Resolution of optical antipodes

The synthesis of optically active polymers was tackled with the purpose not only of clarifying the mechanism of polymerization and the conformational state of polymers in solution, but also to explore the potential of these products in many fields as chiral catalysts, as stationary phases for chromatographic resolution of optical antipodes, for the preparation of liquid crystals, and so on. 

The resolution of optical antipodes on polysaccharides is mainly governed by the shape and size of solutes (inclusion phenomena) and only to a minor extent by other interactions involving the functional groups of the molecules. In the case of microcrystalline cellulose triacetate (MCTA), the type and composition of the aqueous-organic eluent affect the separation because these result in different swelling of MCTA. 

H. Frank. G. Nicholson and E. Bayer, Chiral polysiloxanes for resolution of optical antipodes, Angew.Chem.Int. 

Another elegant example of the imitation of the properties of biopolymers by synthetic polymers comes from the school of E. Bayer of Tubingen (172). They have prepared chiral polysiloxane polymers for resolution of optical antipodes. The prochiral polymeric backbone was a copolymer of poly [(2-carboxypropyl)methylsiloxane], octamethylcyclotetrasiloxane, and hexa-methyldisiloxane. Amino acids or small peptides were covalently linked to this polymer in order to introduce a chiral surface. For this, the free carboxyl function of the polymer was reacted with the L-amino acid in the presence of DCC (see Chapter 2). The individual chiral centers (amino acids) on the polymer surface were separated by siloxane chains of specified length in order to achieve optimum interaction with the substrate and polymer viscosity. An example of great value for optical resolution is the polymer designated chirasil-Val, containing 0.86 mmole of iV-tert-butyl-L-valin-amide per gram of polymer (Fig. 5.14). 

It is with these deviations from planar aromatic systems that this chapter is mainly concerned. Such deviations may be observed in a variety of ways, both qualitatively, as by resolution into optical antipodes, or quantitatively, as by X-ray analysis. The quantitative results obtained vary widely in accuracy and there is much need for revision. It is therefore appropriate that a review of the available results should be made at this time. 

A. Qualitative Methods 1. Resolution into optical antipodes Newman in 1940 first pointed out that optical activity could arise from out-of-plane distortion of overcrowded aromatic compounds. He and his co-workers have confirmed this conclusion incontrovertibly by resolution of 4,5,8-trimethylphenanthrene-l-acetic acid (13) (Newman... 

For a variety of reasons, analytical determination of one or both of the optical isomers is needed. The optical methods that have been traditionally used to determine the extent of optical rotation in racemic mixtures seldom have the required sensitivity. The case in point is a typical problem of peptide synthesis where the racemization of an optical isomer may occur during the chemical reaction, and where it is highly important to know accurately the extent of such racemization. The chromatographic approach to stereoselective analyses is quite attractive resolution of the antipodes, coupled with the sensitivity of the modem chromatographic techniques, makes this approach quite unique. 

Ferroni E. and Cini R. (1960) The resolution of complex antipodes by optically active solids, J. Amer. Chem. Soc., 82, 2427-2428. 

Enantiomeric separations have become increasingly important, especially in the pharmaceutical and agricultural industries as optical isomers often possess different biological properties. The analysis and preparation of a pure enantiomer usually involves its resolution from the antipode. Among all the chiral separation techniques, HPLC has proven to be the most convenient, reproducible and widely applicable method. Most of the HPLC methods employ a chiral selector as the chiral stationary phase (CSP). 

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. 

Most of the phosphorus compounds described in the previous sections are chiral and racemic. Attempting their resolution - that is a physical separation of the enantiomers - was obviously attractive and this was realized as early as 1965 by Hellwinkel, who obtained both optical antipodes of 2 [18]. A patent on the synthesis and possible applications of enantiopure phosphate 2 was even filed at the time [103]. 

All sixteen of the racemic carba-sugars predicted are known, as well as fifteen of the enantiomers. The most accessible starting-material for the synthesis of racemic carba-sugars is the Diels-Alder adduct of furan and acrylic acid, namely, e i o7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylicacid (29). Furthermore, adduct 29 is readily resolved into the antipodes, (—)-29 and (+)-29, by use of optically active a-methylbenzylamine as the resolution agent. The antipodes were used for the synthesis of enantiomeric carba-sugars by reactions analogous to those adopted in the preparation of the racemates. 

D,L-10-Camphorsulfonic acid is used for the preparation of the corresponding chloride (p. 14). The optically active acid has been used widely for the resolution of basic compounds into optical antipodes. 

