ORGANIC
LETTERS
2005
Vol. 7, No. 25
5573-5576
Asymmetric Total Synthesis of
)-Spirofungin A and ( )-Spirofungin B
(−
+
Takeshi Shimizu,* Tomoharu Satoh, Katsunori Murakoshi, and Mikiko Sodeoka
RIKEN (The Institute of Physical and Chemical Research),
Wako, Saitama 351-0198, Japan
Received August 24, 2005
ABSTRACT
The stereocontrolled total synthesis of (−)-spirofungin A (1) and (+)-spirofungin B (2a), polyketide-type antibiotics having various antifungal
activities, has been achieved employing the Weinreb amide 8, the alkyne 9, and the vinyl boronate 5 readily available from the common
intermediate 10. The first synthesis proceeded with a longest linear sequence of 31 steps, affording (−)-1 and (+)-2a in 7.9% and 5.2% overall
yields, respectively.
Spirofungins A (1) and B (2) are novel polyketide-type
antifungal antibiotics isolated from Streptomyces Violaceus-
niger Tu¨ 4113 as a 4:1 mixture.1 Structurally, they are related
to reveromycins, antibiotics produced by another Strepto-
myces strain (Figure 1).2 The relative configurations of the
spiroketal ring systems within 1 and 2 were determined by
various NMR spectroscopic methods. Unfortunately, the
absolute stereochemistry of the stereogenic centers at C(4)
and C(5) was not initially determined.3 Rizzacasa and co-
workers reported the total synthesis of the initially proposed
structure for spirofungin B, namely 2, which was shown to
be incorrect.4 They then proposed a new structure for
spirofungin B (2a), which is simply the C(15) epimer of 1.
Spirofungin B (2a) is a spiroketal with only one anomeric
stabilization and an equatorially oriented large substituent
at C(19). On the other hand, the relative configuration of
the spiroketal core in 1 with its double anomeric stabilization
and its C(19) diene acid side chain in an axial position is
quite similar to reveromycin A (3), a potent inhibitor of
mitogenic activity induced by the epidermal growth factor.2
We have already reported the first asymmetric total synthesis
of 3.5
In connection with our studies on the chemical modifica-
tions and structure-activity relationships of 3,6 we planned
to synthesize 1 and 2a to provide further material for more
extensive biological studies as well as to confirm the absolute
configurations at C(4), C(5), C(11), C(12), C(15), C(18), and
C(19).7 In this paper, we report the first asymmetric total
synthesis of natural spirofungins A and B (-)-1 and (+)-
2a, starting from the common intermediate 10.7b
A brief retrosynthetic analysis of 1 and 2a is shown in
Figure 2. The unsaturated left and right side chains would
be produced by a Horner-Emmons reaction and a Suzuki
coupling.5,8 The construction of 6 would be achieved by the
intramolecular ketalization of the 11,19-dihydroxy-15-ketone
derived from ketone 7 from reduction of the alkyne and
(1) Holtzel, A.; Kempter, C.; Metzger, J. W.; Jung, G.; Groth, I.; Fritz,
T.; Fiedler, H.-P. J. Antibiot. 1998, 51, 699.
(2) (a) Takahashi, H.; Osada, H.; Koshino, H.; Kudo, T.; Amano, S.;
Shimizu, S.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1409. (b)
Takahashi, H.; Osada, H.; Koshino, H.; Sasaki, M.; Onose, R.; Nakakoshi,
M.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1414. (c) Koshino, H.;
Takahashi, H.; Osada, H.; Isono, K. J. Antibiot. 1992, 45, 1420. (d) Ubukata,
M.; Koshino, H.; Osada, H.; Isono, K. J. Chem. Soc., Chem. Commun. 1994,
1877.
(3) The absolute configurations depicted for 1 and 2 were proposed by
analogy with 3 and remained unconfirmed until our total synthesis.
(4) Zanatta, S. D.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6,
1041.
(5) Shimizu, T.; Masuda, T.; Hiramoto, K.; Nakata, T. Org. Lett. 2000,
2, 2153. A second total synthesis: El Sous, M.; Ganame, D.; Tregloan, P.
A.; Rizzacasa, M. A. Org. Lett. 2004, 6, 3001.
(6) Shimizu, T.; Usui, T.; Machida, K.; Furuya, K.; Osada, H.; Nakata,
T. Bioorg. Med. Chem. Lett. 2002, 12, 3363.
(7) Synthetic studies on the spiroketal parts of spirofungin A and B: (a)
Shimizu, Y.; Kiyota, H.; Oritani, T. Tetrahedron Lett. 2000, 41, 3141. (b)
Shimizu, T.; Kusaka, J.; Ishiyama, H.; Nakata, T. Tetrahedron Lett. 2003,
44, 4965. (c) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2004, 6, 2587. (d)
La Cruz, T. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1873.
10.1021/ol052039k CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/09/2005