A-methyl valine

Sandra Pizzarello and her team were the first to publish that carbonaceous chon-dritic meteorites contain distinct a-methylated amino acids in low ee (Cronin and Pizzarello 1997 Pizzarello 2006 Pizzarello et al. 2008). As confirmed independently, the Murchison meteorite contained the following nonproteinogenic amino acids in ee 15.2% L-isovaline, 2.8% L-a-methyl-norvaline, 2.8% L-a-methyl-valine, and 9.1% L-a-methyl-isoleucine (Cronin and Pizzarello 1997). As an example, Fig. 3.2 shows the structure of L-a-methyl-norvaline. 

Starting from the identification of chiral amino acids found in meteorites, a partial transfer to other biomolecules of low ee succeeded (Breslow et al. 2010 and references of Breslow cited therein). Under solvent-free conditions followed by evaporation and heating, D-a-methyl-valine reacted with pyruvate to form D-a-alanine with a relatively low ee of 3% by way of transamination. Higher enantioselectivity was observed with sodium phenyl-pyruvate. In this reaction, the D-a-methyl-valine plays two roles. It carries out the transamination that converts the keto-acid to an amino acid, while becoming a ketone after hydrolysis. Secondly, it is the source of a proton on the alpha carbon atom of the amino acid product, delivering it stereoselectively (Breslow et al. 2010). 

In the same year, KoCovsky et al. published their very powerful activator Sigamide A 4. Instead of proline, they used A-methyl valine derived Lewis bases as activators. After intensive catalyst screening, it mrned out that the N-methylation is as crucial as converting the valine carboxyl terminus into a bulky, aromatic secondary amide. The 3,5-di-tcrt-butylphenyl moiety showed excellent results in terms of yield (95%) and selectivity (94% ee). A wide... 

The biosynthesis of erythroskyrin was investigated by Shibata et al. (1966), who established the distribution of in the molecule which was obtained by cultivation of the mold on Czapek-Dox media containing various "Relabeled substrates. The degradation reactions which were carried out on the labeled erythroskyrin are summarized in Fig. 1 (10-12). Erythroskyrin containing the label from added DL-[l-R"RC]valine was decomposed into A-methylvaline (10) by ozonolysis. The product was converted into its N-(2,4-dinitrophenyl) derivative, which was decomposed photochemically into isobutanal (11). The 2,4-dinitrophenylhydrazone derivative of the aldehyde contained no radioactivity, while the A-(2,4-dinitrophenyl)-A-methyl-valine contained 79% of the activity of the erythroskyrin. The result showed that [l-R"RC]valine was incorporated (essentially) intact into the lactam portion of erythroskyrin, with the radioactivity located mainly at C(4). 

In an attempt to learn more about its properties, the L-aminoamidase from M. neoaurum ATCC 25795, which was responsible for the enantioselective resolution of DL-a-methyl-valine amide, has been purified and characterized [1,49]. The purification procedure included ammonium sulfate fractionation, Superdex 200 gel filtration, and Mono Q anion exchange chromatography. By this procedure, the L-aminoamidase can be purified from the crude extract approximately 280-fold and with a 10% yield. The obtained enzyme preparation is homogeneous as judged by SDS-PAGE. 

CN stereoisomer of /V,iV-[(2-amino-4,6-dimethyl-3-oxo-377-phenoxazine-l,9-diyl)bis[carbonylimino[2-( 1 -hydroxyethyl)-1 -oxo-2,1 -ethanediyl]imino[2-( 1 -methylethyl)-1 -oxo-2,1 -ethanediy 1]-1,2-pyrrolidinediylcarbonyl(methylimino)(l-oxo-2,l-ethanediyl)]]bis[A/-methyl-L-valine] di- -lactone... 

Cyclosporin A contains II amino acids, joined in a cyclic strncture by peptide bonds. The structure is also stabilized by intramolecular hydrogen bonds. Only two of the amino acids, i.e. alanine and valine, are typical of proteins. The compound contains several A-methylated amino acid residues, together with the even less common L-a-aminobutyric acid and an Ai-methylated butenylmethylthreonine. There is one o-amino acid, i.e. o-alanine, and the assembly of the polypeptide chain is known to start from this residue. Many of the other natural cyclosporin structures differ only with respect to a single amino acid (the a-aminobutyric acid residue) or the number of amino acids that have the extra Ai-methyl group. 

Later, Maikov and Kocovsky reported the asymmetric reduction of imines with A -methyl L-valine derivative 37 with high yield and enantioselectivity (Scheme 29) [103]. 

