Enantioselective synthesis of non-proteinogenic amino acids via metallated bis-lactim ethers of 2,5-diketopiperazines

Abstract

Bis-lactim ethers 1 of 2,5-diketopiperazines contain a chiral inducing center, an acidic CH-bond and two sites susceptible to hydrolysis. They react with BuLi to give Li compounds of type 4, 15, 19 or 32, which possess a prochiral C atom. They readily add electrophiles (such as alkylating agents or carbonyl compounds) with unusually high diastereoface differentiation. In many cases the d.e.-value (d.e. = diastereomeric excess = asymmetric induction) of the adduct exceeds 95%. On hydrolysis the adducts are cleaved liberating the chiral auxiliary (used to build up the bis-lactim ether 1) and the target molecules, the optically active amino acid methyl esters of type 8, 19, 25 or 36. The two amino acid esters are separable either by fractional distillation or (eventually after further hydrolysis to amino acids) by chromatography. Transition state models are discussed that could explain the exceptionally high asymmetric induction and the predictability of the induced configuration.