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

Virk, Seerat (2021) Organocatalytic asymmetric Michael, Mannich and aza-Michael reactions in the synthesis of selected quinolizidines, indolizidines and piperidines. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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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.

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