Peptides acids

The triethylamine salts of peptide acids are often relatively insoluble in acetonitrile or nitromethane therefore, the supersaturated solution formed on mixing the amine and the acid should be added to this reaction mixture immediately, before crystallization occurs. If crystallization does occur, the mixture should be heated to dissolve the salt, cooled rapidly, and added to the reaction mixture immediately. If it is impossible to obtain a solution of the salt, the peptide acid and then the triethylamine solution may be added separately to the reaction mixture with only a small sacrifice in yield. 

A second strategy is to attach a linker (also referred to as a handle or anchor) to the resin followed by assembly of the molecule. A linker is bifunctional spacer that serves to link the initial synthetic unit to the support in two discrete steps (Fig. 3). To attach a linker to a chloromethyl-PS resin, a phenol functionality such as handle 4 is used to form an ether bond (Fig. 4). To attach the same handle to an amino-functionalized support, acetoxy function 5 or a longer methylene spacer of the corresponding phenol is applied to form an amide bond. Both of these resins perform similarly and only differ in their initial starting resin [4], An alternative approach is to prepare a preformed handle in which the first building block is prederivatized to the linker and this moiety is attached to the resin. For peptide synthesis, this practice is common for the preparation of C-terminal peptide acids in order to reduce the amount of racemization of the a-carbon at the anchoring position [5],... 

Rich DH, Gurwara SK. Preparation of a new o-nitrobenzyl resin for solid-phase synthesis of tert-butyloxycarbonyl-protected peptide acids. J Am Chem Soc 1975 97 1575-1579. 

NL Benoiton, Y Lee, B Liberek, R Steinauer, FMF Chen. High-performance liquid chromatography of epimeric TV-protected peptide acids and esters for assessing race-mization. Ini J Pept Prot Res 31, 581, 1988. 

RESINS AND LINKERS FOR SYNTHESIS OF PROTECTED PEPTIDE ACIDS AND AMIDES... 

The phosphonium and carbenium salts are efficient reagents for activating and coupling A-alkoxycarbonylamino acids as well as peptide acids. However, the requirement for tertiary amine to effect the reaction has several implications. The base renders hydroxyl groups subject to acylation. Hence, the side chains of serine and threonine and any hydroxymethyl groups of a resin that have not been derivatized... 

Rich, D. H. Gurwara, S. K. Preparation of a New o-Nitrobenzyl Resin for Solid-Phase Synthesis of tert-Butyloxycarbonyl-Protccted Peptide Acids, J. Am. Chem.. Soc. 1975, 97, 1575. 

For the synthesis of simple peptides in which the phosphorus-containing amino acid analogue is at the C-terminal end of the peptide, acid-catalyzed cleavage of the diester has been used to produce the phosphonic diacid.153,6X1 However, the strong acid needed to effect this transformation makes the strategy unattractive for more complex molecules and it has largely been superceded by the use of bromotrimethylsilane (see Section 10.10.3.2.1). 

Table 2 Synthesis of Tripeptide Aldehydes R1-Xaa3-Xaa2-Xaa1-H by Mixed Anhydride Coupling of Semicarbazones to Peptide Acids Followed by Semicarbazone Deprotection 31 ...

Semicarbazones of peptide aldehydes are stable to hydrogenolysis and various coupling procedures (azide and mixed anhydride). Deprotection of the Z-protected amino acid semicarbazones, such as Z-Phe-H semicarbazone, by catalytic dehydrogenation gives the deprotected derivatives in good yields,these can be coupled to peptide azides or peptide acids using the mixed anhydride procedure. The semicarbazone is readily deprotected with 37% formaldehyde/HCl to give the peptide aldehyde. 

Reaction of Activated Amino Acid and Peptide Acid Derivatives with... 

Only one method has been used to prepare various peptidyl diazomethyl ketones. A protected amino acid or peptide acid is activated as the mixed anhydride and reacted with ethereal diazomethane at low temperature. Generally a peptide with the desired sequence is prepared first and then converted into the diazomethyl ketone in the final step of the synthesis. Since the diazomethyl ketone functional group is stable to alkali but unstable to acid, acidic conditions used to deprotect many peptide protecting groups must be avoided. 

In an early report on peptide hydroxamic acids as metalloprotease inhibitors, the peptide acid (Z-Gly-L-Leu-OH) was converted into the V-hydroxysuccinimide ester using DCC, which was subsequently reacted with hydroxylamineJ10 More reactive condensing reagents such as BOP can form the hydroxamic acid directly from the carboxylic acid and hydroxylamine via an intermediate HOBt ester. A number of hydroxamic acids has been synthesized by the treatment of the corresponding methyl esters with hydroxylamine in the presence of KOH 122 this reaction requires careful choice of reagent concentrations and ratios. In addition, the precursor carboxylic acid is treated with diazomethane to make the methyl ester. The use of diazomethane makes the procedure hazardous, but should be useful in special cases that require a better cost performance. 

Goissis, G., Erickson, B.W. and Merrifield, R.B. (1977) Synthesis of protected peptide acids and esters by photosolvolysis of l-peptidyl-5-bromo-7-nitroindolines. Peptides, Proceedings of the 5th American Peptide Symposium, Halsted Press, New York, pp. 559-561. 

In addition to thioesterifications employing the C-terminal condensation with alkyl-thiols, the Danishefsky group demonstrated an alternative type of thioesterification (Scheme 11.6) [74], A suitably side chain-protected peptide acid is condensed with an amino acid 2-dithioethyl phenyl ester. The 2-dithioethyl phenyl ester is prone to rearrangement to a thioester through O S transesterification under reducing (NCL) conditions. 

Commonly used resins in Fmoc/tBu strategy for the synthesis of C-terminal peptide acid are reported in Fig. 5 (11-14). Anchoring reactions must be performed in an anhydrous medium and amino acids containing water should be dried before use. 

Coupling of 4-(4-hydroxymethyl-3-methoxyphenoxy)-butyric acid (HMPB, for synthesis of peptide acids) or p-[(R S)-a-[l- (9H- fluorenyl- methoxyform-amido]- 2,4- dimethoxybenzyl] - phenoxyacetic acid (modified Rink linker, for synthesis of carboxamide peptides) linkers to MBHA resin For Fmoc chemistry several types of solid supports are available, which include hydroxymethyl-based, aminomethyl-based, and trityl chloride resins. We describe the use of the MBHA resin. In this case the respective linker (to achieve peptide acid or amide) is coupled to the resin and first amino acid is then coupled to the linker. Attachment of the linker to the resin is a reaction between the carboxyl-group of the linker and amino-group of the MBHA resin. Commercially available resins with linkers already attached could also be used. 

Attachment of the first amino acid to the linker to produce a peptide acid The first amino acid is coupled to the hydroxyl group of the HMBP linker using symmetrical anhydride of the amino acid. 

Neutral peptides Basic peptides Acidic peptides Peptides with add and basic amino acids Peptides containing proline and hydroigrproUne ... 

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