Total synthesis and determination of the absolute configuration of FD-838, a naturally occurring azaspirobicyclic product

Article abstract of DOI:10.1016/j.bmcl.2009.03.154

The first asymmetric total synthesis of FD-838, a naturally occurring azaspirobicyclic product, has been accomplished allowing determination of its absolute stereochemistry.

Full text of DOI:10.1016/j.bmcl.2009.03.154

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3863–3865
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Total synthesis and determination of the absolute configuration of FD-838,
a naturally occurring azaspirobicyclic product
a
a
c
c
Yujiro Hayashi a,b, , Kuppusamy Sankar , Hayato Ishikawa , Yuriko Nozawa , Kazutoshi Mizoue ,
*
Hideaki Kakeya d
a Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
b Research Institute for Science and Technology, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
c Research Center of Taisho Pharmaceutical Co., Ltd, 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan
d Department of System Chemotherapy and Molecular Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric total synthesis of FD-838, a naturally occurring azaspirobicyclic product, has been
accomplished allowing determination of its absolute stereochemistry.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 March 2009
Revised 27 March 2009
Accepted 30 March 2009
Available online 5 April 2009
Keywords:
FD-838
Total synthesis
Absolute configuration
Pseurotins,1 synerazol,2 and azaspirene3 are natural products
possessing a unique azaspirocyclic framework, such as the 1-oxa-
7-azaspiro[4.4]non-2-ene-4,6-dione ring system (Fig. 1). The pseu-
rotins are a small family of secondary microbial metabolites
isolated from a culture broth of Pseudeurotium ovalis (strain
S2269/F) in 1976 by Bloch et al.1a Pseurotin A was reported to in-
hibit chitin synthase by Sterner and co-workers in 1993,1e and was
also found to induce cell differentiation of PC12 cells by Komagata
et al. in 1995.1f 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.1b Synerazol,
an antifungal antibiotic isolated by Ando and co-workers in 1991
from the culture broth of Aspergillus fumigatus SANK 10588, is ac-
tive against Candida albicans and other fungi, showing marked syn-
ergistic activity with azole-type antifungal agents.2 Azaspirene,
isolated from the fungus Neosartorya sp. by Kakeya and co-workers
was found not only to inhibit the endothelial migration induced by
vascular endothelial growth factor,3 but also to exhibit antiangio-
genic effects by blocking Raf-1 activation.4 These compounds pos-
sess the same highly oxygenated azaspiro core structure with
different side chains. Because of its unique structure and interest-
ing biological properties, there have been several attempts at its
total synthesis.5 Our group has accomplished the first enantiose-
lective total synthesis of pseurotin A,6 F2,6 synerazol,7 and azaspi-
rene,8 in which the aldol chemistry of a chiral benzylidene lactam
with an appropriate aldehyde, followed by successive oxidation
and dehydration, creates the key azaspiro structure (Eq. 1). By
these syntheses, the absolute configurations of synerazol9 and
azaspirene have been determined. Tadano and co-workers also
reported the total syntheses of pseurotin A, F2, and azaspirene
from D
-glucose.10
FD-838, isolated from A. fumigatus fresenius F-838 by Mizoue
and co-workers of Taisho pharmaceutical company in 1985, is
reported to induce the differentiation of leukemia in cultures
and to inhibit the growth of certain Gram-positive bacteria and
fungi.11 Recently, Rovis and Orellana reported the synthesis of
the spirobicyclic core of FD-838 via the asymmetric Stetter reac-
tion.12 Its total synthesis has not been accomplished, and its
absolute configuration has been unknown, with its optical rota-
tion being reported to be zero (½a D26
ꢀ
0 (c 0.1, MeOH)).10 As the
fungus no longer produces FD-838, chemical synthesis is the
only way to obtain this molecule. Despite the interesting biolog-
ical properties, biological investigations cannot be performed be-
cause of lack of supply of FD-838.
Despite the structural similarity of FD-838, pseurotin A,
synerazol, and azaspirene, the reported biological properties of
these natural products are rather different, as described above. Sys-
tematic comparison of the biological properties of these natural
products and their derivatives is highly desirable, and a sufficient
quantity of not only the natural products but also several
* Corresponding author.
E-mail address: hayashi@ci.kagu.tus.ac.jp (Y. Hayashi).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.154

