Novel Approach to the Ansamycin Antibiotics Macbecin I and Herbimycin A. A Formal Total Synthesis of (+)-Macbecin I.

Abstract The asymmetric syntheses of 25 and 29, which constitutes the C(3)–C(15) segment of the stereochemically complex ansa chain of (+)-macbecin I (1) and herbimycin A (2), respectively, have been achieved. The approach features the furan-hydropyranone transformation 9→10 followed by stereoselective introduction of substituents onto the conformationally-biased hydropyran ring of 10 to give 17. Extension of the side chain of 17 led to the pivotal intermediate 22, which was elaborated into 25 and 29. Refunctionalization of the carboxyl terminus of 25 furnished 26, which was converted into 32 by stereoselective addition of an aryllithium to the lactol 30. The structure of 32 was established by its conversion into 34, which was an advanced intermediate in Baker's total synthesis of 1, thereby completing a formal synthesis of optically pure (+)-macbecin I (1).