STEREOCONTROLLED ELABORATION OF QUATERNARY CARBON CENTERS THROUGH THEASYMMETRIC MICHAEL REACTION USING CHIRAL IMINES - ENANTIOSELECTIVE SYNTHESIS OF (-ASIDOSPERMIDINE())

An enantioselective synthesis of (+)-aspidospermidine (1b) has been de veloped. The key strategic element was the stereocontrolled elaboratio n of quaternary carbon centers through the asymmetric Michael reaction , using chiral imines under neutral conditions. Thus, addition of imin e 21, prepared from 2-ethylcyclohexanone and (R)-1-phenylethylamine, t o methyl acrylate, led to cyclohexanone (S)-20 with 90% stereoselectiv ity (Scheme 3). The latter compound was then converted in six steps in to dione 19 (Chart 6). Synthesis of [ABC]-type tricyclic carbazolone 1 8 was next accomplished, starting from this dione, by using the indole synthesis protocol developed by Suzuki. Critical to the success of th is approach was the evolution, after extensive experimentation, of an efficient sequence for assembling D ring to carbazolone 18, having con trolled during the events the ''natural'', cis CD ring junction. Thus, treatment of alcohol 57 with trifluoroacetic acid led to tetracycle 5 8 obtained as a single isomer with 94% yield (Chart 10). The intramole cular capture of a putative intermediary iminium ion, as illustrated i n 52, by the carbamate nitrogen atom of 57 has been evoked to rational ize the observed stereoselectivity. The strategy we have adopted for t he construction of the fifth E ring of 1b was in fact the methodology proposed by Magnus, based on an intramolecular Pummerer rearrangement (17 --> 59). Thus, synthesis of (+)-aspidospermidine (1b) has been ach ieved by a linear sequence of 22 chemical operations, starting with 2- ethylcyclohexanone, with an overall yield of 2.7%.