Peptide synthesis from oxazolones

Carbamates can be used as protective groups for ammo acids to minimize race-mization in peptide synthesis. Raccmi/ation occurs during the base-catalyzed coupling reaction of an W-protected, catboxyl-uc ivated amino acid, and takes place in the intermediate oxazolone that foro S readily from an N-acyl protected amino... 

During a peptide synthesis study, Slebioda (5) apparently independently observed the formation of miinchnone (12) from A -benzoylphenylalanine and DCC. He was able to isolate and fully characterize this crystalline miinchnone along with oxazolone 13. The tautomerization of 13 to 12 as a function of base and solvent is best effected with triethylamine in DMF (68% yield). 

Amino acids have been used as nucleophiles to effect the ring opening of saturated 5(477)-oxazolones 253 as a coupling method in an attempt to describe a general procedure for peptide synthesis (Scheme 7.82). However, the problems arising from racemization, that is, when a proton is present at C-4 of the oxazolone, render this procedure of limited synthetic utility. 

N. L. Benoiton and E. M. E. Chen, 2-Alkoxy-5(4JJ)-oxazolones from A-alkoxycarbonylamino acids and their implication in carbodiimide-mediated reactions in peptide synthesis. Can. J. Chem. 1981 59 384-389. 

In peptide synthesis the use of a suitable protection for the N-terminal amino group is required not only to prevent the formation of a complex mixture of oligo- and cyclo-peptides, but an additional demand on the functionality applied for this purpose is that it should prevent possible racemization of the activated amino acid. Racemization usually takes place via an intermediate oxazolone (7) that forms readily from A -acyl-protected amino acids (Scheme 2). This side reaction can be mostly suppressed by using a carbamate as an N-terminal-protecting group. Therefore, nearly all blocking functions currently applied in this field are of the urethane type. 

This reaction has been modified to heat amino acid with trifiuoroacetic anhydride to form 4-substituted-2-(trifluoromethyl)-6-oxazolone, which can react with the succeeding amino acid to form peptide. The azlactone with a saturated side chain can be prepared from Qf-keto acid and subjected to the peptide synthesis. 

HOBT has also been used in conjunction with amino acid chlorides to facilitate peptide bond formation. This has proved of particular use in the case of FMOC-protected amino acid chlorides in solid-phase peptide synthesis where direct coupling is rather slow and suffers from competing oxazolone formation."... 

A soln. of tosyl-a-methylalanyl-a-methylalanine in acetic anhydride heated 15 min. at 110-120° -> 4,4-dimethyl-2-(r-methyl-r-tosylamino)ethyloxazolone (Y 94%) dissolved with a-methylalanine methyl ester in acetonitrile, and heated 4 hrs. at 100° tosyl-a-methylalanyl-a-methylalanyl-a-methylalanine methyl ester (Y 95%).—Most of the conventional methods of peptide synthesis are not suitable for the joining of a-methylalanyl residues. The absence of a H-atom from the a-position favors the oxazolone method because there can be neither racemization nor acylation at the a-G-atom. F. e., methods, and limitation by ring opening to amidine derivatives, s. M. T. Leplawy et al., Tetrahedron n, 39 (1960). 

Saturated 5(4//)-oxazolones are easily obtained from //-acylamino acids in the presence of a cyclization agent and have been used extensively in coupling reactions as synthetic equivalents of a-amino acids in the synthesis of peptides. In this context, tautomeric equilibrium can be a significant problem due to the racemization associated with the isomerization. For example, trifluoroacetylation of tryptophan in ether affords the 5(4//)-oxazolone 5 without racemization. However, upon dissolution in acetonitrile, 5 completely racemizes. Further, upon heating, an aqueous dioxane solution of 5 cleanly isomerizes to the isomeric 5(2//)-oxazolone 6 (Scheme 7.2). 

Bis-4-arylidene-5(4//)-oxazolones are easily obtained from aromatic dialdehydes by the Erlenmeyer synthesis. Such bis(oxazolones) react with a,co-diamines to provide a convenient approach to macrolactams.Tandem Erlenmeyer condensation-macrolactamization (TECM) has been used to prepare analogues of naturally occurring, biologically active cyclic peptides such as bastadin-5. 

Scheme 5 Synthesis of ferrocenoyl peptides (4) via the ferrocenyl oxazolone (20) starting from a ferrocenoyl amino acid (19) (a) DCC or EDC, (b) amino acid.

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