Reaction of N-benzyloxycarbonyl derivatives of aliphatic amino acids, and threonine, aspartic, and glutamic acids whose side-chains were protected with the t-butyl group, gave the corresponding Nmethylamino acid derivatives in good yields. The methionine derivative could be obtained by using only one mol of methyl iodide. Derivatives of threonine, and aspartic and glutamic acids whose side-chains were not protected could not be methylated. Analysis of the crude products of methylation in three cases showed that they contained 0-1% of racemized material.La rCaction des dCrivCs N-benzyloxycarbonyle d'acides aminis aliphatiques, de la thrConine, et des acides aspartique et glutamique dont les chaines IatCrales furent bloqukes avec le groupe I-butyle, a conduit aux dCrivCs N-mCthylCs correspondants des acides aminks avec d'excellents rendements. Le derivC de la mCthionine a pu &tre obtenu en utilisant seulement une mole d'iodure de mCthyle. Les dCrivCs de la thrtonine et des acides aspartique et glutamique dont les chaines IatCrales ne sont pas protCgCes, n'ont pu ittre methyles. L'analyse des produits bruts de la mkthylation a montrC que dans trois cas, ceux-ci contenaient de 0 a 1% de produits racemisis.[Traduit par le journal]Can.

The preparation of enantiomerically pure N-tert-butyloxycarbonyl,N-methylamino acids by N-methylation of the parent amino acid derivatives using sodium hydride and methyl iodide in tetrahydrofuran at room temperature is described for neutral amino acids including O-benzyl-protected threonine and tyrosine. Methylation of the O-benzylserine derivative under these conditions gives the N-methyldehydroalanine derivative. The β-elimination is completely suppressed, giving the corresponding N-methylserine derivative when the reaction is carried out at 5 °C. Other related data on N-methylation and N-methylamino acid derivatives are presented.

No abstract

Methyl iodide and potassium bicarbonate in methanol is presented as a mild, efficient, and selective reagent for the quaternization of amino groups. It does not attack hydroxyl groups. Its use with amino acids, derivatives of lysine, and small peptides is described.

. Can. J. Chem. 65, 619 (1 987).Pure mixed anhydrides R10CO-Xxx-O-COO~2 (Xxx = NHCHRCO) have been obtained by reaction of N-alkoxycarbonylamino acids RIOCO-Xxx-OH with alkyl chloroformate R 2 0~0 C 1 (R2 = methyl, ethyl, isobutyl, menthyl) in the presence of N-methylmorpholine or N-methylpiperidine (NMP) in dichloromethane at -YC, followed by washing the mixtures with aqueous solutions and removal of the solvent. R'OCO-XXX-0-COOR~ (R2 = ethyl, tert-butyl) have been obtained by reaction of R'OCO-XXX-0-.+ HNMP with the corresponding dialkyl dicarbonates followed by the same work-up. Mixed anhydride generation is much slower when triethylamine is used as base. The initial reaction in the decomposition ofmixed anhydrides is cyclization to the 2-alkoxy-5(4H)-oxazolone (R1O-oxazolone) followed by release of alcohol R~O H .Symmetrical anhydride ( R ' O C O -X X X )~~ and ester R'OCO-Xxx-OR2 are also formed. The ease of cyclization depends on R2, and is in the order methylsulfonylethyl (Ms) >> methyl/ethyl/isobutyl >> menthyl. RIOCO-Xxx-0-COOMS preparations contained a substantial amount of R1O-oxazolone. Attempts to use this reaction as a preparative procedure for obtaining RIO-oxazolones failed because they are too sensitive to hydrolysis and react too quickly with the product, forming the symmetrical anhydride. The effect of various parameters on the amount of urethane generated by aminolysis at the carbonate moiety of R'OCO-Xxx-0-COOR~ was examined without the uncertainty that any urethane arose from arninolysis of unconsumed chloroformate.

