Atrolactic acid

1 Mellon Institute of Industrial Research, Pittsburgh, Pennsylvania. 

Checked by Arthur C. Cope, William F. Gorham, and Roscoe A. Pike. 

Caution This preparation must he conducted in a hood to avoid exposure to the poisonous hydrogen cyanide that is evolved. 

In a 1-1. three-necked round-bottomed flask equipped with a Hershberg stirrer, a thermometer, and a 250-ml. dropping funnel are placed 80 g. (0.666 mole) of acetophenone, 60 ml. of ether, and 100 ml. of water. The apparatus is assembled in a well-ventilated hood, the flask is surrounded by an ice-salt bath, and 82 g. (1.67 moles) of granulated sodium cyanide is added all at once with vigorous stirring. When most of the sodium cyanide has dissolved and the temperature of the mixture has fallen to 5°, 140 ml. (1.7 moles) of concentrated hydrochloric acid is 

Part of the excess hydrogen chloride is removed by blowing (or drawing) air through the solution for 1 hour. The solution then is made alkaline by the slow addition of 50% aqueous sodium hydroxide (Note 4) with mechanical stirring and cooling in an ice bath. Solid sodium hydroxide (24 g.) is added, and the mixture is steam-distilled until no more ammonia and acetophenone pass into the distillate (Note 5). About 3-4 1. of distillate is collected (Note 6). 

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Thus acid hydrolysis of acetophenone cyanohydrin [20102-12-9] (R = CgH, R = CH3) yields the corresponding amide which can be isolated. Further hydrolysis, usually with sodium hydroxide, gives atrolactic acid [575-30-0] in a 30% overall yield (1). 

One of the first examples of this type of reaction, using a chiral alcohol as an auxiliary, was the asymmetric synthesis of 2-hydroxy-2-phenylpropanoic acid (atrolactic acid, 3, R1 =C6H5 R3 = CH3) by diastereoselective addition of methyl magnesium iodide to the men-thyl ester of phcnylglyoxylie acid4,5 (Table 22). 

Water is added to the residue if necessary to make the volume 700 ml., and the solution is treated with 2 g. of Norit and filtered with suction (Note 7). The filtrate is extracted with 100 ml. of ether (which is discarded), and acidified by the addition of 80 ml. of concentrated hydrochloric acid. After thorough chilling, preferably overnight in a refrigerator, the precipitated atrolactic acid is collected on a suction filter (Note 8) and air-dried at a temperature not exceeding 65°. 

The synthesis of atrolactic acid through acetophenone cyanohydrin was first described by Spiegel12 and has since been used by several other investigators.6-13-17 The above preparation is adapted from the methods of McKenzie and Clough16 and Freudenberg, Todd, and Seidler.17... 

Mckenzie prepared (-) atrolactic acid using Grignard reagents. 

It is obvious that any factor which prevents tautomerism would hinder racemisation and this happens when the hydrogen atom attached to the asymmetric carbon atom is replaced by some other group. Thus while mandelic acid, C6H5-CH(OH). COOH having the structure resembling lactic acid is racemised by warming with aqueous aodium hydroxide, atrolactic acid C6H5-C (CH3) (OH) COOH is not racemised under the same conditions. 

Other related chiral erythro selective ketone enolates (iS -139 and (i )-139, readily prepared from (5)- and (i )-atrolactic acid, also exhibit good aldol diastereoface selection (3). From the data summarized in Table 34a, the influence of asymmetry in both condensation partners (entries C-F) has been amply demonstrated. The... 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

The potassium enolate prepared from atrolactic acid derivative II undergoes aldol reaction to give 12 in a highly stereoselective manner. Successive acid treatment gives syn-amino acid 13 in good yield (7). 

Acetamido-2-deoxy-D-arabinose 14 and 2-acetamino-2-deoxy-D-ribose 15 are prepared from (R)- and (S)-atrolactic acid derivatives respectively using the above reaction (8). 

The esters of the optically active alcohols with a-oxobenzeneacetic acid, 18 or ent- 18, are treated with methylmagnesium iodide to give in a diastereoselective reaction two atrolactic acid esters, one of which prevails. The mixture of esters is then hydrolyzed (of course, quantitative hydrolysis is necessary ) and the configuration of the excess atrolactic acid enantiomer (+ )-( )-23 or (-)-(R)-23 is determined by an appropriate method (optical rotation, NMR in the presence of optically active shift reagents or solvents, GLC. of diastereomeric derivatives). 

Arsenic trichloride, 30, 96 Aryl isothiocyanates, 36, 57 Arylureas, 31, 8,10 dl-Aspartic acid, 30, 7 Atrolactic acid, 33,7 Autoclave, use of hydrogenation bomb as, 30, 42... 

Type 2. Reactions in which new asymmetric centers are created in molecules that already possess one asymmetric center or more and in which the new asymmetric center may be liberated from the parent molecule by simple hydrolytic reactions. The most common reactions of this type are those to which the Prelog rule4 applies for example, the addition of methylmagnesium iodide to (—)-phenylpyruvate, followed by hydrolysis to give (—)-atrolactic acid. 

The percentages given in parentheses are the optical yields of (R)-(—)-atrolactic acid liberated after hydrolysis. In this series, the substituent group on C-4 (for example, in 15) is clearly the large... 

The chiral influence in the atrolactic acid synthesis just considered is a reagent which actually forms a chemical bond at the beginning of the process later this bond is broken. The same overall result can be obtained by use of a physical chiral influence (e.g., circularly polarized light) or a catalyst. Biochemists, of course, are... 

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