Peptides and Their Use in Peptide Synthesis free essay sample

Other advantages arise from the stability of a mino acid or peptide esters a s free bases, particularly in allowing their storage and use as such. Comparative stabilities to ethyl esters are reported in s everal examples. T h e synthesis of several t-butyl peptides is reported a s well a s selective removal of this ester group or of amine-protecting groups when both are present. I n recent years naturally occurring peptides with high biological activities in such diverse fields as antibiotics, bacterial growth factors, hormones, smooth muscle stimulants and pain-producing subs tances have been isolated. Synthesis of such peptides has not kept up with structure determination largely because present methods are time-consuming and frequently give poor yields. 2 As p art of an investigation of synthetic methods, the work reported here was directed toward improvements of carboxyl-protecting groups. I t h as been found that t-butyl esters of amino acids and peptides have advantages over the customarily used methyl and ethyl esters. We will write a custom essay sample on Peptides and Their Use in Peptide Synthesis or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Specifically, they are much more stable as the free bases to self-condensation reactions (Table IV) and thus may usually be stored and used as such. This avoids the customary neutralization of hydrohalide alts with bases such as t riethylamine during a peptide synthesis, a complicating procedure which adds to the danger of racemization in sensitive cases a s ell. Â  P erhaps more important, the many side reactions of saponification of peptide csters2 can be avoided since the t-butyl group is readily removed by acid catalysis under mild conditions. In comparison to benzyl esters, t-butyl esters are much more readily removed by acid catalysis and are not affected by hydrogenation in the presence of palladium or platinum. T wo general procedures for the synthesis of a mino acid and peptide t-butyl esters have been nvestigated. I n b oth an amine-protecting group which was subsequently removed was used. In spite of the extra steps necessary it seems likely that the utility of t-butyl esters will make this worth while. T he first method entailed the reaction of silver salts of acylamino acids or acylpeptides with t-butyl iodide (example 1 in Experimental and Table I ). Although this is straightforward, the second method is simpler, gives better yields and is preferable for large-scale reactions. In the latter, acylamino acids or acylpeptides were treated with a large excess of isobutylene in the presence of sulfuric cid or p-toluenesulfonic acid as catalyst. The products were isolated by treatment with aqueous alkali (example 2 a nd Table I). The preferred amine-protecting group in this investigation was benzyloxycarbonyl (carbobenzoxy) but others were used (see experimental). T he benzyloxycarbonyl group was removed by hydrogenation and phosphite salts were prepared for purification and characterization. Since phosphorous acid is weak, danger of cleavage of t he t-butyl group was avoided (example 3 and Table 11). I n some cases, phosphite salts were not isolated, but were converted to the free bases (example 4 a nd Table 111). Several peptides were synthesized from amino acid t-butyl esters by the tetraethyl pyrophosphite, dicyclohexylcarbodiimide5and p-nitrophenyl ester6 procedures. Since commonly used amine-protecting groups have varying degrees of sensitivity to removal by acids, selective or simultaneous removal with t-butyl esters is possible. Thus refluxing with p-toluenesulfonic acid in benzene was used to remove selectively t-butyl esters in the presence of benzyloxycarbonyl or trifluoroacetyl groups (examples 6 a nd SB). A stronger acid, hydrogen bromide in glacial acetic acid, does not affect phthaloyl groups example 11) o r trifluoroacetyl g roups a t 10’ (example SA), but it will simultaneously remove benzyloxycarbonyl or t-butyloxycarbonyl groups along with t-butyl esters (example 15). T he trifluoroacetyl group c an be selectively removed from trifluoroacetylpeptide t-butyl esters ( 1) Presented in part a t the 133rd Meeting of t he American Chemical Society a t San Francisco, Calif. , April, 1 958. D uring preparation of t his manuscript, a brief note o n a mino acid 1-butyl esters appeared (R. . R oeske, C hetnislry I ndustry, S ept. 5 , 1 959). W ( 2) F or a recent review see h l. G oodman and G.