Studies towards complex bridged alkaloids: regio- and stereocontrolled enolate chemistry of 2,5-diketopiperazines

The substitution of symmetrical N-protected diketopiperazines (DKPs) via enolate intermediates has been studied. The enolate reactions were highly diastereocontrolled, leading to enantiopure DKP products if chiral amino acid precursors were employed, and giving racemic products, starting with centrosymmetric DKPs, even when a chiral lithium amide base was used to generate the lithium enolate. With unsymmetrical DKPs derived from proline and either alanine, phenylalanine or valine, the enolate substitution occurred with high regio- and stereoselectivity on the proline residue. This enabled the synthesis of substituted DKPs that could be cyclised via cationic processes to give the bicyclo[2.2.2]diazaoctane core structure present in paraherquamide and stephacidin natural products.