Total Synthesis of Colombiasin A and Determination of Its Absolute Configuration

The recently isolated and biologically active (against Mycobacterium tuberculosis H37Rv) marine natural product colombiasin A features a unique molecular architecture with an unknown absolute stereochemistry. Herein, we provide details for the total synthesis of this complex natural product (see figure) in both racemic and enantiomerically pure forms. Through X-ray crystallographic analysis of a suitably crystalline bromine-containing derivative of an early precursor, it was possible to assign the absolute stereochemistry of colombiasin A. The total synthesis of the recently reported marine natural product colombiasin A (1) and determination of its absolute configuration are reported. Two Diels–Alder cycloadditions and a palladium-catalyzed rearrangement are employed as key reactions to construct the tetracyclic framework of the target molecule. The enantioselective synthesis of colombiasin A utilizes Mikami's [(S)-BINOL-TiCl2] catalyst to asymmetrically introduce the first chiral center during the initial Diels–Alder reaction and, in conjunction with X-ray crystallographic analysis of a bromine containing derivative, led to the assignment of the absolute configuration of the natural product.