Symmetrical anhydride procedure

In a more recent study using dedicated multimode microwave reactors for chemical synthesis, which enable temperature and power control, it was demonstrated that microwave irradiation could be effectively employed to couple aromatic carboxylic acids to polystyrene Wang resin [25], if the symmetrical anhydride procedure was used, and not the three-component O-acylisourea activation method [19]. Almost quantitative loading was achieved in l-methyl-2-pyrrolidone (NMP) at 200 °C within 10 min under... 

Asn and Gin were dissolved in DMF, A -Boc-Arg(Tos) in 10% DMF- DCM. The extent of couplings was monitored by the ninhydrin test. Recouplings carried out by symmetric anhydride procedure in DMF if necessary. 

In a related study the same authors investigated the effect of microwave irradiation on carbodiimide-mediated esterification of benzoic acid on a solid support [24]. The carboxylic acid was activated with N,N -diisopropylcarbodiimide (DIG) via the O-acyl isourea or the symmetrical anhydride procedure. The isourea proce-... 

Load first Boc-protected amino acid onto the resin according to the symmetrical anhydride procedure (dissolve 10 Eq of the residue in a minimum of dichloromethane). 

This procedure is applicable to the preparation of both symmetrical anhydrides (R and R the same) and mixed anhydrides (R and R different)... 

In addition to the more or less popular methods of depsipeptide synthesis discussed vide supra, there are also a limited number of complementary and effective synthetic procedures that have been described for this purpose. Among these, the well-known method of symmetric anhydrides from N-protected amino acids has to be considered. This method has found successful use in the esterification of hydroxy acids in the presence of some catalyst additives. Initially, the addition of pyridine11091 or 1-hydroxybenzotriazole in pyridine1 101 to a symmetric anhydride was utilized for ester bond formation. As an example, Katakai has prepared a number of didepsipeptides in 85-96% yield by means of a 2-nitrophenylsulfenyl /V-carboxy anhydride with lactic acid derivatives in the presence of pyridine.1 09 ... 

Carboxylic mixed anhydrides are very important for the rapid synthesis of peptides by the stepwise procedure,however the use of carboxylic mixed anhydrides,e.g.those derived from pivalic acid and a protected amino acid (1),suffers from two disadvantages. Firstly,regiospecificity of attack at the desired carboxyl function is largely determined by steric effects and will not be 100% for all coupling reactions.Secondly,such mixed anhydrides have a propensity towards disproportionation to symmetric anhydrides which is highly undesirable in terms of reaction efficiency.This latter process can be depressed by operation of the reaction at -15 °C, but with the concurrent decrease in reaction rate and,on large scale manufacture,increased costs. 

For chain-elongation steps with Fmoc-Arg(Adoc)2-OH standard activation procedures are applied, such as active esters and the symmetric anhydride method, but even for the use of more powerful acylating agents, e.g. phosphonium and uronium salts, there are no contraindications. Final deprotection is performed using TFA under standard conditions of Fmoc/tBu chemistry. Properties similar to the Adoc group have been reported for iso-bornyloxycarbonyl protection, whereas increased acid lability is obtained with the 1-(1-adamantyl)- -methylethoxycarbonyl group. ... 

Symmetrical anhydrides are stable to washing by dilute add or aqueous sodium hy-drogencarbonate at room temperature and, consequently, can readily be obtained pure using water-soluble carbodiimide.b l Furthermore, when pure, most of the crystaUine products are stable at room temperature. The symmetrical anhydride method was reported by Chen et al.f to give superior yields of peptides as compared to the normal carbodiimide coupling procedure on a sohd phase and to be superior to the mixed anhydride method in solution. 

The use of symmetrical anhydrides for the synthesis of peptides in solution has not found widespread application, although a number of efficient peptide syntheses have been performed using this procedure.Preparation and use of synunetrical anhydrides for peptide synthesis in solution has been comprehensively reviewed. ... 

However, the method is not substantially better than the mixed anhydride method, the standard DCC method, the active ester method, or the newer procedures (HBTU, BOP, PyBroP, etc.), and it uses double the amount of N-protected annino acid to accomplish the condensation reaction. Although many synometrical anhydrides are isolable and stable,t l they are not commercially available. On the other hand, the use of preformed symmetrical anhydrides is very convenient. One needs only to add an annino acid ester to the protected amino acid anhydride in a nonreactive solvent and, upon completion of the condensation, destroy the excess anhydride and remove the acid components by extraction. 

Boc-Ala-Ala-OBzl Typical Procedure for Symmetrical Anhydride Preparation via Methylethynyl-... 

Symmetrical Anhydrides of Boc Amino Acids Generated In Sitn for SPPS General Procedure ... 

Acylation of Hydroxymethyl Resins Using Fmoc Amino Acids via Symmetric Anhydrides in the Presence of DMAP Gener Procedure ... 

Activation with sulfonic acid chlorides is more general, rendering amides with the possible participation of symmetric anhydrides after disproportionation. This method has also found use in the synthesis of modem 3-lactam antibiotics. However, in peptide chemistry this activation method leads to unwanted side reactions, like formation of nitriles in the cases of glutamine and asparagine, and racemization. In a convenient one-pot procedure, the carboxylic acids are activated by sulfonyl chlorides under solid-liquid phase transfer conditions using solid potassium carbonate as base and a lipophilic ammonium salt as catalyst. ... 

The mixed anhydride procedure has been applied to the preparation of symmetrical anhydrides of fatty acids, particularly those containing hydroxyl groups and hence sensitive to reagents commonly used for anhydride formation. The acid... 

---