N‑Amino-imidazolin-2-one Peptide Mimic Synthesis and Conformational Analysis Caroline Proulx and William D. Lubell* Montreal, Quebec H3C 3J7, Canada william.lubell@umontreal.ca Received July 20, 2012 Departement de Chimie, Universite de Montreal, C.P. 6128, Succursale Centre-Ville, ABSTRACT ORGANIC LETTERS 2012 Vol. 14, No. 17 4552–4555 Base-promoted 5-exo-dig cyclizations of aza-propargylglycinamides provided N-amino-imidazolin-2-one peptide mimics, which exhibited turn geometry in X-ray crystallographic and NMR spectroscopic analyses. Sonogashira coupling prior to cyclization afforded N-amino-imidazolin-2- ones with diverse 4-position aromatic substituents with potential to serve as Phe and Trp mimics. Identification of biologically active conformers is critical for developing therapeutics based on peptide structures, because precise folding is essential for function. Geome- trically restricted analogs are thus valuable tools, because they may reduce energetic costs for folding into binding conformations and, thereby, improve potency, selectivity, and stability.1 To constrain backbone geometry and induce turn conformations, R-amino-γ-lactams,2 so-called Freidinger Veber lactams, have been commonly introduced into peptide sequences; however, their lack of side-chain func- tions may translate into loss of affinity and activity. Aza analogs of amino acids possess a nitrogen atom in place of the CHR. A variety of side chains have been installed onto these semicarbazide structures, which when introduced into azapeptides restrict the backbone φ and ψ dihedral angles, (1) For a selected example, see: Smith, A. B., III; Charnley, A. K.; Hirschmann, R. Acc. Chem. Res. 2011, 44, 180–193. (2) (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J. R.; Saperstein, R. Science 1980, 210, 656. (b) Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem. 1982, 47, 104. (c) Freidinger, R. M. J. Org. Chem. 1985, 50, 3631. (d) Jamieson, A. G.; Boutard, N.; Beauregard, K.; Bodas, M. S.; Ong, H.; Quiniou, C.; Chemtob, S.; Lubell, W. D. J. Am. Chem. Soc. 2009, 131, 7917–7927. (e) Boutard, N.; Jamieson, A. G.; Ong, H.; Lubell, W. D. Chem. Biol. Drug Des. 2010, 75, 40–50. 10.1021/ol302021n r 2012 American Chemical Society Published on Web 08/14/2012 due to the lone pair lone pair electronic repulsion of the adjacent nitrogen and urea planarity, respectively.3 A strat- egy has now been devised to induce peptide turn geometry by combining the covalent constraints of R-amino-γ-lac- tams with the electronic restrictions and side-chain diversity of aza-amino acids through the synthesis of substituted N-amino-imidazolin-2-ones (Figure 1). Imidazolin-2-ones have utility as antitumor agents,4 antibacterial MurB inhibitors,5 dopamine D4 and CGRP (3) Proulx, C.; Sabatino, D.; Hopewell, R.; Spiegel, J.; Garc ı´a Ramos, Y.; Lubell, W. D. Future Med. Chem. 2011, 3, 1139–1164. (4) (a) Congiu, C.; Cocco, M. T.; Onnis, V. Bioorg. Med. Chem. Lett. 2008, 18, 989–993. (b) Xue, N.; Yang, X.; Wu, R.; Chen, J.; He, Q.; Yang, B.; Lu, X.; Hu, Y. Bioorg. Med. Chem. 2008, 16, 2550–2557. (5) Bronson, J. J.; DenBleyker, F. L.; Falk, P. J.; Mate, R. A.; Ho, H.-T.; Pucci, M. J.; Snyder, L. B. Bioorg. Med. Chem. Lett. 2003, 13, 873–875. (6) Carling, R. W.; Moore, K. W.; Moyes, C. R.; Jones, E. A.; Bonner, K.; Emms, F.; Marwood, R.; Patel, S.; Patel, S.; Fletcher, A. E.; Beer, M.; Sohal, B.; Pike, A.; Leeson, P. D. J. Med. Chem. 1999, 42, 2706–2715. (7) (a) Burgey, C. S.; Stump, C. A.; Nguyen, D. N.; Deng, J. Z.; Quigley, A. G.; Norton, B. R.; Bell, I. M.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan, K. S.; Vacca, J. P.; Graham, S. L.; Williams, T. M. Bioorg. Med. Chem. Lett. 2006, 16, 5052–5056. (b) Shaw, A.; Paone, D. V.; Nguyen, D. N.; Stump, C. A.; Burgey, C. S.; Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan, K. S.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Bioorg. Med. Chem. Lett. 2007, 17, 4795–4798.