Synthesis and Structure-Activity Relationships of Novel 2',2'-Difluoro Analogues of Docetaxel.

Abstract

To investigate the role of the 2'-hydroxy group at the C-13 side chain of docetaxel in the antitumor activity, we prepared several 2',2'-difluoro derivatives of docetaxel and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines and their microtubule disassembly-inhibitory activity. These analogues were prepared by esterification of protected 10-deacetylbaccatin III (21) with appropriate alpha, alpha-difluorinated carboxylic acids (Charts 1 and 2). Among these 2',2'-difluorodocetaxel derivatives, 2',2'-difluorodocetaxel (23b) was approximately 3-10 times as active as 2'-fluorodocetaxel (29a) in terms of cytotoxicity. In addition, the 3'-(2-furyl) (23h) and 3'-(2-pyrrolyl) (23p) analogues showed activity comparable or superior to that of docetaxel (2).

Enantioselective acylation of alcohols with fluorinated β-phenyl-β-lactams in the presence of Burkholderia cepacia lipase

“…1 The a,a-difluoro-b-amino acid residue of (S)-4 (Scheme 1) in the side chain of dodetaxel analogues is a good example of an important fluorine-containing b-amino acid. 2 The enantiomers of various b-amino acids and their precursors and intermediates have widespread applications as building blocks and intermediates in the design of medicinally important compounds. 3 Results for the enzymatic kinetic resolution of nonfluorinated b-amino esters and their precursors have previously been reviewed.…”

Asymmetric synthesis of fluorine-containing amines, amino alcohols, α- and β-amino acids mediated by chiral sulfinyl group

“…The proposed explanation for observed stereochemical preferences was based on the attractive electrostatic interactions between electron-deficient benzylidene phenyl ring of the fluoro-and p-nitro-substituted imines and negatively charged sulfoxide oxygen, which could stabilize the sterically unfavorable transition state leading to formation of (R s ,2R)-configured products. It is necessary to note that reactions under thermodynamically controlled conditions (0 8C) afforded 1/1 mixture of diastereomeric products regardless of the substitution on the starting imines (Table 2, [34]. Most recently these derivatives were shown to be important compounds in investigation of the phenomenon of self-disproportionation of enantiomers under the conditions of achiral chromatography [35].…”

Synthesis of fluorofurans and perfluoroalkylfurans

“…Thus compound 1, analog of trovirdine LY 300046 HCl, reveals high anti-HIV activity [13]. The effect of the derivative 2 is similar to that of Docetaxel (Taxotere 1 ), which is used in cancer chemotherapy for the treatment of advanced ovarian and breast cancer [14]. Trifluoromethylfuran 3 is an agonist of the EP prostanoids [15].…”