Semi-synthesis of a biologically inspired library of sesquiterpene derivatives, from the lipophilic marine natural product (+)-β-gorgonene

Natural products and their mimics have a high probability of engaging with biological targets. Hence, natural products have historically been a valuable source of medicines. They continue to inspire the synthesis of biologically relevant compound libraries, useful for drug discovery. Over 50 % of the small molecule drugs approved in the last 30 years are natural products or natural product derived. Sesquiterpenes are widespread in nature and exhibit a range of notable biological activities including antimicrobial, anti-inflammatory, anti-viral and lipid lowering activity. Therefore, sesquiterpene frameworks are suitable templates for biologically relevant screening libraries. Inspired by selected natural bioactive sesquiterpenes, we have transformed a highly lipophilic, non-drug-like, marine natural product (+)-β-gorgonene, available as a by-product from the purification of pseudopterosins, into a library of more drug-like derivatives. Several semi-synthetic techniques were employed to attach suitable structures such as substituted aromatics and heteroaromatics to the gorgonene scaffold to increase its drug-likeness and probability of exhibiting biological activity. Each compound synthesized was chemically characterized, analyzed for drug-likeness and screened for PTP1B inhibition (potential therapeutic target for treatment of type 2 diabetes), antimicrobial activity and cytotoxic properties. With the goal of incorporating the desired substructures in a minimum number of steps, a 2+3 dipolar cycloaddition reaction was used to attach selected motifs to the gorgonene framework via an isoxazoline linker. The series of synthesized isoxazoline derivatives included decahydroazulene and cyclopropane-containing compounds. Several members of the isoxazoline-containing collection displayed selective inhibition of the PTP1B enzyme and others exhibited modest cytotoxic activity. Another family of gorgonene analogues was synthesized through a dione containing intermediate, a product of the ozonolysis of gorgonene. Carbonyl chemistry was then used to incorporate aromatic moieties into the structure such as the aldol reaction and nucleophilic addition. Gorgonene was observed to undergo an intramolecular Alder-ene reaction when catalyzed by FeCl3 or BF3 and produce novel tricyclic sesquiterpene-like hydrocarbons. A hydroboration/oxidation strategy highlighted the tendency for the 1,5-diene system to react intramolecularly to form additional five- and six-membered rings. A glycosyl-containing derivative was synthesized through a dihydroxy-gorgonene analogue. Biotransformation was used as an additional strategy to selectively oxidize synthetically inaccessible carbons on gorgonenes saturated decalin backbone to facilitate further transformations. Incubation of gorgonene with Bionectria ochroleuca resulted in the production of a novel trihydroxylated sesquiterpenoid.