N-Acyl ‘Quat’ pyrrolidinone auxiliary as a chiral amide equivalent via direct aminolysis

摘要

The majority of naturally occurring substances containing thenamide bond carry a stereogenic centre adjacent to the amidicncarbonyl. This, combined with the vast number of naturallynoccurring peptides and pseudopeptides eliciting interestingnbiological and pharmacological properties, highlights thenneed for more efficient asymmetric routes to such importantnstructural moieties.nThe chiral auxiliary has played a regular role in the synthesisnof the key, homochiral fragments contained within manynof these pseudopeptides and related compounds.1 Generally,nthe chiral auxiliaries are cleaved hydrolytically to afford thencarboxylic acid which is then activated and coupled to an aminenor a suitably protected α-amino acid through standardnprocedures.nRecently, we reported a conceptually more simple route tonsuch chiral amides and pseudopeptides via direct aminolysis ofnthe ‘Quat’ pyrrolidinone auxiliary 12 from attached chiral sidenchains,3 Scheme 1.nWe found that efficient, non-racemising cleavage of N-α-nmethylhydrocinnamoyl side chains from the ‘Quat’ pyrrolidinenauxiliary with a range of N-centred nucleophiles was possiblenleading to the production of chiral amides and we wish tonreport herein the full experimental details of these reactions.nIn addition, we report an extension of the methodology tonencapsulate the efficient asymmetric synthesis of succinamidenderivatives and highlight the utility of such a process in thensynthesis of the natural product (S)-(u0001)-amphetamine.nThe pyrrolidinone auxiliary 1 has been shown to inducenhigh diastereoselectivities in both enolate alkylation 4 and aldolnreactions 5 of attached acyl side chains. This combined with thenexceptional propensity for exocyclic- over endocyclic-cleavagenwith O-centred nucleophiles, through steric blocking of the ringncarbonyl by the geminal dimethyl groups, made pyrrolidinonen1 ideally suited as a precursor to chiral amides through directnaminolysis pathways.nInterestingly, there have been only a few reports of the directncleavage from other chiral auxiliaries of chiral N-acyl sidenScheme 1nchains with either ammonia or amines.6 The majority of theseninvolve chiral auxiliaries with a high sulfur content which havenbeen synthesised and utilised for, amongst other qualities, theirnlability towards nucleophilic reagents.7–9 However, chiralnauxiliaries of this type are severely restricted in terms of thennumber of types of asymmetric transformations whichnattached N-acyl side chains can undergo, with tin()-mediatednaldol reactions being the most common.