Optical purity origin

Our approach for chiral resolution is quite systematic. Instead of randomly screening different chiral acids with racemic 7, optically pure N-pMB 19 was prepared from 2, provided to us from Medicinal Chemistry. With 19, several salts with both enantiomers of chiral acids were prepared for evaluation of their crystallinity and solubility in various solvent systems. This is a more systematic way to discover an efficient classical resolution. First, a (+)-camphorsulfonic acid salt of 19 crystallized from EtOAc. One month later, a diastereomeric (-)-camphorsulfonic acid salt of 19 also crystallized. After several investigations on the two diastereomeric crystalline salts, it was determined that racemic 7 could be resolved nicely with (+)-camphorsulfonic acid from n-BuOAc kinetically. In practice, by heating racemic 7 with 1.3equiv (+)-camphorsulfonic acid in n-BuOAc under reflux for 30 min then slowly cooling to room temperature, a cmde diastereomeric mixture of the salt (59% ee) was obtained as a first crop. The first crop was recrystallized from n-BuOAc providing 95% ee salt 20 in 43% isolated yield. (The optical purity was further improved to -100% ee by additional recrystallization from n-BuOAc and the overall crystallization yield was 41%). This chiral resolution method was more efficient and economical than the original bis-camphanyl amide method. 

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... 

R origin of hydrolase yield (%) Nd MeOH optical purity (% )... 

The 2,2 -bipyridyl disulfide/triphenylphosphine coupling reaction was originally formulated as a general process for peptide synthesis (70TL1901). High isolated yields and high optical purities do strongly recommend this simple and mild method of amide formation. 

Scheme 29 shows the results of titration of a chiral amine by hydrochloride with aqueous sodium hydroxide in which the optical purity of the precipitate is lower than that of the original compound (45, 46). This... 

These experiments, which were originally devised to establish whether the stereoregular polymers of racemic a-olefins were substantially random copolymers of (R) and (S) monomers or contained macromolecules prevailingly synthesized from one antipode that is prevailingly (R) and (S) separable polymers, have shown that by this technique it is possible to obtain, in one step only, fractions having optical purity of 40% or more. 

IfK2, kl9 k u and k2 had the same values as K 2, k u k l9 and k 2, then the optical purity of the product, RH, would be determined solely by the value of the diastereomeric equilibrium constant Kv If, however, the primed and unprimed constants were different, the final optical yield could be determined by both thermodynamic and kinetic factors, and in one extreme could result in the observation that the preferred enantiomer of the product originated in the minor dia-stereomer. Clearly, kinetic factors can be important since the steric interactions of the initial two diastereomers are different and these could affect the rate constants of the reaction. Moreover, the o--alkyl intermediate is chiral, as shown for one of the initial olefin diastereomers in Figure 4, and the rate of hydrogen addition and insertion... 

The values of the optical purity are in many cases different from those reported in the original papers since they have been recalculated assuming in all cases ott,5 = 238° (1 = 1, neat) as the maximum value for the rotatory power of hydratropaldehyde381 b (R,R) enantiomer 0 (S,S) enantiomer d The absolute configuration at the P atom is unknown Chirality not specified f Soluble polystyrene containing (4R, 5R)-2-[p-phenyl-4,5-bis(diphenylphosphinomethyl)]-l,3-dioxolane groups ... 

The purpose of most of the investigations of the hydroformylation of racemic olefins has been to contribute to the understanding of the origin of asymmetric induction its significance for synthetic purposes is small. In fact, with few exceptions, this type of reaction never leads to even a fair optical purity of the reaction products (stereoelective synthesis) or of the recovered substrate (kinetic resolution) (Scheme 1, reaction 3). 

The original procedure has been modified by the use of a slow addition of the alkene to afford the diol in higher optical purity, and ironically this modification results in a faster reaction. This behavior can be rationalized by consideration of two catalytic cycles operating for the alkene (Scheme 9.20) the use of low alkene concentrations effectively removes the second, low enantio-selective cycle.145151 The use of potassium ferricyanide in place of A-methylmorpholine-iV-oxide (NMMO) as oxidant also improves the level of asymmetric induction.152153... 

The phosphine ligand (PPhMePr ) had an optical purity of about 70%. In the original publication (12) there is a misprint that shows the chiral phosphine as PPhMePr1 rather than PPhMePr". 

The large-scale production of esomeprazole is now successfully achieved by asymmetric oxidation of the same sulfide intermediate as is used in the production of omeprazole (Scheme 2.5). Using the titanium-based catalyst originally developed by K. Barry Sharpless for allyl alcohol oxidation [56] and by H.B. Kagan for certain sulfide oxidations [57], a process was developed that could achieve initial enantiomeric excesses of about 94% [53]. During the production process, the optical purity is further enhanced by the preparation of esomeprazole magnesium salt, with subsequent re-crystallization. 

A very recent slick investigation by Majewski and Nowak also supports Collum s theoretical and experimental results. They measured decreases in optical purity of (l )-6, originally in the optically pure form, during the course of deprotonation and provided the rate of the enolization (Sch. 7) [31]. Lithiation of bulky ketone 6 with LDA is first-order in the ketone and 0.5-order in the base. This result is consistent with a spectroscopically invisible dimer-monomer pre-equilibrium of LDA which is also suggested by Collum s results. Fractional order in LDA suggests a pathway involving the monomer of the amide and rate-determining proton transfer. Most notably, a combination of both monomer and dimer pathways is possible, especially for substrates less sterically hindered. 

If we examined the NMR spectrum of the starting mixture, we would find only one peak (split into a doublet by the C—H) for the Me protons, since enantiomers give identical NMR spectra. ° But the two amides are not enantiomers and each Me gives its own doublet. From the intensity of the two peaks, the relative proportions of the two diastereomers (and hence of the original enantiomers) can be determined. Alternatively, the unsplit OMe peaks could have been used. This method was satisfactorily used to determine the optical purity of a sample of 1-phenylethy-lamine (the case shown above),as well as other cases, but it is obvious that... 

Once again, the ratio of diastereomers is the same as that of the original enantiomers. High-pressure liquid chromatography has been used in a similar manner and has wider applicability. The direct separation of enantiomers by gas or liquid chromatography on a chiral column has also been used to determine optical purity. " Other methods... 

The checkers note that in the paper by Inouye, et al. the diacid was prepared by ozonolysis of (+)-trans-2-phenylcyclopropanecarboxylic acid having 96.3% optical purity. The product diacid was purified by sublimation and recrystallization from water to obtain material giving the cited physical properties. Although the original publication claims an optical purity of 96.3% for this diacid, it is probably optically pure because of the recrystallization step. 

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