Novel Protoilludane Lead Structure for Veterinary Antibiotics: Total Synthesis of Pasteurestins A and B and Assignment of Their Configurations

Two novel protoilludane sesquiterpenoids, named pasteurestins A and B (1 and 2), were disclosed in a recent patent. These compounds were reported to exhibit strong and selective activity against some Mannheimia haemolytica strains, pathogen causatives for bovine respiratory disease. These properties qualified 1 and 2 as potential lead structures for new veterinary antibiotics; however, neither the absolute nor the relative configurations had been determined, nor were the compounds available any longer. We thus developed total syntheses of 1 and 2 and clarified their structures and their biological profiles. Key steps were two [2+2+2] CpCo(CO)2‐mediated Vollhardt cycloadditions in both syntheses, and a tin‐mediated asymmetric Reformatsky‐type condensation in the synthesis of 2 with a temperature‐dependent product distribution.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) Their strong activities against some Mannheimia haemolytica strains qualified the recently patented pasteurestins A (1) and B (2) as potential lead structures for new veterinary antibiotics. However,neither the absolute nor the relative configurations were determined from the isolated products. We thus completed total syntheses of 1 and 2 and clarified their structures and their biological profiles. Key steps in both syntheses were two [2+2+2] CpCo(CO)2‐mediated Vollhardt cyclotrimerizations.