Resolution, of racemates

The resolution of racemic mixtures, i.e., the separation of at least one of the enantiomers in pure form, is an important step in the manufacture of chiral products in the pharmaceutical, agrochemical, flavour and perfumery industries and for other specialty chemicals. The necessity to resolve racemic mixtures is particularly strong in the pharmaceutical industry since the two component enantiomers (see section 1.9 for definition of terms) in the equimolar mixture can have very different pharmacological activities. Thalidomide is a frequently quoted example one stereoisomer was the beneficial agent for preventing morning sickness in pregnant women while the other caused serious birth defects. 

Examples of different crystallization procedures have been given by Secor (1963) Collet, Brienne and Jacques (1980) Jacques, Collet and Wilen (1981) Asai (1983) Samant and Chandalla (1985) Sheldon (1993) Collins, Sheldrake and Crosby (1995). 

Racemic compound systems, which account for more than 90% of all racemic mixtures, cannot be resolved by direct crystallization, but a common 

The liquid conglomerate is supercooled, following a path from say X through E to point Y below the solidus. The two liquidus curves for D and L may be extended (dotted lines) beyond E into the metastable region. At point Y, seeds of one of the enantiomorphs are added. L seeds, for example, cause L crystals to be deposited and the residual liquid becomes richer in D. By the mixture rule (section 4.3), one mole of racemate gives MY/MO mole of pure L and YO/MO 

The yield from each crystallization depends on the ratio MN/PN, which increases with the supercooling EY. It is, of course, necessary to find the optimal conditions of temperature and agitation which allow maximum yields of D and L without disturbing the metastable conditions on which the process depends (Collet, Brienne and Jacques, 1980). 

This still constitutes the main industrial method for synthesis of optically active compounds. 

Method (i) is particularly attractive when it is accompanied by spontaneous in situ racemisation, when a theoretical once-through yield of 100% is achievable. Such a process is often referred to as deracemisation. 

Although diastereomer resolution has a low technology image it is widely used industrially, and there are many instances where it is the method of choice and is economical. The technique is often considered to be empirical, however, Collet et ai, [12] have described guidelines which permit a more scientific approach. 

Kinetic resolutions can be either catalytic or stoichiometric, and from an economic and environmental stance the former are obviously preferable. 

Chiral HPLC separation techniques have some significant advantages over classical resolution methods  

Reaction conditions 1. pyridine r.t., overnight 2a. HPLC on silica gel, 98 2 dichloroethane/ethyl acetate, b. LiOH, H2O, dimethoxyethane 5 °C, 4 h 

Chemistry-based kinetic resolution methods, which make use of the preferential reaction of one enantiomer with a chiral reagent (e.g. hydroboration of racemic alkenes with diisopinocampheylborane) or an achiral reagent in the presence of an appropriate chiral catalyst (e.g. Sharpless epoxidation of racemic allylic alcohols with t-BuOOH in the presence of (2R,3R)- or (25,35)-diisopropyl tartrate and Ti(Oi-Pr)4) have not been exploited so far for the isolation of e.p. labeled substances. In contrast, biochemical methods have been widely used, particularly for the resolution of racemic a-[ C]amino acids and various [ C]carboxylic acids. Such methods, including  

In the ideal case, methods A, B and C provide equal amounts of (S)- and (i )-a-[ H/ C]-amino acids (or derivatives) upon separation. If complete transformation of racemic material is required, re-racemization of the undesired enantiomer can be accomplished chemically by acid catalysis in the presence of catalytic amounts of salicylaldehyde thermal treatment or enzymatically with the aid of transferases and subjection of the undesired product to repeated resolution cycles, as illustrated for (21 )-[3- C]tryptophan (16). 

Reaction conditions la. PhCHO, NH4CI, aq. NH3, b. HCI, CH3OH 2.PhCHO, (fl,fl)-tartaric acid, EtOH r.t. 

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A minor chemical use for many of the commoner alkaloids is the resolution of racemic compounds (often acids) into their optically active enantiomorphs. 

Acetophenone similarly gives an oxime, CHjCCgHjlCtNOH, of m.p. 59° owing to its lower m.p. and its greater solubility in most liquids, it is not as suitable as the phenylhydrazone for characterising the ketone. Its chief use is for the preparation of 1-phenyl-ethylamine, CHjCCgHslCHNHj, which can be readily obtained by the reduction of the oxime or by the Leuckart reaction (p. 223), and which can then be resolved by d-tartaric acid and /-malic acid into optically active forms. The optically active amine is frequently used in turn for the resolution of racemic acids. 

