Methods of Resolution - Stereochemistry and Conformation - Introduction - March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Part I. Introduction

Chapter 4. Stereochemistry and Conformation

4.H. Methods of Resolution160

A pair of enantiomers can be separated in several ways, but conversion to diastereomers and separation of these by fractional crystallization or chromatographic methods are used most often. In this method and in some of the others, both isomers can be recovered, but in some methods it is necessary to destroy one.

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1. Conversion to Diastereomers. If the racemic mixture to be resolved contains a carboxyl group (and no strongly basic group), it is possible to form a salt with an optically active base. Since the base used is, say, the (S) form, there will be a mixture of two salts produced having the configurations (SS) and (RS). Although the acids are enantiomers, the salts are diastereomers and have different properties. The property most often used for separation is differential solubility. The mixture of diastereomeric salts is allowed to crystallize from a suitable solvent. Since the solubilities are different, the initial crystals formed will be richer in one diastereomer. Filtration at this point will already have achieved a partial resolution. Unfortunately, the difference in solubility is rarely if ever great enough to effect total separation with one crystallization. When fractional crystallizations must be used, the process is long and tedious. Fortunately, naturally occurring optically active bases (mostly alkaloids) are readily available. Among the most commonly used are brucine, ephedrine, strychnine, and morphine. Once the two diastereomers have been separated, it is easy to convert the salts back to the free acids and the recovered base can be used again.

Most resolution of this type is done on carboxylic acids and often, when a molecule does not contain a carboxyl group, it is converted to a carboxylic acid before resolution is attempted. Racemic compounds (e.g., 2-aminocylohexanol derivatives) react with carboxylic acids (e.g., optically active mandelic acid), to give diastereomers that are separated and then converted to enantiopure compounds.161 Racemic bases can be converted to diastereomeric salts with active acids. The principle of conversion to diastereomers is not confined to carboxylic acids, and other functional groups162 may be coupled to an optically active reagent.163 Alcohols164 can be converted to diastereomeric esters, aldehydes to diastereomeric hydrazones, and so on. Amino alcohols have been resolved using boric acid and chiral binaphthols.165 Phosphine oxides166 and chiral calix[4]arenes167 have been resolved. Chiral crown ethers have been used to separate mixtures of enantiomeric alkylammonium and arylammonium ions, by the formation of diastereomeric complexes168 (see also, category 3, below). Even hydrocarbons can be converted to diastereomeric inclusion compounds,169 with urea. Urea is not chiral, but the cage structure is.170 Racemic unsaturated hydrocarbons have been resolved as inclusion complex crystals with a chiral host compound derived from tartaric acid.171trans-Cyclooctene (Sec. 4.C, category 6) was resolved by conversion to a Pt complex containing an optically active amine.172

Fractional crystallization has always been the most common method for the separation of diastereomers. When it can be used, binary phase diagrams for the diastereomeric salts have been used to calculate the efficiency of optical resolution.173 However, it is tedious and the fact that it is limited to solids prompted a search for other methods. Fractional distillation has given only limited separation, but gas chromatography (GC)174 and preparative liquid chromatography using chiral columns175 have proved to be more useful. In many cases, they have supplanted fractional crystallization, especially where the quantities to be resolved are small.176

2. Differential Absorption. When a racemic mixture is placed on a chromatographic column, if the column consists of chiral substances, then in principle the enantiomers should move along the column at different rates and should be separable without having to be converted to diastereomers.176 This has been successfully accomplished with paper, column, thin-layer,177 and gas and liquid chromatography.178 For example, racemic mandelic acid has been almost completely resolved by column chromatography on starch.179 Many workers have achieved separations with gas and liquid chromatography by the use of columns packed with chiral absorbents.180 Columns packed with chiral materials are now commercially available and are capable of separating the enantiomers of certain types of compounds.181

3. Chiral Recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is called chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether (58) partially to resolve the racemic amine salt (59).182 When an aqueous solution of 59 was mixed with a solution of optically active 58 in chloroform, and the layers separated, the chloroform layer contained about twice as much of the complex between 58 and (R)-59 as of the diastereomeric complex. Many other chiral crown ethers and cryptands have been used, as have been cyclodextrins,183 cholic acid,184 and other kinds of hosts.169 Of course, enzymes are generally very good at chiral recognition, and much of the work in this area has been an attempt to mimic the action of enzymes.

