Abstract
The first total synthesis of the alkaloid brevianamide S has been achieved in eight steps. This natural product, isolated from Aspergillus versicolor, exhibits selective antibacterial activity against Bacille Calmette-Guérin (BCG), a commonly used surrogate for Mycobacterium tuberculosis. Brevianamide S is proposed to act through a novel, yet-to-be-elucidated mechanism, making it a promising lead in the development of next-generation antitubercular agents. Our approach employs a bidirectional synthetic strategy, involving a bespoke alkenyl–alkenyl Stille cross-coupling reaction and a double aldol condensation. This represents a flexible and efficient platform for the future synthesis of structurally diverse analogues.