Among chiral dialkylboranes, diisopinocampheylborane (8) is the most important and best-studied asymmetric hydroborating agent. It is obtained in both enantiomeric forms from naturally occurring a-pinene. Several procedures for its synthesis have been developed (151—153). The most convenient one, providing product of essentially 100% ee, involves the hydroboration of a-pinene with borane—dimethyl sulfide in tetrahydrofuran (154). Other chiral dialkylboranes derived from terpenes, eg, 2- and 3-carene (155), limonene (156), and longifolene (157,158), can also be prepared by controlled hydroboration. A more tedious approach to chiral dialkylboranes is based on the resolution of racemates. /n j -2,5-Dimethylborolane, which shows excellent enantioselectivity in the hydroboration of all principal classes of prochiral alkenes except 1,1-disubstituted terminal double bonds, has been... 

EinaHy, kinetic resolution of racemic olefins and aHenes can be achieved by hydroboration. The reaction of an olefin or aHene racemate with a deficient amount of an asymmetric hydroborating agent results in the preferential conversion of the more reactive enantiomer into the organoborane. The remaining unreacted substrate is enriched in the less reactive enantiomer. Optical purities in the range of 1—65% have been reported (471). 

Microorganisms and their enzymes have been used to functionalize nonactivated carbon atoms, to introduce centers of chirahty into optically inactive substrates, and to carry out optical resolutions of racemic mixtures (1,2,37—42). Their utifity results from the abiUty of the microbes to elaborate both constitutive and inducible enzymes that possess broad substrate specificities and also remarkable regio- and stereospecificities. 

Deamination, Transamination. Two kiads of deamination that have been observed are hydrolytic, eg, the conversion of L-tyrosiae to 4-hydroxyphenyUactic acid ia 90% yield (86), and oxidative (12,87,88), eg, isoguanine to xanthine and formycia A to formycia B. Transaminases have been developed as biocatalysts for the synthetic production of chiral amines and the resolution of racemic amines (89). The reaction possibiUties are illustrated for the stereospecific synthesis of (T)-a-phenylethylamine [98-84-0] (ee of 99%) (40) from (41) by an (5)-aminotransferase or by the resolution of the racemic amine (42) by an (R)-aminotransferase. 

One of the homochiral starting materials (45) for the acetylcholinesterase (ACE) inhibitor captopril [62571 -86-2] (47) is produced by a Hpase enzyme-catalyzed resolution of racemic 3-methyl-4-acetylthiobutyric acid (44) and L-proline (46) (65). 

Despite the progress made in the stereoselective synthesis of (R)-pantothenic acid since the mid-1980s, the commercial chemical synthesis still involves resolution of racemic pantolactone. Recent (ca 1997) synthetic efforts have been directed toward developing a method for enantioselective synthesis of (R)-pantolactone by either chemical or microbial reduction of ketopantolactone. Microbial reduction of ketopantolactone is a promising area for future research. 

Enzyme-Catalyzed Asymmetric Synthesis. The extent of kinetic resolution of racemates is determined by differences in the reaction rates for the two enantiomers. At the end of the reaction the faster reacting enantiomer is transformed, leaving the slower reacting enantiomer unchanged. It is apparent that the maximum product yield of any kinetic resolution caimot exceed 50%. 

Resolution of racemic alcohols by acylation (Table 6) is as popular as that by hydrolysis. Because of the simplicity of reactions ia nonaqueous media, acylation routes are often preferred. As ia hydrolytic reactions, selectivity of esterification may depend on the stmcture of the acylatiag agent. Whereas Candida glindracea Upase-catalyzed acylation of racemic-cx-methylhenzyl alcohol [98-85-1] (59) with butyric acid has an enantiomeric value E of 20, acylation with dodecanoic acid increases the E value to 46 (16). Not only acids but also anhydrides are used as acylatiag agents. Pseudomonasfl. Upase (PFL), for example, catalyzed acylation of a-phenethanol [98-85-1] (59) with acetic anhydride ia 42% yield and 92% selectivity (74). 

Resolution of Racemic Amines and Amino Acids. Acylases (EC3.5.1.14) are the most commonly used enzymes for the resolution of amino acids. Porcine kidney acylase (PKA) and the fungaly3.spet i//us acylase (AA) are commercially available, inexpensive, and stable. They have broad substrate specificity and hydrolyze a wide spectmm of natural and unnatural A/-acyl amino acids, with exceptionally high enantioselectivity in almost all cases. Moreover, theU enantioselectivity is exceptionally good with most substrates. A general paper on this subject has been pubUshed (106) in which the resolution of over 50 A/-acyl amino acids and analogues is described. Also reported are the stabiUties of the enzymes and the effect of different acyl groups on the rate and selectivity of enzymatic hydrolysis. Some of the substrates that are easily resolved on 10—100 g scale are presented in Figure 4 (106). Lipases are also used for the resolution of A/-acylated amino acids but the rates and optical purities are usually low (107). 

Optically active thiiranes have been obtained by resolution of racemic mixtures by chiral tri-o-thymotide. The dextrorotatory thymotide prefers the (5,5)-enantiomer of 2,3-dimethylthiirane which forms a 2 1 host guest complex. A 30% enantiomeric excess of (5,5)-(—)-2,3-dimethylthiirane is obtained (80JA1157). 

