Titanium-Mediated Cyclopropanation of N,N-Dibenzylcarboxamides towards Functionally Substituted 2-(1′-Aminocyclopropyl)acetic Acids [1]

Abstract

Straightforward syntheses of cyclopropyl analogues of β-homoornithine and β-homoglutamic acid are reported. The key step is the titanium-mediated cyclopropanation of 3-benzyloxypropionic acid N,N-dibenzylamide (6), affording N,N-dibenzyl-N-[1-(2-benzyloxyethyl)-2-ethenylcyclopropyl]amine (7) in 56% yield as a 2.5:1 mixture of E- and Z-diastereomers. Further transformations of 7 in 9 and 6 simple steps, respectively, furnished 3,6-bis(N-tert-butoxycarbonylamino)-3,4-methanohexanoic acid (13) and 3-(N-tert-butoxycarbonylamino)-3,4-methanohexane-1,6-diacid di­methylester (16) as interesting protected β-(aminocyclopropyl)carboxylic acid building blocks for potentially active small peptide analogues. The structure of the crystalline intermediate tert-butyl (E)-N-{2-[2-(N-tert-butoxycarbonylamino)ethyl-1-(2-hydroxyethyl)]cyclopropyl}carbamate (12) was proved by X-ray diffraction.

Key words

amino acids - low valent titanium - medicinal chemistry - cyclopropanes - structure elucidation

References

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12

Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited as supplementary publication no. CCDC-260818 with the Cambridge Crystallographic Data Centre. Copies of the data can be obtained free of charge on application to The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK Fax: [phone]; E-mail: [e-mail].