Overcoming the Inherent Alkylation Selectivity of 2,3-trans-3,4-cis-Trisubstituted Cyclopentanones

Abstract

Some ketones, especially 2,3-trans-3,4-cis-trisubstituted cyclopentanones, have strong inherent preferences to react through their less-substituted enolates, with neither kinetic nor thermodynamic conditions being able to selectively functionalize their more-substituted enolate isomers. Herein we report a synthetic strategy to overcome this limitation and selectively access the more-substituted alkylation products of these ketones. The strategy’s key feature is to utilize a MeOCH₂O group to temporarily block the more-reactive α position and to direct the ketone to react through its inherently less-reactive enolate isomer. The products formed by this strategy are useful synthetic intermediates on the path to multiple families of natural products.

Key words

ketones - alkylation - regioselectivity - neighboring-group effects - natural products

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