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

Abstract

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.

100 Years of the Wolff Rearrangement

“…Thus 285 produced the intramolecular cycloadduct 287 of ketene 286 on irradiation. [243] On the other hand, rhodium(II) catalysis led to carbenoid attack at the ester group with formation of carbonyl ylide 288 which was then trapped by the double bond to give 289. When 290 was heated in decane, intramolecular CϭC addition (Ǟ 291) and CϪH insertion (Ǟ 292) of the carbonyl carbene competed with the Wolff rearrangement leading to cyclobutanones 293 and 294 (Scheme 40).…”

Unusually Reactive and Selective Carbonyl Ylides for Three-Component Cycloaddition Reactions

“…Of the dipolarophiles in Scheme 3, only maleic anhydride and dimethyl acetylenedicarboxylate have been utlized previously2b,2d,3b in 3-component reactions involving carbonyl ylides. Unsymmetrical dipolarophiles also react efficiently with alkyl-substituted carbonyl ylides: the reactions of cyclohexenone, methyl methacrylate, and dimethyl 2-ethylidenemalonate proceed with high regioselectivity to give 8 , 11 and 17 , respectively.…”

“…Metal-catalyzed cycloadditions involving carbonyl ylides can generate stereochemically complex products from three simple starting materials 2. The scope of such cycloadditions is broad when carbonyl ylides are formed by intramolecular processes 2.…”

“…Metal-catalyzed cycloadditions involving carbonyl ylides can generate stereochemically complex products from three simple starting materials 2. The scope of such cycloadditions is broad when carbonyl ylides are formed by intramolecular processes 2. In contrast, analogous three-component reactions involving aldehydes, diazo compounds and dipolarophiles had been relatively limited in terms of selectivity and substrate scope 3.…”

Tandem Cyclization‐Cycloaddition Reactions of Rhodium Generated Carbenoids from α‐Diazo Carbonyl Compounds.

“…111 This intramolecular cyclization -cycloaddition sequence has been extended as a model route to an alkaloid. The six-membered ring carbonyl ylide dipoles 238 were generated from the o-allyl-substituted diazo ketoester 237 and Rh 2 (OAc) 4 to access the cycloadduct 239 (Scheme 74).…”