Catalytic C-C Coupling via Hydrogen Transfer

Summary/Abstract: Catalytic hydrogenations are the most frequently utilized chemical reactions in the synthesis of pharmaceutical ingredients, constituting 14% of GMP reactions (oxidations = 3% of GMP reactions). Metal-catalyzed cross-coupling and carbonyl addition are the most frequently utilized methods for C-C bond formation among GMP reactions. We seek to develop a family of catalytic methods for C=X/C=C (X = O, NR) and C-X/C-Y (X = Y = halide) reductive C-C couplings mediated by H2, 2-PrOH, NaO2CH that are as clean, scalable and cost-effective as catalytic hydrogenation. This includes catalytic hydrogen auto-transfer reactions that affect direct conversion of lower alcohols/amines to higher alcohols/amines via CH-XH/C=C (X = O, NR) C-C coupling. These methods inform parallel studies on the total synthesis of polyketide natural products with anti-cancer or anti-bacterial properties. Under the NIH-MIRA program, our work on catalysis (R01 GM069445) and total synthesis (RO1 GM093905) will be integrated to maximize their synergy.