Peptides hindered, synthesis

Azirine/oxazolone method, a synthetic method for the introduction of sterically highly hindered a,a-disubstituted a-amino acids into peptides. The synthesis of e.g., Aib-rich peptides requires either highly reactive coupling reagents (e.g., amino acid halides) or special derivatives (such as 3-amino-2H-azirines or a-azido carboxylic acid chlorides). The azirine/oxazolone method utilizes an amino component that... 

At the time of writing this book, SPOS is in an area of reladve infancy but has considerable potential. One of the main difficulties in SPOS lies in the lack of techniques available to monitor reacdons carried out on polymer supports. Unlike reacdons in solution phase, reactions on solid support cannot be monitored with relative ease and this has hindered the progress as well as the efficacy of solid supported synthesis of small non-peptidic molecules. Despite these difficulties, a large body of studies is available for SPOS. Recent reviews incorporate... 

H Kunz, H-H Bechtolsheimer. Synthesis of sterically hindered peptides and depsipep-tides by an acid chloride method with 2-phosphonioethoxycarbonyl-(Peoc)-amino acids and hydroxy acids. Liebigs Ann Chem 2068, 1982. 

FIGURE 2.23 Some tertiary amines used as bases in peptide synthesis. The less hindered amines are able to abstract protons more readily, but the more basic amines bind the protons more tightly. 

The major side reaction associated with the use of mixed anhydrides is aminolysis at the carbonyl of the carbonate moiety (Figure 7.4, path B). The product is a urethane that resembles the desired protected peptide in properties, except that the amino-terminal substituent is not cleaved by the usual deprotecting reagents. Hence, its removal from the target product is not straightforward. The problem is serious when the residues activated are hindered (Val, lie, MeXaa), where the amounts can be as high as 10%. Other residues generate much less, but the reaction cannot be avoided completely, with the possible exception of activated proline (see Section 7.22). This is one reason why mixed anhydrides are not employed for solid-phase synthesis. 

Synthesis and biosynthesis of peptides and proteins reqnires the combination of amino acids via amide bonds. We have seen eariier that the chemicai reaction of amines and acids to prodnce a simpie amide is severeiy hindered by initiai sait formation, and that... 

Carbohydrates and polysaccharides, on the one hand, and peptides and proteins, on the other, have been considered as separate classes of natural products for a long time. Fundamental chemical methodology for the synthesis of both saccharides and peptides was developed by Emil Fischer et al. at the beginning of the 20th century. 1,2 However, the harsh conditions employed in early solution and solid-phase peptide synthesis hindered the combination of peptide and carbohydrate chemistry, i.e. glycopeptide synthesis. Considerable efforts were made to combine the two branches of natural product chemistry, and the state of the art within glycopeptide synthesis has improved dramatically during the last decades, as described in a number of reviews. 3 23,512"514 ... 

More stable iV-acylpyridinium salts can be formed by using 4-(Ar,Ar-dialkyl-amino)pyridines. The salts are less readily hydrolyzed and are effective in the acylation of sterically hindered alcohols (72S619) and in the formation of iV-f-butoxycarbonyl derivatives of a-amino acids in aqueous alkali, for use in peptide synthesis (71CC267). 

Since the first systematic synthetic effort of Leplawy et al)22 the preparation of peptides containing the slow-reacting C -tetrasubstituted a-amino acids has been achieved mainly by solution procedures. However, recent improvements in activation methodologies make solid-phase peptide synthesis (SPPS) an attractive tool as well, at least with the less sterically hindered Ca-tetrasubstituted a-amino acids. 

Due to the suppression of racemization and the ability to couple sterically hindered substrates, this methodology has been utilized in solid-phase peptide synthesis. In particular, 9-fluorenyl-methoxycarbonyl-protected amino acid fluorides have been used with this protocol.110 1,3... 

HATU is the most powerful yet most expensive peptide coupling reagent on the market. It is preferentially used for the coupling of sterically hindered amino acids or during the synthesis of complex peptides (21) without the addition of HOBt. However, due to its high price, amino acids for which high incorporation... 

Angell, Y.M., Garcia-Echeverria, C., and Rich, D.H. (1994) Comparative studies of the coupling of N-methylated sterically hindered amino acids during solid-phase peptide synthesis. Tetrahedron Lett. 35, 5891-5894. 

Inhibition of transpeptidase Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains. Penicillins inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of crosslinks essential for cell wall integrity. As a result of this blockade of cell wall synthesis, the Park peptide , UDP-acetylmuramyl-L-Ala-D-GIn-L-Lys-D-Ala-D-Ala, accumulates. 

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