The racemization of an N-methylamino-acid residue during peptide-bond formationand mixed-anhydride activation has been investigated using Ala-MeLeu-Gly and Ala-MeLeu as model peptides. The results were compared with those for Ala-Leu-Gly, Ala-Leu, and Ala-Pro. The extents of racemization were determined by analysis of the diastereomeric products of the reactions after deprotection, using an amino-acid analyzer. Extensive racemization was detected after the hydrolysis of the mixed anhydrides of Bz-MeLeu, Z-Ala-MeLeu, and Z-Ala-Leu, but not of Boc-Ala-Pro and Z-MeIle. Significant racemization (2.8-39%) was observed when Z-Ala-MeLeu was coupled with Gly-OBzl by various methods in the presence of salts such a s triethylamine hydrochloride orp-toluenesulfonate. Only coupling through the N-hydroxysuccinimide (HONSu) ester gave stereochemically pure product. In the absence of salt, less racemization was observed, but only couplings using N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline and N,N1-dicyclohexylcarbodiimide-HONSu gave essentially pure products. Polar solvents promoted racemization, but excess base did not. Chemical evidence that the racemization intermediate is an oxazolium-5-oxide has been obtained by trapping the intermediate a s an addition product (a pyrrole) in 85% yield.The yields obtained by various coupling methods have been determined for several model peptides. Couplings at the carboxyl group of an N-methylamino acid gave high yields only in the absence of salt, except for coupling by the HONSu ester method. Couplings to an N-methylamino group gave high yields, except for coupling by thep-nitrophenyl ester method. Couplings to Ala-MeLeu-OBu' gave higher yields than couplings to Ala-MeLeu-OBzl, presumably due to piperazine-dione formation by the latter. Une racemisation importante a CtC dCtectte apres hydrolyse des anhydrides mixtes de Bz-MeLeu, Z-Ala-MeLeu et Z-Ala-Leu mais pas pour Boc-Ala-Pro e t Z-MeIle. Une racemisation notables (2.b39%) a etC observCe lors du couplage du Z-Ala-MeLeu sur le Gly-OBzl par les diverses mithodes en prisence de sels tels que le chlorohydrate ou para toluene sulfonate de triethylamine. Seul le couplage par I'ester d e La N-hydroxy succinimide (HONSu) conduit 2 un produit d e puretC sttreochimique. En l'absence de sel, la racemisation est plus faible mais seuls les couplages par le NCthoxycarbonyl Cthoxy-2 dihydro-1,2 quinoleine et le complexe N,N'-dicyclohexylcarbodiimide-HONSu donnent des produits essentiellement purs. Les solvants polaires favorisent la racCmisation mais pas un exces d e base. L'intermCdiaire de racemisation oxyde-5 d'oxazolium a it6 rnis en evidence par piegeage sous forme de produits d'addition (un pyrrole) avec un rendement de 85%.Les rendements obtenus dans les divers couplages ont ete dCterminCs sur differents peptides modeles.

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,...

The racemization of N-methylamino-acid derivatives in aqueous sodium hydroxide and hydrogen bromide in anhydrous acetic acid and other solvents has been investigated by determining the products of the reaction with an amino-acid analyzer after deprotection. Whereas MeIle-OMe, Z-MeIle, and the N-unmethylated derivatives were only slightly racemized (<2%), 2-MeIle-OMe (18-24%), Z-AlaMeLeu-OMe (22%), and 2-Ala-MeLeu-OBuf (7%) were appreciably racemized by aqueous sodium hydroxide. It is suggested that these derivatives racemize because of the absence of an >N-H or carboxyl group whose ionization would suppress ionization of the neighboring wC-H bond. Z-MeIle and ZAla-MeLeu were substantially racemized (68% in 4 h and 34% in I h, respectively) by 5.6 N hydrogen bromide in acetic acid. The extent of racemization by acid varied with acid strength, polarity of solvent, and time. Incorporation of label into both isomers of Ala-MeLeu from a solution of the tritiated reagent established that ionization at the wC-H bond had occurred. No racemization was caused by aqueous acid or by hydrogen chloride. Can.