Enzymatic Synthesis of Variediene Analogs

• Published in: Chemistry : a European journal Vol. 28; no. 15; pp. e202200095 - n/a
• Main Authors: Liang, Lin‐Fu, Dickschat, Jeroen S.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 10.03.2022; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Analogs; Chemistry; Chemistry, Multidisciplinary; configuration determination; Configurations; Deuteration; Enzymatic synthesis; enzymes; Fungi; Hemiterpenes; Isopentenyl diphosphate; isotopes; Magnetic resonance spectroscopy; NMR; NMR spectroscopy; Nuclear magnetic resonance; Organophosphorus Compounds; Physical Sciences; Science & Technology; Stereoselectivity; substrate analogs; Terpenes; terpenoids; terpenoids; OPHIOBOLIN F SYNTHASE; CYCLASES; DIPHOSPHATE; substrate analogs; TAXADIENE SYNTHASE; enzymes; configuration determination; GERMACRENE; SESTERTERPENE SYNTHASE; isotopes; BIOSYNTHESIS; TERPENE SYNTHASES; GENOME MINING APPROACH; SYNTHASE-CATALYZED CYCLIZATION
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202200095

Five analogs of dimethylallyl diphosphate (DMAPP) with additional or shifted Me groups were converted with isopentenyl diphosphate (IPP) and the fungal variediene synthase from Aspergillus brasiliensis (AbVS). These enzymatic reactions resulted in the formation of several new terpene analogs that were isolated and structurally characterised by NMR spectroscopy. Several DMAPP analogs showed a changed reactivity giving access to compounds with unusual skeletons. Their formation is mechanistically rationalised and the absolute configurations of all obtained compounds were determined through a stereoselective deuteration strategy, revealing absolute configurations that are analogous to that of the natural enzyme product variediene. Five DMAPP analogs with additional carbon atoms or with changed methylation patterns were converted with IPP and the bifunctional variediene synthase from Aspergillus brasiliensis AbVS to yield diterpene analogs with unusual skeletons. The DMAPP analogs opened new reaction pathways through the stabilisation of cationic charges at alternative carbon atoms that are naturally not observed.