TANDEM DIPOLAR CYCLOADDITION - MANNICH CYCLIZATION AS AN APPROACH TO TRICYCLIC NITROGEN-HETEROCYCLES

A series of 2-diazo-N-[2-(3,4-dimethoxyphenyl)ethyl] were prepared and treated with a catalytic amount of rhodium(II) perfluorobutyrate. The resultant carbenoids undergo facile cyclization onto the neighboring amide carbonyl oxygen atom to generate isomunchnone-type intermediates . Subsequent 1,3-dipolar cycloaddition across the pendant olefin affor ds intramolecular cycloadducts in high yield. Exposure of these cycloa dducts to boron trifluoride etherate results in a Lewis acid-induced r ing opening to generate N-acyliminium ions which then undergo Mannich cyclization onto the neighboring pi-framework attached to the amide ni trogen atom. The cis stereochemistry of the resulting A/B ring fusion is analogous to similar erythrinane products obtained via a Mondon-ena mide-type cyclization. The stereochemical assignment of the final cycl ized products was determined by X-ray crystallography. Molecular mecha nics calculations show that the ground state energy of the cis-fused d iastereomer is 4.6 kcal lower than that of the trans diastereomer, and presumably some of this thermodynamic energy difference is reflected in the transition state for cyclization. In certain cases, proton loss from the initially formed N-acyliminium ion occurs prior to cyclizati on to give acyl enamides which subsequently cyclize producing epimeric products.