Figure 1. N-Amino-imidazolin-2-one turn mimic conception. receptor antagonists,6,7 antioxidants,8 and unnatural base pairs.9 To the best of our knowledge, however, the synthe- sis and biological evaluation of N-amino-imidazolin-2- ones had not been explored. Previously, the submonomer approach for azapeptide synthesis surmounted issues of hydrazine chemistry to give access to side chains inaccessible by traditional methodology, including propargyl, allyl, and (hetero)aryl moieties.10,11 The aza-propargylglycine side chain was later reacted in copper- catalyzed 1,3-dipolar cycloadditions to make aza-1,2,3- triazole-3-alaninyl peptide mimics.12 Aza-propargylglycina- mides have now been explored in 5-exo-dig cyclizations to access N-amino-imidazolin-2-one peptidomimetics, as well as in Sonogashira cross-coupling reactions prior to cycliza- tion to provide their 4-arylmethyl analogues, which may mimic phenylalanine and tryptophan residues. Imidazolin-2-ones and imidazolidin-2-ones have been respectively prepared from propargylic and allylic ureas by base-promoted 5-exo-dig cyclizations.13 Annulation has typically necessitated an electron-deficient urea nitrogen and activation of the π-system using transition metal salts (8) (a) Smith, R. C.; Reeves, J. C. Biochem. Pharmacol. 1987, 36, 1457. (b) Watanabe, K.; Morinaka, Y.; Hayashi, Y.; Shinoda, M.; Nishi, H.; Fukushima, N.; Watanabe, T.; Ishibashi, A.; Yuki, S.; Tanaka, M. Bioorg. Med. Chem. Lett. 2008, 18, 1478–1483. (9) (a) Hirao, I.; Kimoto, M.; Harada, Y.; Fujiwara, T.; Sato, A.; Yokoyama, S. Nucleic Acids Res. Suppl. 2002, 2, 37–38. (b) Hirao, I.; Harada, Y.; Kimoto, M.; Mitsui, T.; Fujiwara, T.; Yokoyama, S. J. Am. Chem. Soc. 2004, 126, 13298–13305. (10) (a) Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C. B.; Boeglin, D.; Ong, H.; Lubell, W. D. Org. Lett. 2009, 11, 3650. (b) Sabatino, D.; Proulx, C.; Pohankova, P.; Ong, H.; Lubell, W. D. J. Am. Chem. Soc. 2011, 133, 12493–12506. (11) Proulx, C.; Lubell, W. D. Org. Lett. 2010, 12, 2916–2919. (12) Proulx, C.; Lubell, W. D. J. Org. Chem. 2010, 75, 5385–5387. (13) (a) Chiu, S.-K.; Keifer, L.; Timberlake, J. W. J. Med. Chem. 1979, 22, 746–748. (b) Easton, N. R.; Cassady, D. R.; Dillard, R. D. J. Org. Chem. 1964, 29, 1851–1855. (14) Peshkov, V. A.; Pereshivko, O. P.; Sharma, S.; Meganathan, T.; Parmar, V. S.; Ermolat’ev, D. S.; Van der Eycken, E. V. J. Org. Chem. 2011, 76, 5867–5872. (15) (a) Lei, A.; Lu, X. Org. Lett. 2000, 2 (17), 2699–2702. (b) Fritz, J. A.; Wolfe, J. P. Tetrahedron. 2008, 64, 6838–6852. (16) (a) Zhang, G.; Luo, Y.; Wang, Y.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 1–6. (b) Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379–4382. Org. Lett., Vol. 14, No. 17, 2012 (i.e., silver,14 palladium,15 and gold complexes).16 More- over, cyclic amino acids, such as dehydroprolines, had been prepared respectively by Pd- and Ag-catalyzed 5-endo-dig cyclization of N-Ts- and Boc-protected propar- gylglycine analogs.17,18 To study the cyclization, aza-propargylglycinyl dipep- tide 1 was used and prepared by chemoselective alkylation of benzhydrylidene aza-glycinyl-D-phenylalanine tert-bu- tyl ester (5) with propargyl bromide (Schemes 1 and 2).19 Attempted 5-exo-dig cyclization of azadipeptide 1 using homogeoneous gold catalysis [(t-Bu)2(o-biphenyl)PAuCl (5 mol %) and AgOTf (5 mol %)] failed, likely because the urea nitrogen was insufficiently electron-deficient. Scheme 1. N-Amino-imidazolin-2-one synthesis N-Amino-imidazolin-2-one 2 was, however, obtained in 81% yield, by adding 2.5 equiv of NaH to the mixture containing 1 and the cationic gold complex formed in situ in acetonitrile for 2 h. The impact of gold catalysis was later deemed negligible, because 2 was produced in 84% yield on reaction of 1 with 2.5 equiv of NaH in acetonitrile without a catalyst (Scheme 1). From the 5-exo-dig cyclization, an exocyclic double bond was first produced and migrated inside the ring to furnish the thermodynamically more stable N-amino-imidazolin-2-one 3. Among the solvents studied, acetonitrile proved the best (see Supporting In- formation (SI)). Excess NaH was necessary for high yields. To study the effect of N-amino-imidazolin-2-one on peptide conformation, model 10 was synthesized and examined by X-ray crystallography and NMR spectro- scopy (Scheme 2). Benzhydrylidene aza-glycinyl-D-pheny- lalanine isopropyl amide 7 was made from 5 by tert-butyl ester cleavage in a 1:1 v/v mixture of TFA/DCM and coupling to isopropylamine by way of a mixed anhydride.20 Alkylation of semicarbazone 7 with propargylbromide19,20 gave aza-propargylglycinamide 8 in 71% yield without detectable racemization; however, (17) Wolf, L. B.; Tjen, K. C. M. F.; ten Brick, H. T.; Blaauw, R. H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2002, 344, 70–83. (18) Van Esseveldt, B. C. J.; Vervoort, P. W. H.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 1791–1795. (19) Garc ı´a-Ramos, Y.; Proulx, C.; Lubell, W. D. Can. J. Chem. 2012, 90, in press. (20) Bourguet, C. B.; Proulx, C.; Klocek, S.; Sabatino, D.; Lubell, W. D. J. Pept. Sci. 2010, 16, 284–296. 4553