The advantage of this ketal is that unlike the THP group, only a single isomer is produced in the derivatization. Conditions used to hydrolyze the THP group can be used to hydrolyze this acetal. This group may also find applications in the resolution of racemic alcohols. 

Optically pure 5-HETE can be made in quantity by resolution of racemic 5-HETE (Ref. 2). 

Resolution of Racemic Acid.—The racemic acid is dissolved in water (250 c.c.) and divided into two equal volumes. Half of the solution is carefully neutralised with caustic soda and the other half with ammonia, and the two solutions then mixed. 

Bis(phe nylthiomethyl)dihydropyran, CSA, CHCI3, 54-93% yield. This dihydropyran can be used for the resolution of racemic diols or for regio-selective protection, which is directed by the chirality of the dihyropyran. Other 2,2 -substituted bisdihydropyrans that can be cleaved by a variety of methods are available, and their use in synthesis has been reviewed. ... 

The application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

J. Dingenen and J. N. Kinkel, Preparative cliromatograpliic resolution of racemates on chiral stationary phases on laboratoiy and production scales by closed-loop recycling cliromatography , J. Chromatogr. 666 627-650 (1994). 

E. Erancotte, Chromatography as a separation tool for the preparative resolution of racemic compounds in Chiral separations, applications and technology, S. Ahuja (Ed.), American Chemical Society, Washington (1997) Chapter 10. 

Erancotte E. (1996) Chromatography as a Separation Tool for the Preparative Resolution of Racemic Compounds, in Chiral Separations. Applications and Technology, Ahuja S. (ed.), American Chemical Society, p. 271-308. 

Fipases and esterases are often used for Idnetic resolution of racemates, variously by hydrolysis, esterification, or transesterification of suitable precursors. Scheme 8.3-3 illustrates the principal for the resolution of a secondary alcohol by esterification with vinyl acetate. 

Schemes 3-7 describe the synthesis of cyanobromide 6, the A-D sector of vitamin Bi2. The synthesis commences with an alkylation of the magnesium salt of methoxydimethylindole 28 to give intermediate 29 (see Scheme 3a). The stereocenter created in this step plays a central role in directing the stereochemical course of the next reaction. Thus, exposure of 29 to methanol in the presence of BF3 and HgO results in the formation of tricyclic ketone 22 presumably through the intermediacy of the derived methyl enol ether 30. It is instructive to point out that the five-membered nitrogen-containing ring in 22, with its two adjacent methyl-bearing stereocenters, is destined to become ring A of vitamin Bi2. A classical resolution of racemic 22 with a-phenylethylisocyanate (31) furnishes tricyclic ketone 22 in enantiomerically pure form via diaster-eomer 32.

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

A noteworthy feature of the Sharpless Asymmetric Epoxidation (SAE) is that kinetic resolution of racemic mixtures of chiral secondary allylic alcohols can be achieved, because the chiral catalyst reacts much faster with one enantiomer than with the other. A mixture of resolved product and resolved starting material results which can usually be separated chromatographically. Unfortunately, for reasons that are not yet fully understood, the AD is much less effective at kinetic resolution than the SAE. 

A variety of methods for the asymmetric syntheses of aziridine-2-carboxylates have been developed. They can be generally classified into eight categories based on the key ring-forming transformation and starting materials employed (i) cyclization of hydroxy amino esters, (ii) cyclization of hydroxy azido esters, (iii) cyclization of a-halo- and ot-sulfonyloxy-(3-amino esters, (iv) aziridination of ot, 3-unsaturated esters, (v) aziridination of imines, (vi) aziridination of aldehydes, (vii) 2-carboxylation of aziridines, and (viii) resolution of racemic aziridine-2-carboxylates. 

Asymmetric Syntheses with Aziridinecarboxylate and Aziridinephosphonate Building Blocks 3.2.1.8 Resolution of Racemic Aziridine-2-carboxylates... 

Several early reports dealt with the resolution of racemic aziridine-2-carboxylic acids [72, 73], Treatment of ( )-78 (Scheme 3.25) with (-)-trans-2,3-bis(hydroxydi-phenylmethyl)-l,4-dioxaspiro[5.4]decane (79), for example, afforded the 1 1 ratio inclusion compound 80. Upon distillation, the inclusion compound 80 gave en-antiomerically pure (-)-78 in 33% yield. 

The principle cost determinant in typical hydrolytic or phenolic resolutions is the cobalt catalyst, despite the relatively low catalyst loadings used in most cases and the demonstrated recyclability with key substrates. From this standpoint, recently developed oligomeric (salen)Co complexes, discussed earlier in this chapter in the context of the hydrolytic desymmetrization of meso-epoxides (Scheme 7.16), offer significant advantages for kinetic resolutions of racemic terminal epoxides (Table 7.3) [29-31]. For the hydrolytic and phenolic kinetic resolutions, the oligo-... 

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