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A series of R-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.

Intramolecular 1,4-dipolar cycloaddition of an anhydro-4-hydroxy-2-oxo-1,3-thiazium hydroxide across a tethered indole pi-bond has been used for the construction of the pentacyclic skeleton of epi-16,17-dihydroeburnamenine. The reaction of 3-ethyl-3-(alkenyl)piperidinones with diketene and trimethylsilyl triflate in benzene at ambient temperature produced annulated pyridones in good yield. The initial reaction involved formation of a N-acetoacetylated amide which was further converted to the pyridone with TMSOTf. The overall process was found to proceed with complete stereospecificity. Treating a sample of 3-ethyl-3-[(E)-4-phenyl-3-butenyl]-2-piperidone with diketene and TMSOTf produced a cycloadduct in 63% yield whose stereochemistry was elucidated by a X-ray crystallographic study. The epimeric Z-isomer produced a different stereoisomer of the annulated dihydropyridone. The mechanism of the annulation involves a TMSOTf induced cyclization followed by proton removal and generation of a cross-conjugated heteroaromatic betaine. This 1,4-dipole undergoes a subsequent intramolecular dipolar cycloaddition across the neighboring pi-bond, and the resulting cycloadduct is subsequently converted to the annulated lactam. A related annulation sequence leading to a key intermediate previously utilized in the synthesis of the (+/-)-vallesamidine has been developed which is based on the intramolecular dipolar cycloaddition of a mesoionic betaine intermediate.