Peptide synthesis and related examples

One of the first dedicated applications of microwaves in solid-phase chemistry was the synthesis of small peptide molecules [22]. These will be dealt with in detail in Chapter 19. 

The reactions were carried out within 2-6 min, using a modified domestic microwave oven (Fig. 7.5), employing a dedicated custom-made solid-phase reaction vessel under atmospheric pressure conditions. 

The vessel was placed in the middle of the cavity, and a Teflon tube from the side arm was connected to a nitrogen source. During microwave irradiation, a stream of nitrogen gas was blown into the vessel with the gas bubbles serving as an agitator. After irradiation the reaction solution was filtered off via the side arm by suction. 

The microwave protocol increased the reaction rate at least two- to threefold, as conversion was only 60-80% within 6 min under conventional heating. This improved coupling efficiency was duplicated with numerous amino acid derivatives and a further two peptide fragments were coupled with the Gly-Wang resin. These couplings were completed within 2 min as determined by quantitative ninhydrin assay. 

2) coupling reagent, Fmoc-amino acid /-Pr2NEt, DMF, MW, 110°C, 20 min 

With this protocol nine different primary amines (Fig. 7.6) were used to generate different 9-residue homo-oligomers, one 20-residue homo-oligomer and one 9-residue hetero - oligomer. 

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The parent alcohol can be obtained in a straightforward manner from chloromethyltrimethylsilane (Chapter 16). The protection afforded is naturally related to the functionality involved, and liberation is achieved using either fluoride ion or a Lewis acid. For example, 2-trimethylsilylethyl esters (Chapter 16) are stable to a wide variety of conditions such as those used in peptide synthesis, but are readily cleaved by fluoride ion (14,15). 

Dyn is not yet known, it is likely that such changes reflect variations in the activity of the associated pathways. One possible explanation is that increases in neuropeptide tissue levels are due to decreased release of the transmitter, which dunmishes the extracellular peptide metabolism and results in accumulation of these peptide substances. Another possible contributing factor is a drug-related alteration in neuropeptide synthesis. For example, Bannon et al. (1987) reported that METH administration increased the quantity of striatal messenger RNA for the SP precursor preprotachykinin. Thus, increases in peptide synthesis might contribute to increases in peptide content caused by treatment with METH or the other amphetamine analogs. 

For the synthesis of peptides, the phosphonic moiety in most cases should be masked as a diester. Diesters of 1-aminoalkylphosphonic acids can be synthesized directly or by esterification of 1-aminoalkylphosphonic acids. If peptides with the free phosphonic moiety are the desired products, then methods are available for the selective removal of both ester groups. Peptides with a free C-terminal phosphonic acid functionality can be synthesized directly from the free 1-aminoalkylphosphonic acids. In addition, methods for synthesis of the peptides with C-terminal phosphonates directly from the peptides are also available. In general, most methods for the synthesis of peptide bonds work well for the synthesis of peptides with C-terminal phosphonates if diesters of 1-aminoalkylphosphonic acids are used. Bulky diaryl esters give yields similar to the diethyl esters. Therefore, the most challenging step in the synthesis of peptide phosphonates is the synthesis of 1-aminoalkylphosphonic acids and/or their esters. It is not possible in this section to review all of the literature data and only examples of several general methods are included. This will still provide a variety of methods for the efficient synthesis 1-aminoalkylphosphonic acids, their esters, and related peptide derivatives. 

The Wittig, and related reactions, have also found application in the synthesis of peptidomimetics—mimics of natural peptides that possess modified biological properties such as increased bioavailability, biostability, bioselectivity, and bioefficiency relative to the parent peptide. As an example, the phenylalanine-based HWE reagent shown in Protocol 13 reacts with aldehydes to give a modified amino acid that can be used as a building block for the construction of extended peptidomimetics. 

The current review is of necessity selective. Over the two year period covered, there has been impressive advances in several areas of P(V) chemistry. For example, biological aspects of quinquevalent phosphorus acids chemistry continue to increase in importance. A wide variety of natural and unnatural phosphates including inositols, lipids, some carbohydrates and their phospho-nates, phosphinates and fluorinated analogues has been synthesized. Special attention has been paid to the synthesis of phosphorus analogues of all types of amino acids and some peptides. Numerous investigations of phosphate ester hydrolysis and related reactions continue to be reported. Interest in approaches to easier detoxification of insecticides continues. A number of new and improved stereoselective synthetic procedures have been elaborated. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications. 

Free radical-induced additions have been used in the synthesis of a range of phosphines bearing other nucleophilic groups, e.g., (41), useful for specific peptide bond cleavage of proteins.A further example of the formation of the phosphorinanone system by addition of phenylphosphine to a divinyl ketone derivative has been described.Two reports have appeared of the addition of secondary phosphines to maleic anhydride and related activated olefins, to give functionalised tertiary phosphines, e.g., (42). A route to allylphosphines is provided by base-... 

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