Prolyl preparation

The preparation of the fluoroolefin amide isosteres is reviewed. The incorporation of the amide isosteres in peptidomimetics and the influence of that isosteric substitution on biological activity on inhibition of peptidyl prolyl isomerases cyclophilin (CyP) and Pini, dipeptidyl peptidase IV/CD26 (DPP IV) and thermolysin is described. In addition, select fiuoroolefination procedures which may have utility in the construction of fluoroolefin amide isosteres are illustrated. 

The potential utility of peptides as therapeutics with clinical applications is limited by its metabolic instability or poor transmembrane mobility. Consequently, the preparation of metabolically stable peptide analogs that can either mimic or block the function of natural peptides or enzymes is an important area of medicinal chemistry research. Synthesis of fluoroolefin amide isosteres, its incorporation in peptidomimetics, and the influence of that isosteric substitution on the inhibition of several enzymes such as peptidyl prolyl isomerases, dipeptidyl peptidase IV, and thermolysin is described. Moreover, protein folding and activity... 

N-TFA-L-prolyl methyl esters have been most frequently used for the separation of diastereoisomers of amino acids [295,296], although other procedures have been suggested for blocking the imino group of Pro using functional groups such as a-chloro-propionyl and a-bromopropionyl. The preparation of the derivatives consists in conversion of amino acids into methyl ester hydrochlorides by the action of methanol and thionyl chloride and subsequent reaction with TFA-L-prolyl chloride in dichloromethane... 

The second modified BAL strategy accommodates essentially any C-terminal modification stable to piperidine, and is illustrated here (Fig, 3) for the preparation of peptide A,A-dialkylamides containing prolyl or A-afkylamino acyl derivatives at the C-terminus. (Use of the original BAL approach for the synthesis of these target peptides is inappropriate because the initial reductive... 

Preparative Methods reduction of A(-[A((-benzyloxycarbo-nyl)-prolyl]proline methyl ester with Lithium Aluminum Hydride affords the title reagent in 81% yield. 

Aminolysis of peptide esters occurs uneventfully but this approach to peptide bond formation is not used routinely because access to enantiomerically pure active esters of peptides is straightforward only when the activated residue is glycyl or prolyl (Section 3.2.2). Succinimido esters of small peptides with glycine or proline at the carboxy terminus have been used extensively for the preparation of larger segments in solution. Aminolysis by dipeptide ester 85 of dipeptide succinimido ester 84, obtained through the mixed anhydride (Scheme 19), gave enantiomerically pure (<0.5% l-d-l-l isomer) protected tetrapeptide 86 in 88% yield (Scheme 25). 

Prolyl hydroxylase from the earthworm requires the same co-factors as the animal enzymes, but it has a different substrate specificity. It requires that the glycine residue precede the proline rather than follow it. Thus, the peptide (Gly-Pro-Ala)n is a substrate for earthworm prolyl hydroxylase but not for mammalian and bird enzymes (132). Prolyl hydroxylase from carrots appears to be very similar in co-factor requirements and specificity to that of the animal enzymes (119). The plant enzyme could hydroxylate collagen prepared from chick-embryo tibias and the animal enzyme could hydroxylate the unhydroxylated plant substrate dehydroxyextensin. 

Jacobi s group cyclodehydrated iV-carbobenzyloxy-D-prolyl-L-alanine methyl ester 438 using POCVpyridine to prepare large quantities (50 g) of the 5-methoxy-4-methyl-2-substituted oxazole 439 (Scheme 1.121). Both 439 and ent-439 were key starting points for their enantiospecific syntheses of (+)-norsecurinine and (—)-norsecurinine. 

Kokotos and coworkers prepared a series of prolyl sulfonamides and studied their catalytic performance in an asymmetric aldol reaction between acetone 8 (R = Me, R = H) and 4-nitrobenzaldehyde 9 (R = 4-NO2C6H4) (Scheme 10.1). Among these catalysts, 4-ben loxyprolyl and 4-hydro)qq)rolyl sulfonamides 49a-c represented attractive alternatives to proline as they offered about 20% higher enantioselectivity and a significant decrease of the catalyst amount (10% vs. 20-30% for proline). However, the role of 4-hydro)q or l-benzylojq groups in the studied reaction was not clarified by the authors. 

Further difficulties must be expected if the amine component contributes to an already existing steric effect. For instance, in the attempted preparation of prolyl-proline via a hydroxysuccinimide ester, attack on the activated ester carbonyl is accompanied by an attack on one of the succinimide carbonyl groups ... 

P-Melhyl substituted cinnamaldehydes have been reduced under aqueous media employing a resin-supported N-terminal prolyl peptide having a P-tum motif and a hydrophobic polyleucine chain [22]. The reaction, which is performed in a mixture of THF and water (1/2) at rt, allows the preparation of chiral aldehydes with high enantioselectivities (93-96%) employing a 20 mol% of catalyst 10 and 1.2 equivalents of ester 4 in aqueous media at rt (Scheme 2.4). 

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