Item – Theses Canada

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OCLC number
1019468079
Link(s) to full text
LAC copy
Author
Tiong, Erica Anne.
Title
Stereoselective formation of all carbon quaternary centers : synthesis of alpha, alpha-disubstituted beta-amino carbonyl compounds via the Mannich reaction and total synthesis of ( - )-puraquinonic acid.
Degree
Ph. D. -- McGill University, 2011
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, 2013.
Description
1 online resource
Notes
Includes bibliographical references.
Abstract
<?Pub Inc> 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. [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. 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.
ISBN
9780494787113
0494787112
9780494787113