Highly diastereoselective desymmetrizations of cyclo(Pro,Pro): an enantioselective strategy toward phakellstatin and phakellin

[reaction: see text] Monoenolates of C(2)-symmetric, proline-derived piperazine-2,5-diones were generated and trapped with a variety of electrophiles to produce, in a highly diastereoselective fashion, functionalized diketopiperazines (DKPs). These reactions provide the basis for an asymmetric, desymmetrization strategy toward the marine alkaloids phakellstatin and phakellin. The relative stereochemistry of the functionalized DKPs was confirmed by single-crystal X-ray analysis and/or NOE experiments. Bis-functionalization of the DKPs was also found to proceed with high levels of diastereoselectivity.