Ethyl mandelate synthesis

The dimethylaminooxazolidone derivative thozalinone (40-3) is described as an antidepressant. The synthesis of this agent again uses a cyanamide, provided in this case as a preformed reagent. Thus, reaction of alkoxide from ethyl mandelate (40-1) with A,A-dimethylcyanamide leads to the amidine (40-2) by addition to the nitrile. Internal displacement of the ester ethoxide group closes the ring to an oxazo-lidinone, forming the product (40-3) [42]. 

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). 

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. 

Independent synthesis of the crystalline amide LXVII established its identity and its configurational relationship to L-(+)-mandelic acid. The latter acid was converted to ethyl L-(+)-mandelate (LXVIII), and the ether linkage introduced by reaction with ethyl bromoacetate in the presence of silver carbonate, under conditions such that Walden inversion was impossible. The resulting ethyl D-(+)-2-phenyldiglycolate (LXVI), was subjected to ammonolysis, giving a crystalline product, m. p. 174-174.5°, [a]26D 106.2°. This showed no mixed melting point depression and an identical infrared absorption spectrum with the sample of LXVII obtained from /3-D-xylopyranosylbenzene. The enantiomorphic l-(—)-2-phenyldiglycolamide was also prepared by identical synthetic steps from d-( —)-mandelic acid. 

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%). ... 

Microwave irradiation of a mixture of an acid anhydride, an amine adsorbed on silica gel, and TaCl5/Si02 is a solvent-free method for the synthesis of A-alkyl and A-aryl-imides [47]. Ni(II) promotes the conversion of an acrylamide to ethyl acrylate via a Diels-Alder adduct with (2-pyridyl)anthracene [48], Aromatic carboxylic acids [49] and mandelic acid [50] are efficiently esterified with Fc2(S04)3 XH2O as catalyst. Co(II) perchlorate in MeOH catalyzes the methanolysis of acetyl imidazole and acetyl pyrazole [51]. Hiyama et al. used FeCb as a catalyst for the acylation of a silylated cyanohydrin. The resulting ester was then cyclized to 4-amino-2(5H)-furanones (Sch. 5) [52]. 

The hetero-Diels-Alder reaction with inverse electron demand is an attractive route for the synthesis of 3.4-dihydro-2//-pyrans. Enone 7, esterified with D-mandelic acid as chiral auxiliary, adds to ethyl vinyl ether (8) to give a 2 1 mixture of 9 and 10 [d.r. (2S,4S) (2RAR) 67 33]1. The enone 11 requires high pressure to add to the much less reactive enol ether 12, yielding a 2 3 mixture of 13 and 14 [d.r. (2S, 3S,45 )/(21 ,37 ,4/ ) 40 60]8. The introduction of the additional stereogenic center in the enone 15 leads to a substantially improved diastereofacial selectivity, and adducts 16 and 17 are obtained as a 1 10 mixture [d.r. (2S.4S) (2RAR) 9 91]9. 

The mandelate esters serve yet an additional role in chiral synthesis - facilitation of resolution by hplc. The diastereo-mers in entries 1,2, and 4 of Chart 1 are all readily resolved on a Waters Prep 500 column utilizing 2-105S ethyl acetate in hexane (7,8,10,13). The diastereomer labelled S of entry 2,... 

A DKR process was used for the synthesis of (R)-mandelic acid ester from racemic mandelic acid using an aqueous/organic two-phase system with two enzymes. KR first took place with a lipase in the organic solvent and there was an in situ racemization in the aqueous medium by recombinant mandelate racemase. The procedure employed a hollow-fibre membrane bioreactor and gave (R)-mandehc acid ethyl ester in 98% ee and 65% yield (Scheme 4.36) [88]. 

Some years ago, these possibilities were examined [53] with (—)-menthyl benzoylformate and ethyl benzoylformate. A simple asymmetric reduction involving either (—)-menthyl benzoylformate with an acliiral agent, liAlH4(LAH)-cyclo-hexanol, process (a), or ethyl benzoylformate with a chiral reducing agent, LAH-(+)-camphor, process (b), gave (/ )-mandelic acid after hydrolysis, in relatively low optical yields (10 and 4% e.e., respectively). On the other hand, the double asymmetric reduction , process (c), resulted in 49% asymmetric synthesis. This result is more than would be anticipated on the basis of a simple additive effect. 

Another prominent example of a chiral auxiliary for highly diastereoselective synthesis of iyn-aldol adducts was developed by Masamune utilizing (/ )-mandelic acid (Scheme 2.111) [12]. This early example of chiral ethyl ketone takes advantage of the mandelic acid as the chiral source and liberation of the corresponding acid though oxidative cleavage. 

Resolution of a,a-disubstituted a-amino acids (but also of a,a-disubstituted a-hydroxy acids [51]) can also be performed on their esters. We have used pig liver esterase (PLE) for resolution of a variety of a,a-disubstituted esters. Although all substrates tested are hydrolyzed, only for a-substituted phenylglycine esters (17, X = NH2) and a-substituted mandelic esters (17, X = OH) reasonable enanlioselectivities are observed for hydrolysis of the (S) enantiomer (E = 2-114) [44]. For these types of amino acids and hydroxy acids the PLE resolution forms a valuable extension of the M. neoaurum resolution technology, since the corresponding racemic amides are hydrolyzed sluggishly (Scheme 8). The PLE resolution of a-allylphenylglycine ethyl ester has been applied in the synthesis of D-a-phenylproline (vide infra). 

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