Elucidation of the stereocontrol mechanisms of the chemical and biosynthetic intramolecular Diels–Alder cycloaddition for the formation of bioactive decalins

Abstract

The intramolecular Diels–Alder reaction (IMDA) is a powerful method for regioselective and stereoselective construction of functionalised decalin skeletons, and the recent discovery of enzymes that catalyse IMDA cycloaddition in biosynthesis has generated considerable interest. This study focused on the role of the absolute configuration of the C-6 carbon of the substrate polyene in the stereocontrol of the IMDA reaction catalysed by Fsa2 and Phm7, which construct different enantiomeric decalin skeletons. Their enantiomeric precursor polyenes were synthesised and subjected to enzymatic or thermal IMDA reactions to isolate various diastereomeric decalines and determine their absolute configuration. Furthermore, density functional theory calculations were performed to elucidate the stereocontrol mechanism underlying the formation of decalin. The results showed that Fsa2 exhibits the same equisetin-type stereoselectivity for enantiomeric substrates regardless of the 6-methyl group configuration of the substrate, while Phm7 shows two types of stereoselectivity depending on the configuration of the 6-methyl group. We also found a unique stereochemistry–activity relationship in antibacterial activity for decalin diastereomers, including new derivatives. This study provides new insights into the stereoselectivity of DAase, which is important in the synthesis of natural product skeletons.