Applications of the controlled oxidation of pyrroles

The following thesis contains three parts, where the common overall goal was to develop useful applications for synthesis and modification of pyrrole heterocycles. A range of desmethyl, cis-hydroxy analogues of the biologically active natural product (‚Äö-)-codonopsine were prepared, using the controlled oxidation of Nmethylpyrrole with both hypervalent iodine reagents and photooxidation as a key step. Dihydroxylation, Friedel‚Äö-Crafts alkylation using aromatic nucleophiles, and reduction with LiAlH4 were used to transform these ˜í‚â•-lactam intermediates to the desired analogues in mostly good overall yields. The relative stereocontrol observed in these processes was expanded to develop two approaches to asymmetric syntheses of these analogues. The use of chiral bicyclic scaffolds gave complete stereoselectivty, but the intermediates were too stable for further modification. The use of an amino acid methyl ester chiral auxiliary gave separable diastereomers, but further functionalization led to scrambling of stereocenters. Chiral dihydroxylated bicyclic ˜í‚â•-lactam intermediates were applied to the synthesis of chiral fluorinated GABA analogues, due to their selective binding to particular GABA receptors. Direct fluorination of bicyclic diols using Deoxofluor and DAST led to separable mixtures of mono- and difluorinated products. These proved more amenable to ring-opening of the bicyclic lactams through trapping of iminium ions than the corresponding diolsubstituted bicyclic lactams, due to hyperconjugation effects of the fluorine substituents. A proof of concept preparation of a fluorohydrin analogue of GABA was successfully completed. An approach was developed for the selective preparation of stable pyrroles and pyrrolidines from the readily available 1,4-dialdehyde natural product polygodial. A modified Paal-Knorr approach under reducing conditions made it possible to selectively produce stable pyrroles or pyrrolidines in good to excellent yields. One of the pyrroles was taken and subjected to controlled pyrrole oxidation and Friedel‚Äö-Crafts alkylation to give novel analogues of the antifungal natural product (+)-Crispin A. These compounds were also investigated as scaffolds for the preparation of chiral amines with potential applications as organocatalysts.