Model studies directed toward the total synthesis of (±)-ribasine.: A tandem cyclization-cycloaddition route leading to the core skeleton

A series of alpha-diazo-beta-(o-carbomethoxy)-substituted aryl ketones were prepared and employed as model systems for a synthetic approach toward the alkaloid ribasine. Six-membered ring carbonyl ylide dipoles were generated by treating the diazoketones with a rhodium(II) catalyst. The initially formed dipole was trapped using a variety of dipolarophiles including N-benzylidene methylamine. The Rh(II)-catalyzed behavior of ethyl 2-diazo-3-(2-formylphenyl)-3-oxo-propionate was also studied to probe the chemoselectivity of the reaction. The major products isolated are derived from bimolecular trapping of the carbonyl ylide dipole, as well as intramolecular C-H insertion of the rhodium carbenoid into the aldehydic hydrogen. Changing the catalyst from Rh(II) trifluoroacetate to Rh(II) acetate caused a significant alteration in product distribution. A study of the tandem cyclization-cycloaddition reaction of an o-allyl phenyl substituted diazoketone was also carried out. An unexpected low-temperature intramolecular dipolar cycloaddition of the diazo group across the neighboring pi-bond first occurred, followed by nitrogen extrusion to give products derived from a 1,3-biradical intermediate. By subjecting the diazoketone to the Rh(II) catalyst at 110 degrees C, it was possible to prepare the carbonyl ylide derived cycloadduct in high yield. This result provides good precedent for the future implementation of the cycloaddition strategy toward the synthesis of ribasine.