With a-Amino Acids

Although it is reported that the U-5C-4CR can work well with nucleophiles other than methanol, such as primary or secondary amines, the only examples reported in the literature are those where trifunctional a-aminoacids such as lysine [67] or homoserine [66] or bifunctional aldehydes such as glycolaldehyde [65] are employed. In these cases, the side-chain amino or hydroxy group acts as the nucleophile and opens the cyclic intermediate generating the corresponding lactams or lactones. A less nucleophilic solvent such as trifluoroethanol is usually employed, in order to maximize the intramolecular attack. The observed stereoselectivities are, apart from a few examples [66], usually not very high this could be due to different factors (a) the side chains of the a-amino acids are not very bulky (b) the intramolecular nucleophilic attack could be faster than the methanol attack and the cyclic intermediate could not equilibrate to the thermodynamically favored isomer (c) the intramolecular nucleophilic attack on the more stable diastereoiso-meric cyclic intermediate could be kinetically less favored. 

Ketones react with a-aminoacids in the same way [68], although reactions are reported to be slower there is only one example with an unsymmetrical ketone (acetophenone) and the diastereomeric excess is not reported. 

Finally, also N-alkylated a-aminoacids such as proline, azetidinecarboxylic acid or piperidinecarboxylic acid give the U-5C-4CR but, apart from one example [62], diastereoselectivities are very poor [65], 

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Heterocyclizations by reactions of electrophilic carbenes with a-amino acids derivatives 97T3425. 

Substituted derivatives of l-(tetrahydrobenzo[b]thiophen-2-yl-3-carboxylate)-5-phenyl-6-thio-l,2,4-triazin-4-one have been synthesized by heterocyclization reactions of different hydrazones obtained from 2-amino-tetrahydrobenzo[b]thiophene-3-carboxylate with phenyl isothiocyanate <00PS275>. Reaction of 5-methyl isothiosemicarbazide with a-amino acid vicinal tricarbonyl reactive substrates 1 and 2 yields 1,2,4-triazine substituted a-amino acids, as an equimolar mixture of regioisomers 3a/3b and 4a /4b, respectively <00JCS(P1)299>. 

However, with liquid ammonia or anhydrous methylamine 1,2,4-oxadiazines (88) are formed. 5-(Chloromethyl)-l,2,4-oxadiazoles (e.g., (86) react with urotropin to form salts, which are hydrolyzed with hydrochloric acid to 5-(aminomethyl) compounds (the Delepine reaction). Alternatively, 5-(aminomethyl)-l,2,4-oxadiazoles have been prepared by condensation of amidoximes with a-amino-acids <72JHC435>. 

As a result of the principal importance of a-amino acids, their synthesis from glycine or other a-amino acids by a-alkylation of a derivative with a nonracemic auxiliary has been carried out more or less successfully127. Attempts aiming at the same goal, but using heterocyclic starting materials, are described in Sections 1.1.1.3.3.4.2. and 1.1.1.3.3,4.3. 2-Hydroxypinan-3-one (5) was used to induce chirality, when its imines with a-amino acids were a-alkylated,28 l3°. 

Bis-p-nitrophenyl malonate (55M29) reacts with a-alkylamino-isobutyr-onitriles in xylene to give derivatives (16b) of tetramic acids with yields of 30-50% (86UP1 88UP1). The reaction of derivatized malonic acids with a-amino acid esters to 3-alkoxycarbonyl-l,5-dihydro-4-hydroxy-2-pyrrolones presents the same problems (see Section III). (See Fig. 8.)... 

Free primary amino acids are characterized by the following absorptions (most of the work was done with a-amino acids, but the relative positions of the amino and carboxyl groups seem to have little effect) ... 

Three methods for making 4,5,6,7-tetrahydrotriazoIopyridines use two fragments to form the triazole ring. The lithium derivative of A/-nitro-sopiperidine reacts with benzonitrile to give the 3-phenyl derivative 19.28 Diazonium salts react with a-amino acids to give mesoionic triazole oxides if pipecolic acid is used, the product is a tetrahydrotriazolopyridine 3-oxide... 

Dioxanes (337) are also conveniently obtained by acid-catalyzed condensation of oxiranes with glycols, while use of ethanolamine gives morpholine (338). Base-catalyzed reaction of oxiranes with a-amino acids and esters gives tetrahydro-l,4-oxazin-2-ones, e.g. propene oxide + RNHCH2C02H — (339). 1,4-Dithianes have been prepared by the dimerization of thiiranes either in the vapor phase or in the presence of acid catalysts. 

Synthesis of monomers for the preparation of the methyl ester polyisocyanides begin with a-amino acid esters. These polyisocyanides were developed to yield optically active polymers which could be characterized first as non-electrolytes, and, after hydrolysis, as polyelectrolytes in aqueous media. As predicted, poly[a(carboxymethyl) alkyl isocyanides] are soluble in various solvents. Unfortunately, a low ceiling temperature, some instability to alkali and especially to... 

