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

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

Source

Collaborative research 成果 by Associate Professor Li Jian's team from Shanghai Jiao Tong University and Professor Zhang Weidong & Associate Professor Wang Jinxin's team from Naval Medical University. The related study was published in Science on August 15, 2024.

Abstract

A team led by Associate Professor Li Jian from Shanghai Jiao Tong University, in collaboration with Professor Zhang Weidong and Associate Professor Wang Jinxin from Naval Medical University, has developed a method for preparing terpenoids by combining enzymatic reactions with traditional synthetic chemistry. This provides a concise divergent synthesis route for the efficient preparation of immunosuppressants and anti-tumor active natural products. The research addresses the key challenge of difficult epoxidation of the inert double bond in the middle of the farnesol molecule. The artificially evolved enzyme EPO6 achieves highly selective catalysis, and when combined with chemical strategies, significantly shortens the synthesis steps of various heteroterpenoid natural products. The findings are published in Science.

Content

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.