| A bicyclic thioglycolate lactam chiral auxiliary was previously developed in our group for the asymmetric formation of quaternary carbon stereocenters via enolate alkylation. This method is notable for the stereocontrolled generation of alpha,alpha-disubstituted amide enolates, without reliance on the steric differences of the alpha-substituents. Coupled with excellent facial discrimination in electrophilic approach, this led to a general and practical method for enantioselective preparation of quaternary carbon centers via alkylation reactions. This thesis describes the extension of this methodology to the stereoselective formation of alpha,alpha-disubstituted beta-amino carbonyl compounds via the Mannich reaction and also the application of the alkylation method to the total synthesis of (-)-puraquinonic acid.;A concise synthesis of (-)-puraquinonic acid is accomplished using the bicyclic lactam chiral auxiliary to set the lone quaternary center at an early stage. A tandem ring-closing cross metathesis process followed by Diels-Alder cycloaddition generates a dihydroindene, which makes up the bicyclic system of puraquinonic acid. The central quinone is formed by a Curtius rearrangement/Fremy's salt oxidation sequence. Upon completion, the auxiliary is removed via acidic hydrolysis to give the required carboxylic acid functionality. The synthesis is completed in 14 steps from commercially available lactam in 21% overall yield, and represents a 24 step improvement over the previous asymmetric synthesis.;alpha,alpha-Disubstituted lithium enolates, stereoselectively generated from alpha,alpha-disubstituted bicyclic thioglycolate lactams, undergo Mannich addition to benzenesulfonyl imines to form beta-amino acid derivatives with high yield and diastereoselectivity. The reaction is general for a number of aromatic imines, including those with electron rich and electron poor substituents, heteroaromatic, and alpha, beta-unsaturated imines. alpha-Substituents on the amide enolate can be varied to include methyl, ethyl, propyl, benzyl, and allyl groups. The addition occurs via a closed Zimmerman-Traxler transition state with anti/syn relationships controlled by enolate geometry. Methods for N-deprotection and removal of the auxiliary to afford beta-amino acids and alcohols are described. |
