title: Stereoselective chemo-enzymatic oxidation routes for (1R,3E,7E,11S,12S)-3,7,18-dolabellatriene.
abstract: The diterpene (1R,3E,7E,11S,12S)-3,7,18-dolabellatriene from the marine brown alga Dilophus spiralis belongs to the dolabellanes natural product family and has antimicrobial activity against multi-drug resistant Staphylococcus aureus. Recently, we generated a CotB2 diterpene synthase mutant (W288G), which instead of its native product cyclooctat-9-en-7-ol, generates (1R,3E,7E,11S,12S)-3,7,18-dolabellatriene. In vivo CotB2 W288G reconstitution in an Escherichia coli based terpene production system, allowed efficient production of this olefinic macrocycle. To diversify the 3,7,18-dolabellatriene bioactivity we evaluated chemical and enzymatic methods for selective oxidation. Epoxidation by acetic peracid, which was formed in situ by a lipase catalyzed reaction of acetic acid with H2O2, provided efficient access to two monooxidized dolabellanes and to a novel di-epoxidated dolabellane species. These compounds could act as synthons en-route to new dolabellanes with diversified bioactivities. Furthermore, we demonstrate the almost quantitative 3,7,18-dolabellatriene conversion into the new, non-natural compound (1R,3E,7E,11S,12S,18R)-dolabella-3,7-diene-20-ol by hydroboration-oxidation with an enantiomeric excess of 94%, for the first time.
authors.affiliation: Fachgebiet für Industrielle Biokatalyse, Department für Chemie, Technische Universität München Garching, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Görner
authors.affiliation: Fachgebiet für Industrielle Biokatalyse, Department für Chemie, Technische Universität München Garching, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Hirte
authors.affiliation: Fachgebiet für Industrielle Biokatalyse, Department für Chemie, Technische Universität München Garching, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Huber
authors.affiliation: Fachgebiet für Industrielle Biokatalyse, Department für Chemie, Technische Universität München Garching, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrepfer
authors.affiliation: Fachgebiet für Industrielle Biokatalyse, Department für Chemie, Technische Universität München Garching, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brück
keywords: chemo-enzymatic synthesis; diterpenes; dolabellanes; epoxidation; hydroboration