Organocatalytic asymmetric Michael, Mannich and aza-Michael reactions in the synthesis of selected quinolizidines, indolizidines and piperidines

Abstract

Quinolizidines, indolizidines and substituted piperidines are ubiquitous structural motifs present in several naturally occurring alkaloids, pharmaceuticals and other compounds which exhibit a broad range of biological activities. Though many methods have been reported for their construction, there is still a need for novel approaches, especially in terms of high efficiency, good modularity and excellent stereoselectivity. A general introduction to the research work described in this thesis has been provided in Chapter 1. An enantioselective, biomimetic organocatalytic synthesis of 4-arylquinolizidin-2-ones, key intermediates in the synthesis of several Lythraceae alkaloids, was developed. The methodology features S-proline-mediated Mannich/aza-Michael reactions of readily available arylideneacetones and Δ¹-piperideine. The total syntheses of (−)-lasubine II and (+)-subcosine II as well as the formal syntheses of structurally related Lythraceae alkaloids were achieved. The use of Δ¹-pyrroline in the Mannich/aza-Michael reaction provides enantiomerically enriched 5-arylindolizidin-7-ones, which are precursors to nonopiate antinociceptive agents. Details of these studies are described in Chapter 2. An organocatalytic, enantioselective Mannich reaction of α,β unsaturated β´-ketoesters with N-carbamoyl imines was developed. The Mannich reaction uses an aminothiourea catalyst (S,S-Takemoto catalyst), and this was followed by a Pd(0) mediated deallylative decarboxylation, to provide enantiomerically enriched β-amino ketones. The conversion of these β-amino ketones to 2,6-diaryl substituted piperidinones was achieved. These results are described in Chapter 3. The diarylindolizidine alkaloids (-)-fistulopsine A and (+)-fistulopsine B, isolated from the bark and the leaves of Ficus fistulosa, have potent in vitro antiproliferative activity against breast (MCF7) and colon (HCT 116) carcinoma cell lines. Several 2-Indolinone-based analogues of (+)-fistulopsine B, with structural variation in the diaryl substitution, were prepared and examined for their biological activity. The synthesis of the analogues, by employing an organocatalytic Michael addition as a key step, and the biological activity studies are described in Chapter 4.