Model Studies Directed toward the Total Synthesis of (±)-Ribasine. A Tandem Cyclization−Cycloaddition Route Leading to the Core Skeleton

Abstract

A series of α-diazo-β-(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 π-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 °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.