Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid

Mark E. Bunnage, Anthony J. Burke, Stephen G. Davies, Nicholas L. Millican, Rebecca L. Nicholson, Paul M. Roberts, Andrew D. Smith

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


Conjugate addition of homochiral lithium N-benzyl-N-α-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in >95% de. Amination of the lithium (E)-enolates of tert-butyl (3S,αR)-3-N-benzyl-N-α-methylbenzylamino-3-phenylpropanoate or tert-butyl (3S,αS)-3-N-benzyl-α-methylbenzylaminobutanoate with trisyl azide gives the (2R,3R,αR)- and (2S,3S,αS)-anti-2-azido-3-amino esters in good yields and in 85% de and >95% de respectively. Alternatively, tert-butyl anti-(2S,3S,αS)-2-hydroxy-3-N-benzyl-N-α-methylbenzylaminobutanoate may be converted selectively to tert-butyl anti-(2S,3S,αS)-2-azido-3-N-benzyl-N-α-methylbenzylaminobutanoate by aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S,3S,αS)-2-azido-3-aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S,3S)-diamino-butanoic acid in 98% de and 98% ee. The asymmetric synthesis of the diastereomeric syn-(2R,3S)-diaminobutanoic acid (98% de and 98% ee) was accomplished via functional group manipulation of tert-butyl anti-(2S,3S,αS)-2-hydroxy-3-N-benzyl-N-α-methylbenzylaminobutanoate in a protocol involving azide inversion of tert-butyl (2S,3S)-2-mesyloxy-3-N-Boc-butanoate and subsequent deprotection.

Original languageEnglish
Pages (from-to)3708-3715
Number of pages8
JournalOrganic and Biomolecular Chemistry
Issue number21
Publication statusPublished - 7 Nov 2003


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