Studies On The Total Synthesis Of Natural Piperidine, Tropane And Bromopyrrole Alkaloids

Alkaloids are a big family of naturally N-containing organic compounds, most of them have biologically important properties. For understanding the relationship between the structure and the biological activity, developing the asymmetric synthetic methods of alkaloids has been received considerable attention by organic scientists.The units of chiral piperidine, tropane and pyrrolidine are present in many natural alkaloids, and efficient construction of these structures is still a challenging subject. Chiral auxiliary synthesis is one of the efficient methods for this purpose. As a new auxiliary reagent, nonracemic Betti base shows highly potential in enantiopure synthesis of piperidine, tropane and pyrrolidine alkaloids(R)-Betti base was introduced as a chiral auxiliary for the asymmetric synthesis of N-Boc-2-alkene or 2-alkyne substituted piperidines. A novel N-debenzyla- tion of the Betti base residue under basic condition by a retro-Michael addition mechanism was studied and ten chiral N-Boc-2-alkene or 2-alkyne substituted piperi- dines were easily obtained. The total synthesis of natural piperidine-alkaloids (+)-Pelletierine, (-)-Lasubineâ…¡and (+)-Cermizine C were completed by using (S)-N-Boc-2-allyl-piperidine as a key intermediate.By a similar methodology, (2S,5R)-N-Boc-2-alkyne or alkyne-5-allyl-pyrrolidine were obtained by using (S)-Betti base as a chiral auxiliary. 8-Azebicycle[3.2.1]octane (tropane) skeleton was constructed from (2S,5R)-N-Boc-2-vinyl-5-allyl-pyrrolidine by a RCM reaction. Then the total synthesis of natural tropane-alkaloids (-)-Cocaine and (-)-Ferruginine were achieved.A novel strategy of"one pot"tandem ring opening-ring closing- aromatization for the syntheses of pyrrole-2-carboxylic acid ethyl esters was also developed. From 5-aminomethyl-4,5-dihydro-3- isoxazolecarboxylic acid ethyl ester derivatives, sixteen N-substituted pyrrole-2-arboxylic acid ethyl esters were synthesized. By using this novel strategy as a key step, the total synthesis of natural bromopyrrole-alkaloids (-)-Hanishin,(-)-Longmide B and (-)-Longmide B methyl ester was achieved starting from L-aspartic acid.