ja6b05127_si_001.pdf (11.37 MB)
Total Synthesis of (−)-Lasonolide A
journal contribution
posted on 2016-08-22, 00:00 authored by Barry M. Trost, Craig E. Stivala, Daniel R. Fandrick, Kami L. Hull, Audris Huang, Caroline Poock, Rainer KalkofenThe lasonolides are novel polyketides
that have displayed remarkable biological activity in vitro against
a variety of cancer cell lines. Herein we describe our first-generation
approach to the formal synthesis of lasonolide A. The key findings
from these studies ultimately allowed us to go on and complete a total
synthesis of lasonolide A. The convergent approach unites two highly
complex fragments utilizing a Ru-catalyzed alkene–alkyne coupling.
This type of coupling typically generates branched products; however,
through a detailed investigation, we are now able to demonstrate that
subtle structural changes to the substrates can alter the selectivity
to favor the formation of the linear product. The synthesis of the
fragments features a number of atom-economical transformations which
are highlighted by the discovery of an engineered enzyme to perform
a dynamic kinetic reduction of a β-ketoester to establish the
absolute stereochemistry of the southern tetrahydropyran ring with
high levels of enantioselectivity.