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.

This article describes in detail the first total synthesis of grandisine alkaloids, grandisines B, D, and F, which show affinity for the human δ-opioid receptor. The key steps in this synthesis are construction of the isoquinuclidinone moiety of 2 by intramolecular imine formation and the tetracyclic ring system of 4 by stereoselective ring closure of the enolate of amine 8 generated by 1,4-addition of ammonia to 9. Synthesis of key intermediate 9 featured a highly stereoselective Brønsted acid mediated Morita–Baylis–Hillman (MBH) reaction via the N-acyl iminium ion.