Stereochemistry enantiomers, resolution

The fundamentals of structure and stereochemistry have been considered in previous chapters in some detail. There are, however, practical aspects of stereochemistry that have not yet been mentioned, particularly with regard to chiral compounds. How, for instance, can a racemic mixture be separated into its component enantiomers (resolution) what methods can be used to establish the configuration of enantiomers how can we tell if they are pure and how do we synthesize one of a pair of enantiomers preferentially (asymmetric synthesis) In this chapter, some answers to these questions will be described briefly. 

The spontaneous separation of the two enantiomers in a racemic mixture so-dium/ammonium tartrate tetrahydrate into enantiomorphic crystals and their subsequent manual separation by Louis Pasteur [1] in 1848 started the road to modem stereochemistry. The resolution of racemic mixtures by chemical and biocata-... 

The above-mentioned chemical catalytic routes lead to racemic AHA mixtures. For the direct use of LA (or its esters) as a solvent or platform molecule for achiral molecules like acrylic acid and pyruvic acid, stereochemistry does not matter. The properties of the polyester PLA, the major application of LA, however, suffer tremendously if d and l isomers are built in irregularly [28]. This is exemplified by atactic PLA, made from racemic LA, which is an amorphous polymer with low performance and limited application. However, when l- and D-lactic acid are processed separately into their respective isotactic L- and d-PLA, as discovered by Tsuji et al., a stereocomplex is formed upon blending these polymers. This polymer exhibits enhanced mechanical and thermal properties [28, 164]. A productive route to D-Iactic acid is, however, missing today. If the chemocatalytic routes to LA are to become viable, enantiomer resolution of the racemate needs to be performed. Given separation success, a cheap source of o-lactic acid will be unlocked immediately, providing an additional advantage over the fermentation route (cfr. Table 2). 

Harada N. Chiral auxiliaries powerful for both enantiomer resolution and determination of absolute configuration by X-ray crystallography. In Demnark SE, Siegel JS, editors. Topics in stereochemistry. Volume 25. Hoboken (NJ) Wiley 2000. p 177-203. 

Harada N, Nehira T, Soutome T, Hiyoshi N, Kido F. Chiral phthalic acid amide, a chiral auxiliary useful for enantiomer resolution and X-ray crystallographic determination of the absolute stereochemistry of alcohols. Enantiomer 1996 1 35-39. 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Biooxidative deracemization of racemic sec-alcohols to single enantiomers [47,48] is complementary to combined metal-assisted lipase-mediated strategies [49,50]. In general, deracemization can be realized by either an enantioconvergent, a dynamic kinetic resolution, or a stereoinversion process. The latter concept is particularly appealing, as only half of the substrate needs to be converted, as the remaining half already represents the product with correct stereochemistry. 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

The stereochemistry of each enantiomer separated by the chiral HPLC has been studied after methanolysis of the epoxy ring. Examining the H NMR data of esters of the produced methoxyalcohols with (S)- and (R)-a-methoxy-a-(tri-fluoromethyl) phenylacetic acid by a modified Mosher s method [181], it has been indicated that the earlier eluting parent epoxides are (3S,4R)-, (6S,7R)-, and (9R,10S)-isomers (Table 7) [75, 76, 179]. The above three chiral HPLC columns show different resolution abilities but a different elution order is not observed. The resolution profile by the reversed-phase OJ-R column has been generalized with molecular shapes of the epoxy compounds considering the... 

Allenamide ( )-13 was prepared by trapping the corresponding lithioallene with carbon dioxide, followed by conversion of the carboxylate to the amide. Chromatographic resolution of the enantiomers of 13 was easily accomplished on a 10x250mm Chiralcel OD HPLC column. Addition of vinyllithium 14 to (+)-13, followed by quenching the reaction with aqueous NaH2P04, led to cyclopentenone (—)-15 in 64% yield with >95% chirality transfer (Eq. 13.4). The absolute stereochemistry of (-)-5 is consistent with the mechanistic hypothesis put forth in Eq. 13.3 [8]. 

Since the early times of stereochemistry, the phenomena related to chirality ( dis-symetrie moleculaire, as originally stated by Pasteur) have been treated or referred to as enantiomericaUy pure compounds. For a long time the measurement of specific rotations has been the only tool to evaluate the enantiomer distribution of an enantioimpure sample hence the expressions optical purity and optical antipodes. The usefulness of chiral assistance (natural products, circularly polarized light, etc.) for the preparation of optically active compounds, by either resolution or asymmetric synthesis, has been recognized by Pasteur, Le Bel, and van t Hoff. The first chiral auxiliaries selected for asymmetric synthesis were alkaloids such as quinine or some terpenes. Natural products with several asymmetric centers are usually enantiopure or close to 100% ee. With the necessity to devise new routes to enantiopure compounds, many simple or complex auxiliaries have been prepared from natural products or from resolved materials. Often the authors tried to get the highest enantiomeric excess values possible for the chiral auxiliaries before using them for asymmetric reactions. When a chiral reagent or catalyst could not be prepared enantiomericaUy pure, the enantiomeric excess (ee) of the product was assumed to be a minimum value or was corrected by the ee of the chiral auxiliary. The experimental data measured by polarimetry or spectroscopic methods are conveniently expressed by enantiomeric excess and enantiomeric... 

