Dipeptides methylation

A reversal of the 5 4H) 5 2H) equilibrium was established by demonstrating the presence of 4-isopropyl-2-trifluoromethyl-5(2fl )-oxazolone as an intermediate in the reaction of A-TFA-l-valine with the methyl ester of L-valine [Eq. (35)] using gas chromatography. The resulting product is a mixture of 74% l,l- and 26% d,l-A-TFA dipeptide methyl ester (see Section II, B, 4). 

Several prenylated dipeptide methyl esters undergo rapid diketopiperazine formation upon N-terminal... 

Cyclization of free dipeptide methyl esters, liberated from the corresponding amine salts, by the action of... 

Hydrogenolysis of benzyloxycarbonyl dipeptide methyl esters in methanol over palladium or charcoal catalyst. - "... 

The earliest method for such a cyclization was that of Fischer, which involves the action of excess ammonia on dipeptide methyl esters (06CB2893). However, this method is known to lead to a considerable amount of racemization. 

To a stirred soln of isatoic anydride (12) or JV-methylisatoic anhydride (28.8 mmol) and DMAP (0.48 g, 3.93 mmol) in dry DMF (25 mL), the dipeptide methyl ester hydrochloride (32.0 mmol) and NMM (3.23 g, 32.0 mmol) in dry DMF (25 mL) were added at 0°C under N2. After 2h at 0°C and 15 h at 5°C, the mixture was partitioned between EtOAc and H20 and the organic layer washed with brine. Drying and evaporation afforded a residue which was purified by column chromatography (silica gel, CHQ3/ Et20 9 1). 

The amino acid or dipeptide methyl (ethyl) ester hydrochloride (5.0 g) and diphenylketimine (1 equiv) were stirred in CH2CI2 (100 mL) at rt for 18-24 h under exclusion of moisture. The mixture was filtered to remove NH4CI, and the filtrate was washed with H2O (4 x 100 mL), brine (50 mL), and dried. The solvent was removed and the resulting solid was recrystallized from an appropriate solvent. For example Ph2CH>Gly-Gly-OEt (recrystallized from EtOH) yield 91% mp 123-124°C Ph2CH>Gly-D-Phe-OMe (recrystallized from EtOH) yield 92% mp 90-92 °C. 

Sterically pure piperazinediones have been prepared from formate salts of dipeptide methyl esters (1622). The conformation of piperazine-2,5-diones has been reviewed (1623). 

Chemical/Pharmaceutical/Other Class Dipeptide methyl ester... 

Kano, K. Hasegawa, H. Miyamura, M. Chiral recognition of dipeptide methyl esters by anionic P-cyclodextrin. Chirality 2001, 13, 474-482. 

The classification accuracy for 86 pentafluoropropionyl dipeptide methyl esters was 100 % in the N-position and 97 % in the C-position. 

Phenlyalanine and L-aspartic acid are amino acids. When they bond together, the corresponding dipeptide methyl ester is aspartame, known by the brand name Nutra-Sweet or Equal. Production of both amino acids can be accomplished via fermentation of genetically altered bacteria. Production rates of 1,000 and 1,250 tonnes/yr of L-aspartic acid and L-phenylalanine are desired. 

The corresponding sulfonylamino acid methyl esters 518 were prepared by treatment of the sulfonylamino acids 517 with absolute methanol-pure thionyl chloride at low temperature (—5 °C to —10 °C). The esters 518, by hydrazinolysis with hydrazine hydrate, afforded the hydrazides 519. The sulfonylamino acids 517 were coupled with the appropriate amino acid methyl ester hydrochloride in THF-water-triethylamine mixture using DCC as the coupling reagent to yield the corresponding sulfonylamino dipeptide methyl esters 520 (Scheme 16). The synthetic sequence depicted in Scheme 16 has been successfully applied to a number of different aromatic sulfonyl chlorides as illustrated by the following examples. 

Some novel cinnamoyImorpholine-4-sulfonylamino acids were similarly prepared starting from cinnamoylmorpholine-/ -sulfonyl chloride 524 (prepared by chlorosulfonation of cinnamoylmorpholine as described in ref. 286). The sulfonyl chloride 524 was used to obtain the corresponding cinnamoylmorpholine sulfonylamino acids, methyl esters, hydrazides and the dipeptide methyl esters. ... 

Thiophene-2-carboxanilide and its /7-chloro and p-bromo derivatives reacted smoothly with excess chlorosulfonic acid (six equivalents) at 40 C to yield the corresponding sulfonyl chlorides 526-528. The thiophene sulfonyl chlorides were used to prepare the corresponding sulfonylamino acids, methyl esters and hydrazides. The sulfonylamino acids were also coupled with the appropriate amino acid methyl esters to form the sulfonamino dipeptide methyl esters. ... 

The sulfonyl chloride (18) was condensed with amino acids to yield the corresponding A-(benzyIidinehydantoin sulfonyl) amino acids (19) and these were then converted into the dipeptide methyl esters using DCC (Chapter 4, Section 12.18). 

Various dipeptide methyl esters starting from free acyl donor and amino acid methyl ester as nucleophile in methanol [21]... 

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