Synthesis of novel chiral ligands for catalytic asymmetric reactions

Abstract

A series of N-salicyl-beta-aminoalcohol ligands had been synthesized by three component Mannich type reaction followed by ring opening of oxazolidine derivatives with hydroxylamine hydrochloride. The reactions provided a series of chiral N-salicyl-beta-aminoalcohol ligands in high yields (84-92%) without any racemization. These synthesized compounds were evaluated as ligands for catalytic asymmetric Strecker reactions. N-Benzhydrylaldimines derived from aromatic and aliphatic aldehydes reacted withTMSCN in the presence of 10 mol% of Ti-ligand complex to give the alpha-aminonitriles in excellent yields and in up to >98% ee. In addition, the catalyst loading was successfully reduced to 2.5 mol% which is very effective and extremely simple for large scale synthesis. The presence of 2-propanol is essential to ensure good conversion and reaction rate. The absolute configuration of all products derived from the (S)-ligand was confirmed to be S. Racemization of alpha-aminophenylacetonitriles is catalyzed by weak acids such as silica (SiO[subscript 2]) or even methanol. However, the racemization can be suppressed by addition of either a base such as triethylamine (NEt[subscript 3]) or strong acid such as hydrochloric acid (HCI). Importantly, optically active alpha-aminoacetonitriles can be easily converted to arylglycines by complete hydrolysis with minimal racemization. (>80% and >90% ee). A transition state model to explain the enantioselectivity of the reaction is proposed. The present chiral catalysts showed their catalytic ability in not only asymmetric strecker reaction but also asymmetric Pudovic reaction as well as asymmetric Michael addition.