γ-Functionalized carbonyls via homoconjugate addition of organoboronates to cyclopropanes & Electrophilic deborylative strained-ring opening, oxyallyl cation capture, and propargylic substitution
Nguyen, Truong N. 1991-
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Firstly, a novel and practical homoconjugate addition of alkenyl, alkynyl, and aryl/heteroaryl trifluoroborates to arylated cyclopropyl ketones to synthesize challenging γ,γ-disubstituted ketones catalyzed by (n-Bu)₄NHSO₄ was described. The reaction limitation of only electron-rich cyclopropanes and monosubstituted cyclopropanes being useful was overcome by employing GaCl₃ or IPrGaCl₃ as the reaction catalyst. The new conditions allowed electron-deficient aryl, alkenyl, alkyl, and hydrogen-substituted cyclopropanes to be used, affording highly hindered tertiary and quaternary carbons. Control experiments support the formation of carbocation intermediates under both Brønsted and Lewis acid conditions. To further increase the significance of this method, an asymmetric version was systematically sought. A polyfluorinated BINOL-based catalyst was found to catalyze the reaction enantioselectively, affording the product in an 80:20 e.r. Further optimizations and computational studies to improve this challenging transformation are ongoing. Secondly, several synthetic applications utilizing organoboron nucleophiles were developed. These useful transformations include branched amine synthesis via aziridine and azetidine ring-opening catalyzed by cooperative Brønsted and Lewis acids with an acid-dependent divergent mechanism and stereoselectivity, an umpolung approach towards unsaturated α,α-disubstituted silyl enol ethers via oxylallyl cation trapping catalyzed by LiPF₆, and propargylic substitution with aliphatic substrates catalyzed by a Ga complex. The success of these reactions is based on the utilization of a less-developed feature of organoboronates: electrophilic deborylation. Unsaturated organoboronates can serve as π-nucleophiles towards cationic intermediates via electrophilic deborylation, enabling new C–C bond-forming transformations. Lastly, a collaboration to develop a new approach for enantioselective catalyst design that combines DFT-based virtual screening with multivariate linear regression (MLR) to deliver catalysts with improved activity and selectivity is demonstrated as well.