Of a-hydroxy acids

Reaction of cyanohydrins with absolute ethanol in the presence of HCl yields the ethyl esters of a-hydroxy acids (3). A/-substituted amides can be synthesized by heating a cyanohydrin and an amine in water. Thus formaldehyde cyanohydrin and P-hydroxyethylamine lead to A/- (P-hydroxyethyl)hydroxyacetamide (4). 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

A generalized kinetic treatment of the array of processes occurring in condensation polymerization might appear hopelessly complex. In the polyesterification of a hydroxy acid, for example, the first step is intermolecular esterification between two monomers, with the production of a dimer... 

Copolymers of a-hydroxy acids and a-amino acids are one type of poly(ester-amide)s and are called polydepsipeptides (PDPs) [17]. Since some of natural occurring a-amino acids, typically Asp, Glu, lysine (Lys), cysteine (Cys), serine (Ser), and threonine (Thr), possess reactive (hydrophilic) side-chain groups, PDPs... 

The oxidation of a-hydroxy acids is slow41 it has been comprehensively studied, using glycolic acid as a model.42 Three reactions have been proposed as occurring. 

Consider a polyester prepared the polycondensation of a hydroxy acid. From the structure of the polymer it is known that this polyester has a carboxyl group for each molecule and when titrated one mole of sodium hydroxide is used per mole of polyester. To calculate the Molecular weight of the polyester, we have only to calculate how much polyester (in grams) gets neutralised by... 

The Amide Rule as formulated by Freudenberg states. The rotation of amides of a hydroxy acids of the D-series is always shifted to the right as compared with the rotation of corresponding hydroxy acids. 

Remarks on Sections 6 and 7.-—The method here described for the synthesis of cyanohydrins—treatment of the bisulphite compound of the aldehyde with potassium cyanide—cannot be used in all cases. Concentrated solutions of hydrocyanic acid or anhydrous hydrogen cyanide are often used. The general method for the synthesis of a-amino-acids, the nitriles of which are formed by the union of ammonium cyanide with aldehydes or ketones (Strecker), is to be contrasted with that for the synthesis of a-hydroxy acids. For additional amino-acid syntheses see Chap. VII. 2, p. 276. 

This method is generally applicable to the preparation of the amides of a-hydroxy acids. 

Chiral cyanohydrins are versatile intermediates in the synthesis of a-hydroxy acids, /3-amino alcohols, amino nitriles, a-hydroxy ketones and aziridines. For the synthesis of enantiopure cyanohydrins, the use of hydroxynitrile lyases is currently the most effective approach.Application of an organic-solvent-free system allows thermodynamically hindered substrates to be converted with moderate to excellent yields. With the use of the highly selective hydroxynitrile lyase from Manihot esculenta, the syntheses of several acetophenone cyanohydrins with excellent enantioselectivities were developed (Figure 8.2). (5)-Acetophenone cyanohydrin was synthesized on a preparative scale. ... 

For more recent examples involving induced electron transfer linked to cobalt(III) complexes of a-hydroxy acids and hydroquinone esters see Refs. 110, 111. 

Steric effects dominate in the oxidation of dialkyl, alkyl phenyl and benzal methyl phenyl sulfides to their sulfoxides by quinolinium fluorochromate (QFC) in aqueous acetic acid. QFC oxidation of phenoxyacetic acids has been smdied. Imidazolium dichromate oxidations of a-hydroxy acids have been smdied. ... 

Results of HF/3-21G theoretical studies of gas-phase dehydration of a-hydroxy acids suggest that the reaction is favoured by electron-donating substituents via a three-membered ring intermediate formed via a five-membered ring transition state a three-membered ring transition state governs formation of product in the second step. ... 

By analogy with the synthesis of a-hydroxy acids one can envisage a one-pot synthesis of a-hydroxy amides from aldehydes via hydrocyanation and in situ NHase-catalyzed hydrolysis to the amide. Since enantioselective NHases are very rare, the enantioselectivity should be derived from HnL-catalyzed hydrocyanation. The second step has been described for the Rhodococcus erythropolis NHase-catalyzed hydration of (R)-mandelonitrile to give the (R)-amide with retention of enantiopurity [43]. 

