Optical Resolution—Enantiomers

Crystallization continues to be the most widely used method of separating or resolving enantiomers (optical resolutions). The manufacture of chemicals and pharmaceuticals as purified optical isomers, or enantiomers, has taken on a pivotal importance in the pharmaceutical, agricultural and fine chemicals industries over the past 15-20 years. Crystallization has been and continues to be the most widely used method of separating or resolving enantiomers (optical resolutions), and is particularly well suited to separations at large scale in manufacturing processes (Jacques etal., 1981 Roth etai, 1988 Wood, 1997 Cains, 1999). 

The concentration of the chiral selector, for instance, has considerable influence on the mobility and separation of the enantiomers. Optical resolution varies with the chiral selector concentration and reaches a maximum value at a given optimum concentration. Wren and Rowe proposed a model that describes the influence of the selector concentration on selectivity, and which was extended by Vigh s group ° by including the pH as a separation parameter for weak acidic enantiomers. The latter model shows that the chiral selectivity is determined by the complex s relative mobility, the CD concentration, the degree of dissociation... 

The classical method of EPC synthesis is the preparation of the chiral compound in racemic form and subsequent separation of the enantiomers ( optical resolution ). If the compound contains more than one stereogenic center, it is first prepared as a diastereomerically pure racemate and then submitted to optical resolution. 

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). 

J. Jaques, A. CoUet, and S. WiUen, Enantiomers, Racemate, and Resolutions,]o m Wiley Sons, Inc., New York, 1981 The Chemical Society of Japan, eds., Kikan Kagaku Sosetsu (No. 6, Resolution of Optical Isomers), Gakkai Shuppan Senta, Tokyo, Japan, 1989 G. C. Barrett ia Ref. 1, Chapt. 10, pp. 338—353 S. Otsuka and T. Mukaiyama, Progress of ylsymmetric Synthesis and Optical Resolution (ia Japanese), Kagaku Dojia, Kyoto, Japan, 1982. 

From intermediate 28, the construction of aldehyde 8 only requires a few straightforward steps. Thus, alkylation of the newly introduced C-3 secondary hydroxyl with methyl iodide, followed by hydrogenolysis of the C-5 benzyl ether, furnishes primary alcohol ( )-29. With a free primary hydroxyl group, compound ( )-29 provides a convenient opportunity for optical resolution at this stage. Indeed, separation of the equimolar mixture of diastereo-meric urethanes (carbamates) resulting from the action of (S)-(-)-a-methylbenzylisocyanate on ( )-29, followed by lithium aluminum hydride reduction of the separated urethanes, provides both enantiomers of 29 in optically active form. Oxidation of the levorotatory alcohol (-)-29 with PCC furnishes enantiomerically pure aldehyde 8 (88 % yield). 

The question that emerges at the climax of this survey relates to the possibility of using crystalline inclusion phenomena for optical resolutions of molecular species. Can this be done effectively with suitably designed host compounds The definitely positive answer to this question has elegantly been demonstrated by Toda 20) as well as by other investigators (see Ch. 2 of Vol. 140). An optically active host compound will always form a chiral lattice. Therefore, when an inclusion type structure is induced, one enantiomer of the guest moiety should be included selectively within the asymmetric environment. 

The possibility to resolve the two enantiomers of 27a (or 26) by crystalline complexa-tion with optically active 26 (or 27a) is mainly due to differences in topological complementarity between the H-bonded chains of host and guest molecules. In this respect, the spatial relationships which affect optical resolution in the above described coordination-assisted clathrates are similar to those characterizing some optically resolved molecular complexes S4). This should encourage additional applications of the lattice inclusion phenomena to problems of chiral recognition. 

K. Naemura, K. Kittaka, M. Murata, H. Ida, K. Hirose, Y. Tobe, Lipase-Catalyzed Enantioselective Alcoholysis of Enol Acetates Optical Resolution of Ketones and Aldehydes Using Lipases in Organic Solvents , Enantiomer 1996, 1, 219-222. 

From the synthetic viewpoint the optical resolution of sulfonium salt 110 is of great interest because its enantiomers served as starting material for the synthesis of chiral a-dehydrobiotin 111(156). 

Since many useful organic compounds, such as pharmaceuticals and food additives, have asymmetric carbon atoms, there are enantiomers of them. In most cases, only one enantiomer is useful as a biologically active substance, the others not showing such activity and sometimes having a harmful effect. Therefore, a racemic mixture of such compounds which have been chemically synthesized cannot be used, especially for pharmaceuticals, and thus the troublesome optical resolution of the racemic mixture by means of a conventional organic synthetic process for such optically active substances is unavoidable. 

Racemic modifications may be resolved. There are very few examples of this approach having been employed successfully. The racemic cylic ether (RS)-36, which contains two CH2OCH2CO2H arms attached to the 3 and 3 positions on the axially chiral binaphthyl units, has been resolved (48-50, 93, 94) to optical purity in both its enantiomers by liquid-liquid chromatography using a chiral stationary phase of either (R)- or (S)-valine adsorbed on diatomaceous eaitii. Very recently, the optical resolution of crown ethers (/ S)-37 and (/ 5)-38, incorporating the elements of planar chirality in the form of a rron -doubly bridged ethylene unit, has been achieved (95) by HPLC on (+)-poly(triphenyl-methyl methacrylate). 

