Resolution into enantiomers

Annelation can introduce large conformational barriers, to the extent of making possible the resolution into enantiomers of a tribenzoxepine (71CB2923). Chapters 5.16, 5.17, 5.18 and 5.19 contain much more information on inversion barriers, bond lengths and bond angles. 

Thus, racemic acid 12 (R = H) was obtained by [3+2] cycloaddition in 90-95% yield (Scheme 5.9) [28]. Its resolution into enantiomers could be achieved either by chiral preparative HPLC, or by fractional crystallization of its cinchonidine salts. Better results were obtained upon enzymatic kinetic resolution of its iso-butyl ester 12 (R = i-Bu) [29]. However, further work showed that racemic thiolester 13, which... 

X-ray data showed that the two pyrrole rings are nearly orthogonal with an inter-ring angle equal to 84.5°. Diastereomers were formed by transesterification with optically pure 2-(S)-methylbutyl alcohol. Unfortunately classical crystallization or GC did not separate the diastereomers. Resolution into enantiomers should be attempted by liquid chromatography on a chiral support. 

Problem 6.4. These questions refer to the material in Scheme 6.5. (a) At higher temperatures, all of the hydrogens in 2-methylbutane react with equal facility. What ratio of products A-D are expected under such conditions (b) Sketch the H nuclear magnetic resonance (NMR) spectrum of each of the products A-D and show how you would, therefore, know which isomer corresponded to which letter, (c) Which of the isomers A-D are, at least in principle, capable of resolution into enantiomers ... 

Diaziridines also show slow nitrogen inversion, and carbon-substituted compounds can be resolved into enantiomers, which typically racemize slowly at room temperature (when Af-substituted with alkyl and/or hydrogen). For example, l-methyl-3-benzyl-3-methyl-diaziridine in tetrachloroethylene showed a half-life at 70 °C of 431 min (69AG(E)212). Preparative resolution has been done both by classical methods, using chiral partners in salts (77DOK(232)108l), and by chromatography on triacetyl cellulose (Section 5.08.2.3.1). 

From the pioneering studies of Ito et al. [117], CCC has been mainly used for the separation and purification of natural products, where it has found a large number of applications [114, 116, 118, 119]. Moreover, the potential of this technique for preparative purposes can be also applied to chiral separations. The resolution of enantiomers can be simply envisaged by addition of a chiral selector to the stationary liquid phase. The mixture of enantiomers would come into contact with this liquid CSP, and enantiodiscrimination might be achieved. However, as yet few examples have been described in the literature. 

Most methods for the resolution of enantiomers contained in a reaction mixture consist in the conversion of the compounds into stable or transient diastereoisomers and separation of the latter on the basis of their different physico-chemical properties. 

C-chiral racemic y-hydroxy sulfides were also resolved using PEL under kinetic resolution conditions. The products were transformed into optically active 3-(alkanesulfonyloxy)thiolane salts (Scheme 1). Similarly, 1,2-cyclic sulfite glycerol derivatives cis and trans) were resolved into enantiomers via a Pseudomonas cepacia-catalysed acylation with vinyl butyrate. The E values depended on the solvent used and varied from 2 to 26. ... 

The first P-chiral hydroxy phosphoryl compounds that were enzymatically resolved into enantiomers were o-hydroxyaryl phosphines and their oxides 75. The resolution was achieved via enzyme-assisted hydrolysis of their O-acetyl derivatives 74, the most effective enzymes being CE and Upase from C. rugosa (CRL) (Equation 35). The highest enanfioselectivity was observed in the case of naphthyl derivatives (Equation 36), having a P=0 moiety. ... 

Many optically active hypervalent chalcogen compounds, particularly sulfur compounds, have been synthesized and proposed as important key intermediates in various reactions of the chalcogen compounds.46 Since the synthesis of spirosulfurane by Kapovits and Kalman,47 many optically active spir-osulfuranes were isolated in the last decade. Spirosulfurane 28 was separated into enantiomers by kinetic resolution using a chiral host molecule and found to be optically stable by Drabowicz and Martin.48 Spirosulfurane 29 was separated into enantiomers by chromatographic method by Allenmark and Claeson, and characterized by chiroptical methods.49 Optically active... 

