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Application in Solution Peptide Synthesis Molecules 2010, 15, 9403-9417; doi:10.3390/molecules15129403 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Synthesis of 2-(4,6-Dimethoxy-1,3,5-triazin-2-yloxyimino) Derivatives: Application in Solution Peptide Synthesis Tarfah I. Al-Warhi 1,*, Hassan M.A. AL-Hazimi 2, Ayman El-Faham 2,3 and Fernando Albericio 4,5,6 1 Women Students-Medical Studies and Sciences Sections, Chemistry Department, College of Science, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia 2 Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia 3 Chemistry Department, Faculty of Science, Alexandria University, 426 Ibrahimia, 21321 Alexandria, Egypt 4 Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona 08028, Spain 5 CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona 08028, Spain 6 Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, Barcelona 08028, Spain * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 29 November 2010; in revised form: 14 December 2010 / Accepted: 15 December 2010 / Published: 20 December 2010 Abstract: A new class of 1,3,5-triazinyloxyimino derivatives were prepared, characterized and tested for reactivity in solution peptide synthesis. The new triazinyloxyimino derivatives failed to activate the carboxyl group during formation of peptide bonds, but gave the corresponding N-triazinyl amino acid derivatives as a major product. The oxyma (ethyl 2-cyano-2-(hydroxyimino)acetate) uronium salt was superior to other uronium salts in terms of racemization, while 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 9) gave the best results. Keywords: coupling reagents; triazinyloximino derivatives; solution phase peptide synthesis; uronium salt; racemization Molecules 2010, 15 9404 1. Introduction For many years, 1-hydroxybenzotriazole (HOBt, 1, Figure 1) has been used as a coupling reagent in peptide synthesis, especially in combination with dicyclohexylcarbodiimide (DCC, 2, Figure 1) [1-4]. Later, other benzotriazole derivatives such as 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt, 3, Figure 1) and 1-hydroxy-7-azabenzotriazole (HOAt, 4, Figure 1) [5,6] have been introduced and shown more efficient that the parent (HOBt, 1). Figure 1. Structure of additives and DCC. N N N N N N N N N Cl N OH C OH N N OH 1, HOBt 2, DCC 3,6-Cl-HOBt 4, HOAt During the last decade, iminium/uronium and phosphonium salts of 1-hydroxybenzotriazole and 1- hydroxy-7-azabenzotriazole, 5 and 6 (Figure 2) have shown the supremacy of these kind of derivatives over carbodiimides in the presence of an additive [5-33]. Despite their widespread use, these reagents are not without ptoblems. The explosive properties of 1-hydroxybenzotriazoles are often not referenced in literature. Sometime, Material Safety Data Sheets warn that 1-hydroxybenzotriazoles may be unstable, with a relatively high sensitivity to friction and sparks, but in most cases, there is no mention of how sensitive such substances are to heating under confinement and no warning is given with respect to their ability to propagate a deflagration or a detonation. More recently a new class of coupling reagents such as 7 and 8 (Figure 2) based on changes to the carbon skeleton structure [34-36] gave more marked increases in coupling efficiency, as well as reduced racemization levels during the coupling step. Particularly noteworthy are the morpholino derivatives 8, because the oxygen in the carbon skeleton increases the solubility as well as the reactivity, which reduces the racemization during the coupling step [34-36]. Figure 2. Structure of uronium/iminium salts. O O O N N N N N N N N X N X N X N X N O P(NR ) Me Me 2 3 PF6 N N Me2NNMe2 N N Me Me O PF PF 6 6 PF6 5a, X = CH 6a, X = CH 7a, X = CH 8a, X = CH 5b, X = N 6b, X = N 7b, X = N 8b, X = N Molecules 2010, 15 9405 Although 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 9) has been successfully applied for the preparation of peptides, the mechanism of its participation in coupling reactions remains unknown [37,38]. Furthermore, in order to be successfully stored the reagent itself must be of high purity, the formation of gaseous products may generate a rapid pressure increase in the container, and accordingly, precautions should be taken to avoid the serious risk of blowout of toxic gases. Successful activation of carboxylic acids by means of CDMT (9) confirmed the feasibility of a multistep process proceeding via triazinylammonium salts such