Syntheses of Epoxyguaiane Sesquiterpenes (−)-Englerin A, (−)-Oxyphyllol, (+)-Orientalol E, and (+)-Orientalol F: A Synthetic Biology Approach

Abstract

A combined approach toward syntheses of epoxyguaiane sesquiterpenes is presented. By use of a fungus sesquiterpene cyclase, guaian-6,10(14)-diene was produced through metabolic engineering of the isoprenoid pathway in E. coli. (−)-Englerin A, (−)-oxyphyllol, (+)-orientatol E, and (+)-orientalol F have been synthesized in two to six steps. This strategy provided rapid access to the epoxyguaiane core structure and would facilitate syntheses of (−)-englerin A and its analogues for evaluation of their therapeutic potentials in drug discovery.Letter pubs.acs.org/OrgLett

Syntheses of the Carotane-type Terpenoids (+)-Schisanwilsonene A and (+)-Tormesol via a Two-Stage Approach

“…Although some terpenes from bacteria have the opposite absolute configurations of plant terpenoids, these findings have enriched the toolbox for synthetic biologists to reconstruct the biosynthetic pathways of terpenoids in microorganisms. For example, two groups reported the heterologous production of guaian-6,10(14)-diene in E. coli and S. cerevisiae and the synthesis of (−)-englerin A, a potent and selective inhibitor toward renal cancer cell lines . Additionally, Smanski and coworkers reported the production of ent -atiserenoic acid in an engineered Streptomyces strain and the synthesis of serofendic acid, a natural neuroprotective compound found in fetal calf serum .…”

New Trends and Future Opportunities in the Enzymatic Formation of C−C, C−N, and C−O bonds

“…[77] Through metabolic engineering of the isoprenoid pathway in E. coli, Mou and co-workers were able to produce the molecular scaffold, guaian-6,10(14)-diene, with a high degree of stereo-and regio-selectivity exploiting the cyclases, STC5. [78] This enzyme catalyses the cyclisation of the natural substrate FPP to afford a guaian-6,10(14)-diene intermediate, which they then converted chemically into a number of bioactive compounds (Scheme 8). [79] A total of six chemical and enzymatic steps were employed to convert FPP into (À )-englerin A with an overall yield of 14 %.…”

Practical Enzymatic Production of Carbocycles

“…Aiming at a more scalable synthesis, they further engineered the enzymes in the MVA pathway by CRISPR/Cas9 system in S. cerevisiae , and the production of 7.4 was further increased to 0.8 g/L in 5 L fed‐batch fermentation of S. cerevisiae YL06. In a parallel study, the Xiang group [107] used a two plasmid system to produce 7.4 in E. coli (129 mg/L). The MVA pathway was divided into two parts and was overexpressed from the vector pACYCDuet‐T1‐B1 while the FPP synthase (FPPS) ERG20 and the sesquiterpene synthase STC5 were overexpressed from the vector pETDuet‐ERG20‐STC5.…”