Catalytic, asymmetric aldol reaction equivalents: Development and mechanistic studies of Lewis acid-catalyzed acyl halide-aldehyde cyclocondensations

Catalyzed asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions have been developed as catalyzed direct aldol reaction variants. The AAC reactions utilize acetyl bromide or propionyl bromide in the presence of diisopropylethylamine to generate ketene in situ as an enolate surrogate. Ensuing ketene-aldehyde cyclization occurs in the presence of a substoichiometric amount (10 mol%) of optically active AI(III)-triamine complex 27a affording enantioenriched β-lactones (≥90% ee) as masked aldol adducts. The operational simplicity of these reactions and the use of inexpensive, commercially available reaction components are particularly attractive characteristics.*; Solid state and solution studies of the active catalyst demonstrated that a neutral, pentacoordinate Lewis acid-base adduct derived from 27a is the catalytically active species in the asymmetric AAC reactions. The solid state structure indicates 27a to be a four-coordinate complex adopting a trigonal monopyramidal (tmp) geometry ideally disposed to accept a fifth ligand in a vacant apical site. The ligand, therefore, acts primarily to define a catalytically active coordination geometry rather than assisting in defining electronic properties within the metal complex necessary for catalysis. The ligand-defined catalysis can be interpreted as arising from a combination of ground state destabilization of the distorted metal complex and a stabilization of the transition state leading to Lewis acid-base association for the preorganized tmp catalysts relative to analogous tetrahedral complexes.; The empirical rate expression of the asymmetric AAC reaction of hydrocinnamaldehyde catalyzed by Al(III)-triamine complex 27a was determined. The AAC reaction was first order in catalyst 27a and ketene, but a fractional dependence on aldehyde concentration and a first order dependence on bromide ion concentration were also identified. The observed kinetic behavior of the asymmetric AAC reaction is consistent with a novel mechanism incorporating a chiral acid bromide enolate intermediate. The kinetic observations from a variety of acyl halide aldehyde cyclocondensation reactions suggest that the reaction occurs by competing bromide-dependent and bromide-independent pathways.; *Please refer to dissertation for diagram.