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Title:Intermolecular and intramolecular asymmetric induction at the beta-benzylic position of carboxamides in directed lithiation-substitution sequences
Author(s):Du, Hua
Doctoral Committee Chair(s):Beak, Peter
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Chemistry, Organic
Abstract:Asymmetric induction at the $\beta$-benzylic position of secondary carboxamides in directed lithiation-substitution reactions has been achieved intermolecularly by using ($-$)-sparteine as the external chiral ligand and intramolecularly by using $\alpha$-methylbenzylamine as the covalently attached chiral auxiliary.
The lithiation of N-methyl-3-phenylpropanamide with sec-butyllithium/($-$)-sparteine followed by reactions with a variety of electrophiles give highly enantioenriched (R)-3-substituted-N-methyl-3-phenylpropanamides. This methodology has been applied to the synthesis of (R)-3-phenylalkanoic acids with enantiomeric excesses of 78% to 88%. The synthetic utility of this methodology is also illustrated by the synthesis of (R-)-3-phenyl-4,4-disubstituted $\gamma$-lactones with enantiomeric excesses of 54% to 84% and the synthesis of (3R, 5R)-3-phenyl-5-iodomethyl-$\delta$-lactone with an enantiomeric excess of 80%.
This methodology is extended to N-methyl-3-(o-methoxyphenyl)propanamide. The lithiation-substitution reactions with alkyl halides as the electrophiles give (R)-3-substituted-N-methyl-3-(o-methoxyphenyl)propanamides in yields of 63% to 71% with enantiomeric excesses of 80% to 86%. Asymmetric synthesis of (R)-substituted hydrocoumarins have been achieved in the following hydrolysis and demethylation.
The reaction of racemic lithiated intermediate with the electrophile in the presence of ($-$)-sparteine is shown to proceed in high enantioselectivity. A series of lithium-tin exchange reactions and a study of lithiations of racemic 3-deuterated-N-methyl-3-phenylpropanamide are reported which show that lithiation of N-methyl-3-phenylpropanamide with sec-butyllithium/($-$)-sparteine gives racemic carbanion that is complexed by ($-$)-sparteine and reacts stereoselectively with the electrophiles. Ground state structures of N-lithio-N-methyl-3-lithio-3-phenylpropanamide-($-$)-sparteine and rationalization for the enantioselectivity observed are presented. This work demonstrates that high enantioenrichment can be achieved in the reaction of a racemic carbanion with the electrophile in the presence of an external chiral ligand.
The lithiation and alkylation of (R)-N-$\alpha$-methylbenzyl-3-(o-methoxyphenyl) propanamide gives $\beta$-substituted amides in yields of 55% to 72% with diastereomeric excesses of 90% to 96%. The synthesis of (S)-substituted hydrocoumarins is reported.
Issue Date:1995
Type:Text
Language:English
URI:http://hdl.handle.net/2142/21368
Rights Information:Copyright 1995 Du, Hua
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9624337
OCLC Identifier:(UMI)AAI9624337


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