Total synthesis and biological evaluation of leptostatin analogs

ORGN 178

Ann M. Mikowski and James A. Marshall. Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, VA 22903

The total synthesis and biological evaluation of four leptostatin analogs is described.  Leptostatin is a cytotoxic unnatural hybrid of the C1-C11 fragment of leptomycin B and the C12-C22 fragment of (-)-callystatin A, both of which are cytotoxic natural compounds.  Leptomycin and callystatin have identical lactone portions, except that leptomycin incorporates an additional C4 methyl stereocenter.  Since recent studies have shown the pharmacophore of callystatin A to be the C1-C5 fragment, or lactone portion, incorporating an additional C4 methyl stereocenter in this pharmacophore and altering the C4,C5 stereocenters could result in bioactive hybrid analogs.  Four leptostatin analogs, including the one with the same lactone configuration as leptomycin, were synthesized and tested for biological activity.  Key features of the highly convergent synthesis include a non-racemic chiral allenyl metal addition to install the lactone stereocenters and a B-alkyl Suzuki coupling to join the C1-C11 and C12-C22 fragments.