| Nitrogen-containing heterocycles are common structural features of many alkaloid natural products, bioactive compounds, drugs, and drug candidates. The goal of the research in the thesis is the development of new methodologies for the asymmetric synthesis of five- and six-membered nitrogen heterocyclic pyrrolidines, piperidines, and bicyclic quinolizidine alkaloids using sulfinimines (N-sulfinyl imines).; N-Sulfinyl delta-amino beta-ketophosphonates, new sulfinimine derived chiral building blocks, are prepared by addition of lithium dimethyl methyl phosphonate to N-sulfinyl beta-amino esters. Diazo transfer reaction of these building blocks provided alpha-diazo delta-amino beta-ketophosphonates and a metal-catalyzed intramolecular NH insertion reaction provide the first examples of cis-5-substituted 3-oxo pyrrolidine 2-phosphonates, proline surrogates.; 5-Substituted pyrrolidine enones are prepared from cis-5-substituted 3-oxo pyrrolidine 2-phosphonates and aldehydes using the Homer-Wadsworth-Emmons reaction. Hydrogenation or acidic reduction of these enones afforded cis- and trans-2,5 disubstituted pyrrolidines, respectively. This new methododology was applied to the asymmetric syntheses of the ant toxin pyrrolidine 225C, and the tetrasubstituted pyrrolidine alkaloid (-)-condonopsine.; 2,4,5-Trisubstituted dihydropyridine carboxylates are a common structural motif found in numerous biologically active alkaloids. These dihydropyridines are prepared from N-sulfinyl delta-amino beta-keto ester enaminones using a novel one-pot, five-step intramolecular Michael addition followed by retro-Michael type elimination reaction. The new enaminone chiral building blocks are readily prepared by treating N-sulfinyl delta-amino delta-ketoesters with dimethylformamide dimethyl acetal. This methodology was utilized in the formal asymmetric synthesis of the marine alkaloid pseudodistomin B triacetate.; 2,4,5-Trisubstituted dihydropyridine phosphonates are prepared from N-sulfinyl delta-amino beta-ketophosphonates using the new enaminone chemistry. Michael-type addition of alkyl cuprate to the C-C double bond in the dihydropyridine phosphonates followed by a novel dephosphonylation reaction provide trans-2,6-disubstituted 1,2,5,6-tetrahydropyridines. Hydrogenation of tetrahydropyridines afford trans-2,6-disubstituted piperidines. This methodology was illustrated by the asymmetric synthesis of the quinolizidine alkaloid (-)-myrtine and by a formal synthesis of clavepictines A & B, quinolizidine alkaloids that have antitumor and antimicrobial activity. |
