Combining total synthesis and genetic engineering to probe dihydropyran formation in ambruticin biosynthesis

• DOI: 10.1039/d4sc00720d
• Publication Date: 2024-03-12T08:52:36Z
• Authors: James I. Bowen; Xiaotong Zhong; Kaining Gao; Benjamin Reed; Matthew P. Crump; Luoyi Wang; Christine L. Willis
• Keywords: Dihydropyran

The ambruticins are a family of potent antifungal polyketide derived natural products isolated from the myxobacterium Sorangium cellulosum. Their unusual structures include trisubstituted cyclopropyl group and two oxygen heterocycles, tetrahydropyran (THP) dihydropyran (DHP). Herein we report flexible modular approach for total synthesis which is used to prepare F S as well in first 20,21-dihydroambruticin F. strategy unites 3 fragments via Julia-Kocienski olefinations provides important standards investigation formation ambruticin biosynthesis. Cultures wild-type S. cellulosum So ce10 produce mainly VS series metabolites. An efficient electroporation method enabled gene knockout experiments revealed that ΔambP-S mutant accumulated bisTHP In contrast, ΔambN-S gave with 20,21-alkene major metabolite confirming AmbP AmbO (a Rieske enzyme flavin-dependent monooxygenase respectively) implicated formation. results feeding studies strain containing only ambP ambO accord occurring prior generation C3 C7 dihydroxylated