A diastereoselective approach to the total synthesis of quinine

Abstract

In order to determine the viability of a conceptually different approach to the synthesis of quinine, a model study was initiated to synthesize all-carbon structural analogs of quinine. Thus, syn-6-vinylbicyclo (2.2.2) oct-2-one (1) was synthesized. The enolate generated from 1 and LDA was condensed with benzaldehyde and reduced in situ to give two diols in which the major isomer, resulting from addition to the enolate face opposite that of the vinyl group, predominated in a ratio of 9:1. When 7-methoxy-1-napthaldehyde was used as the electrophile, HPLC analysis indicated a selectivity of 33:1 for the major to minor isomers. The benzylic coupling constant indicated the major isomer to be threo. The enolate generated from 3-quinuclidinone and LDA was condensed with quinoline-4-carboxaldehyde and reduced in situ to give 7-hydroxydesvinylcinchonidine (2). The structure of 2 was confirmed to be the erythro, trans diole by converting it to its diacetate 3 and obtaining an x-ray crystallographic analysis of the product 3. The synthesis of syn-5-($\beta$-hydroxyethyl)-3-quinuclidinone was improved by an ortho lithiation strategy starting with isonicotinic acid anilide. syn-5-Vinyl-3-quinuclidinone was synthesized as its acetate salt from the pyrolysis of syn-5-($\beta$-acetoxy-ethyl)-3-quinuclidinone. Condensation and reduction, as in the case of 2, gave a product whose mass spectral data was consistent with formation of 7-hydroxyquinine.