Total Syntheses of Tubulysins

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.