Total Synthesis of Bioactive Natural Products Employing 3 2 Cycloaddition and Chiral Catalysts

Abstract

The total synthesis of flinderoles A-C, desmethylflinderole C, 1-deoxygalactonojirimycin, (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine, formal synthesis of cis-(-)-3-hydroxypipecolic acid, (R)-, (S)-rolipram and also made an attempt to synthesize (S,S)-reboxetine. A short and expeditious biomimetic divergent approach for the synthesis of functionalized pyrrolo[1,2-and#945;] indoles framework, along with its application to the total syntheses of flindersial alkaloids have been described employed Heck cross coupling and [3 + 2] cycloaddition reactions as the key step. The overall yield for flinderoles A-C and desmethylflinderole C were 51% in three steps starting from readily available phthalimide protected bromo-indole. Moreover, the synthetic strategy described has signiand#64257;cant potential for the syntheses of other analogues of flindersial alkaloids and isoborreverine with interesting pharmacological activities. The synthesis of hydroxylated piperidines and its applications to the total synthesis of 1-deoxygalactonojirimycin, (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine and formal synthesis of cis-(-)-3-hydroxypipecolic acid were achieved by employing the proline catalyzed MacMillan s asymmetric aldol reaction, Mitsunobu inversion and Upjohn reaction as key steps. The 1-deoxygalactonojirimycin was synthesized in six steps with 46% overall yield and (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine synthesized in five steps with 56% overall yield. Moreover, the described synthetic strategy has significant potential for further stereochemical variations at all the possible positions to synthesize the other hydroxylated piperidine alkaloids. Next, a short and protecting group free enantioselective syntheses of (R)- and (S)-rolipram were achieved from commercially available isovanillin employing the (R)- and (S)-diphenylprolinol silyl ether mediated asymmetric Michael addition reaction as key step. The overall yields for the (R)-rolipram were 66% and 69% with two different strategies after three column chromatographic purification