Hydroxy acids, from ketones

Mandelic Acid.—The reaction furnishes a simple and general method for obtaining hydroxy-acids from aldehydes or ketones by the aid of the cyanhydrin. The formation of the cyanhydrin may be effected in the manner described or by the action of hydrochloric acid on a mixture of the aldehyde or ketone with potassium cyanide, or, as in the case of the sugais, by the use of liquid hydrocyanic acid and a little amme-nia. 

From aldehydes, we always obtain an fl//>/ffl-hydroxy acid in which the hydroxyl group is linked to the carbon atom which is itself directly linked to carboxyl. Also the resulting hydroxy acid will always contain one more carbon than the aldehyde with which we start. Thus, by starting with any saturated alcohol or acid and obtaining the aldehyde, we may pass to the hydroxy acid next higher in the series. Acetic aldehyde yields a-hydroxy propionic acid. From ketones we also always obtain an alpha- iy 6xoxy acid and likewise increase the number of carbon atoms by one. The a//>/ffl-hydroxy acid obtained, however, will be isomeric with the one obtained from the aldehyde of equal carbon content. This will be seen from the above reactions. 

An elegant synthesis of -hydroxy acids from the next-lower (non-hydr-oxylated) carboxylic acids has been described by Weygand and Bestmann.43 They converted the acid chloride into the diazo ketone by means of diazomethane, treated the diazo ketone with ethanesulfenyl chloride, and decomposed the resulting ketone with aqueous alkali, e.g. ... 

In the absence of sodium acetate, 2-phenylsulfonyl ketones give the typical Pummerer product. Since -keto sulfoxides are available by the reaction of esters with the dimsyl anion, this overall process leads to one-carbon homologated a-hydroxy acids from esters (eq 24). ... 

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

Table 3. (R)-Cyanohydrins by Enzymatic Formation from Ketones and Hydrocvamic Acid as well as (7 )-a-Hydroxy-a-methyl Carboxylic Acids by Hydrolysis...

Given these facts, what would be the structure of the hydroxy-acid formed by hydrolvsls of the Baeyer-Villiger product from bicyclic ketone (32) ... 

Products detected or isolated from these oxidations include the corresponding a-hydroxy ketone and a-diketone and also adipic acid (from cyclohexanone) in up to 95 % yield. However, IrCI gives a-chloroketone in quantitative yield . Evidently when the rate of oxidation exceeds enolisation attack is on the keto form, probably via a complex, although this is definite only for Ce(IV) perchlorate, to give a radical, e.g. 

A closely related reaction of ketones and ketoesters with chiral f-butyl (+)-(i )-p-toluenesulfinylacetate 50 was utilized for the synthesis of chiral (3-hydroxy acids as shown in Scheme 32 (317). The optical purities of the final reaction products varied from 8.5 to 91%. 

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

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. ... 

The synthesis of -hydroxy acids via their esters from ketones and the Reformatsky reagent is still one of the best approaches for this class of compounds. This reagent. 

Reformatsky reaction. Tetrahydropyranyl esters are recommended for use in Rcformatsky reactions. They are formed from a-bromo acids in quantitative yield In dry benzene without need of an acid catalyst and they arc readily hydrolyzed by dilute hydrochloric acid. The Reformatsky reaction is generally conducted in THF at a temperature below 10". The reaction is more rapid if the zinc is activated with a trace of HgCI2. Yields of -hydroxy acids arc generally 70-90% when aldehydes are used, hul usually somewhat lower with ketones. 

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