This paper is dedicated to Prof. Raymond U. Lemieux on the occasion of his 60th birthday N. LEOBENOITON and FRANCIS M. F. CHEN. Can. J. Chem. 59,384(1981). Reaction of N-ethyl,N1-(y-dimethylaminopropy1)-carbodiimide HC1 with one equiv. of N-tert-butoxycarbonyl-L-valine (3a) in dichloromethane at 23' C gives, besides the symmetrical anhydride (5a), the optically pure 2-tert-butoxy-4-isopropyl-5(4N)-oxazolone (40) which can be obtained in 50% yield under selected conditions. The 2-benzyloxycarbonyl-4-isopropyl-5(4N)-oxazolone (46) is similarly obtainable from N-benzyloxycarbonyl-L-valine (36). Anhydrous acid converts 4a to the oxazolidinedione. Simple preparations of the N-carboxyanhydrides of valine and isoleucine have been devised from these reactions. Compound 4 reacts with 3 to give 5. Compound 4 reacts with an amino acid ester to give the optically pure peptide even in the presence of salts, but partial racemization occurs for reactions in the presence of a tertiary amine. Evidence for the implication of 2-alkoxy-5(4N)-oxazolones in the couplings of N-alkoxycarbonylamino acids is presented. Compound 4a has been isolated in 6-11% yield from carbodiimide-mediated reactions of 3a with itself or amino acid methyl esters which have been terminated before completion. Chem. 59,384(1981). La reaction du chlorohydrate de N-Cthyl,N1(y-dimethylaminopropyl)carbodiimide avec un equivalent de N-tertbutoxycarbonyl-L-valine (3a) dans le dichloromethane a 23°C donne en plus de I'anhydride symCtrique (5a), le compost tertbutoxy-2 isopropyl-4 (4H)oxazolone-5 (4a) que I'on peut obtenir dans des conditions choisies avec un rendement de 50%. D'une f a~o n analogue, on obtient le benzyloxycarbonyl-2 isopropyl-4 (4H)oxazolone-5 (46) a partir de la N-benzyloxycarbonyl-L-valine (36). L'acide anhydre transforme le compose 4a en oxazolidinedione. A partir de ces reactions, on a mis au point des preparations simples de N-carboxyanhydrides de la valine et de I'isoleucine. Le compose 4 reagit avec 3et donne le compose 5. Leproduit 4 reagit avec un ester d'acide amine pour conduire au peptide optimiquement pur mtme en presence de sels, mais il se produit une racemisation partielle au cours des reactions conduites en presence d'une amine tertiaire. On presente la preuve de I'implication des alkoxy-2 (4H)oxazolones-5 dans les couplages des acides amines N-alkoxycarbonyles. On a isole le compose 4a partir des reactions d'autocondensation du compose 3a ou de sa condentation sur les esters methyliques d'acides amines en presence de carbodiimide qui s'arrttent avant d'avoir totalement reagi.[Traduit par le journal]When an acylamino acid or a protected peptide (1) is coupled with a nucleophile (amine or phenol), racemization frequently occurs. The change in stereochemistry is the result of the formation of the 2-alkyl-5(4H)-oxazolone (2) by cyclization of the activated N-substituted amino acid moiety. Compound 2 racemizes faster than it couples with the nucleophile. However, no racemization occurs when an N-alkoxycarbonylamino acid (3) is coupled,...

[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...