Mandelic acid synthesis

Other references related to the mandelic acid synthesis are cited in the literature. ... 

Mandelic acid. This preparation is an example of the synthesis of an a-hydroxy acid by the cyanohydrin method. To avoid the use of the very volatile and extremely poisonous hquid hydrogen cyanide, the cyanohydrin (mandelonitrile) is prepared by treatment of the so um bisulphite addition compound of benzaldehj de (not isolated) with sodium cyanide ... 

L-Menthol [2216-51-5] (75) and D-menthol [15356-70-4] have been used as chiral auxiharies in the synthesis of optically active mandehc acids. Reduction of (-)-menthol ben2oylfomiate (76) with a stericaHy bulky reducing agent, ie, sodium bis(2-methylethoxy)aluminum hydride (RED-Al), followed by saponification, yields (R)-mandelic acid (32) of 90% ee. 

He, Y.C., Xy, J.H., Xu, Y. et al. (2007) Biocatalytic synthesis of (R)-(—)-mandelic acid from racemic mandelonitrile by a newly isolated nitrilase -producer Alcaligenes sp. ECU0401. Chinese Chemical Letters, 677-680. 

Mateo, C., Chmura, A., Rustler, S. et al. (2006) Synthesis of enantiomerically pure (S)-mandelic acid using an oxynitrilase-nitrilase bienzymatic cascade a nitrilase surprisingly shows nitrile hydratase activity. Tetrahedron Asymmetry, 17, 320-323. 

A patent procedure for formation of compounds 19 from simple tartaric acid derivatives has appeared <06USP047129> and various new routes to chiral dioxolanones include synthesis of dioxolan-2-ones either by transition metal-mediated asymmetric synthesis <06T1864> or enzyme-mediated kinetic resolution <06H(68)1329> and a new synthesis of the chiral dioxolan-4-ones 21 from lactic or mandelic acid involving initial formation of intermediates 20 with trimethyl orthoformate in cyclohexane followed by reaction with pivalaldehyde <06S3915>. 

Mckenzie carried out a number of asymmetric synthesis by reducing the keto groups in several ketoesters in which the ester group contained a chiral group. Thus he synthesized 1-mandelic acid from benzoyl formic acid by the following steps using 1-menthol... 

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 original synthesis of duloxetine (3) is relatively straightforward, involving a four-step sequence from readily available 2-acetylthiophene 30 (Scheme 14.7). Understandably, the main synthetic challenge stems from the presence of a chiral center, because duloxetine (3) is marketed as the (5)-enantiomer as shown. Thus, a Mannich reaction between 30 and dimethylamine generated ketone amine 31, which was then reduced to provide intermediate racemic alcohol amine 32. The desired optically active (5)-alcohol 32a was accessed via resolution of racemate 32 with (5)-(+)-mandelic acid, which provided the necessary substrate for etherihcation with 1-fluoronaphthalene to afford optically active amine 33. Finally, A -demethylation with 2,2,2-trichloroethyl chloroformate and cleavage of the intermediate carbamate with zinc powder and formic acid led to the desired target duloxetine (3). 

The original Sanofi synthesis of ( )-clopidogrel (2) began with the formation of the methyl ester 13. Thus methyl mandelate 13 was prepared by refluxing chlorinated mandelic acid 12 with methanol in the presence of concentrated HCl. Chlorination of... 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

This general method has been applied to the synthesis of a variety of alkyl-substituted mandelic acids.2... 

---