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[摘要]：(Biomolecules and Their Synthetic Analogs) Section An optimized and highly efficient synthesis of potent, bioactive N-Me tubulysin analogs I and II has been achieved with > 40% overall yields. This synthesis represents a significant improvement over previously reported syntheses of these and related tubulysin analogs. The stereoselective synthesis of the unnatural amino acid tubuvaline is accomplished using tert-butanesulfinamide chem. N-Alkylation to form N-Me tubuvaline is performed without protection of the tubuvaline alc. by implementing a unique N-methylation strategy via formation and redn. of a 1,3-tetrahydrooxazine heterocycle. Acylation of the hindered N-Me tubuvaline amine utilizes a novel sequence of O-acylation followed by an O- to N-acyl transfer to form the hindered amide bond between N-Me tubuvaline and isoleucine. This high-yielding synthesis should enable the prodn. of large quantities of material for biol. studies. |
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