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.
Shibue
Taku
T
Exploratory Research Laboratories, Kyorin Pharmaceutical Co. Ltd, 2399-1, Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan.
Hirai
Toshihiro
T
Okamoto
Iwao
I
Morita
Nobuyoshi
N
Masu
Hyuma
H
Azumaya
Isao
I
Tamura
Osamu
O
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D061565:Cycloaddition Reaction; D006601:Hexoses / Q000737:chemistry; D006801:Humans; D009589:Nitrogen Oxides / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023303:Oxazolidinones / Q000737:chemistry; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D006601:Hexoses; D009589:Nitrogen Oxides; D009842:Oligopeptides; D023303:Oxazolidinones; D010875:Pipecolic Acids; D050257:Tubulin Modulators; C015388:nitrones; C502386:tubulysin D; C516471:tubulysin U; C516472:tubulysin V; C057406:gulose