C“ “-Dialkylated amino acids

Although their suitability for peptide synthesis has been demonstrated,Boc amino acid fluorides have not yet found widespread application in polypeptide synthesis. Conversely, Z-amino acid fluorides have been used in the solution synthesis of stericaUy demanding peptides consisting solely of C -dialkylated amino acids, such as Z-[Val(aMe)]g-OtBuP l and Z-Iva-Val(aMe)-Iva-Val(aMe)-MePhe-Val(aMe)-Iva-NHMe.P3]... 

For two transaminases the remaining unknown stereochemical parameter was determined by demonstrating an internal transfer of tritium (dialkyl amino acid transaminase) [28] or deuterium (pyridoxamine-pyruvate transaminase) [27] from the a-position of the substrate L-alanine to C-4 of the cofactor. Internal hydrogen transfer from the a-position of the substrate amino acid to C-4 of PLP has also been demonstrated for two of the abortive transamination reactions, those catalyzed by tryptophan synthase fi2 protein [32] and by aspartate-/8-decarboxylase [31]. In addition, the same phenomenon must occur in alanine transaminase, as deduced from the observation that the enzyme catalyzes exchange of the /8-hydrogens of... 

Peptaibols are small, linear neurotoxic peptides, of molecular weight between 500 and 2200 Da. They are present in diverse species of filamentous fungi of terrestrial or marine origin, principally of the genus Trichoderma. They are characterized by the presence of original a,a-dialkylated amino acids such as a-aminoisobutyric acid (Aib) and isovaline (Iva) and by a C-terminal amino alcohol residue. Peptaibols are biosynthesized through a non-ribosomal... 

In contrast to their acyclic counterparts, Boc-BMl (195) and Schollkopf s lactim ether (196) are useful for the preparation of labeled a,a-dialkylated amino acids of high enantiomeric purity. This is exemplified by the preparation of (S)-a-methyl-p-chloro-[j8-"C]phenylalanine of >98% e.e. (Figure 11.72) " . 

Mildly basic liquiddiquid conditions with a stoichiometric amount of catalyst prevent hydrolysis during alkylation [101] and, more recently, it has been established that solid-liquid or microwave promoted reactions of dry materials are more effective for monoalkylation [102-106] of the esters and also permits dialkylation without hydrolysis. Soliddiquid phase-transfer catalytic conditions using potassium f-butoxide have been used successfully for the C-alkylation of diethyl acetamido-malonate and provides a convenient route to a-amino acids [105, 107] use of potassium hydroxide results in the trans-esterification of the malonate, resulting from hydrolysis followed by O-alkylation. The rate of C-alkylation of malonic esters under soliddiquid phase-transfer catalytic conditions may be enhanced by the addition of 18-crown-6 to the system. The overall rate is greater than the sum of the individual rates observed for the ammonium salt or the crown ether [108]. 

Various diastereomeric di-, tri-, and tetrapeptides that carry the sterically demanding trifluoromethyl group instead of the natural a-proton at different positions within these short peptide sequences have been designed, and their stability towards enzymatic hydrolysis has been investigated. The structures of the a-trifluoromethyl (aTfm)-substituted amino acids are shown in Scheme 1. From these studies we gained valuable information on how a-trifluoromethyl-substi-tuted peptides may interact with proteins. The aTfm amino acids used in this study combine the conformational restrictions [49-52] of C -dialkylation with the unique stereoelectronic properties of the fluorine atom and have shown interesting effects on peptide-enzyme interactions [53,54]. 

With the support of quantum mechanics this proteolysis study has readily shown that fluorinated amino acid side chains are able to direct enzyme substrate interactions, which can have an influence on proteolytic stability. Depending on the absolute stereochemistry and on the position within the sequence, aTfm amino acids can considerably stabilize peptides against proteolysis. The unique electrostatic properties of carbon-bound fluorine, however, may also induce a contrary effect. The conformational restrictions of C -dialkylation seem to be partly dimin-ishable by the electrostatic consequences of fluorination. With this knowledge. 

The thermal cycloaddition of 3-acyl-2(3/7)-oxazolones 157 to dialkyl azodicar-boxylates 228 proceeds smoothly under mild conditions (at 80 °C) to give the regiocontrolled cycloadducts 229 exclusively, although two other possible addition modes exist neither diazetidines 230 (1,2-addition) nor isoxazolidines 231 (1,3-addition) are detected. In the case of chiral N-substituents diastereoselectivities of up to 72% de have been obtained. Treatment of the chiral cycloadducts 229 with acidic methanol gives tra i-5-hydrazino-4-methoxy-2-oxazolidmone derivatives 232 that are precursors for a variety of optically active a-amino acids 233 and 2-oxazolidinone auxiliaries 234 (Fig. 5.56 Table 5.10, Fig. 5.57)7 ... 

Alkylation of saturated 5(4//)-oxazolones at C-4 is a well-known reaction that can be achieved under a wide variety of conditions. Numerous articles have described this reaction as a means to prepare 4,4-dialkyl-5(477)-oxazolones 147 that are valuable intermediates to prepare ot,ot-disubstituted a-amino acids. For instance,2-phenyl-5(4//)-oxazolone 146 readily obtained from hippuric acid and A,A -dicyclohexylcarbodiimide (DCC), is alkylated at C-4 with allyl, benzyl, or phenacyl halides if the reaction is conducted in dipolar aprotic solvents in the presence of weak bases. Hydrolysis of the resulting 5(477)-oxazolones leads to a,a-dialkylglycines 148 (Scheme 7.43). 

