Nucleophilic catalysis using chiral phosphines.

Abstract

Chiral phosphines are powerful nucleophilic catalysts for use in enantioselective reactions. New chiral aryl phosphabicyclo[3.3.0]octane (PBO) catalysts were designed, synthesized, and tested in the kinetic resolution (KR) of aryl alkyl carbinols to determine how phosphine structure and conformation affect reactivity and selectivity. Aided by computational modeling, a general trend was observed that correlated phosphine reactivity to the twist of the <italic> P</italic>-aryl group away from the phosphorus lone pair. An unsubstituted PBO catalyst and a benzo-fused catalyst were prepared via phosphinyl radical cyclization reactions. A norbornane fused catalyst was made in one step from cyclic organometallic intermediates. The rates of these catalysts were compared in the acylation of secondary alcohols and the norbornane catalyst showed rates and <bold>s</bold> values comparable to the best PBO catalysts in the KR of several alcohols. PBO catalysts were employed in the KR of allylic alcohols. Rigid alcohols demonstrated low selectivities. Conversely, several unconstrained tri-substituted allylic alcohols were isobutyroylated with <bold>s</bold> = 32--82 at -40&deg;C. Protonation of PBO catalysts with HBF₄ provided air stable salts that could be easily handled on the benchtop. KRs were performed via in situ deprotonation with NEt₃ to afford comparable <bold>s</bold> values to direct addition of PBOs. Parallel kinetic resolution (PKR) was demonstrated for racemic aryl alkyl carbinols using two catalysts (a PBO catalyst and a chiral DMAP) and two anhydrides (nicotinic and isobutyric) in a single homogeneous reaction mixture. Each catalyst selectively activated one of the two achiral acyl donors. Moderate ee's were obtained for both products (41--92% ee) with high overall yields. An enantioselective intramolecular vinylogous Mortia-Baylis-Hillman reaction was demonstrated. Using PBO catalysts, ee's of 18--44% were obtained. In an attempt to increase the rate of the cyclization reaction, an allenolate variant of the reaction was discovered. The cyclization of activated enoate-ynoate substrates is achieved in moderate yields with trialkyl phosphine catalysts and TMSCN although low ee's were obtained using PBO catalysts. A mechanistic rationale for the products and low enantioselectivity is proposed.