Like other methods of asymmetric synthesis, the solid-state ionic chiral auxiliary procedure has an advantage over Pasteur resolution in terms of chemical yield. The maximum amount of either enantiomer that can be obtained by resolution of a racemic mixture is 50%, and in practice the yield is often considerably less [47]. In contrast, the ionic chiral auxiliary approach affords a single enantiomer of the product, often in chemical and optical yields of well over 90%. Furthermore, either enantiomer can be obtained as desired by simply using one optical antipode or the other of the ionic chiral auxiliary. 

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... 

Optical resolution of 6-methyl-4-oxo-6,7,8.9-tetrahydro-4ff-pyrido-[l,2-n]pyrimidine-3-carboxylic acid was carried out with the antipodes of... 

Stereoselective enzymatic hydrolyses of esters represent a further type of biotransformation that has been used for the synthesis of optically active organosilicon compounds. The first example of this particular type of bioconversion is illustrated in Scheme 15. Starting from the racemic (l-acetoxyethyl)silane rac-11, the optically active (l-hydroxyethyl)silane (5)-41 was obtained by a kinetic racemate resolution using porcine liver esterase (PLE E.C. 3.1.1.1) as the biocatalyst7. The silane (5)-41 (isolated with an enantiomeric purity of 60% ee bioconversion not optimized) is the antipode of compound (R)-41 which was obtained by an enantioselective microbial reduction of the acetylsilane 40 (see Scheme 8). 

Enantioselective enzymatic transesterifications have been used as a complementary method to enantioselective enzymatic ester hydrolyses. The first example of this particular type of biotransformation is the synthesis of the optically active 2-acetoxy-l-silacyclohexane (5 )-78 (Scheme 19). This compound was obtained by an enantioselective transesterification of the racemic l-silacyclohexan-2-ol rac-43 with triacetin (acetate source) in isooctane, catalyzed by a crude lipase preparation from Candida cylindracea (CCL, E.C. 3.1.1.3)62. After terminating the reaction at 52% conversion (relative to total amount of substrate rac-43), the product (S)-78 was separated from the nonreacted substrate by column chromatography on silica gel and isolated in 92% yield (relative to total amount of converted rac-43) with an enantiomeric purity of 95% ee. The remaining l-silacyclohexan-2-ol (/ )-43 was obtained in 76% yield (relative to total amount of nonconverted rac-43) with an enantiomeric purity of 96% ee. Repeated recrystallization of (R)-43 led to an improvement of enantiomeric purity by up to >98% ee. Compound (R)-43 has already earlier been prepared by an enantioselective microbial reduction of the l-silacyclohexan-2-one 42 (see Scheme 8)53. The l-silacyclohexan-2-ol (R)-43 is the antipode of compound (.S j-43 which was obtained by a kinetic enzymatic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-78 (see Scheme 15)62. For further enantioselective enzymatic transesterifications of racemic organosilicon substrates, with a carbon atom as the center of chirality, see References 64 and 70-72. 

As the Diels-Alder cyclic adduct 33 has been recognized as the most accessible starting compound for the synthesis of racemic pseudo-sugars, a resolution of 33 has been attempted to prepare enantiomeric pseudo-sugars, starting from an optically active antipode of 33. It has been revealed that 33 was readily separated into the enantiomers by using optically active a-methylbenzylamines as resolution reagents. 

The C2S-dinitrobis(ethylenediamine)cobalt(III) ion was first resolved by Werner1,213 through the d-camphorsulfo-nate. However, that method, though it ultimately gives good yields of both optical antipodes, is laborious, and the resolving agent is comparatively expensive. Resolution is readily accomplished by the use of potassium cZ-antimony tartrate, and yields of each antipode of the order of 40 to 50% are obtained. 

The preparation of homochiral compounds by formation and separation of diastereoisomers or by kinetic resolution of racemates, at or near the end of a total synthesis, has been a method of choice. This avoids the possibility of racemization should chirality be introduced earlier. However, the costs are high because only half by weight of the homochiral compound is theoretically possible from the racemate unless the optical antipode can also be easily inverted to the desired product. Indeed, previous methods for producing levomethadone based on the classical resolution at the end, or at the penultimate stage of the synthesis, were costly and not very effective. Levomethadone hydrochloride has previously been marketed as L-Polamidon and Levadone16 but was subsequently withdrawn because of the high cost of production. 

As the resolution of the racemic lysergic acid into its optical antipodes and the synthesis of ergometrine had been described earlier by Stoll and Hofmann (25, 66), this meant that not only had the synthesis of d-lysergic acid been achieved but also the first total synthesis of an ergot alkaloid. 

Figure 1.9. Kinetic resolution of D2-C76 based on a differential reactivity of enantiomerically pure osmium complexes toward the optical antipodes of the fullerene.

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