Resolution of Racemates by Crystallization

At present, the resolution of racemates via dassical diastereomer crystallization as a method of chiral target production is somewhat hampered by a rapid development of other methods, mainly asymmetric synthesis, including biocatalysis [9] and enantioselective chromatography [11], Diastereomer crystallization remains, however, an important technique because of its two fundamental advantages, especially attradive for industry. First, process development (practical know-how and accessibility to wide libraries of the resolving agents) is usually fast and easy. Second, the cost is often low compared to other methods. 

The X-ray-determined structure of the complex of 16 and 19 with quaternary salt 15 revealed that the primary discriminative forces leading to an efficient resolution are the formation of directional hydrogen bonds of hydroxy groups of cinchonidine and BINOL with the halide anion as well as aryl-aryl interaction between the naphthyl and the quinoline rings [40]. 

426 7 3 Resolution of Racemates and Enantioselective Analytics by Cinchona Alkaloids and Their Derivatives 

Target/fu notion Resolving agent (number of recrystallization steps) Yield of crystalline diastereomeric salt (%) Configuration or optical rotation sign of resolved enantiomer ee or optical purity (op) (%) Reference 

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Origins of Optical Activity in Nature (Ed. D. C. Walker), Elsevier, New York, 1979 resolution of racemates by crystallization succeeds by Tamura s Preferential Enrichment in the mother liquor T. Ushio, R. Tamura, H. Taka-hashi, N. Azuma, K. Yamamoto, Angew. Chem. 1996, 108, 2544-2546 Angew. Chem. Int. Ed. Engl. 1996, 35, 2372-2374 R. Tamura, T. Ushio, H. Takahashi, K. Nakamura,... 

Resolution of racemates by the selective liquid-liquid extraction (Figure 13.8) of diastereomers due to their different solubility in two-phase system is by far a less common technique than crystallization of diastereomers. In this process, a highly discriminative chiral ionic reagent transfers (preferably in one extraction step) a highly enriched enantiomer as an ionic pair from one phase to another, which dissolves selectively the formed diastereomeric associate but not the starting enantiomers. The following back-extraction with an appropriate acid or base produces the desired enantiomer and recovered chiral selector (SO). 

Resolution of racemates by classical separation of diastereomeric salts remains a valid alternative to enantioselective synthesis. A simple but ingenious idea has recently been proposed and shown to work successfully the use of families of resolving agents that would work as a library on the racemate to be resolved, so that the least soluble salt would crystallize out. As a matter of fact, Broxterman [21] has shown that a mixture of acylated tartaric acids like 6a-c of Fig. 8, gave immediate crystallization in 97 out of 100 amine racemates studied, allowing a more rapid choice of resolving agents to be made in a more suitable manner than was previously possible. 

Bonner concluded that efficient polymerization mechanisms that involve enantiose-lective enrichment via a-helix or /3-sheet secondary structures during polypeptide growth, are applicable to prebiotic environments. Total spontaneous resolution of racemates during crystallization involving secondary asymmetric transformations can also be important. The polymerization amplification concept involves the partial polymerization of a slightly enriched amino acid mixture, followed by an autocatalytic sequence of additional partial hydrolysis and polymerization steps. These amplification reactions occur because reactions of one enantiomer with another to form two diastereomeric products occur at different rates for each diastereomer. 

Fig. 4a. Resolution of racemic (67) by column chromatography on microcrystalline cellulose triacetate (column B) and by recrystallization 35) C = crystals M = mother liquor the index following C or M gives the number of recrystallizations the fraction has undergone. The value of [ot] ° is given, followed by the quantity obtained...

D-Pantolactone and L-pantolactone are used as chiral intermediates in chemical synthesis, whereas pantoic acid is used as a vitamin B2 complex. All can be obtained from racemic mixtures by consecutive enzymatic hydrolysis and extraction. Subsequently, the desired hydrolysed enantiomer is lactonized, extracted and crystallized (Figure 4.6). The nondesired enantiomer is reracemized and recycled into the plug-flow reactor [33,34]. Herewith, a conversion of 90-95% is reached, meaning that the resolution of racemic mixtures is an alternative to a possible chiral synthesis. The applied y-lactonase from Fusarium oxysporum in the form of resting whole cells immobilized in calcium alginate beads retains more than 90% of its initial activity even after 180 days of continuous use. The biotransformation yielding D-pantolactone in a fixed-bed reactor skips several steps here that are necessary in the chemical resolution. Hence, the illustrated process carried out by Fuji Chemical Industries Co., Ltd is an elegant way for resolution of racemic mixtures. 

Resolution of a racemic mixture is still a valuable method involving fractional crystallization [113], chiral stationary phase column chromatography [114] and kinetic resolutions. Katsuki and co-workers demonstrated the kinetic resolution of racemic allenes by way of enantiomer-differentiating catalytic oxidation (Scheme 4.73) [115]. Treatment of racemic allenes 283 with 1 equiv. of PhIO and 2 mol% of a chiral (sale-n)manganese(III) complex 284 in the presence of 4-phenylpyridine N-oxide resulted... 

