An Approach to Lysergic Acid Utilizing an Intramolecular Isomuenchnone Cycloaddition Pathway

Article abstract of DOI:10.1021/jo00114a017

A series of alkenyl- and alkynyl-substituted diazo imides were prepared to demonstrate that the intramolecular cycloaddition across a transient isomuenchnone dipole was a viable approach to the quinoline ring system (rings C and D) of the ergot alkaloids.The diazo imides were synthesized by N-malonylacylation of the appropriate amide followed by exposure to standard diazo transfer conditions.The carbenoid intermediate derived by treatment of the diazo imide with rhodium(II) acetate undergoes ready cyclization onto the neighboring amide carbonyl oxygen to generate an isomuenchnone intermediate.Subsequent 1,3-dipolar cycloaddition across the pendant olefin affords the cycloadduct in high yield.The stereochemical assignment of several of the cycloadducts was deduced by X-ray crystallography.The stereochemical outcome of the reaction is the consequence of an endo cycloaddition of the neighboring ?-bond across the transient isomuenchnone dipole.Exposure of the olefinic cycloadduct to boron trifluoride etherate resulted in exclusive carbon-oxygen bond cleavage producing a transient N-acyliminium ion which undergoes rapid proton loss to afford an enamide derivative.In contrast, exposure of the acetylenic cycloadduct to boron trifluoride etherate resulted in exclusive carbon-nitrogen bond cleavage.The resulting oxonium ion underwent reduction with triethylsilane, producing a dihydrofuran derivative.In the absence of a reducing agent, the alkyne cycloadduct underwent a retro Diels-Alder reaction to give a substituted furan derivative in high yield.The Rh(II) acetate catalyzed reaction of the appropriate diazo imide precursor to lysergic acid resulted in a mixture of the desired dipolar cycloadduct as well as a C-H insertion product.Switching to rhodium(II) perfluorobutyrate as the catalyst significantly enhanced the cycloaddition pathway.The inability to carry out a double-bond isomerization thwarted our efforts to synthesize lysergic acid.