Synthesis and characterization of a compact tricyclic resorcinol from (+)- and (-)-3-pinanol.

Resorcinol derivatives are important building blocks in the synthesis of natural products and pharmaceutical compounds including cannabinoids. Here we describe the synthesis and the structural characterization of a key resorcinol which carries a fully restricted bridged bicyclic group. We also report a potential mechanism for the acid catalyzed condensation of (+)- or (-)-3-pinanol with 2,6-dimethoxyphenol. The synthesized resorcinol facilitates the development of novel conformationally restricted cannabinoid analogs.

Tandem ring-opening/closing reactions of N-Ts aziridines and aryl propargyl alcohols promoted by t-BuOK.

t-BuOK was found to be an effective promoting reagent for tandem ring-opening/closing reactions of various N-Ts aziridines and aryl propargyl alcohols to afford dihydroxazine derivatives in moderate to good yields. A plausible reaction mechanism has been proposed.

3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach.

The present work focuses on the study of the three-dimensional (3D) structural requirements for selective antagonist activity of arylpyrazole compounds at the cannabinoid CB1 and CB2 receptors. Initially, a combined high-resolution two-dimensional (2D) NMR and computer modeling approach was carried out to study the solution structure of the key pyrazole derivative N-(piperidin-1-yl)-5-phenyl-1-(n-pentyl)-4-methyl-1H-pyrazole-3-carboxamide (AM263). By using the NMR-determined molecular conformers as templates, the 3D quantitative structure-activity relationship (QSAR) studies were performed with the comparative molecular field analysis (CoMFA) approach on a set of arylpyrazole cannabinoid receptor antagonists. Molecular alignments suitable for deriving valuable pharmacophoric features for this series of compounds were determined. Such systematic 3D-QSAR/CoMFA analyses of 29 molecules and their receptor affinities gave guidance for understanding the binding affinities of arylpyrazoles at the CB1 and CB2 binding sites, respectively. Comparison of CoMFA steric and potential contour maps for affinity at the two cannabinoid receptor subtypes helps to differentiate structural requirements for each subtype and serves as a basis for the design of later-generation analogues.

Two new iridoid glycosides from the Tibetan folk medicine Swertia franchetiana.

Two new iridoid glycosides designated as senburiside III (2) and senburiside IV (3), together with one known iridoid glycoside senburiside I (1) and three known secoiridoid glucosides swertiamarin (4), gentiopicroside (5) and sweroside (6), were isolated from the whole plant of Swertia franchetiana. The structures of the two new compounds were elucidated by spectroscopic methods.

Preferred conformations of endogenous cannabinoid ligand anandamide.

Anandamide (arachidonyl-ethanolamide, AEA) is an important endogenous cannabinoid ligand isolated from porcine brain. AEA has a flexible molecular structure with a series of four non-conjugated double bonds, a hydrophobic alkyl chain, and a carboxyamide head group. It is known that AEA binds to cannabinoid receptor and induces cannabimimetic activity. However, questions still remain about the three-dimensional arrangement of the pharmacophoric groups of AEA that facilitate its interaction with cannabinoid receptor, a member of transmembrane G-protein coupled receptors (GPCRs). Such information is of critical importance for the design of novel analogs of potential therapeutic values. In the present studies, we developed a combined approach of 2D high-resolution NMR and computer modeling to investigate conformational features of AEA in solution. The developed method and experimental data is then applied to study the structural properties of AEA in a membrane-like environment that will be reported elsewhere. In addition to the measured NOEs, the dihedral angle constraints were for the first time being used as experimentally-determined structural constraints for performing molecular dynamics simulations to refine the NMR-determined AEA conformations. Our results showed that AEA prefers an extended pseudo-helical conformation in solution with two oxygen atoms pointing towards the same side and a straight pentyl chain, which was an averaged conformation observed on the basis of NMR time scale. The results were correlated to the computer predicted AEA models reported by others. The established NMR-based computational approach provides an alternative way to explore further the detailed conformational properties of AEA that encodes important pharmacophoric and conformational information regarding the activation of cannabinoid receptors.

Synthesis and highly enantioselective hydrogenation of exocyclic enamides: (Z)-3-arylidene-4-acetyl-3,4-dihydro-2H- 1,4-benzoxazines.

Highly enantioselective hydrogenation of exocyclic enamides, (Z)-3-arylidene-4-acyl-3,4-dihydro-2H-benzoxazines, was achieved in up to 98.6% ee by using Rh/(R,R)-Me-Duphos complex as the catalytic system. The absolute configuration of the product was assigned as R by chemical interrelations.

Xanthone glycosides from Swertia franchetiana.

A new xanthone glycoside (1) has been isolated from Swertia franchetiana together with five known xanthone glycosides. Their structures were elucidated as 7-O-[beta-D-xylopyranosyl-(1-->2)-beta-D-xylopyranosyl]-1,7,8-trihydroxy-3-methoxyxanthone (1), 7-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranosyl]-1,7,8-trihydroxy-3-methoxyxanthone (2), 8-O-beta-D-glucopyranosyl-1,3,5,8-tetrahydroxyxanthone (3), 1-O-beta-D-glucopyranosyl-1-hydroxy-3,7,8-trimethoxyxanthone (4), 1-O-[beta-D-xylopyranosyl-(1-->6)-beta-D-glucopyranosyl]-1-hydroxy-2,3,5-trimethoxyxanthone (5) and 1-O-[beta-D-xylopyranosyl-(1-->6)-beta-D-glucopyranosyl]-1-hydroxy-3,5-dimethoxyxanthone (6) on the basis of spectroscopic evidence.

Highly enantioselective iridium-catalyzed hydrogenation of heteroaromatic compounds, quinolines.

The highly enantioselective hydrogenation of quinoline derivatives is developed using [Ir(COD)Cl]2/(R)-MeO-Biphep/I2 system, and this methodology has been applied to the asymmetric synthesis of three naturally occurring alkaloids angustureine, galipinine, and cuspareine. This method provided an efficient access to a variety of optically active tetrahydroquinolines with up to 96% ee.