3864
Y. Hayashi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3863–3865
O
HO
O
HO
O
oxidation;
R
O
H
N
O
O
NH
NH
aldol reaction
O
dehydration
Ph
Ph
Ph
OMe
(1)
+
R
Et
R
H
O
OH
OTIPS
OTIPS
O
OH
O
OH
O
O
O
H
O
Et
O
O
O
O
H
O
H
N
O
O
O
H
O
O
N
O
N
Ph
N
Ph
OMe
Ph
OMe
Ph
Et
OH
OH
Et
OMe
OH
OH
OH
OH
O
FD-838 (1)
pseurotin A
synerazol
azaspirene
Figure 1. FD-838 (1), pseurotin A, synerazol, and azaspirene.
derivatives is required for such biological studies. Because we had
established a synthetic method for the latter three natural prod-
ucts, we began to investigate the total synthesis of FD-838. In this
communication we report the first total synthesis of FD-838 along
with the determination of its absolute configuration.
Because we have already established the synthesis of the
azaspirocyclic framework, the same synthetic strategy would
be applicable to the synthesis of FD-838. The aldol reaction
between 5-ethyl-2-formylfuran and the functionalized benzyli-
dene lactam 2, which was a key intermediate for other azaspiro
compounds prepared from methyl pentenoate via Sharpless
dihydroxylation as a key step, was examined.6–8 The lithium
enolate of 2 reacted with 5-ethyl-2-formylfuran, affording the
(DMP)13 in CH2Cl2 in the presence of NaHCO3 afforded the 1,3-
diketone 5. When 1,3-diketone 5 was treated with silica gel on
TLC, cyclization followed by dehydration proceeded because of
the acidity of the silica gel to produce azaspiro derivative 4 in
20% yield with recovery of 1,3-diketone 5 in 37% yield over
two steps. Recovered 1,3-diketone 5 was further transformed
into azaspiro derivative 4 in 27% yield (54% br sm) by the same
reaction conditions. Oxidation of the benzylidene moiety with
dimethyldioxirane (DMD)14 in MeOH afforded
a mixture of
methoxy derivative 6 and hydroxy derivative 7 in 56% yield (sin-
gle diastereomers at the benzylic alcohol position), the mixture
of which was treated with DMP in CH2Cl2 to provide benzoylat-
ed methoxy 8 and hydroxy 9 derivatives in 49% and 16% yields,
respectively, which can be separated by TLC. Removal of the TIPS
group with NH4F in MeOH afforded FD-838 (1) in 62% yield
(89%, br sm). Synthetic FD-838 exhibited identical properties to
those of the natural substance (1H NMR, 13C NMR, IR).
desired aldol product
3
(mixture of four diastereomers,
1:1:3:3.5) in 40% yield with recovery of the lactam 2 in 49%
yield (78% yield based on the recovered starting material (br
sm)). Oxidation of the alcohol 3 with Dess–Martin periodinane
O
H
N
O
H
N
HO
O
HO
O
LDA
Ph
Ph
+
O
CHO
THF-HMPA
O
OTIPS
OTIPS
OH
−78 ~ −50 ºC
2
3
40% (78% brsm)
1) Dess-Martin
periodinane
H
O
H
N
O
O
O
HO
O
N
O
Ph
Ph
+
O
2) SiO2 (TLC)
OTIPS
O
5
OTIPS
20% (2 steps)
4
37% (2 steps)
SiO2 (TLC)
27% (54% brsm), SM 50%
OH
OH
Ph
O
O
H
N
O
O
H
N
DMD
O
O
O
O
O
O
+
+
4
Ph
MeOH-acetone
-60 ºC, MS 3A
OMe
OH
OTIPS
OTIPS
O
7
56% (64% brsm), 6:7 = 3:1
6
O
O
H
N
H
N
O
Dess-Martin
O
O
O
Ph
periodinane
Ph
OH
OTIPS
OMe
OTIPS
O
16% 9
49%
8
O
H
N
O
O
NH4F
O
Ph
8
MeOH
OMe
OH
FD-838 (1)
O
62% (89% brsm)
Scheme 1. The synthesis of FD-838.