Racemic pipecolic acid (6) is obtained by ring closure of TV-alkylglycines by ionic 203 or radical 204 mechanisms. It also may be obtained by conversion of suitable substituents at the C2 of piperidine into the 2-carboxy group, e.g. hydrolysis of a nitrile group 205 or oxidation of a 1,2-dihydroxyethyl group. 206 Resolution of the racemic mixture can be carried out by fractional crystallization. 207-209 Enzymatic resolution of racemic pipecolic acid 210-213 or of synthetic intermediates 214 has been reported. 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

Resolution of racemic 1,3/4/6,7,llb-hexahydro-2H-pyrazino[l,2-a]iso-quinolin-4-one into enantiomers was unsuccessful either through the crystallization of diastereomeric chiral salts prepared from enantiopure acids in different solvent mixtures, or with kinetic resolution by an enzymatic acylation using different enzymes (08EJO895). 

Cramer, F., and Dietsche, W. 378 (1959) Occlusion compounds. XV. Resolution of racemates with cyclodextrins, Chem. Ber. 92 b) Toda, F., and Tohi, Y. (1993) Novel optical resolution methods by inclusion crystallization in suspension media and by fractional distillation,/. Chem. Soc., Chem. Commun., 1238-1240 c) Toda, F., and Tanaka, K. (1988) A new chiral host compound... 

It is worth to mention that both coordination compounds, namely [Ca(7)2]DBTA and [Ca(H20)](12)DBTA form conglomerates with their enantiomers, respectively. Thus, optical resolution of racemic DBTA by preferential crystallization of these coordination complexes is also possible. [26, 27]... 

Kozma, D., Bocskei, Zs., Kassai, Cs., Simon, K., and Fogassy, E. Optical resolution of racemic alcohols by diastereoisomeric complex formation with 0,0 -dibenzoyl-(2R,3R)-tartaric acid, the crystal structure of the (-)-lR,2 S, 5R-menthol.O,0,-dibenzoyl-(2R,3R)-tartaric acid complex. J. Chem. Soc. Chem. Commun. 1996, 753-754. 

Haring and Schreier have modified the active site of subtilisin cross-linked enzyme crystals by introducing selenium into it and thereby converting the enzyme into a peroxidase [36], The rigid CLC matrix allowed them to chemically modify subtilisin without loss of the tertiary structure. The kinetic resolution of racemic 2-hydroxy- 1-phenylethyl hydroperoxide was demonstrated using the semisynthetic CLC (Fig. 12). The reaction time was 25-30 min with an ee of 97%. The authors demonstrated the stability of these semisynthetic CLCs by cycling their enzyme 10 times. 

Finally, libraries aimed to chiral resolution of racemates will be covered here in particular, the use of chiral stationary phases (CSPs) has recently been reported for the identification of materials to be used for chiral separation of racemates by HPLC. The group of Frechet reported the selection of two macroporous poly methacrylate-supported 4-aryl-1,4-dihydropyrimidines (DHPs) as CSPs for the separation of amino acid, anti-inflammatory drugs, and DHP racemates from an 140-member discrete DHP library (214,215) as well as a deconvolutive approach for the identification of the best selector phase from a 36-member pool library of macroporous polymethacrylate-grafted amino acid anilides (216,217). Welch and co-workers (218,219) reported the selection of the best CSP for the separation of a racemic amino acid amide from a 50-member discrete dipeptide iV-3,5-dinitrobenzoyl amide hbrary and the follow-up, focused 71-member library (220). Wang and Li (221) reported the synthesis and the Circular Dichroism- (CD) based screening of a 16-member library of CSPs for the HPLC resolution of a leucine ester. Welch et al. recentiy reviewed the field of combinatorial libraries for the discovery of novel CSPs (222). Dyer et al. (223) reported an automated synthetic and screening procedure based on Differential Scanning Calorimetry (DSC) for the selection of chiral diastereomeric salts to resolve racemic mixtures by crystallization. Clark Still rejxrrted another example which is discussed in detail in Section 9.5.4. 

Resolution of Alcohols. In addition to generally providing highly crystalline derivatives that are usually suitable for X-ray crystallographic studies, diastereomeric esters derived from camphanic acid have been widely used in organic synthesis for the resolution of racemic alcohols by fractional crystallization or chromatography. This is one of the methods of choice to resolve inositol derivatives. Selected examples are shown in (7)-<10). ... 

Platinum complexes incorporating an optically active amine have been employed for resolution of racemic mixtures of optically active olefins by reaction of the olefin with dichloro-platinum(II). The differing solubility of the diastereoisomers permits separation by fractional crystallization and the olefin can be recovered by reaction of the complex with aqueous alkali cyanide. Using either (-f)-l-phenyl-2-aminopropane (Dexedrine) or (-f)- or (—)-a-phenyl-ethylamine. Cope and co-workers have resolved the optical isomers of trans double bond coordinated and, with (—)-phenylethyl-amine)dichloroplatinum(II), a bridged complex with each double bond coordinated to a different platinum atom. 

Weissbuch, 1. Zbaida, D. Addadi, L. Leiserowitz, L. Lahav, M. Design of polymeric inhibitors for the control of crystal polymorphism - induced enantiomeric resolution of racemic histidine by crystallization at 25 degrees. J. Am. Chem. Soc. 1987,109 (6), 1869-1871. 

Resolution of racemic material. IngersolP worked out a procedure in which the d-amine is obtained by crystallization as the salt with /-malic acid and the /-amine is isolated by treatment of the mother liquor amine with D-tartaric acid. Helferich and Portz" discovered a novel method of resolution in which an ethereal solution is prepared from 1/20 mole of the d/-amine and 3/40 mole of 2,3,4,6-tetra-O-acetyl-D-glucose. A crystalline addition complex which separates on being split with hydrochloric acid affords the salt of the d-amine in 48% yield. The ethereal mother liquor serves for isolation of the /-amine. 

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