Asymmetric catalysis of cyanide addition reactions using metal(salen) complexes

Abstract

Chiral cyanohydrins and α-aminonitriles are versatile intermediates and are of great importance to the pharmaceutical industry due to the ability to convert them into useful chemicals via simple chemical transformations. Chiral cyanohydrins and α-aminonitriles can be obtained from asymmetric cyanohydrin synthesis and asymmetric Strecker reactions respectively. In this project, bimetallic aluminium(salen) complex 1 was studied extensively and was shown to be very active in cyanohydrin synthesis using trimethylsilylcyanide (TMSCN), giving the cyanohydrin trimethylsilyl ether derived from benzaldehyde with 89% (S) enantioselectivity and 80% conversion after 18 hours at -40 oC. A variety of substituted benzaldehydes were screened giving moderate to excellent enantioselectivities. Ketones were also shown to be substrates when used in this catalytic system. Extensive kinetic studies of complex 1 gave the rate equation; rate = k[TMSCN][Ph3PO][1] which is zero order with respect to benzaldehyde. A Hammett study using complex 1 showed that this catalytic system was dominated by Lewis basic catalysis, resulting from the activation of trimethylsilylcyanide by triphenylphosphine oxide. The catalyst was then responsible for the chirality of the product rather than the activation of the aldehyde. A variety of other titanium and vanadium(salen) complexes, containing various substituents on the aromatic ring of the salen ligand were synthesised and screened in the Strecker reaction and cyanohydrin synthesis under different reaction conditions. Enantiomeric excesses of 10-95% (R and S) were achieved with conversions of 10-100% for both reactions.