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4. Biochemical Processes.185 Reactions catalyzed by enzymes can be utilized for this kind of resolution.186 Biological molecules may react at different rates with the two enantiomers. For example, a certain bacterium may digest one enantiomer, but not the other. Pig liver esterase has been used for the selective cleavage of one enantiomeric ester.187 This method is limited, since it is necessary to find the proper organism and since one of the enantiomers is destroyed in the process. However, when the proper organism is found, the method leads to a high extent of resolution since biological processes are usually very stereoselective. This process has been called chemoenzymatic dynamic kinetic resolution.188

5. Mechanical Separation.189 This is the method by which Pasteur proved that racemic tartaric acid was actually a mixture of (+)- and (−)-tartaric acids.190 In the case of racemic sodium ammonium tartrate, the enantiomers crystallize separately: all the (+) molecules going into one crystal and all the (−) into another. Since the crystals too are nonsuperimposable, their appearance is not identical and a trained crystallographer can separate them with tweezers.191 However, this is seldom a practical method, since few compounds crystallize in this manner. Even sodium ammonium tartrate does so only when it is crystallized <27°C. A more useful variation of the method, although still not very common, is the seeding of a racemic solution with something that will cause only one enantiomer to crystallize.192 An interesting example of the mechanical separation technique was reported in the isolation of heptahelicene (Sec. 4.C. Category 7). One enantiomer of this

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compound, which incidentally has the extremely high rotation of img = +6200° spontaneously crystallizes from benzene.193 In the case of 1,1′-binaphthyl, optically active crystals can be formed simply by heating polycrystalline racemic samples of the compound at 76–150°C. A phase change from one crystal form to another takes place.194 Note that 1,1′-binaphthyl is one of the few compounds that can be resolved by the Pasteur tweezer method. In some cases, resolution can be achieved by enantioselective crystallization in the presence of a chiral additive.195 Spontaneous resolution has also been achieved by sublimation. In the case of the norborneol derivative 60, when the racemic solid is subjected to sublimation, the (+) molecules condense into one crystal and the (−) molecules into another.196 In this case, the crystals are superimposable, unlike the situation with sodium ammonium tartrate, but the investigators were able to remove a single crystal, which proved optically active.

6. Kinetic Resolution.197 Since enantiomers react with chiral compounds at different rates, it is sometimes possible to effect a partial separation by stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed in Section 4.C, category 5. A method has been developed to evaluate the enantiomeric ratio of kinetic resolution using only the extent of substrate conversion.198 An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane,199 since alkenes do not easily lend themselves to conversion to diastereomers if no

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other functional groups are present. Another example is the resolution of allylic alcohols (e.g., 61) with one enantiomer of a chiral epoxidation agent (see Reaction 15-50).200 In the case of 61, the discrimination was extreme. One enantiomer was converted to the epoxide and the other was not, the rate ratio (hence the selectivity factor) being >100. Of course, in this method only one of the enantiomers of the original racemic mixture is obtained, but there are at least two possible ways of getting the other: (1) use of the other enantiomer of the chiral reagent and (2) conversion of the product to the starting compound by a reaction that preserves the stereochemistry.

Kinetic resolution of racemic allylic acetates201 has been accomplished via asymmetric dihydroxylation (Reation 15-48), and 2-oxoimidazolidine-4-carboxylates have been developed as new chiral auxiliaries for the kinetic resolution of amines.202 A planar chiral cyclic ether was found to be stable at ambient temperatures, but resolved by kinetic resolution.203

7. Deracemization. In this type of process, one enantiomer is converted to the other, so that a racemic mixture is converted to a pure enantiomer, or to a mixture enriched in one enantiomer (enantioenriched). This finding is not quite the same as the methods of resolution previously mentioned, although an outside optically active substance is required. To effect the deracemization, two conditions are necessary: (1) the enantiomers must complex differently with the optically active substance and (2) they must interconvert under the conditions of the experiment. When racemic thioesters were placed in solution with a specific optically active amide for 28 days, the solution contained 89% of one enantiomer and 11% of the other.204 In this case, the presence of a base (Et3N) was necessary for the interconversion to take place. Biocatalytic deracemization processes induce deracemization of chiral secondary alcohols.205 In a specific example, Sphingomonas paucimobilis NCIMB 8195 catalyzes the efficient deracemization of many secondary alcohols in up to 90% yield of the (R)-alcohol.206