This project focuses on the development of metal-catalysts that promote direct byproduct-free C-C coupling of alcohols and pi-unsaturated compounds. In the proposed funding period, this novel pattern of reactivity will be applied to enyne-mediated propargylation of carbonyl compounds from the alcohol oxidation level. A feature of these transformations is the ability to achieve carbonyl addition directly from the alcohol oxidation state by exploiting alcohols and conjugated enynes as redox-pairs. Here, alcohol dehydrogenation drives reductive generation of allenylmetal species and aldehyde electrophiles, which combine to furnish homo-propargyl alcohols. Unlike classical approaches to carbonyl propargylation, which require carbonyl electrophiles in combination with pre-metallated nucleophiles (e.g. organo-tin or organo-magnesium reagents), the C-C coupling processes employ pi-unsaturated compounds as surrogates to pre-metallated nucleophiles, thus avoiding generation of stoichiometric metallic waste. Further, through the direct C-C coupling of alcohols, one circumvents discrete redox manipulations otherwise required for pre-generation of aldehyde electrophiles.
With this award, the Chemical Synthesis Program is supporting the research of Professor Michael J. Krische of the Department of Chemistry and Biochemistry at the University of Texas at Austin. Professor Krische, who leads the Center for Green Chemistry and Catalysis, is engaged in the development of catalytic C-C bond forming processes that enable sustainable, byproduct-free manufacture of chemical products from abundant, renewable resources. Successful development of the methodology will have an impact on any area of activity in which the synthesis of organic molecules is needed, such as the pharmaceutical, chemical, agricultural industry, and the biological and chemical research activities. In addition, this project will provide excellent training of students, from pre-undergraduate to post-doctoral, including those from groups historically underrepresented in the sciences.
The vast majority of commercial chemical products (plastics, pharmaceuticals, agrochemicals, flavor-fragrance ingredients, etc.) are organic molecules, which are defined as compounds composed of carbon and hydrogen. The manufacture of these products has enormous economic significance and is singularly dependent on technologies for the formation of carbon-carbon (C-C) bonds. Classical methods for C-C bond formation typically rely on the use of chemical reagents that give rise to large quantities of undesired byproduct or waste: A + B → C + D, where C = desired product, D = byproduct. In many chemical manufacturing processes, especially those that target more complex molecules (e.g. pharmaceuticals, agrochemicals), the quantity of desired product is often dwarfed by the amount of waste that is generated. Hence, one broad goal of modern chemical research resides in the design of cost-effective catalytic processes for C-C bond formation that minimize or entirely circumvent byproduct generation (A + B → C, where all atoms of A and B appear in C). To meet these challenges, the Krische laboratory has pioneered a broad, new class of byproduct-free catalytic C-C bond forming processes, wherein hydrogen exchange between alcohols and π-unsaturated reactants triggers generation of aldehyde-organometal pairs that combine to give products of carbonyl addition. Under the aegis of this NSF-sponsored collaborative research (Award 1008551), this new pattern of reactivity was applied successfully to the coupling of alcohols to conjugated enynes or propargyl chlorides to furnish products of "carbonyl propargylation" – a type of reaction frequently used to construct polyketide natural products, which figure prominently in human medicine (approximately 20% of the top-selling small molecule drugs are polyketides). Whereas conventional methods for polyketide construction generate stoichiometric amounts of metallic waste, the methods we have developed utilize only small quantities of metal catalysts. "Designing new routes to commodity and fine chemicals" as given by the NSF Division Director in 2002 lies at the heart of our reported research accomplishments. Our findings were described in 83 invited lectures at research symposia at universities and chemical companies across the USA and abroad. These findings were reported in three high-impact publications: (a) "Diastereo- and Enantioselective Iridium Catalyzed Carbonyl Propargylation from the Alcohol or Aldehyde Oxidation Level: 1,3-Enynes as Allenylmetal Equivalents," Geary, L. M.; Woo, S. K.; Leung, J. C. Krische, M. J. Angew. Chem. Int. Ed. 2012, 51, 2972. (b) "Enantioselective Carbonyl Propargylation by Iridium-Catalyzed Transfer Hydrogenative Coupling of Alcohols and Propargyl Chlorides," Woo, S. K.; Geary, L. M.; Krische, M. J. Angew. Chem. Int. Ed. 2012, 51, 7830. (c) "Ruthenium Catalyzed Reductive Coupling of 1,3-Enynes and Aldehydes via Transfer Hydrogenation: anti-Diastereoselective Carbonyl Propargylation," Geary, L. M.; Leung, J. C.; Krische, M. J. Chem. Eur. J. 2012, 18, 16823. Another significant outcome of this research resides in the training of students – undergraduates, graduate students and postdoctoral researchers – in the broad areas of organic chemistry, organometallic chemistry and catalysis. Two students involved in this research are now professors. For example, Dr. Laina Geary is now an assistant professor at the University of Nevada, Reno. During the course of this award, Professor Krische’s work in catalysis was recognized by the following awards: Japanese Society for the Promotion of Science (JSPS) Research Fellowship (2013) ACS Cope Scholar Award (2013) GlaxoSmithKline Scholar Award (2012) Mukaiyama Award, Society of Synthetic Organic Chemistry, Japan (SSOCJ) (2010)
