Chiral N-Phosphonyl Imine Chemistry: a New Asymmetric Synthesis Strategy

The amine functionality is incorporated into more than 75% of all drugs and drug candidates and is also prevalent in natural products, materials and catalysts.[1] Therefore, the chemistry of chiral amines has become very important in asymmetric synthesis because the discovery and development of new biologically active chemicals is increasingly dependent on the synthesis of imines with a high degree of diastereoselectivity.[ 2,3] The chiral auxiliary N-sulfinyl can activate the imine, and the configurationally stable stereocentre at sulfur can provide diastereofacial selectivity for nucleophilic addition.[4] However, its use is not straightforward owing to its high sensitivity to oxidative conditions and to difficulties with its deprotection. Attempts to solve these problems lead to loss of chirality and make impossible the recovery of the chiral auxiliary.[5] Moreover, N-sulfinyl imine does not tolerate strong Lewis acids, such as titanium tetrachloride (TiCl4), for instance. Recent studies have led to the use of a new chiral auxiliary, N-phosphonyl imine, which is a more stable electrophile than N-sulfinyl imine in nucleophilic reactions, to give chiral amino compounds with a very high degree of diastereoselectivity in good yields.[5,6] The electrophilicity can be modulated by the use of donator and acceptor groups on the nitrogen atom. This strategy is a real advantage relative to N-sulfinyl imine, which does not tolerate this kind of interference.[5,6]. © 2010 CSIRO.