The enantiomers of many compounds are eluted in reverse order on the 3,5-dimethylphenylcarbamates of cellulose (23x) and amylose (24n), suggesting that these two CSPs may be complementary in recognizing chirality. Many enantiomers unresolved on 23x can be resolved on 24n, and vice versa. Consequently, when two 23x and 24n columns were used for the resolution of 500 racemates, nearly 80% of the racemates were separated into enantiomers at least on either of 23x and 24n. 

An extremely important aspect in pharmaceutical research is the determination of drug optical purity. The most frequently applied technique for chiral separations in CZE remains the so-called dynamic mode where resolution of enantiomers is carried out by adding a chiral selector directly into the BGE for in situ formation of diastereomeric derivatives. Various additives, such as cyclodextrins (CD), chiral crown ethers, proteins, antibiotics, bile salts, chiral micelles, and ergot alkaloids, are reported as chiral selectors in the literature, but CDs are by far the selectors most widely used in chiral CE. 

When Novozyme 435 enzyme was filled into a column to achieve kinetie resolution of enantiomers, comparative bateh reaetions were also carried using supereritical carbon dioxide. The results showed that both the enantiomeric excess (90.6% in batch 99.5% in flow... 

Antimalarials Mefloquine is a major drug for malaria, in particular, for chloroquine-resistant malaria." However, some cases of neuropsychiatric adverse events and the apparition of resistance tend to limit its use. Metabolism into inactive and phototoxic 1 -7/-2-oxoquinoline is blocked by the presence of the CF3 group." Instead of performing the resolution of enantiomers at the end of the synthesis," the asymmetric reduction of the carbonyl group in the presence of ruthenium catalyst and a chiral diphosphine provided mefloquine with an excellent enantiomeric excess (Figure 8.25). °... 

Compound (6) contains 3 centers of dissymmetry, and its resolution into separated enantiomers could effected using ( )-mandelic acid [7]. The least soluble diastereomer was found to be the (-)-mandelate salt (m.p. 164.5-164.8°C). Formation of the hydrochloride salts of both enantiomers gave (-i-)-isoxsuprine HCl (m.p. 196-196°C) and (-)-isoxsuprine HCl (m.p. 195-196°C). The two asymmetric centers at C-1 and C-2 were correlated with those of the erythro (p-OH-C6H4-CH(OH)-CH(CH3)-NH-) residue. 

Furthermore, a clear definition of the term meso-trick is apparently not available. Seebach13 implies that the meso-trick involves an KPC synthesis which starts with a we.vocompound that is completely transformed, via a sequence of reactions involving a stereoselective reaction or resolution, into one enantiomer. 

As in the case of [njparacyclophanes the torsional barrier(s) as well as the distortion of the benzene rings (as reflected for example in optical properties) depend on the size of the bridges, i.e. on m and n Both reach their maximum if m = n = 2. Up to [3.4]paracyclophanecarboxylic acid (26) a separation into enantiomers could be accomplished 34137), whereas the [4.4] homologue is optically too labile for a resolution 37). 

The Z-protected derivative, again prepared by standard methods using benzyl chloroformate,t208 may serve in the case of racemic pipecolic acid for resolution into the pure enantiomers by fractional crystallization with L-tyrosine hydrazide/208 Acylation with N-protected pipecolic acid or of pipecolyl peptides is performed by standard procedures via the active ester methods, e.g. A-hydroxysuccinimide ester/121 by the mixed anhydride method, e.g. with isobutyl chloro-formate 95-114 or pivalic acid chloride/121 as well as by DCC/HOBt/118 In the synthesis on solid support, longer coupling times are required when compared to N-protected proline.1[235 ... 

