Further studies on the synthesis of symmetrical anhydrides and 2,4-disubstituted-5(4H)-oxazolones from N-alkoxycarbonylamino acids using soluble carbodiimide

Abstract

[err-butyl, trichlorocthyl, p-nitrobcnzyl, p-mcthoxybenzyl, and 9-fluorcnylmethyl, and N-ethoxycarbonylaminoisobutyric acid have been prepared using 0.5 equivalents of N-ethyl-N'-(3-dirncthylaminopropyl)carbodiimide hydrochloride in dichloromcthane followed by rcmoval of sideproducts by washing with aqueous solutions. When an excess of carbodiimidc was used. 2-alkoxy-5(4H)-oxazolonc was also generated. exccpt when R = trichloroethyl. High yields of pure 5(4H)-oxazolone wcre obtained when R = ethyl. Thc Chem. 62. 1335Chem. 62. (1984. On a prtparC les anhydrides symitriques purs de la N-alkoxycarbonyl (ROC0)-valinc (ou R = Cthyl, rerr-butyl, trichlorotthyl, p-nitrobenzyl, p-mCthoxybenzy1 et fluorenyl-9 mtthyl) et de I'acide N-Cthoxycarbonyl aminoisobutyrique en utilisant 0.5 tquivalents de chlorhydrate de N-tthyl, N'-(dimtthylamino-3 propy1)carbodiimide dans le dichloromtthane et en enlevant cnsuite les produits sccvndaires par lavage avec des solutions aqueuses. Lorsqu'on utilise un excks de carbodiimide, il y a aussi formation de I'alkoxy-2 (4H)-oxazolone-5 (sauf lorsque R = trichloroithyl). On a obtenu de bons rendements de la (4H)-oxazolonc-5 lorsquc R = Cthyl. La (fluorenyl-9 methyloxy)-2 (4H)-oxazolone-5 subit lentement une tlimination au cours des nlanipulations ou de I'entreposage.[Traduit par Ic journal]The solid phase method of peptide synthesis according to Merrifield ( 1 ) involves the carbodiimide-mediated reaction of i an N-alkoxycarbonylamino acid (1) with the amino group of a I polymer-supported peptide chain. The activated intermediates undergoing aminolysis are the 0-acylisourea (2) which is 1 formed initially, the symmetrical anhydride (3) produced by the reaction of 2 with 1 , and in some cases the 2-alkoxy-5(4H)-oxazolone (4) generated by cyclization of 2(2) or the reaction of carbodiimide with 3(3) (see refs. 4 and 5 for reviews). In the modified version, the symmetrical anyhrides are preformed by reaction of 1 with 0.5 equiv. of dicyclohexylcarbodiimide and used without isolation after removal of the dialkylurea by filtration (see ref. 4).Purified anhydrides 3 (R' = (CH,)?C) are available from the acid salt and phosgene (6). Their use to eliminate side-reactions has been recommended (7). Our realization that (Boc-Val),02 was resistant to aqueous washes (8) led us to develop a simple procedure for preparing anhydrides 3 using a soluble carbodiimide. Reaction of 1 with 0.5 equiv. of EDC in dichloromethane followed by washing the solution with aqueous acid and sodium hydrogen carbonate gave excellent yields of 3 (Rr = (CH3)3C and C6HSCH,) except for derivatives of valine and isoleucine (9). It transpired that-in the latter cases a second neutral product, the 2-alkoxy-5(4H)-oxazolone (4), was also 'On sabbatical leave, 198 1 -1982. Permanent address: Food Research Institute, Canada Department of Agr~culture, Ottawa, Ont , Canada KIA 0C6.'~hbrevlorions: Alb, am~norsobutyrrc acrd; Boc, rerr-butoxycarbonyl; Eoc, ethoxycarbonyl; Fmc. 9-fluorenylmethlyoxycarbonyl; Mbc, p-methoxybenzyloxycarbonyl...

Preparation of 2‐alkoxy‐4‐alkyl‐5(4H)‐oxazolones from mixed anhydrides of N‐alkoxycarbonylamino acids

“…The pure compounds for valine and isoleucine derivatives could be obtained from the parent acid and excess EDC (5). AlkOx's with R = other substituents were similarly obtained with varying degrees of difficulty (6). It has now become apparent that the common Abbreviations: Bzl, bcnzyl: Boc, tert-butoxycarbonyl; Fmoc, 9-fluorenylmethoxycarbonyl; 2, benzyloxycarbonyl; DCM, dichloromethanc; DMF, dimethylformamide; EDC.…”

Diisopropylethylamine eliminates dipeptide formation during the acylation of amino acids using benzoyl chloride and some alkyl chloroformates

“…Reference mixtures of 3a and 5a were prepared by reaction of 7a (11,12) with 2 in aqueous DMF (5). Separation and quantitation were done by hplc (C18-~Bondapak column, isocratic elution, uv absorbance monitoring at 208 nm, or 215 nm for aromatics) as previously described (5).…”

2-alkoxy-5(4H)-oxazolones and the enantiomerization ofN-alkoxycarbonylamino acids

“…It is rationalized on the basis that the oxazolone is slightly basic and that one molecule deprotonates the ~t h e r .~' Evidence for the validity of this hypothesis resides in the fact that a 2-( 9'-fluorenylmethoxy)-4-alkyl-5 (4H)-oxazolone decomposes to liberate dibenzofulvene on storage. 44 This results from a p elimination triggered by the same phenomenon except that a different proton is involved.…”