A-Methylamino acids

Transformation of the amino nitriles to the corresponding amino acids, with removal of the dioxane ring, is carried out in two steps. Treatment with concentrated hydrochloric acid results in the hydrolysis of both the nitrile and the acetal group, and in cyclization to the corresponding 3-substituted 5-hydroxyniethyl-3-methyl-2-oxo-6-phenylmorpholinc hydrochlorides. Oxidative cleavage with 2 N sodium hydroxide solution, air and Raney nickel at 120 CC (ca. 30 h) delivers the hydrochlorides of the free a-methylamino acids in high yield. 

This reaction has been used to prepare a-A-methylamino acids using (CH3)2BBr.191... 

The question was whether impurities were present in the samples analysed (Bada et al., 1983). In a more recent publication, Cronin and Pizzarello (1997) reported amino acid analyses using Murchison material in which an excess of L-enantiomers was present. Contamination with terrestrial biological material can be ruled out, as the amino acids in question are not proteinogenic a-methylamino acids, which occur either extremely seldom or not at all in terrestrial life forms, were detected. GLPC/mass spectrometry (MS) analysis gave the following enantiomeric excess (ee) values ... 

FIGURE 2.21 Experimental evidence indicates that products from BOP-mediated reactions do not originate from the benzotriazolyl ester. The use of BOP allows successful coupling of A-alkoxycarbonyl-A-methylamino acids, whereas the benzotriazolyl esters of these acids undergo aminolysis only with great difficulty. The higher ratio of products obtained from the BOP-mediated reaction in the competing reactions described implies a compound other than the benzotriazolyl ester as the precursor of the peptides. 

FIGURE 8.17 Preparation of Fmoc-A-methylamino acids by methylation of Fmoc-amino acids.90 Acid-catalyzed reaction of substrate with formaldehyde at elevated temperature with removal of water by azeotropic distillation produces the oxazolidinone, which is then opened and reduced to the A-methylated derivative. 

JR McDermott, NL Benoiton. A-Methylamino acids in peptide synthesis. IV. Race-mization and yields in peptide-bond formation. Can J Chem 51, 2562, 1973. 

For aromatic amino and hydrazino acids and several other structurally related compounds, the influence of MeOH content in both RP and POM was investigated on a teicoplanin CSP [90]. Using a hydroorganic mobile phase, complete enantiosep-arations of a-methylamino acids were not attained. However, this type of separation was suitable for the enantiomers of dopa. Further experiments performed by the same authors in POM allowed the complete enantioseparation of a-methyl-ooPA enantiomers [91]. 

Incorporation of an a-methylamino acid into a small model peptide is achieved usmg oxazolone methodology. a-Methylvaline (ocMe)VaI and a-methylphe-... 

Methylaluminum dichloride, 7 a-Methylamino acids, 192 Methyl a-arylacetates, 268 Methyl a-arylalkanoates, 471 a-Methylbenzylamine, 411 Methyl bis(methylthio)sulfonium hexachloroantimonate, 335-336 N-Methyl-N-(t-butyldimethylsilyl)acetamide, 336... 

Lakner FJ, Hager LP (1997) Chloroperoxidase-Mediated Asymmetric Epoxidation. Synthesis of (R)-Dimethyl 2-Methylaziridine-l,2-dicarboxylate - A Potential a-Methylamino Acid Synthon. Tetrahedron Asym 8 3547... 

On hydrolysis the alkylated bis-lactim ethers 8 yield (besides L-Ala-OCH3) the corresponding (R)-a-methylamino acid methyl esters 11. Their ee is 85% corresponding to the de of table 1 and taking into account 93 % ee of 6 9). 

