On the origins of diastereoselectivity in the alkylation of diketopiperazine enolates

High levels of diastereoselectivity are observed for benzylation of the lithium enolates of (S)- N, N'-bis- para-methoxybenzyl-3-iso-propyl-piperazine- 2,5-dione, ( S)- N( 1)- para-methoxybenzyl-N( 4)methyl- 3-iso-propyl-piperazine-2,5-dione and ( S)- N( 1)- methyl- N( 4)- para-methoxybenzyl-3-isopropylpiperazine- 2,5-dione. These data suggest that the high diastereofacial selectivity observed for alkylation of these diketopiperazine templates is mainly a consequence of the relay of stereochemical information from C( 3) to C( 6) via the influence of 1,2-torsional strain introduced by the N-alkyl substituents, rather than through minimisation of steric interactions alone.