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.

Public Health Relevance

The proposed research will provide powerful tools for the synthesis of pharmaceutically relevant compounds and their congeners from readily available alkenes, 1,3-dienes, enynes, and alkynes. Since highly catalytic reactions and readily available precursors are involved in the proposed new processes, successful conclusion of this project will also add to our repertoire of benign synthetic methods useful for large scale manufacture of useful pharmaceutical intermediates. This effort, if successful, will deliver tangible economic and environmental benefits; we hope that the discoveries made will shorten the considerable distance between the conceptualization of a molecule as a drug candidate and its large-scale synthesis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Yang, Jiong
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Ohio State University
Schools of Arts and Sciences
United States
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