Scientists Develop a Concise Chemo-Biological Synergistic Synthesis Method for Terpenoids

Terpenoids are a class of important natural products with wide applications in fields such as immunosuppressants and anti-tumor drugs. Asymmetric epoxidation reactions have greatly promoted the synthesis of such compounds. However, farnesol, a crucial raw material for terpenoid synthesis, has a C6–C7 double bond in the middle of its molecule that is sterically hindered and lacks activating groups, making it impossible to be directly converted through existing asymmetric epoxidation reactions—a major bottleneck in the field of synthesis.

To tackle this problem, the research team screened out the initial catalyst EPO1 from their self-built enzyme library. Through 5 rounds of saturation mutagenesis-based directed evolution of EPO1, they successfully obtained the artificial enzyme EPO6. This artificial enzyme can efficiently and selectively catalyze the epoxidation of the middle alkene of farnesol, achieving 93% regioselectivity and 94% enantioselectivity, which is significantly better than existing chemical catalysis methods. Using EPO6, the team successfully prepared 10-gram-scale chiral epoxy intermediates, achieving high-selectivity functionalization of the most inert double bond in the farnesol molecule for the first time. Furthermore, by utilizing the high reactivity of the remaining double bonds, they efficiently and concisely constructed various synthetic intermediates.

On this basis, the research team verified the trimethylsilyl (TMS)-promoted middle-tail polyene tandem cyclization strategy, which effectively solved the problem of cyclization assembly energy barriers caused by large steric hindrance side chains. Based on this chemo-biological synergistic method, the team successfully synthesized 11 heteroterpenoid natural products, with the number of synthesis steps reduced by 50% to 74% compared with traditional routes. Among them, Emindole DA was fully synthesized for the first time, Emindole SA was completed in 6 steps, and Subglutinol B was fully synthesized in only 9 steps, greatly improving synthesis efficiency.

The research team stated that this achievement promotes the paradigm shift in natural product and drug synthesis, marking that synthetic chemistry has entered a new stage of "designing and optimizing ideal biocatalysts on demand according to synthetic strategy requirements," and opens up a new path for the efficient preparation of complex natural products and drugs.