Expedient synthesis of N-methyl tubulysin analogues with high cytotoxicity

J Org Chem. 2008 Jun 20;73(12):4362-9. doi: 10.1021/jo800384x. Epub 2008 May 15.


An optimized and highly efficient synthesis of potent, bioactive N-methyl tubulysin analogues 2 and 4 has been achieved with > 40% overall yields. This synthesis represents a significant improvement over previously reported syntheses of these and related tubulysin analogues. The stereoselective synthesis of the unnatural amino acid tubuvaline is accomplished using tert-butanesulfinamide chemistry. N-Alkylation to form N-methyl tubuvaline is performed without protection of the tubuvaline alcohol by implementing a unique N-methylation strategy via formation and reduction of a 1,3-tetrahydrooxazine heterocycle. Acylation of the hindered N-methyl 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-methyl tubuvaline and isoleucine. This high-yielding synthesis should enable the production of large quantities of material for biological studies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Drug Screening Assays, Antitumor
  • Magnetic Resonance Spectroscopy
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / pharmacology*
  • Spectrometry, Mass, Fast Atom Bombardment


  • Oligopeptides