From a Biosynthetic Pathway toward a Biocatalytic Process and Chemocatalytic Modifications: Three-Step Enzymatic Cascade to the Plant Metabolite cis-(+)-12-OPDA and Metathesis-Derived Products.

A biotechnological approach toward the plant metabolite and regulator cis-(+)-12-oxophytodienoic acid (cis-(+)-12-OPDA) in a one-pot process with >99% conversion, at least 90% selectivity and ≤10% of side products as well as a high diastereoselectivity (leading to d.r. of at least 90:10) is reported. The optimized organic-synthetic enzyme cascade for preparing this bioactive and commercial molecule with pharmaceutical relevance on a gram per L scale is designed based on its biosynthetic pathway starting from cheap and readily accessible linolenic acid. Toward this end, a recombinant biocatalyst system has been prepared for carrying out the most critical two key steps in a tailored manner, thus avoiding sensitive intermediate decomposition. Furthermore, cis-(+)-12-OPDA is successfully modified via a cross-alkene metathesis reaction with conversions of up to >99%, leading to a compound library of new cis-(+)-12-OPDA derivatives with different substitution pattern of the side chain at the 2-position. By means of such a combined biotechnological and chemocatalytic route, a straightforward approach to a structurally unique oxylipin library is realized, which would be highly difficult or not accessible by pure chemical and biotechnological methods, respectively.