Camphor-derived chiral auxiliaries: a synthetic, mechanistic and computational study

Abstract

A broadly based approach has been undertaken to the development and use of camphor derivatives as chiral auxiliaries in asymmetric synthesis "“ an approach which has embraced synthetic, mechanistic and computational studies. The unambiguous characterization of mono- and dihydroxy-derivatives, obtained by reduction of chiral camphor ether dimers, has been achieved through detailed one- and two-dimensional NMR spectroscopic analysis. The resulting data has been used to establish both the regio- and stereochemistry of the hydroxyl groups. A camphor-derived cyclic iminolactone has been shown to provide a convenient platform for the synthesis of chiral α-amino acids, stereoselective monoalkylation of the iminolactone affording a range of products in yields of 52 - 65 % with up to 85 % d.e. The attempted development of chiral bifunctional Morita-Baylis-Hillman substrates has revealed an unexpected equilibration between isomeric bornane 2,3-diol monoacrylates via acid-catalysed intramolecular transesterification. A detailed [superscript 1]H NMR-based kinetic study of the rearrangement in various media and at various temperatures has permitted the determination of the kinetic and thermodynamic parameters. A computational study at the DFT level has been used to explore the potential energy surfaces of the acid-catalysed and uncatalysed transesterification of the monoacrylate esters. The theoretical data supports the involvement of cyclic intermediates and has provided a rational basis for predicting the favoured reaction pathways. Novel camphor-derived phenyl sulfonate esters and N-adamantylsulfonamides have been synthesised for use as chiral auxiliaries in the Morita-Baylis-Hillman reaction. Modeling at the Molecular Mechanics level has provided useful insights into possible conformational constraints and an adamantyl sulfonate auxiliary has been successfully used in the stereoselective synthesis of a range of products, generally in excellent yield and with up to 95 % d.e.