Development of a new strategy for the enantiospecific synthesis of aspidosperma alkaloids: Total synthesis of aspidospermidine and aspidophytine.

Abstract

A large number of aspidosperma alkaloids display interesting and important biological properties. For this reason, over the last three decades, different synthetic approaches have been developed for the total syntheses of this family of compounds. More recently, a number of quite efficient asymmetric syntheses also appeared in the literature. The formation of one of the two chiral quaternary centers was the key step for those asymmetric syntheses. As part of our ongoing efforts to further exploit the ketene-lactonization reaction, a powerful tool for setting up the chiral quaternary carbon centers, a novel sequence of reactions was planned for the enantiospecific synthesis of aspidosperma alkaloids. Aspidospermidine was chosen as the first target to demonstrate the concept. Evans' chiral <italic>N</italic>-sulfinyloxazolidinone was used for the first time in place of (-)-menthyl 4-methylphenyl sulfinate to prepare {4-(<italic> S</italic>_S)-[(4-methylphenyl) sulfinyl] but-3-yn-1-y1}-2-propyl-1,3-dioxolane in a much higher yield. A stereo-defined trisubstituted alkenyl chiral sulfoxide was then formed from a Michael addition of an (ortho-Boc amino) aryl organocuprate to the chiral alkynyl sulfoxide. The ketene lactonization of the chiral alkenyl sulfoxide with a dichloroketene delivered a high yield of lactone with a newly formed chiral quaternary carbon center. The enantiospecificity of this transformation was not determined until the lactone was converted to a more advanced intermediate (chloropropyl amide) through the transformations of lactone opening, intramolecular aldol condensation and amide formation. A chiral HPLC analysis was carried out on this amide and there was essentially only one enantiomer in the sample of amide. The result proved that the ketene lactonization reaction was a highly enantiospecific process. A tandem Michael addition-alkylation reaction furnished a tetracyclic system. A modified Saegusa reaction dramatically improved the yield of the enone formation reaction over the previous adopted alpha-sulfoxide elimination protocol. An intramolecular Michael addition of the deprotected aniline to the enone constructed the last indoline ring. Finally, reductions of the ketone (a Wolff-Kishner reduction) and the lactam completed the total synthesis of (+)-Aspidospermidine. More complex aspidosperma alkaloids, aspidophytine and haplophytine, were then selected as the synthetic targets to assess the successfully developed synthetic strategy. A substituted aniline (2, 3-dimethoxyaniline) and a functionalized alkynyl sulfoxide were the starting materials for the synthesis of aspidophytine. The ketene lactonization was successfully carried out on the more complex alkenyl sulfoxide and the chiral HPLC analysis on the subsequently formed amide again showed only one enantiomer. The amide underwent a tandem Michael addition-alkylation to form an advanced tricyclic intermediate. Deprotection/formylation of the aniline with concomitant Michael addition to the enone formed the indoline scaffold of aspidophytine with all four chiral centers set. Enolization of the ketone to form its enol triflate ester, followed by a Stille reduction afforded the C₃--C₄ alkene. Conditions of PDC/DMF were then used to oxidize the debenzylated C-5 side chain primary alcohol to a carboxylic acid after some routine protocols failed. The selective reduction of the amide bonds in the presence of the carboxylic acid was carried out using the Meerwein's salts along with NaBH₄ in ethanol. Aspidophytine was finally obtained after the oxidation of the tertiary amine to its iminium salt followed by the treatment with sodium bicarbonate to close the lactone ring. A few synthetic pathways were proposed for the construction of haplophytine from aspidophytine.