Racemic mandelic acid derivatives

Faber et al. have reported a novel process for the overall deracemization of racemic mandelic acid derivatives using a combination of an enantioselective lipase and a mandelate racemase activity from Lactobacillus paracasei (Figure 5.19) [32]. 

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. 

Blaschke, G. Chromatographic resolutions of racemates. III. Chromatography of racemic mandelic acid on polyacrylic esters and amides of optically active ephedrine derivatives, Chem. Ber., 1974, 107, 237-252. 

Epichlorohydrin-cross-linked cyclohexa- and cyclohepta-amylose gels have been used for the chromatographic resolution of racemic mandelic acid and its derivatives. Modified cyclohepta-amylose bound the L-(- -)-isomers preferentially, and resolved D,L-methyl mandelate to give the D-(—)-isomer of 100% optical purity in the first fraction. Cross-linked cyclohexa-amylose bound D-(—)-isomers more strongly than L-(-t-)-isomers, resolving D,L-methyl mandelate to a smaller extent than cross-linked cyclohepta-amylose. Binding was studied quantitatively by the equilibrium method. 

For an asymmetric reaction to be really useful enantiomeric excesses typically above 90% are needed and preferably even higher. The recent use of a chiral proton donor attached to polystyrene achieves this and perhaps equally important offers a methodology far superior to the nonsupported analogue [93]. In this work (D)-mandelic acid has been bound to chloromethylated polystyrene via its carboxylic acid. This species was then employed as a proton donor to the silyl enol ether derived from racemic mandelic acid to reform specifically one optical isomer of man-delic acid. Enantiomeric excesses up to 94% have been achieved. The chiral polymer has been recycled satisfactorily and one could speculate that a continuous process could be established converting racemic acid into one pure enantiomer using the corresponding polymer-bound enantiomer as the mediator. 

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]. 

In 1978, Harada et al. [17] used polymerized CD with gel support for the chiral resolution of mandelic acid and its derivatives. Later Zsadon et al. [18-21] used cyclodextrin-based CSPs for the chiral resolution of indole alkaloids, with aqueous buffers as the mobile phases. Today CD-based CSPs have a good reputation. In separate studies, Fujimura [22] and Kawaguchi [23] and their colleagues resolved the enantiomers of aromatic compounds in the reversed-phase mode. Armstrong et al. [29,30,33,34,41,44 46,48,54-63] carried out extensive and remarkable work on the chiral resolution of various racemic compounds using CD-based CSPs. 

Biphenyl-bridged bis-Cp titanocene dichloride and dimethyl complexes have been synthesized, and the kinetic resolution of the racemic final mixture of the products has been carried out. A mixture of diastereomers is obtained by treatment of the dimethyl compound with O-acetyl-mandelic acid, while enantiomerically pure products result in the reaction of the dichloro derivative with (i )-binaphthol and 1 equiv. of LiBun (Scheme 661).1050... 

As shown in Table 5.4, the resolution efficiencies for the p-substituted 1-phenyl-efhylamine derivatives were greatly improved, as was expected, when p-methyl-and p-methoxymandelic acids were used in the place of mandelic acid. These results strongly support our explanation that two factors, hydrogen-bonding interaction to form a supramolecular sheet consisting of 2i-columns and van der Waals interaction between the sheets, govern the stability of diastereomeric salts [11]. The same factors were also found in the diastereomeric salts of racemic arylalka-noic acids with enantiopure amino alcohols [12]. 

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. ... 

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.). 

The L-form composition in eutectic solution is constant at 70% at atmospheric pressure as seen in Figure 5. It shifts to the racemic side when the pressure is elevated (conq>are Figure 4 and Figure 5). It is clear that the region of chiral formation Incomes wider at elevated pressure. In these experimental conditions, the zone of racemic con und formation didn t disi pear but only diminished. The mandelic acid in mother liquor separated from the feed C (L-70%) was 62 to 64% in its L-form concentration and the concentration were higher than the solubility of both the chiral and the racemic of mandelic acid. The analytical results showed that the obtained crystals contained both L-form and D-form Furthermore, XRD analysis of these crystals revealed that L-form and D-form in these crystals are derived from L-form crystals and from the racemic crystals respectively. 

The diastereomers can be separated by crystallisation. While the marketed products contain the racemic mixture of (RJi)-and (S,S)-enantiomers, their separation may be possible using tartaric acid, its 0,0 -dibenzoyl or 0,0 -di-p-toluoyl derivatives, or mandelic acid. [114,115]... 

CDs are produced from starch by the action of Bacillus macerans amylase or the eitzyme cyclodextrin transglycosylate (CTG) [16-19]. The latter enzyme can be used to produce CDs of specific sizes by controlling the reaction conditions. In the past few years, enantiomers have been resolved using peralkylated a-, and y-CDs dissolved in polysiloxanes and coated within glass or fused silica capillary tubing [20, 21]. Subsequently, the CDs were linked to the solid supports. In 1979, Harada etal. [22] polymerized and crosslinked a CD with a gel support, and the CSP developed was tested for the chiral resolution of mandelic acid and its derivatives. Various workers have subsequently bonded all three CDs with different solid supports [23-33]. Of course, these CDs bonded to gel support have been used for the chiral resolution of different racemates, but they suffer from certain drawbacks because of their poor mechanical strength and efficiency in both GC and HPLC. An improvement to these... 

Two details in the above scheme are worth mentioning. Initial attempts at nitrosa-tion of 1,4-BZD ring at C(3) with isoamyl nitrite, the most frequently used agent, failed, due to concomitant attack by isoamyl alkoxide on the oxime. Indeed, when the sterically more crowded t-butyl nitrite (t-BuONO) was substituted for isoamylnitrite oxime, 15 was obtained reproducibly in 85% isolated yield. Second, the effective resolution of racemic 16 was completed with (/ )-(—)-mandelic acid. For complete conversion of the racemate to the mandelate of (3/ )-16, however, 1-2 mol equivalents of water in iso-propylacetate were required, in additimi to the salicaldehyde derivative, whose function is explained in Scheme 6.2. On isolation and structural determination, it became clear that the mandelate of (3/ )-16 crystallizes as the hydrate. 

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. 

Cationic surfactants derived from d(—)-ephedrine analogues show different catalytic efficiencies in hydrolyses of p-nitrophenyl esters of d- and L-mandelic acid (165). Hydrolysis of the racemic mixture is slower than its enantiomers with d(—)-surfactant, suggesting that more than one substrate molecule is incorporated into each micelle. Therefore, an enantiomeric substrate molecule perturbs the micellar structure in such a way that the resulting complex then exhibits markedly different activities toward the two enantiomers. 

He, Y.C., et al.. Preparation of (R)-(-)-mandelic acid and its derivatives from racemates by enantioselective degradation with a newly isolated bacterial strain Alcaligenes sp. 

Deracemization of mandelic add with the combined action of two enzymes has been reported. rac-MandeUc acid is acylated by a Pseudomonas sp. lipase in diisopropyl ether. After solvent removal the mfacture of mandeUc acid enriched in the R-form and the 0-acetyl derivative of the S-configuration are subjected to the mandelate racemase-catalyzed racemization in aqueous buffer. In these conditions only the non-acetylated hydroxy acid is racemized. In order to obtain (S)-0-acetylmandelic acid in an 80% isolated yield and a >98% e.e. the process must be repeated four times [9]. 

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