Michael J. Krische, Wandi Zhang, Seung Wook Kim
Merging the characteristics of transfer hydrogenation and carbonyl addition, we have developed a new class of catalytic enantioselective C–C bond formations. In these processes, hydrogen transfer between alcohols and π-unsaturated reactants generates carbonyl–organometal pairs that combine to deliver products of addition. On the basis of this mechanistic paradigm, lower alcohols are converted directly to higher alcohols in the absence of premetalated reagents or discrete alcohol-to-carbonyl redox reactions. In certain cases, due to a pronounced kinetic preference for primary versus secondary alcohol dehydrogenation, diols and higher polyols are found to engage in catalytic stereo- and site-selective C–C bond formation—a capability that further enhances efficiency by enabling skeletal construction events without extraneous manipulations devoted to the installation and removal of protecting groups. While this Account focuses on redox-neutral couplings of alcohols, corresponding aldehyde reductive couplings mediated by 2-propanol were developed in parallel for most of the catalytic transformations reported herein. Mechanistically, two distinct classes of alcohol C–H functionalizations have emerged, which are distinguished by the mode of pronucleophile activation, specifically, processes wherein alcohol oxidation is balanced by (a) π-bond hydrometalation or (b) C–X bond reductive cleavage. Each pathway offers access to allylmetal or allenylmetal intermediates and, therefrom, enantiomerically enriched homoallylic or homopropargylic alcohol products, respectively. In the broadest terms, carbonyl addition mediated by premetalated reagents has played a central role in synthetic organic chemistry for well over a century, but the requisite organometallic reagents pose issues of safety, require multistep syntheses, and generate stoichiometric quantities of metallic byproducts. The concepts and catalytic processes described in this Account, conceived and developed wholly within the author’s laboratory, signal a departure from the use of stoichiometric organometallic reagents in carbonyl addition. Rather, they reimagine carbonyl addition as a hydrogen autotransfer process or cross-coupling in which alcohol reactants, by virtue of their native reducing ability, drive the generation of transient organometallic nucleophiles and, in doing so, serve dually as carbonyl proelectrophiles. The catalytic allylative and propargylative transformations developed to date display capabilities far beyond their classical counterparts, and their application to the total synthesis of type-I polyketide natural products have evoked a step-change in efficiency. More importantly, the present data suggest that diverse transformations traditionally reliant on premetalated reagents may now be conducted catalytically without stoichiometric metals. This Account provides the reader and potential practitioner with a catalog of enantioselective alcohol-mediated carbonyl additions—a user’s guide, 10-year retrospective, and foundation for future work in this emerging area of catalytic C–C bond formation.