Chen et al.[57] reported the synthesis of the 2-hydroxyethylene isostere using two methods. The first method is initiated with readily available a-amino acids and utilizes the Evans chiral aldol condensation to control the stereochemistry (Scheme 25). The second method does not start with a-amino acids, and thus allows for the synthesis of isosteres having side chains other than those obtained from the available a-amino acids (Scheme 26). Thus, this synthesis relies on an anti-aldol product for the 2-hydroxyethylene isosteres via an E-selective ethyl hydrocinnamate enolization. 

Table 13.13. Acylation of support-bound aliphatic alcohols with a-amino acid derivatives.

Pyridoxal-5 -Phosphate Is Required for a Variety of Reactions with a-Amino Acids Nicotinamide Coenzymes Are Used in Reactions Involving Hydride Transfers Flavins Arq Used in Reactions Involving One or Two Electron Transfers... 

Pyridoxal-5 -Phosphate Is Required for a Variety of Reactions with a-Amino Acids... 

Pyridoxal-5 -phosphate participates in many reactions with a-amino acids, including transaminations, a decarboxylations, racemizations, a,/3 eliminations, j8,y eliminations, aldolizations, and the (3 decarboxylation of aspartic acid. 

The fundamental biochemical function of pyridoxal-5 -phosphate is the formation of aldimines with a-amino acids that stabilize the development of carbanionic character at the a and /3 carbons of a-amino acids in intermediates, such as those in figures 10.4b and c. Enzymes acting alone cannot stabilize these carbanions and so cannot, by themselves, catalyze reactions requiring their formation as intermediates. 

The utility of these promoters to achieve an efficient coupling of a-amino (3-lactams with a-amino acid esters has also been documented [89]. For example, (3-lactam 51, Scheme 19, upon treatment with (S)-PheOMe and (S)-ValOMe in DMF, in the presence of NaN3, furnishes dipeptides 52 and 53 respectively, in good... 

Further examples of the coupling of p-lactams with a-amino acid esters are shown in Scheme 20. For instance, 57, prepared from 56, reacts with a-amino acid esters in the presence of NaN3 to give tripeptides 58 and 59. In addition, simple exposure of 57 to hydrogen over Pd/C at room temperature produces the piperazinedione 60 in 90% yield. 

Scheme 20 Coupling of Af-Boc [3-lactams with a-amino acid esters...

Following a similar strategy, Miller [92] has documented the ring opening of a-azido (3-lactams with a-amino acid esters, Scheme 24. Treatment of a-azido (3-lactams 68/69 with glycine methyl ester thus afforded dipeptides 70/71 with differentially protected amino groups. From dipeptide 70, a synthesis of the rhodo-peptin B5 analogue 72 was further demonstrated. 

Phthalimidines (isoindolin-l-ones) can be valuable intermediates for the synthesis of isoindoles and some natural products, and there has been recent interest in the development of simple methods for the direct conversion of o-phthalaldehyde into /V-substituted phthalimidines. Condensation of o-phthalaldehyde with primary aliphatic amines using acetonitrile as solvent gives disappointing yields with a-methylbenzylamine, for example, the yield of the phthalimidine 1 is only 21%. By contrast, treatment of o-phthalaldehyde with a-amino acids in hot acetonitrile gives generally excellent yields of the corresponding phthalimidines. With L-valine, for example, 2 is formed in 87% yield. 

Note. (1) Ninhydrin (p. 630) is the 2-hydrate of indane-l,2,3-trione. It reacts with a-amino acids to yield highly coloured products. Contact with the skin should be avoided since it produces a rather long-lasting purple discoloration. 

The data presented in Table 3.1 demonstrate that 0.3% (w/v) ninhydrin has a marked effect at pH 5.0 on bubble production in agarose gels containing distilled water. This concentration of ninhydrin reduced bubble production at pH 5.0 to only one third of that observed in the control buffered at the same pH, whereas no significant effect at pH 8.0 was observed (Table 3.1). This pH dependence of the chemical effect is important for the reason that ninhydrin is known to react appreciably with a-amino acids, peptides, and proteins in various buffered aqueous solutions ranging in pH from 5.0 to a maximum of 7.0 (ref. 232,233) and specifically in aqueous solutions containing citrate buffer (as used in this study) at pH 5.0 (ref. 233). While ninhydrin is also known to react with many amino compounds and ammonia (ref. 233), such interfering... 

Beumer, R. Reiser, O. /j-Aminocyclopropane-carboxylic acids with a-amino acid side chain functionality. Tetrahedron 2001, 57, 6497-6503. 

CMD and mixed derivatives based on CMD may be used for the fixation of antibiotics and enzymes on a polysaccharide matrix. A procedure was developed for amidation of CMD and its ethyl ester (CMDEE) with various aromatic amines in dioxane (100 °C), ethanol (78 °C), n-propanol (97 °C) and 2-propanol (82 °C) in the presence of a small amount of water [301]. CMDEE reacts with aliphatic and aromatic amines but in the case of amino acids the degree of amidation depends on the position of the amino moieties in the acids [302,303]. The DS decreases from S-, y-, /3, to a-amino acids. For the reaction with a-amino acids, carboxymethyl and carboxyethyl dextran azides are used [304],... 

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