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Total Synthesis and Selective Activity of a New Class of Conformationally Restrained Epothilones
Author(s) -
Alhamadsheh Mamoun M.,
Gupta Shuchi,
Hudson Richard A.,
Perera Lalith,
Tillekeratne L. M. Viranga
Publication year - 2008
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200701143
Subject(s) - epothilones , stereoselectivity , stereochemistry , chemistry , aldol reaction , epothilone , ring closing metathesis , enantiomer , metathesis , total synthesis , alkylation , stereoisomerism , combinatorial chemistry , molecule , biochemistry , organic chemistry , polymer , polymerization , catalysis
Stereoselective total syntheses of two novel conformationally restrained epothilone analogues are described. Evans asymmetric alkylation, Brown allylation, and a diastereoselective aldol reaction served as the key steps in the stereoselective synthesis of one of the two key fragments of the convergent synthetic approach. Enzyme resolution was employed to obtain the second fragment as a single enantiomer. The molecules were assembled by esterification, followed by ring‐closing metathesis. In preliminary cytotoxicity studies, one of the analogues showed strong and selective growth inhibitory activity against two leukemia cell lines over solid human tumor cell lines. The precise biological mechanism of action and high degree of selectivity of this analogue remain to be examined.