as 10 and (DMTMM, 11) (Figure 3) formed in situ in the presence of the appropriate amine [37,38]. Figure 3. Structure of triazinylammonium salts. O R' R'' + R''' N Cl- N Cl N N N N R N R MeO N OMe 10 11, DMTMM The related triazine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 11), formed by a simple reaction of CDMT (9) with N-methylmorpholine (NMM), has been found applications in amidation [38-42], esterification [42], glycosidation [43,44] and phosphonylation [45] methodology. The present work presents the synthesis and application of a new family of 1,3,5-triazine derivatives and their comparison with CDMT (9) as well as the uronium based type coupling reagents [46]. 2. Results and Discussion The new triazinyloxyimino derivatives 12a-c were prepared from the reaction of the oxime derivatives 13a-c with CDMT (9) in the presence of triethylamine. The potassium salts were used in case of the synthesis of malononitrile and diethylmalonate derivatives (Scheme 1). Scheme 1. Synthesis of triazinyloxyimino derivatives. 4' 5' 3' X Y X Y 6' Et N 3 Cl Et N N O N O 3 O N N 2 OH N N OH 13a,c O N N 2 46 MeO N OMe or X Y N N MeO N OMe 4 6 (CDMT, 9) 13b MeO N OMe N OK (DMTOPy, 12d) 13a, X = CN, Y = COOEt (DMTOC,12a) 13b, X = Y = CN 4' (DMTODC, 12b) 13c, X = CN, Y = 5' 3' (DMTOPyC, 12c) 6' 2' N Molecules 2010, 15 9406 The pyridinyl derivative was prepared using the same conditions to afford 12d. All the products 12a-d have been identified on the basis of their spectroscopic data (see Experimental). In order to have a good comparison to the triazinyloxyimino coupling reagents, some of the related uronium-type coupling reagents were prepared according to the reported method [36] as shown in Scheme 2. Scheme 2. Synthesis of uronium salts. X R R2 2 X R1 N N N Et3N/DCM R i) (COCl)2 R1 N O Y 1 O Cl PF6 + HO N Y or KON-R R2 ii) PF6 N R N N R3 3 R R4 4 R3 R4 PF6 15a-f 15a (HOTU), R1 =R2 =R3 =R4 =CH3;X=CN,Y=COOEt 15b (COMU), R1 =R2 =CH3,R3,R4 =CH2CH2OCH2CH2;X=CN,Y=COOEt 15c (HTODC), R1 =R2 =R3 =R4 =CH3;X=CN,Y=CN 15d (HDMODC), R1 =R2 =CH3,R3,R4 =CH2CH2OCH2CH2;X=Y=CN 15e (HTOPC), R1 =R2 =R3 =R4 =CH3; X = CN, Y = 2-pyridyl 15f (HTOPT), R1 =R2 =R3 =R4 =CH3; X,Y = COCH=CH-CH=CH CH3 CH3 CH N CH N 3 Cl 3 Cl PF6 PF6 N N H3C CH3 O (DCMH, 14a) (TCFH, 14b) The uronium salt coupling reagents were prepared by reaction of the chloro salts DCMH 14a or TCFH 14b with the oxime derivatives in the presence of triethylamine in DCM or with the potassium salt of the oxime derivatives in acetonitrile to give the oxyimino uronium base coupling reagents 15a-f (Scheme 2). To investigate the retention of configuration induced for the new coupling reagents, several previously studied model peptide system 16a,b and 17a-c (Figure 4) were examined [36]. These models involve stepwise coupling and (2+1) segment coupling as well. Figure 4. Model of peptide used in racemization studies. Z-Phe-Ala-OMe Z-Phe-Val-OMe 16a 16b Z-Gly-Phe-Ala-OMe Z-Gly-Phe-Val-OMe Z-Gly-Val-Val-OMe 17a 17b 17c Results comparing the coupling of Z-Phe-OH to H-Ala-OMe.HCl (18a) with different coupling agents to afford the Z-Phe-Ala-OMe (16a) are indicated in Table 1. All the uronium type coupling reagents (HOTU, 15a), (HTOPC, 15e), and (HTOPT, 15f), used gave less than 1% racemization according to the NMR data but CDMT (9) gave about 15% of the racemized product (Table 1). Molecules 2010, 15 9407 Table 1. Yield (%) and Racemization (%) of Z-Phe-Ala-OMe (16a) using the Uronium Salts 15a,e,f and CDMT (9). Coupling Reagent Yield % DL % (HOTU, 15a) 100 <1 (HTOPC, 15e) 54 <1 (HTOPT, 15f) 66 <1 (CDMT, 9) 55 15 CH3 DL (d) at δ = 1.20 ppm; CH3 LL (d) at δ = 1.32 ppm. The other triazinyloxyimino derivative (DMTOC, 12a) failed to give the expected product Z-Phe- Ala-OMe (16a), due to the low activation for the carboxylic group and fast attack by the N-terminal of the amino acid which led to formation of the N-triazinyl amino acid derivative methyl 2-(4,6- dimethoxy-1,3,5-triazin-2-ylamino)propanoate (19a) in 77-85% yield, as confirmed by NMR data (Scheme 3). Scheme 3. Coupling of Z-Phe-OH with H-Ala-OMe.HCl (18a) using DMTOC (12a) and CDMT (9). O H + NMM N N OCH3 Z-Phe-OH H-Ala-OMe.HCl H3CO 12a (DMTOC), 24hr, at rt 18a NN NMM 19a OCH3 9 (CDMT) or (15a,e,f) Z-Phe-Ala-OMe 16a Another example, the coupling of Z-Phe-OH to H-Val-OMe.HCl (18b) to afford the dipeptide Z- Phe-Val-OMe (16b) showed the same behavior for the uronium salts and triazinyloxyimino derivatives (Scheme 4, Table 2).
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