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

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 Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines.

The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1'-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.

Application of Lithiation-Borylation to the Total Synthesis of (-)-Rakicidin F.

The stereochemistry of the lipophilic side chain of (+)-rakicidin F had not been determined until recently. Using our lithiation-borylation methodology ("assembly line synthesis") we were able to efficiently prepare the all-syn isomer as well as the C-21 epimer of the side chain, and comparison with the natural product suggested that the natural product had all-syn stereochemistry. Completion of the total synthesis using a macrolactamization of the northern amide enabled us to confirm Wang and Chen's stereochemical findings for the structure of (+)-rakicidin F.

Studies toward the Synthesis of an Oxazole-Based Analog of (-)-Zampanolide.

Studies are described toward the synthesis of an oxazole-based analog of (-)-zampanolide (2). Construction of (-)-dactylolide analog 22 was achieved via alcohol 5 and acid 4 through esterification and Horner-Wadsworth-Emmons (HWE)-based macrocyclization; however, attempts to attach (Z,E)-sorbamide to 22 proved unsuccessful. The C(8)-C(9) double bond of the macrocycle was prone to migration into conjugation with the oxazole ring, which may generally limit the usefulness of zampanolide analogs with aromatic moieties as tetrahydropyran replacements.