Absolute configuration of scyphostatin

Article abstract of DOI:10.1021/ol991351p

(Formula presented) The absolute configuration of the side chain of scyphostatin (1) has been established. The chemical degradation of 1 gave 4 and 9, which correspond to the C7′-C12′ and C13′-C16′ fragments of the natural products, respectively. The spec

Full text of DOI:10.1021/ol991351p

ORGANIC
LETTERS
2000
Vol. 2, No. 4
505-506
Absolute Configuration of Scyphostatin
Shoichi Saito, Natsuki Tanaka, Katsumi Fujimoto, and Hiroshi Kogen*
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., Hiromachi 1-chome,
2-58, Shinagawa-ku, Tokyo 140-8710, Japan
hkogen@shina.sankyo.co.jp
Received December 14, 1999
ABSTRACT
The absolute configuration of the side chain of scyphostatin (1) has been established. The chemical degradation of 1 gave 4 and 9, which
correspond to the C7′−C12′ and C13′−C16′ fragments of the natural products, respectively. The spectroscopic data and [r]D values of both
compounds were compared to those of authentic samples. The results show that the absolute configuration of 1 is 8′R,10′S,14′R.
Scyphostatin (1) was isolated as a potent inhibitor of neutral
sphingomyerinase by Ogita et al. in 1997.1 This compound
is the first low-molecular-weight inhibitor of the enzyme,
either from natural sources or of synthetic origin. These
factors combine with interesting biological activity and
unique structure to make 1 a synthetic target of enormous
interest (Figure 1).
The stereochemistry of the side chain, containing three
asymmetric centers, still remains unelucidated. In this
communication, we describe the entire stereochemical struc-
ture of 1, including the absolute stereochemistry, by degrada-
tion of the side chain followed by correlation to known chiral
compounds.
Natural scyphostatin (1) was treated with potassium
hydroxide in methanol under reflux conditions, and subse-
quent reaction with (trimethylsilyl)diazomethane gave methyl
ester 2 ([R]D ) -2.5 (c 0.50, CHCl3)) in 61% yield (two
steps). Oxidative cleavage of the ester 2 was accomplished
by ozonolysis followed by reductive workup to yield diol 3,
corresponding to the C7′-C12′ fragment. It contains both
the C8′ and C10′ asymmetric centers as a mixture of
inseparable diastereoisomers. Treatment of the diol 3 with
benzoyl chloride and triethylamine followed by the Dess-
Martin reagent2 provided keto ester 4 ([R]D ) -7.0 (c 0.53,
CHCl3)) in 80% yield (two steps) as a single isomer. To
determine the absolute stereochemistry of 4, the optically
active carboxylic acid 6, a chiral starting material which has
a known absolute configuration,3 was readily derived from
lactone (()-5.3,4 Reduction of 6 ([R]D ) -5.7 (c 4.60,
Figure 1.
A previous structure elucidation of 1 only determined the
absolute stereochemistry of the epoxy cyclohexenone moiety.1a
(1) (a) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.; Ogita, T.
J. Am. Chem. Soc. 1997, 119, 7871. (b) Nara, F.; Tanaka, M.; Hosoya, T.;
Suzuki-Konagai, K.; Ogita, T. J. Antibiot. 1999, 52, 525. (c) Nara, F.;
Tanaka, M.; Masuda-Inoue, S.; Yamamoto, Y.; Doi-Yoshioka, H.; Suzuki-
Konagai, K.; Kumakura, S.; Ogita, T. J. Antibiot. 1999, 52, 531.
(2) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(3) Mori, K.; Kuwahara, S. Tetrahedron 1986, 42, 5539.
(4) (a) Ungnade, H. E.; Nightingale, D. V. J. Am. Chem. Soc. 1944, 66,
1218. (b) Mori, K.; Kuwahara, S. Tetrahedron 1986, 42, 5545.
10.1021/ol991351p CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/15/2000

Scheme 1
CHCl3), lit.3 [R]D ) -4.2 (c 8.69, CHCl3)) with borane-
mp 52.5-53.5 °C) in 64% yield (two steps).7 An authentic
sample was prepared from commercially available (S)-(+)-
2-methylbutyric acid (10)8 under the same esterification
conditions in 98% yield. The physical and spectroscopic data
of the authentic p-bromophenacyl ester (+)-9 ([R]D ) +12.1
(c 0.60, CHCl3); mp 53-54 °C) were identical with those
of the degradation product (-)-9 (1H NMR, 13C NMR, IR,
and HRMS), with the exception of the sign of the optical
rotation ([R]D ) -12.6). This result means that the absolute
configuration of C14′ is R. These results in total offered the
complete stereochemical structure of scyphostatin (1) as
8′R,10′S,14′R, as shown in Figure 1.
methyl sulfide complex followed by treatment with benzoyl
chloride and triethylamine provided the monobenzoyl ester
7 in 47% yield (two steps). Dess-Martin oxidation of the
secondary hydroxyl group of 7 afforded the keto ester 8 ([R]D
) -7.0 (c 2.35, CHCl3)) in 71% yield (Scheme 1). Its
spectral data and physical properties (1H and 13C, IR, and
[R]D) were identical with those of the degradation product
4. This result shows that the absolute configuration of 4 is
8′R,10′S. During these operations the compound correspond-
ing to the C13′-C16′ moiety could not be isolated.
To determine the stereochemistry of chiral center C14′,
we attempted the isolation of the C13′-C16′ fragment as
its 2-methylbutyric acid derivative (Scheme 2). The ester 2
Acknowledgment. We thank Drs. Takeshi Ogita and
Masahiro Tanaka in our laboratories for providing us with
natural scyphostatin.
Supporting Information Available: Spectral data for
Scheme 2
compounds 2, 4, 8, 9, and 11 and representative 1H and 13
C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL991351P
(5) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, L. B. J. Org.
Chem. 1981, 46, 3938.
(6) Clark, J. H.; Miller, J. M. Tetrahedron Lett. 1977, 599.
(7) Another p-bromophenacyl ester, 11, was also obtained in 70% yield
without epimerization. The compound was identical with an authentic
sample, which was derived from 6 in two steps ((a) p-bromophenacyl
bromide, KF, DMF (90%); (b) Dess-Martin oxidation (93%)).
5
was treated with RuCl3/NaIO4 and esterified with p-
bromophenacyl bromide and KF in DMF,6 furnishing the
p-bromophenacyl ester (-)-9 ([R]D ) -12.6 (c 0.64, CHCl3);
(8) (S)-(+)-2-Methylbutyric acid was purchased from Aldrich Chemical
Co.
506
Org. Lett., Vol. 2, No. 4, 2000