A New Chemo-Enzymatic Approach to Synthesize Isavuconazole Using an Engineered Benzaldehyde Lyase

Isavuconazole, a clinically important triazole antifungal drug, relies on α-hydroxymethyl ketone as a key synthetic precursor. Here, we present a novel chemo-enzymatic approach for the synthesis of isavuconazole. Using 2,5-difluorobenzaldehyde as the starting material, engineered benzaldehyde lyase (BAL) catalyzes the crucial benzoin reaction to form the key intermediate α-hydroxymethyl ketone. Notably, this biocatalytic process operates without extra cofactors (thiamine pyrophosphate, ThDP) and Mg²⁺, achieving a time-space yield (TSY) of 17.2 g·L^-1·day^-1 under optimized conditions. After further chemical reactions on the intermediate, isavuconazole is obtained through an eco-friendly process that outshines traditional chemical synthesis. This optimized protocol is efficient and scalable, yielding isavuconazole at 28.9%, double that of the current industrial chemical process (14.2%), highlighting the remarkable advantages of enzyme-catalyzed synthesis.