For many step polymerizations there are different combinations of reactants that can be employed to produce the same type of polymer (Table 1-1). Thus the polymerization of a hydroxy acid yields a polymer very similar to (but not the same as) that obtained by reacting a diol and diacid ... 

Optically pure D- and L-glyceric adds were made by cleavage of vicinal diols or of a-hydroxy acids by RuCyaq. Na(C10) pH 8 (Fig. 4.6) [398], The system RuCyaq. Na(IOyCH3CN-CCl oxidised PhCMeCH(0H)CH20H to PhCMeCOOH [260], and RuCyaq. Na(ClO)/0°C converted 1,2-dihydroxycyclohexane to adipic add [35,256]. 

N-acylamino acids does not appear to have been studied previously. In solution, N-acyl-N-nitroso-a-amino acids are moderately stable to weak bases, such as triethylamine or sodium carbonate, but are decomposed rapidly at 0° to expel nitrogen on addition of sodium hydroxide (43). For example, treatment of N-nitroso-N-benzoyl-D,L-pheny1-alanine LXIIb with an aqueous sodium hydroxide solution at 0 gives benzoic acid and 1-hydroxy-3-phenylpropanoic acid LXVa in a 93% yield. The facile base-catalysed formations of a-hydroxy acids LXV are a general reaction and probably occur by intramolecular attack as shown in LXII->LXIII->LXIV. Oxadiazolone LXIV can decompose by various possible pathways to give LXV among which the carbonium ion pathway is least likely. 

Scheme 1 Representative Examples of Depsipeptides Whose Ester Bonds are Formed by the Hydroxy Group of a-Hydroxy Acids[4 141...

The hydrolysis of the dihydrofuran (347) to the pyran-2-one proceeds through the intermediacy of a hydroxy acid (Scheme 108). Ring opening is accompanied by hydrolysis of the nitrile (38JA2404). 

Although oligomers of a-hydroxy acids (depsides) and mixed oligomers of cx-hydroxy and a-amino acids (depsipeptides) are found in nature (antibiotics, ion-transporters [249,250]), little solid-phase methodology has been developed for their preparation. One recent strategy is based on sequential acylation with THP-protected cx-hydroxy acids (DIC, DMAP, THF, 2 h see Entry 6, Table 13.13), followed by deprotection with TsOH/MeOH [249,251]. Under these conditions, no racemization was observed. A similar approach to the solid-phase synthesis of depsipeptides is outlined in Figure 16.24. 

As a rule, qualitative and quantitative determinations of fatty acids are performed by g.l.c. of their methyl esters, obtained by treating the glycolipid with HC1 in methanol.160 To raise the volatility of the methyl esters of a-hydroxy acids, they are methylated161 or trimethylsilylated.162... 

From the pearl oyster Pinctada martensii, a glycosylceramide was isolated in which —80% of the fatty acids are comprised of a-hydroxy acids, and the main, long-chain base is CI9 , sphingosine.127... 

Figure 5 Conformations of a-hydroxy acids around the C(l)—C(2) bond ...

The oxidation of a-hydroxy acids by benzyltrimethylammonium tribromide (BTMAB) to the corresponding carbonyl compounds shows a substantial solvent isotope effect, A (H20)/A (D20) = 3.57, but no KIE for a-deuteromandelic acid.133 The oxidation of glucose by hypobromous acid is first order in glucose and the acid.134 [l,l-2H2]Ethanol shows a substantial kinetic isotope effect when oxidized by hexamethylenetetramine-bromine (HABR) in acetic acid to aldehyde.135 Kinetics of the oxidation of aliphatic aldehydes by hexamethylenetetramine-bromine have been studied by the same group.136 Dioxoane dibromide oxidizes y-tocopherol to 5-bromomethyl-y-tocopherylquinone, which spontaneously cyclizes to 5-formyl-y-tocopherol.137... 

The nitrile group in the readily available a-hydroxynitriles (the cyanohydrins) may also be similarly hydrolytically converted into a carboxyl group to afford a convenient synthesis of a-hydroxy acids (Expt 5.168). 

In this context, the report that in the Fenton reaction the -OH yield (as determined by spin trapping) is considerably increased in the presence of a-hydroxy acids (Ali and Konishi 1997) may find an explanation if the a-hydroxy acid/ Fe(III)/H202 complex oxidizes the spin trap thereby mimicking an increased yield of OH. 

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