Nucleophilic addition to conformationally rigid cyclohexanones can provide two stereoisomeric alcohol products via reaction at the 'axial' or the 'equatorial' face of the carbonyl. The facial selectivity for addition to these rigid systems is related to the size of the nucleophilic reagent; the convention is that small nucleophiles add to the axial face to avoid torsional strain, whereas bulky nucleophiles add to the equatorial face to avoid 1,3-diaxial interactions. However, this trend in facial selectivity does not hold true for some six-membered cyclic ketones; namely, cis-2,6-disubstituted N-acylpiperidones (but not the related bridged tropinone analogs) have been reported to favor hydride addition from the equatorial face, even when a small hydride reagent is used. Herein, we describe DFT studies to explore the factors influencing the experimentally observed differences in facial selectivity of hydride addition to these and other cyclic ketones. Our calculations suggest that a twist-boat transition state is a significant contributor to the reduction of this class of piperidones using small hydride reagents (LiAlH4). This result is unusual, as 6-membered cyclic ketones are typically considered to react through a chair conformation. Importantly, attack at the equatorial face of the piperidone twist boat involves less torsional strain than axial attack. Additionally, calculations with tert-butylcyclohexanone suggest that the convention that equatorial attack to a chair conformation involves more torsional strain than axial attack does not necessarily hold true with bulky nucleophiles. With LiHB(iPr)3, attack at the experimentally preferred equatorial face of tert-butylcyclohexanone is driven by minimization of both steric interactions and torsional strain. As such, our results suggest that it may be appropriate to reevaluate the sterics vs. torsional strain paradigm for addition of bulky nucleophiles to cyclic ketones and for substrates for which a twist boat conformation may be relevant.

New twist on the sterics vs. torsional strain model for facial selectivity of nucleophilic addition to cyclic ketones

248th National Meeting (2014)

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