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DOI: 10.1055/s-0029-1219274
Hydrazinopeptide Motifs Synthesized via the Ugi Reaction: An Insight into the Secondary Structure
Publication History
Publication Date:
25 January 2010 (online)
Abstract
A number of N α-alkyl,N β-acylhydrazines have been synthesized via the Ugi reaction of N-acylhydrazones with an isocyanide and trifluoroacetic acid. The trifluoroacetic acid acted as a ‘silent partner’ and becomes removed upon basic workup of the reaction. These compounds have been efficiently modified further via reductive alkylation to produce N α,N α-dialkyl,N β-acylhydrazines. The two groups of novel hydrazinopeptide motifs have been shown by simple ¹H NMR spectroscopic experiments to display two different secondary structure patterns. These observations were confirmed by X-ray crystallographic analysis. Combining the hydrazone and carboxylic acid moieties in one reaction precursor offers the opportunity for an ‘intramolecular’ hydrazino-Ugi reaction, which was also demonstrated.
Key words
multicomponent reactions - hydrazones - substituent effects - peptidomimetics - secondary structures
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References
Efforts are currently underway in our laboratories to realize a strategy of stereochemistry relay from nonracemic partners in the hydrazino-Ugi reaction and, thus, prepare short nonracemic hydrazinopeptide compounds via diastereomeric resolution.
17The ¹H NMR spectroscopic chemical shifts showed the α-nitrogen proton in 4 as well as the analogous proton in 10 to be negligibly sensitive to the solvent change, most likely because the protons are less acidic.
19All reference fragments 10 and 11 used in this work are known and commercially available compounds.
20Crystallographic data (excluding structure factors) for structures 4i and 9h have been deposited with the Cambridge Crystallographic Data Centre (CCDC) as supplementary publications CCDC 743067 (4i) and CCDC 752329 (9h), respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)336033, e-mail: deposit@ccdc.cam.ac.uk].
21Molecular mechanics (MM2) calculations performed using ChemBio3D (Ultra) v11.0 demonstrated that the observed conformations for compounds 4i and 9h displayed minimized energies of 6.48 and 7.62 kcal/mol, respectively. Alternative hydrogen-bonded conformations displayed significantly higher minimized energies (14.1 and 14.0 kcal/mol, respectively).