Y. Hayashi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3863–3865
3865
2. Ando, O.; Satake, H.; Nakajina, M.; Sato, A.; Nakamura, T.; Kinoshita, T.; Furuya,
K.; Haneishi, T. J. Antibiot. 1991, 44, 382.
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4. Asami, Y.; Kakeya, H.; Komi, Y.; Kojima, S.; Nishikawa, K.; Beebe, K.; Neckers, L.;
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5. Synthetic studies of pseurotin A; see: (a) Dolder, M.; Shao, X.; Tamm, C. Helv.
Chim. Acta 1990, 73, 63; (b) Shao, X.; Dolder, M.; Tamm, C. Helv. Chim. Acta
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Antibiot. 2004, 57, 748.
Because the optical rotation of natural FD-838 was reported
to be zero using MeOH as a solvent,11 the optical rotation was
measured in other solvents, such as CHCl3. The optical rotations
of natural FD-838 and synthetic FD-838 show large negative val-
ues (synthetic FD-838: ½a D26
ꢁ41.9 (c 0.4, CHCl3), natural FD-838:
ꢀ
½
a 2D6
ꢀ
ꢁ32.4 (c 0.7, CHCl3)), indicating that both compounds have
the same absolute configuration.15 Thus, the absolute configura-
tion is determined, as shown in Scheme 1.
In summary, we have accomplished the first asymmetric total
synthesis of FD-838 along with the determination of its absolute
configuration.
6. Hayashi, Y.; Shoji, M.; Yamaguchi, S.; Mukaiyama, T.; Yamaguchi, J.; Kakeya, H.;
Osada, H. Org. Lett. 2003, 5, 2287.
7. Hayashi, Y.; Shoji, M.; Mukaiyama, T.; Gotoh, H.; Yamaguchi, S.; Nakata, M.;
Kakeya, H.; Osada, H. J. Org. Chem. 2005, 70, 5643.
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T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am. Chem. Soc. 2002, 124,
12078.
9. Igarashi and co-workers also determined the absolute configuration of
synerazol using modified MTPA method, see: Igarashi, Y.; Yabuta, Y.;
Furumai, T. J. Antibiot. 2004, 57, 537.
Acknowledgment
This work was supported by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Government of Japan.
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Bull. Chem. Soc. Jpn. 2004, 77, 1703; Review, see: (c) Takao, K.; Aoki, S.; Tadano,
K. J. Syn. Org. Chem. Jpn. 2007, 65, 460.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.03.154.
11. Mizoue, K.; Okazaki, T.; Hanada, K.; Amamoto, T.; Yamagishi, M.; Omura, S.
Eur. Pat. Appl. EP 216607,
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References and notes
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Acta 1976, 59, 133; (b) Weber, H. P.; Petcher, T. J.; Bloch, P.; Tamm, C. Helv.
Chim. Acta 1976, 59, 137; (c) Bloch, P.; Tamm, C. Helv. Chim. Acta 1981, 64,
304; (d) Breitenstein, W.; Chexal, K. K.; Mohr, P.; Tamm, C. Helv. Chim. Acta
1981, 64, 379; (e) Wenke, J.; Anke, H.; Sterner, O. Biosci., Biotechnol.,
Biochem. 1993, 57, 961; (f) Komagata, D.; Fujita, S.; Yamashita, N.; Saito, S.;
Morino, T. J. Antibiot. 1996, 49, 958.
15. A small quantity of the natural FD-838 would cause the inconsistency of the
optical rotation.