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-α] 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 significant 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 steps. The merits of our synthesis are high enantioselectivity (i.e. >99% ee) and high yielding reaction steps. The synthetic approach also has significant potential for the variation at O-alkyl site to synthesize various γ-pyrrolidone derivatives with expected increase in biological activities. Also, an attempt towards a simple and flexible enantioselective total synthesis of (S,S)-reboxetine was made by employing Jacobsen’s HKR and Henry reaction as key steps. The merits of this synthesis are high regio- and enantioselectivity with high yielding reaction steps.