DPP-IV Inhibitor by Proline-Catalyzed Mannich Reaction

Significance

A novel lead structure (1) for DPP-IV inhibitors, which are important for type 2 diabetes treatment, was identified (S. D. Edmondson et al. Bioorg. Med. Chem. Lett. 2005, 3048-3052). The authors describe a (S)-proline-catalyzed Mannich reaction as the key step in the synthesis of β-phenyl aspartic acid derivative 6. Starting from PMP-protected imine 2 and phenylacetaldehyde 3, (S)-proline-catalyzed Mannich reaction and reduction gave alcohol 4 in 92:8 syn/anti-rate and >90% ee. Four more steps were required to yield the diamide aspartic acid derivative 6 in >99% optical purity after recrystallization and an overall yield of 24%.