The bisthieno[2,3-c 3, 2 -/]azocine 157 containing a bicyclic azocine fragment has been obtained for the first time by cyclization of A/ ,N -bis-(thienyl-2-methyl)valine ester 156 with organolithium compounds (Scheme 42). Compound 156 has been formed by the alkylation of valine ester with thienylmethylbromide in acetonitrile in the presence of potash (98SL1355). 

The disadvantage in using such symmetrical bislactim ethers is that half the chiral auxiliary ends up as part of the product molecule thus only half of the auxiliary can be recovered and reused. This drawback is avoided in the mixed bislactim ether prepared from a chiral auxiliary (L-valine) and a racemic amino acid (e.g., DL-alanine). Regiospecific deprotonation followed by diastereoselective alkylation leads to the required a-methyl amino acid ester (193) (83T2085) the de is >95%. In this method, the chiral auxiliary (L-valine) is recovered intact. (Scheme 59). 

XXVII Inden BFj-Atherat + optiscli aktive Co-katalysatorcn (1-a-Methyl-benzyl-alkohol, Tosyl-L-Valin, Campher) in n-Hexan odcr CHClj bei 0° bzw. -SO C disyndiotaktisch (84,104)... 

Two molecules of pyruvate can react to give a common precursor to valine, leucine, and pantoic acid. An isomerization step involving shift of a methyl group from one carbon to another is involved. 

Table 1.2. CHEMICAL STRUCTURES OF CYCLOSPORINS A-Z Bmt = (2S, 3R, 4R, 6 -2-amino-3-hydroxy-4-methyl-6-octenoic acid (= (4R)-4-(( )-2-butenyl)-4-methyI-L-threonine) Abu = L-a-aminobuty-ric acid Nva = L-norvaline MeVal = V-methyl-L-valine MeLeu = A -methyl-L-leucine. 

Enniatin A R = A/-methyl-L-isoleucine Enniatin B R = A/-methyl-L-valine Enniatin C R = A/-methyl-L-leucine Baeuvericin R = /V-methyl-L-phenylalanine... 

Peters et al. reported on rod-CEC on a chiral monolith [50] which was prepared by copolymerization of the chiral monomer 2-hydroxyethyl methacrylate (A -L-valine-3,5-dimethylanilide) carbamate with ethylene dimethylacrylate, 2-acrylamido-2-methyl-l-propanesulfonic acid and butyl or glycidyl methacrylate in the presence of a porogenic solvent. The electrochromatographic enantiomer separation of 7V-(3,5-dinitrobenzoyl)leucine diallylamide was feasible at 25 kV the inlet and outlet buffer vials were both pressurized. 

Of course, the (3S)-compounds would also be formed if D-valine would be employed as chiral auxiliary. Hence, this method with valine as chiral auxiliary reagent solves the problem of enantioselective synthesis of a-methyl amino acids satisfactorily. Probably it can also be used — mutatis mutandis — for the asymmetric synthesis of a variety of a-alkyl amino acids, provided, the corresponding bis-lactim ether (type I) with valine as C-6 is regiospecifically metallated by butyl-lithium. This, for instance, is not be case with the mixed bis-lactim ether (20c) of cyclo(L-Leu-D,L-Ala)17). 

Amino-4,6-dimethyl-3-oxo-3//-phenoxazine-l,9-dicarboxylic acid also named actinocin is the chromophor of the red antineoplastic chromopeptide actinomycin D (formula A). Two cyclopenta-peptide lactone rings (amino acids L-threonine, D-valine, L-proline, sarcosine, and A-methyl-L-valine) are attached to the carboxy carbons of actinocin by two amide bonds involving the amino groups of threonine. 

A fruitful approach to obtain asymmetric polymer synthesis was proposed by Overberger (126) who suggested that propagation could be influenced and optically active polymers could be synthesized by using optically active gegen-ions. Schmidt and Schuerch (127) followed up this suggestion and used boron trifluoride in conjunction with asymmetric Lewis bases (1-a-methyl benzyl alcohol, tosyl L-valine, camphor) to polymerize certain cyclic olefins. However, in spite of careful work and various modifications in reaction conditions, no optical activity was obtained in the polymers in this first attempt to test this ingenious hypothesis. 

Subsequently, shallow water collections of Lyngbya majuscula from Puerto Rico and the Dry Tortugas yielded additional supplies of ATX as well as a new congener termed antillatoxin B (Figure 6.10) [149]. The structure of the new metabolite was determined largely by comparison with the spectroscopic data set for ATX, and stereochemistry deduced by Marfey s analysis for L-alanine while the i-N-methyl homophenylalanine was proposed based on nuclear Overhauser effect (nOe) and bioassay results. Substitution of i-N-methyl homo-phenylalanine, an intriguing amino acid of quite rare occurrence in natural products, for i-N-methyl valine... 

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