 19 was obtained in moderate yield (62%) as a single
isomer, the stereochemistry of which has not been deter-
mined, with recovery of the starting material 18 in 33% yield
without formation of the methoxylactam. Diol 19 would be
formed via opening of the intermediate epoxide with
contaminating water.14a At higher temperatures or with
There are literature precedents for this intramolecular
addition of an amide to nonactivated alkynes,14 and this is a
powerful method for construction of the γ-lactam portion.
As the benzylidene moiety can be transformed into a benzoyl
group by mild oxidation, this ketone containing a benzylidene
moiety should be a suitable aldol donor. As benzyl (Bn)
group could not be removed at the late stage of the synthesis,
Scheme 5. Total Synthesis of Pseurotin A
Org. Lett., Vol. 5, No. 13, 2003
2289

prolonged treatment with DMD, the alkene in the side chain
was also oxidized to its epoxide. Oxidation of alcohol 19
with DMP proceeded smoothly, affording benzoyl derivative
20 in moderate yield (68%).
pseurotin A and 8-O-demethylpseurotin A exhibited proper-
ties identical to those of the natural products.
In summary, asymmetric total syntheses of pseurotin A
(1) and of 8-O-demethylpseurotin A (22) have been achieved.
There are several noteworthy features to the route used: the
NaH-promoted intramolecular cyclization of an alkynylamide
to form the γ-lactam 13, the aldol reaction of ketone 14
containing a benzylidene group, and the late-stage introduc-
tion of a benzoyl group by the selective oxidation of this
benzylidene moiety with DMD.
Deprotection of the TIPS group, followed by treatment
with AcCl in MeOH provided 8-O-demethylpseurotin A (22)
and pseurotin A (1) in 67 and 25% yields, respectively. 8-O-
Demethylpseurotin A (22) is also a natural product, isolated
along with pseurotin A from submerged cultures of an
osmophilic Aspergillus fumigatus strain and is an inhibitor
of chitin synthase.2 8-O-Demethylpseurotin A (22) can be
converted into pseurotin A (1) in 26% yield with recovery
of 8-O-demethylpseurotin A (22) in 52% yield by acid
treatment. Prolonged treatment of 22 with acid caused the
rearrangement of allylic alcohol of the side chain. Synthetic
Acknowledgment. We thank Nippon Kayaku Co., Ltd.,
for a natural sample of pseurotin A. This work was supported
by a Grant-in-Aid for Scientific Research on Priority Areas
(A) “Exploitation of Multi-Element Cyclic Molecules” from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
(14) (a) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.; Nagasaka, T.
Tetrahedron 2000, 56, 8855. (b) Cid, M. M.; Dominguez, D.; Castedo, L.;
Vazquez-Lopez, E. M. Tetrahedron 1999, 55, 5599.
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(16) Mild acidity of TLC can be successfully employed in our total
synthesis of epolactaene for the hydrolysis of nitrile via intramolecular
hydroxy group assistance; see: Hayashi, Y.; Kanayama, J.; Yamaguchi, J.;
Shoji, M. J. Org. Chem. 2002, 67, 9443.
Supporting Information Available: Detailed experi-
1
mental procedures, full characterization, copies of H and
13C NMR and IR spectra of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
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