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The development of new methodologies for the asymmetric synthesis of homotropinone and tropane alkaloids using enantiopure sulfinimines [RS(O)N=CR1R²] is the primary objective of this thesis. In one study a four-step intramolecular Mannich cyclization cascade reaction was devised for the asymmetric synthesis of substituted homotropinone alkaloids from enantiopure sulfinimine-derived N-sulfinyl ß-amino ketone ketals. These amino ketone ketal chiral building blocks were prepared in 67-71% yields and high dr (25-14:1) by addition of the Weinreb amide enolate of N-methoxy-Nmethylacetamide to masked oxo sulfinimines (N-sulfinyl imines). Treatment of these Weinreb amides with Grignard reagents gave the N-sulfinyl ß-amino ketone ketals in 93- 95% yields without epimerization. Heating the acyclic ß-amino ketone ketals with the buffer solution NH4OAc:HOAc resulted in a one-pot 4 step intramolecular Mannich cyclization cascade reaction to give substituted homotropinones including (–)- euphococcinine and (–)-adaline in 82-90% yields. In another study a sulfinimine-derived α,ß-unsaturated pyrrolidine nitrone was utilized in the development of a Lewis acid catalyzed [3+2] nitrone cycloaddition reaction for the asymmetric synthesis of the tropane alkaloid (+)-cocaine. The masked oxo sulfinimine was treated with an excess of the sodium enolate of methyl acetate to give N-sulfinyl ß-amino ester in 87% yield and high dr (97:3). Reduction of the ester to aldehyde followed by a Horner-Wadsworth-Emmons olefination reaction afforded the α,ß-unsaturated N-sulfinyl amino acetal. Hydrolysis of the unsaturated amino acetal gave a pyrrolidine, which was selectively oxidized to the pyrrolidine nitrone. The nitrone on heating with the Lewis acid Al(O-t-Bu)3 for 96 h underwent an intramolecular [3+2] cycloaddition to give a tricyclic isoxazolidine, which was transformed into (+)-cocaine in three steps 25% overall yield. This 9 step, 25% overall yield synthesis of (S)-(+)-cocaine from the masked oxo sulfinimine is the most efficient enantioselective route to cocaine from acyclic starting materials. This new methodology is adaptable to the preparation of various cocaine analogs including the first cocaine C-1 analogs. In other studies conformationally constrained novel pyrrolidine analogs (methanopyrrolidines) were synthesized stereoselectively to study the substituent (H, OH, or F) effect on amide conformational preferences. A nucleophilic displacement synthetic route was devised to prepare highly functionalized 5(6)-anti-substituted-methanopyrrolidines from N-benzyl-2-azabicyclo[2.1.1]hexylbromide(s) intermediates with the aid of neighboring group participation. These methanopyrrolidines were then transformed to constrained proline analogs (methanoprolines) to evaluate the impact of proline ring pucker on amide conformations. An α-methoxycarbonyl group was introduced in methanopyrrolidines by treating tert-butoxycarbonyl protected methanopyrrolidines with s-BuLi and quenching with various electrophiles such as CO2, DMF or ClCO2Me. Amide trans-cis conformational preferences (Ktrans/cis) of N-acetyl-methanopyrrolidines and N-acetyl-methanoprolines were determined in various solvents such as CDCl3 and D2O using NMR techniques, including NOE. The small trans amide preference for substituted fluoro- and hydroxy-methanopyrrolidines shows that it is the interaction of the !-methyl ester group and the amide moiety of the methanoprolines that plays a major role in determining amide conformational preferences. The gamma-substituent effect is primarily related to ring pucker and a resultant enhancement of the interaction between the amide carbonyl oxygen and ester carbonyl carbon. The results are relevant to the conformational stability of collagen and protein engineering. / Chemistry

A novel application of the Pauson-Khand reaction was applied to the synthesis of a series of bridged azatricyclic piperazines. This method represents the first application of the Pauson-Khand reaction to synthesize azabridged scaffolds. The ubiquity of bridged azabicyclic ring systems in biologically active natural product skeletons has provided the synthetic chemist with a wealth of opportunity for development over the last century. To this day, the development of new methodologies to tackle these structurally challenging systems remains at the forefront of synthetic chemistry. During our efforts to achieve a total synthesis of the stemofoline alkaloids, we have thus far developed a novel and scalable synthetic strategy to access the fully functionalized caged azatricyclic core of these challenging alkaloids. The overall synthetic strategy we have implemented began with the commercially available and affordable 2-deoxy-D-ribose as a chiral starting material. Furthermore, we have developed a novel 1,3-dipole cascade cycloaddition, which was successfully employed as the key step in the construction of the bridged azatricyclic core of the stemofoline alkaloids. / text