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Total Syntheses of Tubulysins
Author(s) -
Shibue Taku,
Hirai Toshihiro,
Okamoto Iwao,
Morita Nobuyoshi,
Masu Hyuma,
Azumaya Isao,
Tamura Osamu
Publication year - 2010
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.201000963
Subject(s) - computer science
The total syntheses of tetrapeptides tubulysins D ( 1 b ), U ( 1 c ), and V ( 1 d ), which are potent tubulin polymerization inhibitors, are described. The synthesis of Tuv ( 2 ), an unusual amino acid constituent of tubulysins, includes an 1,3‐dipolar cycloaddition reaction of chiral nitrone D ‐ 6 derived from D ‐gulose with N ‐acryloyl camphor sultam (−)‐ 9 employing the double asymmetric induction, whereas the synthesis of Tup ( 20 ), another unusual amino acid, involves a stereoselective Evans aldol reaction of ( Z )‐boron enolate generated from ( S )‐4‐isopropyl‐3‐propionyl‐2‐oxazolidinone with N ‐protected phenylalaninal and a subsequent Barton deoxygenation protocol. We accomplished the total syntheses of tubulysins U ( 1 c ) and V ( 1 d ) by using these methodologies, in which the isoxazolidine ring was used as the effective protective group for γ‐amido alcohol functionality. Furthermore, to understand the structure‐activity relationship of tubulysins, we synthesized tubulysin D ( 1 b ) and cyclo‐tubulysin D ( 1 e ) from 2 ‐Me and 20 , and ent ‐tubulysin D ( ent ‐ 1 d ) from ent ‐ 2 ‐Me and ent ‐ 20 , respectively. The preliminary results regarding their biological activities are also reported.