Direct asymmetric aldol reactions in water catalysed by a highly active C2-Symmetrical bisprolinamide organocatalyst

A novel C2-symmetrical bisprolinamide organocatalyst was synthesised and used to facilitate asymmetric direct aldol reactions in a water emulsion. Reactions were performed at room temperature with very low catalyst loadings (12.5 mol%) without the required use of additives, co-catalysts or extended reaction times (24 h). This catalyst system was then used with a variety of aldehyde substrates showing good reaction generality for benzaldehydes with cyclohexanone (dr range 77/23 to >99/1, anti/syn; ee range 33% to >99%) and moderate scope with cyclopentanone (dr range 45/55 to 76/24, anti/syn; ee range 14% to 68%). Ultra-low catalysts loadings (0.1 and 0.05 mol%) were also investigated demonstrating catalyst turnover numbers in the order of 1000.

Synergistic effects within a C2-symmetric organocatalyst : the potential formation of a chiral catalytic pocket

This study describes the synthesis of five novel C2-symmetric organocatalysts that facilitate the on-water asymmetric aldol reaction at low catalyst loading (1 mol%) without the use of additives. Each catalyst is composed of two diprolinamide units joined by a symmetric alkyl bridging group allowing for systematic modulation of catalytic site proximity. Typically, catalysts in this manuscript which bear the catalytic units in close proximity gave the best reaction outcomes in terms of conversion (up to >99%), diastereomeric ratio (4/96, syn/anti) and enantiomeric excess (up to 97%). This effect has been attributed to the assembly of a chiral pocket, facilitated by hydrogen bonding at the oil-in-water interface.

The synthesis and evaluation of novel, C2-symmetric organocatalysts

This thesis presents the synthesis and evaluation of a series of C2-symmetric, diprolinamide based organocatalysts. These catalysts were designed to investigate the effect that catalyst bridge length imparted on activity and chiral selectivity through catalytic site cooperation. Evaluation of these compounds led to the postulation of a novel “chiral pocket” transition state that will aid in the design of future catalysts.