Atrolactic acid synthesis

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... 

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). 

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... 

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). 

Diastereospecific reaction of a Grignard reagent. This reagent has been used as the chiral adjunct in place of 4,6,6-trimethyl-l,3-oxathiane (8, 508-509) in a synthesis of atrolactic acid methyl ether (6) in 97 2% enantiomeric excess... 

A related reagent (186) is prepared in three steps from (5)-atrolactic acid. The lithium enolate of (186) reacts with phenylacetaldehyde to give two aldols in a ratio of 94 6 (Scheme 12). [The full relative stereochemistry of aldols (187) and (188) was not rigorously determined, but may be deduced from the stereochemistry of (190). It is surprising that the lithium enolate of (186) has a diastereofacial preference that is opposite that of the related ketone (181).] Compound (186) has been used in a synthesis of the Prelog-Djerassi lactonic acid (191), as shown in Scheme 12. Reagents related to (181) and (186) have been used as their boron enolates for other synthetic purposes (see Chapter 1.7, this volume). 

Several syntheses from acetophenone have definitely established structure III for atropic acid. In the first instance the ethyl ether (IV) of atrolactic acid was synthesized and the atropic acid was derived from this by splitting the ether and dehydrating (HCl) the resulting atrolactic acid (83). The synthesis of atrolactic acid ethyl ether involved the conversion of acetophenone to a,a-dichloroethylbenzene (PCh), thence to a-ethoxy-a-cyanoethylbenzene (alcoholic KCN) followed by hydrolysis (Ba(OH)s) to IV. This may be illustrated by the following reaction sequence ... 

An alternative and more favorable route to the same acid lies in the synthesis and dehydration of atrolactic acid (V) (213). Atrolactic acid is obtained in good yield (73%) by the hydrolysis (HCl) of acetophenone cyanohydrin. Various reagents (82) have been used for the dehydration... 

Atrolactic acid is also addressed as 2-hydroxy-2-phenylpropionic acid or a-methylmandelic acid and shown in Figure 1.15. The configuration of atrolactic acid and methods of synthesis and reactions have been described (42). 

An efficient asymmetric synthesis of 3-phenylalkanals has been developed, based on a chiral homoenolate equivalent, using a recoverable chiral auxiliary derived from atrolactic acid (Scheme 10). ... 

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