In the optical resolution of DL-threonine mixtures by batch preferential crystallization, changes of solution concentration and crystal purity were measured. The mechanism of nucleation of the un-seeded enantiomer was discussed to explain the purity decrease of the resolved crystals. From the observation of crystallization behavior of the seed crystals of L-threonine, it was concluded that the existence of the D-enantiomer on the surface of the seed caused the sudden nucleation when they grew to attain sufficient amounts. 

Optical. - This adjective exclusively refers to measurements of optical rotation. It must not be used other than in the combinations optical rotation and optical purity. In particular, the terms optical resolution (better separation of enantiomers) and optical yield must be avoided. 

It is quite common in EPC synthesis either by asymmetric synthesis or by optical resolution via diastereomers (vide infra) that chiral compounds arc obtained in an enantiomerically enriched, yet optically impure, form. In these cases the optical purity may be increased by crystallization if the compound forms either a conglomerate or a racemic mixture. In the case of conglomerates. one simply adds the amount of solvent necessary for dissolving the racemate. The excess enantiomer remains in crystalline form. 

In the process of optical resolution normally one enantiomer, and hence 50% of the total material, is discarded. When valuable compounds are resolved, this is an intolerable loss. Therefore, methods have been devised which allow recycling of the undesired enantiomer back to the racemate, so that after a few cycles most of the material has been converted into the desired enantiomer. This process has been called optical resolution with chiral economy 46. It can be performed in several variations. 

Contrary to the optical resolutions described in Sections 2.1.1.-2.1.3., which depend on the solubility or chromatographic properties ( Thermodynamic resolution ), the kinetic resolution rests on rate differences shown by the enantiomers when reacted with an optically active reagent. In the ideal case, only one enantiomer is converted into the envisaged product and the other enantiomer is unchanged. In this way, optical resolution is reduced to the more simple separation of two different reaction products. In practice, only two methods of kinetic resolution are reasonably general and reliable the Sharpless epoxidation of allylic alcohols and the enzymatic transesterification of racemic alcohols or carboxylic acids. 

In conclusion, optical resolution may be a very efficient method for obtaining enantiomer-ically pure material, particularly in large quantities. A flow chart leading to possible resolution methods for specific compounds is shown in Scheme 2. 

Shortly after the first announcement of optical resolution of ( )-cyclooctene, Moscowitz and Mislow 13) published a communication in which, on the basis of their MO calculation/they assigned the (S)-configuration to the (—)-enantiomer. Eventually, this conclusion was proved wrong 14,15) and the opposite configuration was assigned when the absolute configuration of (—)-( )-cyclooctene was shown to be directly correlated with that of (+)-tartaric acid 16a,b). 

Optical resolution employing a chiral Pt(II) complex enabled them to obtain (—)-l,2-cyclononadiene (the enantiomer of 116), [a] —71° (neat) which was estimated to have an optical purity of 44%. In their second approach, (—)-(R)-( )-cyclooctene (6) was treated with dibromocarbene to yield the ( + )-adduct 115, which was further treated with methyllithium to give (+)-116, [[Pg.19]

All structures mentioned become chiral by appropriate mono-or disubstitution (C, or C2 in metacyclophanes with m = n = 2). However, according to the variable racemization (= inversion) barriers only for [2.2]metacyclophane derivatives con-formationally stable enantiomers result which permit optical resolutions. 

From other approaches to optically active [2.2]metacyclophanes the following are noteworthy as just mentioned for 64 (medium pressure) liquid chromatography on microcrystalline triacetylcellulose (cf. Ref. 82 ) in ethanol or ether (practicable also at lower temperatures) is a very efficient and successful method for the optical resolution of many axial and planar chiral (aromatic) compounds 83). In many cases baseline-separations can be achieved and thereby both enantiomers obtained with known enantiomeric purity and in amounts sufficient for further investigations, especially for studying their chiroptical properties (see also 3.2 and 3.3). The disub-stituted [2.2]metacyclophanes 57 and 59 (which had been previously correlated to many other derivatives) 78- 79) were first resolved by this method83). 

Introduction of nitrogen into the anulene ring (e.g. of 95) leads to a methano-azaanulene 107 121) with Q-symmetry which is therefore chiral (like its mono- or disubstituted derivatives)118). The low basicity of 107 (pKa 3.20) prevented its optical resolution by conventional methods (e.g. through salts with optically active acids). Excellent results were obtained, however, (as also in the case of the two isomeric carbocyclic methylesters 97 and 101 and of several derivatives of azaanulene) by chromatography on microcrystalline triacetyl cellulose in ethanol at 7 bar 1221 (see also Section 2.7.1). In many cases base line separations were accomplished to give both (optically pure) enantiomers. Enantiomeric relations were confirmed in all cases by recording the CD-spectra of both fractions. Some results of these separations are shown in Fig. 4 together with the optical rotations ([a]D in ethanol) of the enantiomers. 

Yeast-mediated reductions predominantly form a single enantiomer and it is often difficult to find conditions which produce the opposite stereoisomer selectively. It has, however, been possible to obtain both enantiomers in 50% yield in 100% via enzymatic optical resolution. Chiral fluorinated secondary alcohols possessing the mono-, di- and/or trifluoromethyl group have been prepared by enzyme-catalyzed kinetic resolutions [27]. 

---