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.
Highlights
Dolabellane diterpenoids have originally been reported in the herbivor sea hare Dolabella california (Ireland and Faulkner, 1977)
The variations between each batch were minor. This scalable biotechnological production route enables independent access of (2), which is a prerequisite for subsequent chemical functionalization studies reported here
We demonstrated that a sustainable, biotechnological production of the bioactive (1R,3E,7E,11S,12S)-3,7,18-dolabellatriene (2) by the mutant diterpene cyclase CotB2 W288G is feasible
Summary
Dolabellane diterpenoids have originally been reported in the herbivor sea hare Dolabella california (Ireland and Faulkner, 1977). In later studies marine algae, sponges, and terrestrial plants such as liverworts were found to be rich sources of dolabellane natural products (Cai et al, 2010). All dolabellane diterpenoids share a 5,11-bicyclic skeleton and are frequently functionalized by hydroxyl, epoxide, and glucoside groups. The efficient total chemical synthesis or biotechnological production process for structurally complex terpenoids such as dolabellanes, arteminisin, or taxol remains challenging (Kusama et al, 2000; Lozama and Prisinzano, 2009; Malik et al, 2011). Total chemical synthesis of functionalized natural products often involves multiple steps, resulting in racemic intermediates, and low product yields. In this respect, the synthetic assembly of olefinic macrocycles containing numerous
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
