Hydroxy acids from cyanohydrins

The mechanism for this hydrolysis is discussed in Section 17.8H. The preparation of a-hydroxy acids from cyanohydrins is part of the Kiliani-Fischer synthesis of simple sugars (Section 22.9A) ... 

The synthesis of a-hydroxy acids from carbonyl compounds by way of the cyanohydrin was an early discovery in organic chemistry. In 1867 Simpson and Gautier, working in Wurtz laboratory, described the cyanohydrin from acetaldehyde and hydrocyanic acid, and its conversion to racemic lactic acid by strong hydrochloric acid. 

Figure 3. The Strecker and cyanohydrin mechanisms for the formation of amino-and hydroxy-acids from ammonia, cyanide, aldehydes and ketones.

Frequently, it is the bisulfite addition product that is treated with CN. This method is especially useful for aromatic aldehydes, since it avoids competition from the benzoin condensation. If desired, it is possible to hydrolyze the cyanohydrin in situ to the corresponding a-hydroxy acid. This reaction is important in the Kiliani-Fischer method of extending the carbon chain of a sugar. 

Another important class of pharmaceuticals which is prepared from chiral 2-hydroxy acids is the angiotensin-converting enzyme (ACE) inhibitors. (R)-3-phenylpropionaldehyde cyanohydrin is transformed into the corresponding 2-hydroxy ester which after activation by sulfonylafion reacts with dipetides to give, under inversion of configuration, ACE inhibitors known as prils (Scheme 6). ... 

Warmerdam, E.G.J.C., van Rijn, R.D., Brussee, J. et al. (1996) Synthesis of a-hydroxy-/3-amino acids from chiral cyanohydrins. Tetrahedron Asymmetry, 7, 1723-1732. 

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. ... 

Another notable new advance is the development of hydroxynitrile lyases for the synthesis of enantiomerically active aromatic and aliphatic cyanohydrins. For instance, an S-specific hydroxynitrile lyase has been obtained from Hevea brasiliensis and the resulting fS)-cyanohydrin can be used to obtain both hydroxy acids and aminoalcohols. 

Figure 7.8 a) Enzymatic (oxynitrilase-catalyzed) formation of cyanohydrins from aldehydes, b) Chemical hydrolysis of cyanohydrins to hydroxy acids. 

The desired hydroxy acid is available from hydrolysis of the corresponding cyanohydrin, which may be prepared by reaction of the appropriate aldehyde with cyanide ion. 

The hydroxynitrile lyase (HNL) class of enzymes, also referred to as oxynitrilases, consists of enzymes that catalyze the formation of chiral cyanohydrins by the stereospecific addition of hydrogen cyanide (HCN) to aldehydes and ketones (Scheme 19.36).275 279 These chiral cyanohydrins are versatile synthons, which can be further modified to prepare chiral a-hydroxy acids, a-hydroxy aldehydes and ketones, acyloins, vicinal diols, ethanolamines, and a- and P-amino acids, to name a few.280 Both (R)- and (.S )-selective HNLs have been isolated, usually from plant sources, where their natural substrates play a role in defense mechanisms of the plant through the release of HCN. In addition to there being HNLs with different stereo-preferences, two different classifications have been defined, based on whether the HNL contains a flavin adenine dinucleotide (FAD) co-factor. 

What procedure is available for preparing an a-hydroxy acid. Answer The hydrolysis of a cyanohydrin from an aldehyde or ketone wili yield an a-hydroxy acid. 

A drawback of this reaction has recently been addressed. Only very few S-selective nitrilases were known this problem has been solved a systematic screening program yielded a number of S-selective nitrilases that have successfully been employed in this dynamic kinetic resolution (Scheme 5.17) [38]. In an alternative approach, combining the enantioselectivity of an HNL with the hydrolytic power of a not very selective nitrilase that did accept cyanohydrins as substrates, the synthesis of optically enriched a-hydroxy acids starting from alde-... 

The cyanohydrin synthesis of a-hydroxy acids is very often carried out without isolation or purification of the cyanohydrins. The various techniques for the preparation of the cyanohydrins are discussed elsewhere (method 390). Hydrolysis to the a-hydroxy acids is usually effected by heating with concentrated hydrochloric acid. Excellent directions are given for mandelic acid (52% over-all from benzaldehyde), a-methyl-a-hydroxybutyric acid (65% from methyl ethyl ketone), and eighteen dialkyl- and alkylphenyl-glycolic acids (60-80%). Sodium hydroxide solution is used in the preparation of /S-hydroxypropionic acid from the /S-hydroxy nitrile (80%). ... 

The analogous reaction with a ketone is illustrated from the work of Staedeler in 1859, who prepared a-hydroxy-isobutyric acid from acetone, hydrocyanic acid and hydrochloric acid, without isolating the intermediate acetone cyanohydrin. 

Amines. Chiral a-amino acids are obtained from cyanohydrins via a Mitsunobu reaction employing A-f-butoxycarbonyl-A-(2-trimethylsilyl)ethylsulfonamide as the nucleophile. The a-aminonitrile derivatives thus generated are hydrolyzed with acid. By means of an intramolecular displacement (3-hydroxy acids are transformed into (3-amino acids. Thus, subjecting the derived 0-benzylhydroxamides to Mitsunobu reaction conditions leads to (3-lactams which are readily processed (LiOH H, Pd/C). 

Cyanohydrins in concentrated hydrochloric acid yield -hydroxy carboxylic acids, whereas on alkaline hydrolysis a large part of the cyanohydrin is cleaved to the starting materials. Directions for synthesis of mandelic acid from mandelonitrile are given in Organic Syntheses621... 

MJnsaturated acids are rarely formed from -hydroxy acids by means of dehydrating agents, which, instead, afford lactides and anhydrides or, with loss of formic acid, aldehydes. However,, / -unsaturated nitriles can be obtained from a-hydroxy nitriles (cyanohydrins) by means of thionyl chloride45 or phosphorus(v) oxide,46 and are readily hydrolysed to the corresponding <%,/ -unsaturated acids. 

Some of the fine-chemical manufacturers who supply the pharmaceutical industry now specialize in the use of enzymes for the synthesis of chiral synthons. Chiral cyanohydrins, as well as a- and /S-amino and hydroxy acids, are just a few of the products now available, often produced directly from achiral precursors. Many of the hydroxy acids, such as citric acid (5) and both enantiomers of lactic acid, are fermentation products. The synthesis of some others (Scheme 6.20) resembles the manufacture of aspartate (see... 

Kinetic and Dynamic Resolution of rac-Nitriles. a-Hydroxy and a-amino acids can be obtained from the corresponding a-hydroxynitriles (cyanohydrins) and a-aminonitriles [684], which are easily synthesized in racemic form from the corresponding aldehyde precursors by addition of hydrogen cyanide or a Strecker synthesis, respectively (Schemes 2.107 and 2.108). In aqueous systems, cyanohydrins are stereochemically labile and undergo spontaneous racemization via HCN elimination, which furnishes a dynamic resolution process. From aliphatic rac-cyanohydrins, whole cells of Torulopsis Candida yielded the corresponding (S)-a-hydroxy acids [685], while (R)-mandelic add is produced from rac-mandelraiitrile... 

Many other hydroxy compounds bearing a secondaiy hydroxy group can be enan-tioselectively acylated. In the case of a few cyanohydrins, optically active acetates are prepared in a one-pot procedure from the aldehyde and acetone cyanohydrin, followed by a lipase-catalyzed transesterification [196]. Also, 2-hydroxy acids and esters [197-201] can be enzymatically resolved, as shown in Scheme 43. 

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