Concise syntheses of substituted indolizidine alkaloids via cyclization based on α-sulfinyl carbanions: preparation of (±)-indolizidines 167B and 209D, their epimers, and (±)-tashiromine

(±)-Indolizidines 167B and 209D, their epimers and (±)-tashiromine have been successfully synthesized, starting from simple γ- or α-lactams. The strategy involves the cyclization of α-sulfinyl carbanion onto the carbonyl group of the lactam ring as the key step, leading to the indolizidines containing the phenylsulfinyl group, which are used as precursors for the preparation of the title compounds.     

Computational Analysis and Biological Activities of Oxyresveratrol Analogues,the Putative Cyclooxygenase-2 Inhibitors

Polyphenols are a large family of naturally occurring phytochemicals. Herein, oxyresveratrol was isolated from ethanolic crude extracts of Artocarpus lacucha Buch.-Ham., and chemically modified to derive its lipophilic analogues. Biological screening assays showed their inhibitory potency against cyclooxygenase-2 (COX-2) with very low cytotoxicity to the MRC-5 normal cell lines. At the catalytic site of COX-2, docking protocols with ChemPLP, GoldScore and AutoDock scoring functions were carried out to reveal hydrogen bonding interactions with key polar contacts and hydrophobic pi-interactions. For more accurate binding energetics, COX-2/ligand complexes at the binding region were computed in vacuo and implicit aqueous solvation using M06-2X density functional with 6-31G+(d,p) basis set. Our computational results confirmed that dihydrooxyresveratrol (4) is the putative inhibitor of human COX-2 with the highest inhibitory activity (IC₅₀ of 11.50 ± 1.54 µM) among studied non-fluorinated analogues for further lead optimization. Selective substitution of fluorine provides a stronger binding affinity; however, lowering the cytotoxicity of a fluorinated analogue to a normal cell is challenging. The consensus among biological activities, ChemPLP docking score and the binding energies computed at the quantum mechanical level is obviously helpful for identification of oxyresveratrol analogues as a putative anti-inflammatory agent.     

A general synthetic route to 1-azabicyclo[m.n.0]alkenes via cyclisation based on alpha-sulfinyl carbanions

The intramolecular nucleophilic addition of alpha-sulfinyl carbanions derived from the corresponding sufinyl lactams afforded 1-azabicyclo[m.n.0]alkenes in good yields.