https://pubs.rsc.org/en/Content/ArticlePDF/2016/NP/C6NP00074F

Phytocannabinoids: a unified critical inventory.

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Current Applications of Suzuki–Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update

Pyrrolo[1,2-a]indoles are privileged structural elements of many natural products and pharmaceuticals. An efficient one-step process for their highly diastereo- and enantioselective synthesis, comprising a direct [3+2]-cycloaddition, has been developed. A chiral BINOL-derived phosphoric acid catalyzes the reaction of in situ-generated 2-methide-2H-indoles with 2-vinylindoles, furnishing the target products incorporating three contiguous stereogenic centers as single diastereoisomers and with excellent yields and enantioselectivities.

Brønsted Acid Catalyzed [3+2]-Cycloaddition of 2-Vinylindoles with In Situ Generated 2-Methide-2H-indoles: Highly Enantioselective Synthesis of Pyrrolo[1,2-a]indoles

Prenylation of natural compounds adds structural diversity, alters biological activity, and enhances therapeutic potential. Because prenylated compounds often have a low natural abundance, alternative production methods are needed. Metabolic engineering enables natural product biosynthesis from inexpensive biomass, but is limited by the complexity of secondary metabolite pathways, intermediate and product toxicities, and substrate accessibility. Alternatively, enzyme catalyzed prenyl transfer provides excellent regio- and stereo-specificity, but requires expensive isoprenyl pyrophosphate substrates. Here we develop a flexible cell-free enzymatic prenylating system that generates isoprenyl pyrophosphate substrates from glucose to prenylate an array of natural products. The system provides an efficient route to cannabinoid precursors cannabigerolic acid (CBGA) and cannabigerovarinic acid (CBGVA) at >1 g/L, and a single enzymatic step converts the precursors into cannabidiolic acid (CBDA) and cannabidivarinic acid (CBDVA). Cell-free methods may provide a powerful alternative to metabolic engineering for chemicals that are hard to produce in living organisms.

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A cell-free platform for the prenylation of natural products and application to cannabinoid production

The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase.

Synthesis of Photoswitchable Δ9-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling

Enantiospecific total syntheses of (+)-hapalindole H and (-)-12-epi-hapalindole U as well as the formal syntheses of (+)-hapalindole Q and (+)-12-epi-fischerindole U isothiocyanate have been described. Key steps of our approach feature expedient, highly regio- and diastereoselective Lewis acid catalyzed Friedel-Crafts reaction of indole with cyclic allylic alcohols and intramolecular reductive Heck reaction. Efficiency of the synthetic route also relies on an alkynyl aluminate complex driven regioselective nucleophilic epoxide opening from a sterically hindered site.

Saikat Das

Papers

Enantiospecific Total Syntheses of (+)‐Hapalindole H and (−)‐12‐epi‐Hapalindole U

Femtosecond dynamics of photoinduced cis-trans isomerization of ethyl-3-(1H-indole-3-yl)acrylate