Mandelic acid derivatives, preparation

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. 

A library of enantiomerically pure mandelic acid derivatives has been prepared in excellent yields using a palladium-on-carbon catalyzed Suzuki reaction. During the coupling reaction, no racemization was observed (Equation 85) [124]. 

Blixt, H.J., et al, June 2011. Process for the preparation and resolution of mandelic acid derivatives. US patent 7960582. 

The pyridine subcycle unit has been introduced into a wide range of 18-crown-6 derivatives. For example, reaction of 2,6-pyridinedicarbonyl chloride with the dimethyl substituted tetraethylene glycol (SS)-84, derived from (S)-lactic acid, afforded (126) the chiral macrocyclic polyether diester (5S)-184. A similar preparative approach (127) gave (SS)-185, where the source of the chirality is (5)-mandelic acid. 

In a safer route, the sodium bisulfite derivative of benzaldehyde is first prepared, whereupon compound II is obtained by reaction of that product with KCN. In the second step, mandelic acid (III) is obtained by the acid hydrolysis of compound II ... 

In 1990, Brunner [5], McKervey [6], and Ikegami [7] and their respective coworkers independently introduced chiral rhodium(II) carboxylates for asymmetric diazocarbonyl transformations. At that time the only chiral rhodium(II) carboxylates known were those derived from (R) and (S)-mandelic acid which had been prepared by Cotton and co-workers [8] for structural and chiroptical studies. Enantiopure carboxylates (1) on a dirhodium core (substituents varied from H, Me, and Ph to OH, NHAc, and CFj) were assessed by Brunner [5] for enantioselective cyclopropanation of alkenes with ethyl diazoacetate. McKervey... 

Since racemic monomer was used to prepare 1 and 3 it is quite possible that only one of the two enantiomeric forms can be attacked by the enzyme. Earlier we found that the poly(amide-urethane) derived from natural mandelic acid was degraded more readily by both enzymes and fungi than the corresponding nonsubstituted poly(amide-urethane) derived from glycolic acid (6J. ... 

The first highly enantioselective construction of a-methyl-p-hydroxycarbonyl units, described by Masamune et al., used alkenyloxyboranes (29) prepared by enolization of ethyl ketone (30) derived in three steps from enantiomerically pure mandelic acid. Various dialkylboryl triflates are used with diiso-propylethylamine for enolization. The alkenyloxyboranes (29) exhibit striking stereoselectivity as chiral reagents in reactions with representative aldehydes. With judicious choice of the alkyl ligands on the... 

Many semisynthetic or synthetic compounds, including quaternary ammonium derivatives, have been prepared, primarily with the objective of altering gastrointestinal activity without causing dry mouth or pupillary dilation. Homatropine (Fig. 11) is prepared synthetically by esterification of mandelic acid with 3oc-tropine. Its range of action corresponds to... 

Unlike lactic acid, mandelic acid (7) occurs in nature only in small amounts and is therefore more expensive. Formerly, it was obtained by resolution of the racemate with a chiral base, such as l-phenylethylamines or ephedrine6, but enantioselective reductions of a-oxo-a-phenylacetic acid by chemical or biochemical methods have become feasible (Section D.2.3.I.). Esters of mandelic acid, e.g.. 8. can be prepared by any convenient esterification technique (see. for example, refs 7 and 46) and have been used for enantioselective protonation reactions (Sections C. and D.2.I.). Similar to the corresponding lactic esters, fumaric acid derivatives 9 are obtained from the mandelic esters and used as chiral dienophiles in diastereoselective Diels Alder reactions (Section D. 1.6.1.1.1.2.2.1.). 

Mandelic acid is a -hydroxyl phenyl acetic acid. Mandelic acid and its derivatives are very useful in medicinal chemistry some of them have been used in pharmaceutical applications. A few methods have been developed to synthesize mandelic acid and even optically pure mandelic acid. Shown here is the general method for the preparation of mandelic acid from benzaldehyde and sodium cyanide. 

Because NaCN is extremely poisonous, other methods have been developed to prepare mandelic acid and its derivatives, as shown in Section G. 

The Pd-catalyzed reaction of allylic carbonates with the lithio derivatives of diox-olanone prepared by the treatment of mandelic acid with acetone dimethyl acetal gives the desired a-allylation products in good yields. Upon treatment with HCl in ethanol the corresponding a-hydroxy ethyl esters can be obtained " (Scheme 11). 

A new diphosphine ligand, Norphos , catalyses the reduction of Z-a-(acetyl-amino)cinnamic acids to the expected dihydrocinnamic acids with optical yields of ca. 96%. ° The ligand is prepared from trans-vinylidenebis(diphenylphosphine oxide) by a Diels-Alder reaction with cyclopentadiene, classical resolution using (L)-(-)-dibenzoyltartaric acid, and finally reduction. The same substrates can also be reduced in ca. 80% optical yields using diphosphine ligands derived from enantiomerically pure menthoP or mandelic acid. ... 

The preparation of myo-inositol 1,4,5-triphosphate by a process involving selective formation of diastereomeric menthyl esters in a similar way to that described in Vol. 25, p. 209, ref. 59 or by resolution of racemic derivatives with R-mandelic acid or l-/-menthoxyacetyl chloride (which involves the use of a new phosphitylating agent, o-xylene AT,lV-diethylphosphoramidite) have been reported. 

Catechol-O-methyltransferase from rat liver requires S-adeno-sylmethionine as a methyl donor and can methylate catechol but not monohydroxy derivatives of phenylethylamine. In vivo, O-methylation occurs exclusively in the meta position to the carbon side chain, but with purified preparations of the enzyme in vitro methylation can lead to both meta and para methylation. The ratio of products is susceptible. to both the polarity of the substrate and the pH of the medium . In man 3-methoxy-4-hydroxy-mandelic acid (18) comprises about 40 per cent of the total urinary metabolites produced from the catecholamines whilst in other pecies 3-methoxy-4-hydroxyphenylglycol (19), isolated as a sulphate ester, is the predominant breakdown product . A typical metabolic grid which indicates the possible types of pathway leading from noradrenalin (17) to both of these metabolites is shown in Figure 4.4 analogous metabolic schemes may be drawn up for both adrenalin and dopamine. 

---