Optically stable racemates, resolution

The classification rests on the recognition of the four broad categories (A) resolution of optically stable racemates, (B) optically selective inversion of configuration in optically labile racemates, (C) optically selective synthesis of new centers of dissymmetry, and (D) optically selective inactivation of existing centers of dissymmetry. 

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 ... 

Substituted 3,4-dihydropyrimidines are inherently asymmetric. They are usually obtained as racemic mixtures. Enantiomerically pure and optically stable dihydropyrimidine-5-carboxylic acids (381) have been obtained by optical resolution effected by fractional crystallization of their diastereo-meric a-methylbenzylammonium salts. The absolute stereochemistry was established by x-ray analysis of diastereomeric a-methylbenzylammonium carboxylate. The enantiomeric acids (/ )-(381) and... 

Resolution of Racemic Amines and Amino Acids. Acylases (EC3.5.1.14) are the most commonly used enzymes for the resolution of amino acids. Porcine kidney acylase (PKA) and the fungaly3.spet i//us acylase (AA) are commercially available, inexpensive, and stable. They have broad substrate specificity and hydrolyze a wide spectmm of natural and unnatural A/-acyl amino acids, with exceptionally high enantioselectivity in almost all cases. Moreover, theU enantioselectivity is exceptionally good with most substrates. A general paper on this subject has been pubUshed (106) in which the resolution of over 50 A/-acyl amino acids and analogues is described. Also reported are the stabiUties of the enzymes and the effect of different acyl groups on the rate and selectivity of enzymatic hydrolysis. Some of the substrates that are easily resolved on 10—100 g scale are presented in Figure 4 (106). Lipases are also used for the resolution of A/-acylated amino acids but the rates and optical purities are usually low (107). 

Optically active arenetellurinic acid 23 was obtained for the first time by chromatographic resolution of the racemic sample on a chiral column in 2004.37 It is stable toward racemization in solution, whereas the corresponding seleninic acids racemize in solution under similar conditions. Its absolute configuration was assigned by comparing the circular dichroism spectra with that of an optically active seleninic acid (Scheme 10). 

Disubstituted (cyclobutadiene)Fe(CO)3 complexes in which the two substituents are different may exist as enantiomers. Racemic cyclobutadiene carboxylic acids or cyclobutadiene amine complexes of this type have been separated by classical resolution methodology234. These optically active (cyclobutadiene)Fe(CO)3 complexes are stable with respect to racemization at 120°C for 24 h. This stability contrasts with acyclic... 

A number of Co(III) complexes, such as Co(edta) and Co(phen)3, can be resolved into optical isomers and are extremely stable towards racemization. The Co(II) analogs are configurationally labile and resolution has proved impossible. Suggest how with a double mixing apparatus it might be possible to measure half-lives in the 10 -1 s range for the first-order racemization of the Co(Il) complexes. 

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. 

Paul Pfeiffer discovered a very interesting stereochemical phenomenon, which now bears his name — the Pfeiffer effect this has received a good deal of attention.30 When an optically active substance which is stable in solution is added to a solution of a labile chiral substance, the optical rotation of the solution changes, reaching a new level in some hours. Several theories have been advanced to explain the phenomenon, the most satisfactory based on the supposition that the optically active ion or molecule forms an association with one isomer of the racemic pair of the labile substance and thus shifts the dextro—levo equilibrium. In general it is not possible to use this as a means of resolution, for when the added optically active substance is removed from the labile material, the latter immediately racemizes. 

To what extent the 2-(a do-poly hydroxy alkyl) benzimidazoles can be used in resolving other optically active acids has not been determined. The benzimidazoles are relatively weak bases and do not form stable salts with weakly ionized acids. Haskins and Hudson15 found that when a solution of racemic lactic acid and 2-(D-gluco-D-gulo-hepto-hexa,hydroxy-hexyl)benzimidazole was concentrated, it was the free base that precipitated rather than one of the expected salts. It seems probable, however, that the method will be found useful in other resolutions, especially of the stronger organic acids. 