Such conventional kinetic resolution reported above often provide an effective route to access to the enantiomerically pure/enriched compounds. However, the limitation of such process is that the resolution of two enantiomers will provide a maximum 50% yield of the enantiomerically pure materials. Such limitation can be overcome in several ways. Among these ways are the use of meso compounds or prochiral substrates,33 inversion of the stereochemistry (stereoinversion) of the unwanted enantiomer (the remaining unreacted substrate),34 racemization and recycling of the unwanted enantiomer and dynamic kinetic resolution (DKR).21... 

The importance of resolution and determination of absolute configuration cannot be overemphasized. There was, in this writer s opinion, little significant progress in developing useful receptor models prior to the determination of the absolute configurations for the active enantiomers of apomorphine, I, certain N-substituted 5-hydroxy-2-amino-l,2,3,4-tetrahydronaphthalenes, and of 6,7-ADTN (X). It is very common to see structures drawn in the literature with their chiral center shown as a particular absolute configuration, for example similar to that of apomorphine. Yet, in many of these cases there is no evidence as to which isomer is active. The reversed stereochemistry for the active enantiomers of apomorphine and... 

G. B. Kauffman, I. Bernal and H.-W. Schiitt, Overlooked opportunities in stereochemistry, Part IV. Eilhard Mitscherlich s near discovery of conglomerate crystallization on the sesquicentennial of Pasteur s resolution of sodium ammonium racemate , Enantiomer, 1999, 4, 33—45. 

Qin, X. R., Ando, T., Yamamoto, M., Yamashita, M., Kusano, K. and Abe, H. (1997). Resolution of pheromonal epoxydienes by chiral HPLC, stereochemistry of separated enantiomers, and their field evaluation. J. Chem. Ecol., 23, 1403-1417. Roelofs, W. and Biostad, L. (1984). Biosynthesis oflepidopteran pheromones. Bioorg. Chem., 12, 279-298. 

Even if the resolution of an amino acid is relatively easy, the synthesis of a racemic mixture when only one enantiomer is desired is wasteful, because half of the product cannot be used. Recently, considerable effort has been devoted to the development of methods that produce only the desired enantiomer by so-called asymmetric synthesis. As was discussed in Chapter 7, one enantiomer of a chiral product can be produced only in the presence of one enantiomer of another chiral compound. In some asymmetric syntheses a chiral reagent is employed. In others a compound called a chiral auxiliary is attached to the achiral starting material and used to induce the desired stereochemistry into the product. The chiral auxiliary is then removed and recycled. 

Summary Fischer Projections andTheir Use 201 Diastereomers 201 Summary Types of Isomers 203 5-12 Stereochemistry of Molecules withTwo or More Asymmetric Carbons 204 5-13 Meso Compounds 205 5-14 Absolute and Relative Configuration 207 5-15 Physical Properties of Diastereomers 208 5-16 Resolution of Enantiomers 209 EssentialTerms 213 Study Problems 215... 

This nitrilase dynamic kinetic resolution (DKR) methodology depends on the availability of highly enantioselective biocatalysts that generate a minimum amount of amide. This latter issue may seem trivial and has long been disregarded somewhat, but reports of modest amounts of amide co-products date back to the early days of nitrilase enzymology. Only recently has the subject come under more intense scrutiny [3-5] and has a relationship with the stereochemistry of the nitrile been demonstrated [3, 5]. Hence, we set out to investigate the enantiomer and chemical selectivity of nitrilases in the hydrolysis of a representative set of cyanohydrins. 

J. Gal, Indirect methods for the chromatographic resolution of drug enantiomers, in I. W. Wainer (ed.), Drug Stereochemistry Analytical Methods and Pharmacology, Marcel Dekker, New York, 1993, pp. 65-106. 

The transketolase (TK EC 2.2.1.1) catalyzes the reversible transfer of a hydroxy-acetyl fragment from a ketose to an aldehyde [42]. A notable feature for applications in asymmetric synthesis is that it only accepts the o-enantiomer of 2-hydroxyaldehydes with effective kinetic resolution [117, 118] and adds the nucleophile stereospecifically to the re-face of the acceptor. In effect, this allows to control the stereochemistry of two adjacent stereogenic centers in the generation of (3S,4R)-configurated ketoses by starting from racemic aldehydes thus this provides products stereochemically equivalent to those obtained by FruA catalysis. The natural donor component can be replaced by hydroxy-pyruvate from which the reactive intermediate is formed by a spontaneous decarboxylation, which for preparative purposes renders the overall addition to aldehydic substrates essentially irreversible [42]. 

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