Enantioselective synthesis using bromoacetals.
A brief overview of why it is important to prepare a chiral compound as a specific enantiomer rather than as a racemate is discussed along with several general strategies on how they maybe prepared. The area of research into the preparation of racemic and enantiomerically pure arylpropanoic acids is briefly reviewed by reference to some of the more important synthons. Some of the more general procedures that have been developed for the construction of arylpropanoic acids are discussed. The preparation of substituted alkyl aryl ketones and their subsequent two step conversion into diastereomerically enriched dimethyl tartrate (S)-bromoalkyl aryl acetals is described. An investigation into the effects of solvent, source of anhydrous acid, workup procedure, source of bromine and temperature upon the bromination of these dimethyl tartrate acetals is discussed. Direct conversion of these diastereomerically enriched dimethyl tartrate (S)-bromoalkyl aryl acetals into enantiomerically pure (S)-bromoalkyl aryl ketones and their subsequent conversion into (S)-bromoalkyl aryl esters via a Baeyer-Villiger reaction is described. Hydrolysis of these (S)-bromoalkyl aryl esters followed by treatment with diazomethane afforded the corresponding methyl (S)-bromoalkyl esters with minimal racemisation, while treatment of these (S)-bromoalkyl aryl esters with an amine gave the corresponding amide with minimal racemisation. Reduction with sodium borohydride at low temperature of a (S)-bromoalkyl aryl ketone afforded exclusively the corresponding (1S,2S) alkyl aryl bromohydrin as predicted using the Felkin-Anh model. Stereospecific conversion of our diastereomerically enriched dimethyl tartrate (S)-bromoalkyl aryl acetals into (S)-arylcarboxylic acids using a silver promoted or solvent promoted rearrangement is discussed. Subsequent conversion of these (S)-arylcarboxylic acids into the corresponding Boc amide via a modified Curtius rearrangement is described.Possible further uses of dimethyl tartrate bromoacetals leading to the synthesis of highly functionalised lactones, lactols, epoxides, chiral diacids, diamines, chiral ligands, resolving agents etc are also discussed.
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Sheffield Hallam University (United Kingdom).