LETTER ▌ 1913 letter Synthesis of N-Urethane Protected α-Aminoalkyl-α′-cyanomethyl Ketones; Application to the Synthesis of 3-Substituted 5-Amino-1H-pyrazole Tethered Peptidomimetics N-Urethane Protected α-Aminoalkyl-α′-cyanomethyl Ketones M. K. Sharnabai, G. Nagendra, Vommina V. Sureshbabu* #109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India Received: 05.04.2012; Accepted after revision: 08.06.2012 Abstract: The preparation of N-protected amino/peptide α-cyano- methyl ketones through cyanation of the corresponding α-bromo- methyl ketones is described. The utility of the resulting α- cyanomethyl ketones in the synthesis of 3-substituted-5-amino-1H- pyrazoles has also been demonstrated. In both steps a wide range of N-protected amino/peptide acids has been employed and the prod- ucts are obtained in good yield. The enantiomeric purity of both the α-cyanomethyl ketones and pyrazoles were confirmed by chiral HPLC analysis of the corresponding Z-protected D- and L-Ala-OH as model substrates. The synthesis of peptide pyrazolecarbox- amides is also delineated. Key words: peptidomimetics, amino acid mimics, ketones, pyr- azole An important aspect of peptidomimetic design involves the use of suitable building blocks. To this end, either the -NH 2 or -COOH group of enantiopure α-amino acids are converted into the desired functionality. Among them, azides, 1 isonitriles, 2 nitriles, 3 and acetylenes 4 have been generated at the amine or acid termini of α-amino acids. Employing these key constituents, the insertion of scaf- folds such as a tetrazole, thiazole, imidazole, triazole, and oxadiazole in place of the peptide bond has also been a subject of interest, particularly for studying the physio- chemical and biological properties of peptides (Figure 1). 5–8 Figure 1 Selected examples of N-heterocycles derived from amino acids N-Protected α-aminoalkyl-α′-halomethyl ketones 9 have emerged as attractive targets for the design of peptidomi- metics. 10–12 Our group has developed a simple route for the preparation of N-protected α-aminoalkyl-α′-halo- methyl ketones and employed them for the construction of thiazole, 13 selenazole, 14 and triazole 15 tethered peptidomi- metics (Scheme 1). In the present letter we describe the synthesis of N-ure- thane protected α-aminoalkyl-α′-cyanomethyl ketones and their utility in the synthesis of amino acid derived 3- substituted 5-amino-1H-pyrazoles. The α-cyanomethyl ketone is an important scaffold that is found in many phar- maceutical compounds 16 with a broad spectrum of biolog- ical activity. 17,18 Sauve et al. reported amino acid derived α-cyanomethyl ketones and carboxy group modified di- peptides. 19 Boc/Ac-protected Phe/Leu-Phe derived cya- nomethyl ketones were synthesized through alkylation of Boc/Ac-amino thioamide with methyl triflate and the re- sulting intermediate was treated with a nucleophile. N- Acetyl protected cyanomethyl ketones have also been pre- pared by the reaction of activated carboxylic acids and the carbanion of tert-butyl cyanoacetate, and the resulting enols were then subjected to hydrolysis followed by de- carboxylation. 20 α-Cyanomethyl ketones derived from N,N′-bisbenzyl protected benzyl phenyl alaninate was prepared by the reaction of MeCN and NaNH 2 . 21 Some of the above approaches either require a cumbersome proto- col or are incompatible with the use of urethane-type pro- tecting groups. We describe herein a convenient method for the synthesis of urethane-protected α-cyanomethyl ke- tones and their conversion into N-Boc/Z-protected α-ami- noalkyl-5-amino pyrazoles. Pyrazole 22 derivatives of α- amino acids have received considerable attention because of their diverse range of biological properties such as po- tent angiotensin II antagonist activity both in vitro and in vivo, 23 anti-hypertensive, anti-bacterial, and anti-inflam- matory activity, 24 muscle relaxant properties, and inhibi- tion of cyclin dependent kinases. 25 They have also been used as building blocks for the synthesis of peptidomimet- ics. 26,27 The required urethane-protected α-aminoalkyl-α′-bromo- methyl ketone precursors were prepared by using a two- step procedure reported by our group. 13 A similar ap- proach was employed for the preparation of bromomethyl ketones containing the Boc-protected compounds with suitable modifications. 28 In all cases, bromomethyl ke- BocHN R HN N N PgHN N S R CO 2 Et BocHN N N O R CO 2 Et CO 2 Et ZHN N N R Ph Boc or Z CO 2 Me Me X = O or S N N N N ZHN R 1 R 2 OBn O SYNLETT 2012, 23, 1913–1918 Advanced online publication: 23.07.20120936-52141437-2096 DOI: 10.1055/s-0032-1316586; Art ID: ST-2012-D0308-L © Georg Thieme Verlag Stuttgart · New York This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.