Peptide with phosphonium hexafluorophosphate

NMR data were used to prove the structure of peptide-coupling reagents -[(6-nitrobenzotriazol-lyl)oxy]tris(dimethylamino)-, -(pyrrolidino)phosphonium hexafluorophosphates [829-831], l-(2-nitrobenzenesulfonyloxy)-6-nitrobenzotri-azole [832], and l-(2-naphthylsulfonyloxy)-6-nitrobenzotriazole [833], complexes of 5-nitrobenzotriazole with palladium(II) and platinum(II) [834], some explosive substances such as 1-picrylbenzotriazole mono- and polynitro derivatives [835] as well as that of the Mesenheimer a-complexes and 4,6-dinitrobenzotriazole-l-oxide [836, 847],... 

Peptide coupling reagent bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrOP) was used in synthesis of 10-membered succinyl bis(amide) 27 in 57% yield (Equation 3) <2002TL2593>. Similarly, 1,6-diazacyclo-decane substituted on only one nitrogen atom was prepared by reaction of A -trityl-protected linear triamine with succinyl anhydride. The amides were further reduced to amines using LAH <2002TL2593>. 

This is the reason why peptide chemists, to decrease the problems of purification prefer for long peptides to use protecting groups (tert-butyloxycarbonyl (t-Boc), benzyloxycarbonyl (Z), fluorenylmethyloxycarbonyl (FMOC).) and classical reagents such as T.B.T.U. (0-lH-benzotriazol-l-yl)-l,l,3,3-tetramethyl uronium tetrafluoroborate), B.O.P.(benzotriazol-l-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate and so on in polar solvents such as N,N-dimethylformamide or N-methylpyrrolidone. But this solvents are not compatible with the acidic deprotection reagents such as trifluoroacetic acid and... 

The chloro and bromo derivatives of phosphonium and uronium salts have not been extensively used in solid-phase strategy. Thus, chloro- and bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate [PyCloP (63) and PyBroP (64)1 [109] and bromotris(dimethylamino)-phosphonium hexafluorophosphate (65) (BroP) [110], which have been used with success in solution for the synthesis of peptides containing A-methylamino acids, have not been found to be effective in the solid-phase mode. The active species detected for PyCloP, PyBroP, and BroP in the absence of HOBt are the symmetrical anhydride, the 5(4JT)-oxazolone, and, for Boc-amino acids, the iV-carboxyanhydride [99]. Furthermore, 2-chloro-l,3-dimethyl-4,5-dihydro-117-imidazolium hexafluorophosphate (66) (CIP, DCIH) [107,108,111] has been found effective only in the presence of 1 equiv. of HO At. 

Figure 2.2 Modern solid phase peptide synthesis. Process begins with a-N terminal Fmoc deprotection of resin bound C-terminal amino acid residue with piperidine (mechanism illustrated). Peptide link formation follows (typical solvent Al-methylpyrrolidone [NMP]) by carboxyl group activation with dicyclohexylcarbodiimide (DCC) (mechanism illustrated) in presence of hydroxybenzotriazole (HOBt). HOBt probably replaces DCC as an activated leaving group helping to reduce a-racemization during peptide link formation. Other effective coupling agents used in place of DCC/HOBt are HBTU 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate Py-BOP benzotriazole-l-yl-oxy-tns-pyrrolidino-phosphonium hexafluorophosphate. The Process of a-N deprotection, and peptide link formation, continues for as many times as required (n-times), prior to global deprotection and resin removal.

Several reports have dealt with the use of phosphinic pseudodipeptide building blocks in peptide couplings where both phosphinic and carboxylic acids are unprotected. Among the coupling reagents used successfully for such transformations are W,W -carbonyldiimidazole (CDl) [66-68], (benzotriazol-l-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate (BOP) [69, 70],... 

In the absence of the carboxylic component, HBTU reacts with amino groups leading to the formation of a Schiff base (eq 2). Thus in syntheses conducted in solution, the excess of both HBTU and amino component should be avoided. In both solution and solid-phase strategies the sequence of reagent addition is critical. HBTU should be delivered to the carboxylic component for preactivation, prior to the addition of the amine. The Schiff base formation can also occur during slow reactions, such as the preparation of cyclic peptides, where both amino and carboxylic components are in equimolar amounts and an excess of the uronium salt can block the amino group. For the synthesis of cyclic peptides the phosphonium derivatives Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (BOP) and benzotriazol-l-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), can be more useful. 

Another potential problem with DCC is that at the completion of the reaction some DCU remains in solution with the product, necessitating additional purification. Water-soluble carbodiimide derivatives such as l-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide Metho-p-toluenesulffonate and l-Ethyl-3-(3 -dimethylaminopropyl)carbodiimide Hydrochloride (EDCI) obviate this problem, as they are removed by a simple extraction. Many newer coupling agents have been developed for peptide synthesis and other acylation reactions. These include Benzotriazol-l-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (BOP)," 0-Benzotriazol-l-yl-N,N,N, N -tetramethyluronium Hexafluorophosphate (HBTU)," Bis(2-oxo-3-oxazolidinyl)phosphinic Chloride (BOP-Cl), and (1 //-1,2,3-benzotriazol-1 -yloxy)tris(pyrTolidino)phosphonium hexafluorophosphate (PyBOP). In addition to linear and polymeric amides, lactams of various ring sizes have been synthesized using these methods (eq 1)."... 

As mentioned earlier, HOBT has also been incorporated into the peptide coupling reagent itself and one example of such a reagent is benzotriazol-1 -yloxytris(dimethylamino)phosphonium chloride (BOP). BOP is prepared by the reaction of HOBT with Hex-amethylphosphorous Triamide in the presence of carbon tetrachloride, and is very effective in the coupling of amino acids (eq 6). See also Benzotriazol-l-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (also known as BOP). 

Special phosphonium salts, such as (benzotriazol-l-yl-oxy-)tris(dimethylamino)-phosphonium and (benzotriazol-l-yl-oxy-)tris(pyrrolidino)phosphonium salts with hexafluorophosphate counter anion (Fig. 10) have been introduced as coupling reagents in the synthesis of four model peptide sequences. ... 

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