An interesting approach to translating remote chirality into enantiomer discrimination relies upon blocking one face of the heterocycle using axially chiral DMAP analogs. To this end, Spivey and co-workers have examined catalysts 39 and 40, obtained in optically pure form by preparative HPLC [38]. Catalyst 39 is effective for the kinetic resolution of aryl alkyl carbinols with good selec-tivities (krei=8.4-27, see Scheme 7). The substitution on the 4-position nitrogen... 

Resolution of racemic 1,3/4/6,7,llb-hexahydro-2H-pyrazino[l,2-a]iso-quinolin-4-one into enantiomers was unsuccessful either through the crystallization of diastereomeric chiral salts prepared from enantiopure acids in different solvent mixtures, or with kinetic resolution by an enzymatic acylation using different enzymes (08EJO895). 

A related phenomenon can also occur when the crystal lattice packing is chiral. This intrinsic handedness can result in formation of a 1 1 mixture of enantiomeric crystals. In this case, although there has been self-resolution into (+)- and (—)-crystals, both molecular enantiomers remain unseparated in each crystal. The fundamental distinction is that a conglomerate single crystal contains only one molecular enantiomer and therefore would be optically active in solution, while, for the latter, a single crystal contains both molecular enantiomers and its solution would be optically inactive. 

The only difference is that in conventional kinetic resolution the enantiomer (5)-substrate is left behind as unreacted starting material while in case of dynamic kinetic resolution the substrate is continuously isomerised during the resolution process, thus (R) and ( )-substrates are in equilibrium, which allows for the possibility of converting all starting materials of (A)-substrate into (A)-product. Several conditions should be applied and are reviewed in literature.21 For instance, Backvall et al20 used a combination of enzyme and transition metal complex (Ru-catalyst) to perform the DKR of a set of secondary alcohols. Depending on the substrate, the chemical yield was ranging from 60 to 88 % with more... 

A similar effect has been reported in the crystallization of non-chiral molecules, where the presence of small amounts of chiral additive forces the entire system to crystallize in an enantiomorphous crystal, which upon further solid-state reaction can be converted into polymers of a single handedness [184,185]. Chiral auxiliaries, which affect crystal nucleation enantios-electively, have been successfully used for the large-scale optical resolution of enantiomers [186-188]. 

The extent of stereoselectivity in the chiral synthesis can be checked by determining the enantiomeric excess of the optically active olefins in the products. The optical purity was determined by gas chromatographic resolution of enantiomers by means of an optically active column. Thermostable substituted cyclodextrins are well suited as asymmetric phases (206). The trimer, 2,4-dimethyl-l-heptene, was resolved into its enantiomers by capillary gas chromatography with an octakis(6-0-methyl-2,3-r/-0-pentyl-)-7-cyclodextrine phase. 

In a field closely related to biphenyl, hindered rotation around the pyridyl-amide bond allowed the resolution of the nicotinamide analogue 142 into enantiomers. Compound 142 was optically stable at 25°C in water at higher temperatures racemization occurs (e.g., t1/2 = 3.1 hr at 100°C) (82RTC191 ... 

In 1848, Louis Pasteur noticed that a salt of racemic ( )-tartaric acid crystallizes into mirror-image crystals. Using a microscope and a pair of tweezers, he physically separated the enantiomeric crystals. He found that solutions made from the left-handed crystals rotate polarized light in one direction and solutions made from the right-handed crystals rotate polarized light in the opposite direction. Pasteur had accomplished the first artificial resolution of enantiomers. Unfortunately, few racemic compounds crystallize as separate enantiomers, and other methods of separation are required. 

To our knowledge, topologically chiral molecules have not yet been resolved into enantiomers. However, we may anticipate that their energy barrier to racemization will be extremely high, compared to Euclidean chiral molecules. Therefore they are expected to be useful in enantioselective interactions or reactions. For example, it has been shown that tetrahedral copper(I) bis-2,9-diphenyl-l,10-phenanthroline complexes (which form the catenate subunits) are good reductants in the excited state [97] therefore the chiral Cu(I) catenates could be used for enantioselective electron-transfer reactions. Alternatively, the resolution of topologically chiral molecules would allow to answer fundamental questions, such as what are the chiroptical properties of molecular trefoil knots ... 

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