A particularly successful synthesis of Epothilone A is based on two DERA-cata-lyzed steps. In these two of the seven stereocentres of Epothilone A were established. When a racemic aldehyde was released in situ from its acetal, DERA converted only the R-enantiomer into the stable cyclic hemiacetal. This is a combined kinetic resolution and carbon-carbon bond formation yielding a building block with two chiral centers. Since the alcohol function was oxidized, the optical information obtained from the kinetic resolution was lost. Thus, for the overall yield it would have been better if DERA had displayed no stereoselectivity towards the acceptor (Scheme 5.32). In the DERA-catalyzed synthesis of another part of Epothilone A DERA is again highly stereoselective. Fortunately its preference is for the S-enan-tiomer of the acceptor aldehyde, the enantiomer that has to be submitted to the carbon-carbon bond formation in order to obtain the desired building block, again a stable hemiacetal (Scheme 5.32). Indeed, both DERA-catalyzed reactions yield open chain products that form stable cyclic hemiacetals. This ensures that the equilibria of these aldol reactions are shifted towards the desired products. Further synthetic manipulations converted these intermediates into Epothilone A [55]. 

Optically active cathinone has been obtained through the optical resolution of racemic norephedrine using 0,C>-dibenzoyl-D-tartaric acid (26). Each enantiomer was formylated (9) and oxidized with chromium trioxide in pyridine, and the product (13) was then deformylated by heating with 20% hydrochloric acid at 40 C (Scheme 2). Estimation of the optical purity by formation of a urea (14) with (—)-l-phenylethyl isocyanate and HPLC scrutiny, showed an optical purity exceeding 98% for each enantiomer. Cathinone as the free base racemizes and dimerizes readily in hydroxylic media, and similar behavior, at a somewhat reduced rate, is also observed for solutions of the oxalate salt sometimes used for isolation purposes. Cathinone base is fairly stable in dilute solution in nonhydroxy lie, nonpolar media. It readily decomposes during drying of the leaf, hence the desire to use fresh material for hedonistic purposes 14,27). 

The active C(j-bromoamminebis(ethylenediamine)cobalt(III) salts, like the racemic compounds, are similar in properties to the corresponding cis-chloroamminebis(ethylenediamine)cobalt(III) salts, but they have been less extensively investigated. They are quite stable, and their solutions do not race-mize on standing at room temperature or even on heating to incipient boil-ing.i They can be converted from one salt to another without loss of optical activity. Treatment of the active bromide or(+)-a-bromocamphor- r-sulfonate with liquid ammonia yields the corresponding optically active cw-diammine-bis(ethylenediamine)cobalt(III) salts. A partial resolution of the racemic bromide into optical isomers on ( +)- and ( — )-quartz has been reported.The specific magnetic susceptibility has been found to be 3.49 X... 

Tris(ethylenediamine)platinum(IV) chloride is a white crystalline solid which is readily soluble in water and stable toward decomposition in both acidic and basic solution. Resolution of the complex cation into its optical isomers has been achieved by fractional precipitation of i-[Pt(en)3]-Cl2(d-C4H406) on addition of ammonium d-tartrate to the racemic mixture. Racemization of the cation occurs only under extreme conditions and is accompanied by little exchange of bound ethylenediamine. A solution of the complex is quantitatively reduced to platinum metal by magnesium and hydrochloric acid. The solid complex is quantitatively reduced to platinum metal upon ignition. 

In the years following, various stable heterocyclic arsonium salts were synthesized and resolved, including the isoarsinolinium iodide 4 and the spirocyclic arsonium iodides 5 and 6 , in which dissociation was unlikely to occur the optically active iodides in each case were stable in chloroform. The attempted resolutions of a variety of tetra-arylarsonium salts, however, failed, which was attributed to manipulative difficulties, particularly that of crystallization . In 1961, (-1- )-amylbenzylethylphenylarsonium bromide having [a]o -l-16.5° was isolated, but the salt was reported to racemize rapidly in solution ... 

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