Figure 1.
To this end, we designed the substrate analogue 1 as an
inhibitor candidate on the basis of the results reported for
the phospholipase C inhibitors by Martin’s group5 and our
previous results obtained on sphingomyelin analogues.3 In
the analogue 1, one of the oxygen atoms of the phosphoester,
at which sphingomyelin is hydrolyzed by the enzyme, is
replaced by a methylene group, and the stereochemistry of
the asymmetric centers must be in D-erythro form, (3S,4R),
and in addition, the double bond in the backbone skeleton
is saturated. In this paper, we describe the highly efficient
stereocontrolled synthesis of the short chain substrate me-
thylene analogue 1 (Figure 2).
hydrogenation.6 Thus, hydrogenation of the â-ketoester 2
quantitatively yielded the corresponding alcohol in the
presence of a catalytic amount of (R)-BINAP-RuCl2 in CH2-
Cl2 under 100 atomospheres pressure of hydrogen at 60 °C
for 10 days according to the literature.7 The diastereoselec-
tivity and enantioselectivity of 3 were determined to be 98%
de by 1H NMR and 95% ee by HPLC after benzylation under
acidic conditions.8 With enantiomerically pure alcohol 3 in
hand, our attention turned to construction of the amino
alcohol equivalent. After the lactone ring of 3 was opened
by treatment with a large excess of aqueous NH3, we tried
to react the obtained amide 4 with silver acetate and
N-bromosuccinimide in DMF. The Hofmann rearrangement
of 4 followed by the intramolecular cyclization successfully
proceeded and produced the substituted oxazolidinone 5 in
54% yield in two steps. The intermediary isocyanate resulting
from the Hofmann rearrangement was selectively trapped
with the secondary hydroxy group to spontaneously produce
the five-membered oxazolidinone ring with retention of the
stereochemisry.9 Thus, the protected amino alcohol was
efficiently synthesized.
Figure 2. The methylene analogue that is designed as a SMase
inhibitor.
The next subjects were the introduction of a phosphoryl
group, protection of the secondary hydroxy group resulting
from opening the oxazolidinone ring, and then introduction
of an acyl group at the amino group. After bromination of
the primary alcohol in 5 with carbon tetrabromide and
triphenylphosphine, the phosphoryl group was successfully
introduced by the Arbuzov reaction with triethyl phosphite
under reflux to yield the corresponding phosphoric ester 6,
the carbamate nitrogen of which was activated by the
introduction of a tert-butyloxycarbonyl group without any
purification of the reaction mixture to give 7 quantitatively.
To achieve the efficient synthesis of 1, a convenient
method for the preparation of an erythro amino alcohol
derivative such as 5 was required. Stereospecific oxazolidi-
none formation resulting from an intramolecular trap with
the vicinal hydroxy group of the reactive isocyanate, which
was produced by the Hofmann rearrangement of an amide
such as 4, was a very attractive strategy for the synthesis of
5.
We then started the synthesis with reduction of R-acyl-
γ-butyrolactone 2 by the method of Noyori’s asymmetric
(6) (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi,
H. J. Am. Chem. Soc. 1989, 111, 9134. (b) Kitamura, M.; Tokunaga, M.;
Ohkuma, T.; Noyori, R. Org. Synth. 1993, 71, 1.
(7) Nishizawa, M.; Garcia, D. M.; Minagawa, R.; Noguchi, Y.; Imagawa,
H.; Yamada, H.; Watanabe, R.; Yoo, Y. C.; Azuma, I. Synlett 1996, 452.
(8) Hatakeyama, S.; Mori, H.; Kitano, K.; Yamada, H.; Nishizawa, M.
Tetrahedron Lett. 1994, 35, 4367.
(9) Recently, the Curtius rearrangement for the similar oxazolidinone
formation was reported. (a) Pais, G. C. G.; Maier, M. E. J. Org. Chem.
1999, 64, 4551. (b) Ghosh, A. K.; Hussain, K. A.; Fidanze, S. J. Org. Chem.
1997, 62, 6080. (c) Ghosh, A. K.; Liu, W. J. Org. Chem. 1996, 61, 6175.
(4) (a) Nara, F.; Tanaka, M.; Hosoya, T.; Suzuki-Konagai, K.; Ogita, T.
J. Antibiot. 1999, 52, 525. (b) Nara, F.; Tanaka, M.; Masuda-Inoue, S.;
Yamasato, Y.; Doi-Yoshioka, H.; Suzuki-Konagai, K.; Kumakura, S.; Ogita,
T. J. Antibiot. 1999, 52, 531. (c) Uchida, R.; Tomoda, H.; Dong, Y.; Omura,
S. J. Antibiot. 1999, 52, 572. (d) Tanaka, M.; Nara, F.; Suzuki-Konagai,
K.; Hosoya, T.; Ogita, T. J. Am. Chem. Soc. 1997, 119, 7871.
(5) (a) Martin, S. F.; Josey, J. A.; Wong, Y. L.; Dean, D. W. J. Org.
Chem. 1994, 59, 4805. (b) Martin, S. F.; Wong, Y. L.; Wagman, A. S. J.
Org. Chem. 1994, 59, 4821.
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Org. Lett., Vol. 2, No. 17, 2000