The oxazol-5(4//)-one coupling method (Scheme 4) is uniquely appropriate for C -tetra-substituted a-amino acids, since racemization or epimerization is unlikely to occur with these compounds. It represents the main methodology exploitable for fragment condensation of peptides based on C -tetrasubstituted a-amino acids. Due to the gem-dialkyl effect on the C°... 

A small discrete hbrary L15 explored the replacement of the amino indane scaffold with aromatic, mono- and dialkylated linear or cychc amino acids. Even small modifications were found to destroy the activity (9.44-9.46, Fig. 9.21). Only the amino tetralone replacement (9.47) afforded a weakly active compound (Fig. 9.21). Finally, a three-member discrete set of substituted amino indane-based compounds 9.52a-c... 

Racemic or achiral a-azido acids are synthesized by direct azide substitution on commercially available a-bromo carboxylic acids or by radical bromination of carboxylic acids followed by azide substitution. In general, azido acids are stored in the dark to avoid photolytic degradation with loss of nitrogen temperatures above 50 °C should be avoided. Radical a-bromination of a-branched carboxylic acids as required for the synthesis of a,a-dialkyl or a,a-diaryl amino acids is performed with A-bromosuccinimide. This is followed by nucleophilic substitution with sodium azide or other azide donors, e.g. tetrabutylannmonium azide, to produce achiral or racemic a-azido-a,a-diaIkyl or a-azido-a,a-diaryl carboxylic acids (Scheme 74).Synthesis of more sterically hindered a,a-disubstituted azido acids leads to hydroxy compounds when prolonged reaction times are required and not sufficient care is taken to operate under dry conditions and an inert atmosphere.t ... 

In view of the observation that A-o-nitrophenyl derivatives of glycine and other a-amino acids could be converted into benzimidazolones by the action of heat, and the assumption that iV-oxides were intermediates in the thermolysis [156], it was thought tliat flash vacuum pyrolysis with a very short reaction time might allow isolation of the IV-oxides. This approach, however, did not turn out to be as synthetically efficient as the base treatment method [97]. Indeed, heating such compounds in sand at 200° C is probably of more use for making benzimidazoles or benzimidazolones [156]. Benzimidazole iV-oxides can be made from acid-catalysed thermal or photochemical reactions of AyV-dialkyl-o-nitroanilincs, but not from purely thermal reactions. 

Dialkyl-l-(te/ t-butylamino)cyclopropanecarbonitriles5 are suitable substrates for the synthesis of c/M-dialkylated analogs 6 of the plant growth regulator 1-aminocyclopropanecar-boxylic acid. These strained a-amino acids 6 were formed by treatment with acid which resulted in hydrolysis of the nitrile moiety and, in addition, dealkylation of the amino group. 

Another route to a)-amino-a)-(hydroxycarbonyl)alkylphosphonic acids involves the intermediacy of ethyl oc-azidoacetate. Addition of MeONa in MeOH to a solution of dialkyl 4-formylben-zylphosphonate and ethyl cx-azidoacetate in MeOH at -30°C provides Ihe vinyl azide. Subsequent hydrogenation with 10% Pd/C in MeOH gives the aminoester, which, at reflux with 3 M HCl, delivers the free amino acid (Scheme 8.77). °... 

Many ring-fused imidazole derivatives have been synthesized by various methods. Domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates provided a synthesis of 2,3-dihydroimidazo[l,2-a]pyrimidin-5-(l//)-ones <05T5303>. A single step synthesis of 3,5-dialkyl-9-nitroimidazo[l,2-c]quinazolin-2(3//)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitrobenzonitrile has been published <05TL5778>. Diels-Alder reaction of azadienes and benzimidazole-4,7-diones afforded imidazo[4,5-g ]quinoline-4,9-dione derivatives <05EJ01903>. Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 4,5-diphenyl-l,3-dihydro-2//-imidazol-2-one provided a one-pot synthesis of 5//-imidazo[2,l-ft][l,3]oxazine derivatives <05T2645>. Microwave irradiation was employed in the synthesis of 1-ary 1-3-acetyl-1,4,5,6-... 

Dialkylamino acids, C -dialkylamino acids, amino acids bearing two alkyl substituents at the a-carbon atom. Examples are the naturally occurring amino acids diethylglycine (Deg), a-aminoisobutyric acid (Aib), or isovaline (Iva, 2-amino-2-methylbutyric acid). Such amino acids are often incorporated into peptides to study the conformational requirements of receptors, and are used as building blocks for the stabilization of short peptides in a well-defined conformation, depending on the nature of the two substituents attached to the C -carbon. 3io-Hdices are stabilized by the incorporation of Aib and other C -dialkyl-substituted building blocks [P. Balaram, T. S. Sudha, Int.J. Pept. Protein Res. 1983, 21, 381 I. L. Karle, Biopolymers 1996, 40,157 B. Pispisa et al.. Biopolymers 2000, 53,169]. 

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