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Total Synthesis and Biological Evaluation of a C(10)/C(12)‐Phenylene‐Bridged Analog of Epothilone D
Author(s) -
End Nicole,
Furet Pascal,
van Campenhout Nathalie,
Wartmann Markus,
Altmann KarlHeinz
Publication year - 2004
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200490133
Subject(s) - chemistry , pharmacophore , stereochemistry , yield (engineering) , epothilone , aryl , aldol reaction , bromide , total synthesis , alkyl , combinatorial chemistry , organic chemistry , catalysis , materials science , metallurgy
The total synthesis of compound 8 , a conformationally constrained analog of epothilone D ( 2 ), has been achieved through a convergent strategy based on three key fragments comprising C(1)C(6) ( 26 ), C(7)C(12) ( 16 ), and C(13)O(16) ( 19 ) of the macrocyclic framework. Construction of the C(12)C(13) bond involved Pd 0 ‐mediated B ‐alkyl Suzuki coupling between aryl bromide 16 and olefin 19 , and proceeded in excellent yield, while formation of the C(6)C(7) bond through aldol reaction was somewhat less efficient. Surprisingly, macrolactonization was rather low‐yielding and gave protected 8 only in 39% yield. Although 8 had been suggested by pharmacophore modeling to adopt a conformation similar to the bioactive conformation of epothilone B, the compound was devoid of any significant antiproliferative activity.