Project Summary/Abstract
A recent critical analysis of biologically active molecules and reactions most often used for their
preparation suggests that fraction of saturated carbons and presence of chiral centers correlate with
success as a compound moves from discovery, through clinical trials to an approved drug. About a
third of the compounds had at least one chiral center. In addition, practical aspects of manufacturing
still need to be addressed to market a cost effective drug. Thus discovery of fundamentally new
catalytic reactions, especially enantioselective ones, showing high turnover frequencies (i.e.,
substrate/ catalyst/unit time), that use readily available precursors, will have a significant impact on
medicinal and process chemistry. Through an approach that relies heavily on mechanistic insights
we strive to discover new enantioselective reactions of alkenes and alkynes. For example, use of
low-valent chiral (L*)cobalt complexes has enabled heterodimerization between a broad range of
1,3-dienes, and, ethylene and alkyl acrylates, which are feedstock materials. The products of these
reactions are synthetically valuable chiral 1,4-skipped dienes (produced in >90% yield and ee)
which can be turned into pharmaceutically relevant classes of compounds. Examples cited include
anti-microbial and anti-tumor and antifungal agents, GABA analogs, and metalloproteinase
inhibitors. On-going mechanistic studies strongly suggest the intermediacy of a cationic
{[P~P)Co(L)]+}X– species in these exceptionally selective C-C bond-forming reactions that proceed
under ambient conditions. Most remarkably, we recently (2018/2019) found that the chiral cationic
Co(I) complexes with custom-designed ligands catalyze enantioselective [2+2]-additions of alkynes
and vinyl-X derivatives, opening, arguably, the best route to enantiopure 3-substituted cyclobutenes,
potential precursors other valuable compounds. In sharp contrast to 1,3-dienes, 1,3-enynes form,
initially, vinylcyclobutenes and then, in a tandem fashion, highly functionalized cyclobutanes with an
all-carbon quaternary centers. Such reactions are highly efficient and uncommon. Preliminary
results also indicate that chiral cationic Co(I)-complexes catalyze at least 4 other types of reactions
(hydroboration, hydroacylation and hydrosilylation of prochiral 1,3-dienes, and, cyclizaion/HV of 1,6-
enynes). We plan to explore how many of the combinations of reactions can be run in tandem, in
attempts to exploit the full potential of the new cobalt chemistry in organic syntheis. Historically
some of the reactions we work on had been carried out using precious metals. We expect, when
fully devloped, cobalt (which is 100 to 200 time cheaper than Rh for example), will be able to
catalyze some of these basic reactions. The interdisciplinary nature of the work proposed here
provides outstanding opportunities to train future scientists at every level of their education.
