2-Halo-diketopiperazines as chiral glycine cation equivalents

A range of (2S,5S)-5-isopropyl-2-halo-N,N′-bis-(p-methoxybenzyl)-piperazine-3,6-diones 8 (Cl), 11, 12 (F) and 13 (Br) have been prepared, either via electrophilic halogenation of the corresponding lithiated diketopiperazine, or via transhalogenation from fluoro-11 and 12. The product distribution and stereoselectivity of additions of allyltrimethylsilane, sodium thiophenolate and a range of organomagnesium reagents to chloro 8 are reported. In the reactions with Grignard reagents the observed stereo- and regioselectivities are dependent on the reagent employed, with C-3 carbonyl addition products predominating upon addition of allyl or methylmagnesium chloride and stereodivergent formal C-2 addition predominating with benzyl or isopropylmagnesium chloride. A model to account for the different reactivity and stereoselectivity in these reactions is proposed.