Reactions of 4,5-bis(morpholin-4-yl)cyclopent-2-en-1-one with sodium salts derived from methyl dichloroacetate and ethyl (dimethyl-λ4-sulfanylidene)acetate

Abstract

An attempt was made to synthesize fused cyclopropane derivatives suitable for subsequent transformation into vicinal diamino-substituted cyclohexenecarboxylic acids via reactions of 4,5-bis(morpholin-4-yl)cyclopent-2-en-1-one with sodium salts derived from methyl dichloroacetate and ethyl (dimethyl-λ 4 -sulfanylidene)acetate.III, X = Cl, H. Oseltamivir (I) phosphate is the active substance of the popular antiviral drug Tamiflu. Compound I is a derivative of cyclohexenecarboxylic acid. Several syntheses of Tamiflu have recently been reported [1-10]; however, they include a number of steps and require the use of expensive reagents, as well as of sodium azide, to introduce the amine and acetamide moieties. Therefore, the described procedures cannot be regarded as practical from the viewpoint of largescale synthesis.With a view to develop a new approach to Oseltamivir (I) in the present work we examined transformations of model cyclopentenone II [11] which could led to key precursor III and cyclohexenone IV. Accessible cyclopentenone II having vicinal amine moieties could be a promising starting compound for the preparation of compound IV provided that bicyclo-[3.1.0]hexan-2-one III would be obtained therefrom.Several versions were tried to synthesize compound III. In particular, cyclopentenone II was reacted with methyl dichloroacetate sodium salt (generated by the action of hexamethyldisilazane sodium salt in THF at -78°C) [12]. We anticipated that 1,4-conjugate addition of methyl dichloroacetate anion to cyclopentenone II would give stabilized carbanion VII with subsequent intramolecular cyclization to bicyclo[3.1.0]hexane structure V. According to the TLC data, the reaction afforded the only product which underwent complete transformation into cyclopentenone derivative VI during purification by column chromatography on silica gel. The structure of VI was determined on the basis of spectral data. Presumably, protonation of VII yields unstable 1,4-conjugate addition product VIII which loses morpholine molecule during chromatographic purification with formation of thermodynamically more stable unsaturated ketone VI (Scheme 1).