In a variant (15) of the carbodiimide method, two moles of an A-alkoxycarbonylamino acid are reacted with one mole of DCC in dichloromethane (DCM). After 30 minutes, the DCU is removed by filtration and the solution is mixed with the aminolyzing component. The DCM is sometimes replaced with dimethylformamide (DMF) for the aminolysis step. SyAn formation is very slow in DMF. The method is wasteful of substrate but gives clean reactions. Some SyAn have been isolated and stored (16, 17), but the practice is no longer in vogue. SyAn are less reactive and hence more selective than OAIU they do not acylate hydroxy groups that have not been deprotonated. They are especially effective for acylating secondary amines such as A-methylamino-acid residues. 

Condensation of A-methyl or a,a-disubstituted amino acids is difficult. In the coupling of A-methylamino acids problems can occur with reaction times and yields when the amine component or both the amine and the acid components are N-methylated. In these cases OBt-based reagents such as BOP, PyBOP, HBPyU, or DCC/HOBt are often ineffective since... 

Advantages have been claimed for DPPCl and BOP-Cl ° in the condensation of A -methylamino acids, namely high yields and low racemization rates. For cyclization to cyclopeptides both DPP A and (5-nitropyridyl)diphenylphosphinate, to p-lactams NPTP ° and DMPC, ° have been applied. 

Homophthalic anhydrides in synthesis of heteroeycies 84KGS1587. Metallation as key step in heterocyclic synthesis 83S957. a-Methylamino acids—heterocyclic derivatives, synthesis of 85MI21. Polysubstituted heteroeycies in syntheses of bi- and polycyclic systems ... 

The phase transfer alkylation of Schiff bases has been extended to several other alkyl bromides as a route to new amino acids [24], and the enantioselectivities in these cases are comparable (50 to 70% ee) to those reported by O Donnell. In addition, the methodology has been used for the synthesis of a-methylamino acids, with ee s of about 50% [25]. Futher optimization using an 0-alkylated catalyst and a no solvent process with solid KOH/K2CO3 led to improved ee s of 70%... 

The abilities of various compounds to inhibit the specific histidine decarboxylase of rat hepatoma and the non-specific enzyme of guinea-pig kidney have been compared . Some of these results are given in Table 4.8. Of the a-methylamino acids tested, DL-a-methyI-5-HTP was the most potent inhibitor of the specific enzyme. Hydrazine was a strong inhibitor, and the various hydrazides were moderately effective. The 0-substituted hydroxylamines (XXII, XXIII, and XXIV) and the substituted hydrazine (XXV), which we have seen to be potent inhibitors of non-specific histidine decarboxylase, were similarly effective inhibitors of the specific enzyme. The potencies of these compounds may be due, at least in part, to their ability to react with pyridoxal phosphate. 

The chloro and bromo derivatives of phosphonium and uronium salts have not been extensively used in solid-phase strategy. Thus, chloro- and bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate [PyCloP (63) and PyBroP (64)1 [109] and bromotris(dimethylamino)-phosphonium hexafluorophosphate (65) (BroP) [110], which have been used with success in solution for the synthesis of peptides containing A-methylamino acids, have not been found to be effective in the solid-phase mode. The active species detected for PyCloP, PyBroP, and BroP in the absence of HOBt are the symmetrical anhydride, the 5(4JT)-oxazolone, and, for Boc-amino acids, the iV-carboxyanhydride [99]. Furthermore, 2-chloro-l,3-dimethyl-4,5-dihydro-117-imidazolium hexafluorophosphate (66) (CIP, DCIH) [107,108,111] has been found effective only in the presence of 1 equiv. of HO At. 

Another ruthenium catalyst, such as an Ru(t/ -arene)-A-perfluorosulfonyl-l, 2-diamine, was applied to the asymmetric transfer hydrogenation of jS-keto-a-methylamino acid esters, affording /l-(3,4-dimethoxyphenyl)serine methyl esters as shown in Scheme 2.11 °... 

Scheme 2.11 Transfer hydrogenation of -keto-a-methylamino acid esters.

X-Methylamino acids. a-Methylamino acids are very important as specific enzyme inhibitors. Furthermore, they can be directly inserted into numerous biologically active peptides to modify their range of activity. 

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