Studies on the reduction and reductive alkylation of amino acid-derived spirocyclic 2,6-dioxopiperazines

The regio- and diastereoselective reduction and reductive alkylation of 3-spiro-2,6-dioxopiperazines are described via a two-step process, which involves addition of NaBH4 or Grignard reagents, followed by TFA-mediated dehydration with a second NaBH4 addition. The results show that the reactivity of 2,6-dioxopiperazines is limited by their steric hindrance and by the volume of the nucleophile, which preferably add to the C6 carbonylic carbon with complete diastereoselectivity. The diastereoselectivity of the first step is mainly governed by electronic factors, which direct the addition of the nucleophile from the most hindered face, while in the second step, the NaBH4 attacks from the less crowded face. This second step proceeds with partial or complete racemization.