Pentachlorophenyl esters

A general step ahead in polycondensation was achieved by the application of the active ester method by DeTar et al.19) and Kovacs et al.291 Very soon, the nitrophenyl ester, the pentachlorophenyl ester, or the hydroxysucdnimido ester were used exclusively. The esters of the protected tripeptides could be purified by crystallization, then the N-protecting group was split off and the free peptide esters were purified again. Addition of base starts the polycondensation, resulting quickly in the formation of a viscous solution at low temperature. 

S.P. solid-phase technique L.P. liquid-phase technique OPTcp pentachlorophenyl ester TEEP tetraethyl pyrophosphit OTCp trichlorophenyl ester ONp p-nitrophenyl ester ONSu N-hydroxysuccinimido ester OPFp pentafluorophenyl ester OQu 8-hydroxyquinyl ester OPy 3-hydroxy-pyridyl ester ODnp 2,4-dinitrophenyl ester DCC dicyclohexylcarbodiimide HOBn 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazin Opi JV-hy-droxypiperidine EEDQ 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline Tos p-toluenesulfonyl PTC propanetricarboxylic acid OBu tm-butyl ester Nva norvaline Aha aminohexanoic acid Om ornithine... 

G Kupryszewski, M Formela. Amino acid chlorophenyl esters. HI N-Protected amino acid pentachlorophenyl esters. Rocz Chem 35, 931, 1961. 

Kinetic studies of the alkaline hydrolyses (pH 11-14) of a series of pentachlorophenyl esters of >-(/7-hydroxyphenyl)alkanoic acids (19 m = 1-4) have been reported. The reasonably high nucleofugality of the pentachlorophenoxide (pK ... 

Galbis et al. [31] described the preparation of the pentachlorophenyl esters of 2,3,4-tri-O-methyl-L-arabinaric and xylaric acids (26 and 27) as suitable bifunctional monomers for linear polycondensations. 

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

As mentioned above, thiazolidine-4-carboxylic acid is characterized by an anomalously low basicity and thus difficult acylation in peptide synthesis. 189 Therefore, the incorporation of this amino acid residue into a growing peptide chain is preferentially preformed via dipeptide derivatives. 139 Suitably N-protected amino acids are coupled directly to the thiazolidine-4-carboxylic acid by the acid fluoride 139 or iV-carboxyan hydride 1392111 methods. The resulting dipeptides are used as building blocks without risk of racemization 139 and standard coupling procedures are applied as pentachlorophenyl esters prepared by the mixed anhydride procedure 121 or PyBOP. 171 ... 

Carbonic acid, tert-butyl pentachlorophenyl ester (8) Carbonic acid,... 

Chloroacetic acid pentachlorophenyl ester (ClAcOPcp) was prepared in our laboratory from chloroacetic acid and pentachlorophenoC with aid of DCC (Fluka). 

Chloroacetic aeid pentachlorophenyl ester (ClAe-Opep) (Fluka). 

From a protected amino acid C6F5OSO2C6H4NO2, HOBt, TEA, DMF, 20-30 min, 61-98% yield/ This method can also be used to prepare other electron deficient phenolic esters such as the 4-nitrophenyl, 2,4,5-trichloro-phenyl, and the pentachlorophenyl ester. 

Active pentachlorophenyl esters of amino acids have also been prepared by ester exchange of trialkylammonium salts of acylamino acids with pentachlorophenyl trichloroacetate or dichloroacetate.2 2M. Fujino and C. Hatanaka,Chem. Pharm. Bull., 16,929 (1968)... 

Reduction of carboxylic acids. After derivatizing into the pentachlorophenyl esters, acids are reduced to alcohols by this reagent system. This method is applicable to A-pro-tected amino acids and peptides. 

In the discussion of side reactions we have dealt, so far, only with electronic effects. It would be a mistake, however, to underestimate the importance of geometric factors and, in particular, the influence of bulky side chains. Branching of the aliphatic chain in valine and in isoleucine is at the jS-carbon atom, near to the reactive carbonyl group in activated intermediates. Hence, acylation reactions in which these amino acids are involved, do not proceed at a rate observed with other amino acids, for instance with leucine, in which branching is at the y-carbon atom. Steric hindrance becomes even more pronounced when the activating group is similarly bulky as in pentachlorophenyl esters ... 

Synthesis of sequential peptides usually relies on an activated derivative of the repeating unit from which the amine-protecting group is removed by acid-olysis. Pentachlorophenyl esters were found to produce high molecular weight materials. The reaction is started by deprotonation with a tertiary amine but the addition of a small amount of a secondary amine as initiator is also advisable ... 

Better reaction rates were observed with the already inherently more reactive o-nitrophenyl esters, in part because they are less sensitive to steric hindrance than their para-substituted analogs. Bulkyness of the activating groups renders N-hydroxysuccinimide esters and pentachlorophenyl esters less well suited for acylation inside the matrix of a polymer than in solution. Only the introduction of the powerful pentafluorophenyl esters led to a revival of the active ester idea in the praxis of solid phase peptide synthesis. Pentafluorophenyl esters of Fmoc amino acids... 

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