Coupling reagents phosphonium

Another family of coupling reagents frequently used with the Fmoc method is related to A-hydroxybenzotriazole and A-hydroxy 7-azabenzotriazole but also incorporates phosphonium or amidinium groups. The latter can exist in either the O-(uronium) or A-(guanidinium) forms.48 Both can effect coupling. The former are more reactive but isomerize to the latter. Which form is present depends on the protocol of preparation, including the amine used and the time before addition of the carboxylic acid 49 The... 

Scheme 13.77. Phosphonium, Uronium, and Guanidinium Coupling Reagents...

B Castro, JR Dormoy, G Evin, B Castro. Peptide coupling reagents IV (1) — benzotriazole V-oxytrisdimethylamino phosphonium hexafluorophosphate (B.O.P.) Tetrahedron Lett 1219, 1975. 

FIGURE 2.22 Couplings using phosphonium and uronium salt-based reagents with 1-hydroxybenzotriazole as additive.60 The additional HOBt promotes formation of the benzotriazolyl ester, which is the precursor of the peptide. 

Method 1 addition of a coupling reagent (carbodiimide, EEDQ, phosphonium and carbenium salts, trisubstituted phosphates, etc.) and tertiary amine, if necessary, to a mixture of the acid and the amine nucleophile that are to... 

Historically, the methods used for ring closure of linear precursor peptides via amide bond formation evolved in parallel to the methods applied in segment condensations from the azide and active ester procedures to the use of coupling reagents such as DCC in the presence of additives, or of the more recently developed phosphonium and uronium/gua-nidinium reagents. In all cases the choice of method is mainly dictated by the epimerization problem when chiral amino acids act as the carboxy component in the cyclization reaction, and by other side reactions. 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

The reactivity of uronium- (and phosphonium-) based coupling reagents is mainly determined by the type of activated acid derivative formed during activation (see Figure 13.2). Unlike phosphonium salts, uronium salts can react with amines to yield guanidines [84]. This side reaction can interfere with amide formation if more uronium salt than carboxylic acid is used. Illustrative examples of the use of uronium salts are listed in Table 13.6. 

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>. 

Scheme 5 Phosphonium Salt Coupling Reagents A (MejNjapUw...

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