SYNTHESIS OF NEOCARZILIN A: AN ABSOLUTE STEREOCHEMISTRY

Article abstract of DOI:10.1016/S0040-4039(00)60821-3

Neocarzilin A (1) was synthesized from L-isoleucine for determination of the absolute configuration of an alkyl branch at C-11, and for the precise analysis of biological activities.

Full text of DOI:10.1016/S0040-4039(00)60821-3

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SYNTHESIS OF NEOCARZILIN A: AN ABSOLUTE STEREOCHEMISTRY
Shigeo
Kohichi Kikuchi, Naoyuki Ishii, and Tomihisa Ohta
Tohoku University,
980, Japan
Pharmaceutical Institute,
Aoba-ku, Sendai
from
for determination of
the precise analysis of
Abstract: Neocarzilin A (1) was synthesized
the absolute configuration of an alkyl branch at C-l 1, and for
biological activities.
In the course of our investigation on biologically active substances from natural
sources, new polyenone antibiotics, neocarzilin A and B have been isolated from the
carzinostaticus var. F41, as described in a previous
Succeeding the structural elucidation by spectroscopic analysis, we
synthesized neocarzilin A (1) and found that 1 has at C-l 1. In this
mycelium of Streptomyces
report.
communication we would like to report a synthesis of neocarzilin A (1) and its
biological activities.
The synthesis was started from
terminal, and directed toward preparation of variously substituted halogen analogs
via the versatile intermediate (3). The hydroxy acid (4) derived from
was first oxidized with periodate under neutral condition, to avoid racemization.
aldehyde (5) was transformed, without isolation, to the enoate (6) by treatment with
(2) as an optically active
The
a stable ylid.
analysis of the
The preservation of the optical purity was determined by
ester (7).
NMR
After conventional elongation of the ester
the trienone (3) was obtained in 25% yield from
transformed regioselectively into “kinetic’:
The trienone (3) was
and treated with
then
trichloroacetic anhydride to give the trichloride (1). Overall yield from
Acylation with halogenated acid chlorides or acid anhydrides gave
(2) was 18%.
variously halogenated
The synthesized trichloride
whose biological activity will be reported elsewhere.
(c 0.09, gave identical spectral
data including optical rotation with those of natural neocarzilin A.
Thus the
stereostructure of neocarzilin A was proved to be represented by the formula 1.
The synthesized compound (1) showed weak antimicrobial activity against gram
positive bacteria, Micrococcus
and Bacillus megaterium, and showed essentially
the same cytotoxic activity with that of natural product, against K562 chronic
myelogenous leukemia cells with
of neocarzilin A (1) is as potent as
the same actinomycete, S. carzinostaticus var. F41.4
(1) on ICR mice, 88.1
of 0.06
which indicated that the activity
0.09 produced by
Acute toxicity of neocarzilin A
was lower than that of neocarzinostatin,
2
7551

b
C H O
6:
7:
3
6
6
h
1
a)
-10
A; C)
from 4; d)
73%.
(-)-menthol, DCC, DMAP,
hexane;
56% e)
from 6; g)
A, 86% from h)
THF, -78
The authors are grateful to Mrs Kin-ya Nagata, Toshihiro
Hinokitani and Toyohiko Miki at Pharmaceutical Research Labs., Pola Chemical
Industries, Inc., for carrying out the biological assays.
References and Notes
1. S. Nozoe, N. Ishii, G. Kusano, K. Kikuchi, and T. Ohta, accompanying report.
2. M.
and D. F. Crowe, J. Chem.
Chem. Commun., 564 (1973).
3. N. Ishida, K. Miyazaki, K.
and M. Rikimaru, J. Antibiot., Ser. A, 18, 68
(1965); K. Edo, M. Mizugaki, Y. Koide, H. Seto,
Furihata, N. Otake, and N. Ishida,
Lett., 26, 331 (1985).
4. Biological activities of neocarzilin A (1) including cytocidal activity on other tumor
cells will be reported elsewhere.
(Received in Japan 10 August 1992)