Nickel Cross-Coupling Cascades with α-Heteroatom Radicals to Prepare Sterically Hindered Alcohols and Amines

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Project Summary The overarching theme of this proposal is to apply robust and reliable reaction mechanisms to improve the efficiency of forming C–C bonds adjacent to alcohol or amine functionality. Among the most common strategies to these products is the addition of a Grignard reagent (or other carbon nucleophile) to a ketone or ketimine electrophile, but the broad applicability of these methods is limited by (1) the poor compatibility of organometallic nucleophiles with many functional groups common to drug scaffolds and (2) significant limitations inherent to migratory insertion mechanisms, such as sluggish or undesired reactivity. The central hypothesis of this proposal is that α-heteroatom radical generating processes can be implemented in tandem with nickel cross-coupling for C–H functionalization to install hindered stereocenters. The emergence of nickel catalyzed cross-electrophile coupling strategies has provided novel and complementary reactivity to traditional cross-couplings and the controlled generation of organic free radicals is central to the development of new methods in this area. Intramolecular hydrogen atom transfer (HAT) mechanisms proceed at a higher rate than nickel capture of alkyl radicals, and should be an appropriate approach to generate the radical. The Specific Aims of this proposal are: (1) development of a 1,5-HAT and nickel C–C bond forming cascade to synthesize tertiary alcohols from readily available secondary alcohols and a traceless auxiliary group; (2) a strategy in which α-heteroatom radicals formed through 1,5-HAT are intercepted for nickel facilitated C–C bond formation to prepare functionalized amino alcohols and amino acids; and (3) an approach for Csp3–Csp3 coupling of α-heteroatom radicals to primary radicals is presented, in which cross-selectivity should be driven by radical stability differences. All three of these Aims can be adopted into enantioconvergent reactions by employing chiral ligands to generate stereocenters, which is highly desirable in the context of pharmaceutical and natural product synthesis. The development and synthesis of drug candidates is limited by the reactions available to make them, and the strategies described in this proposal will facilitate Csp2–Csp3 and Csp3–Csp3 bond formation at α-heteroatom carbon centers, an important motif found in pharmaceuticals and bioactive natural products. The continued improvement of catalytic conditions that employ a large pool of coupling partners to prepare sterically congested alcohols and amines will be of significant interest to both academia and industry, and will enable broader chemical space accessible in future drug discovery endeavors.