Diastereomers racemate chiral resolution

A special case of host-guest inclusion is the resolution of a racemic mixture of chiral guests. This has important implications for the pharmaceutical industry, where the production of enantiomerically pure drugs has recently become increasingly important. A common method of chiral resolution is via the formation and separation of diastereomers. For example, a racemic acid AH may be treated with a chiral base B [21] ... 

Based on chiral functional monomers such as (15) in Table 5.6C MIPs capable of chiral resolution can be prepared using a racemic template. Thus, using racemic N-(3,5-dinitrobenzoyl)-a-methylbenzylamine (16 in Table 5.6C) as template, a polymer capable of racemic resolution of the template was obtained [86]. Another chiral monomer based on L-valine (17) was used to prepare MIPs for the separation of dipeptide diastereomers [94]. In these cases, the configurational chirality inherent in the pendant groups of the polymer are to some extent themselves chiral selectors and the effect of imprinting is merely to enhance the selectivity. Alternative approaches to imprint peptides via strong monomer-template association have recently been... 

Rhodium-catalysed hydroboration is a powerful tool for introducing chirality into a styrene-derivative. (Figure 1.1)[2] This was in competition to the established route based on chiral resolution using separation of diastereomers formed from reaction of the racemic amines with homo-chiral acids (natural pool). However, although the process appeared favourable from the chemical synthetic route, the process was practically impossible owing to there being no supplier of catecholborane on large scale at the time. 

This reaction was first reported by Marckwald in 1904. It is the synthesis of chiral L-valeric acid (a-methyl propanoic acid) from the pyrolysis of brucine salt of racemic o -methyl-o -ethylmalonic acid. Therefore, it is generally known as the Marckwald asymmetric synthesis. Occasionally, it is also referred to as the Marckwald method. In this reaction, the brucine salts of racemic a-methyl-a-ethylmalonic acid essentially exist as a pair of diastereomers that are separated by fractional crystallization the one with lower solubility is isolated. Upon pyrolysis of such crystalline salt at 170°C, the corresponding brucine salt of L-valeric acid forms upon decarboxylation, resulting in a 10% e.e. In addition, Marckwald defined the asymmetric synthesis as reactions that produce optically active molecules from symmetrically constituted compounds with the use of optically active materials and exclusion of any analytical processes, such as resolution. However, this work was challenged as not being a trae asymmetric synthesis because the procedure was similar to that of Pasteur. In fact, the If actional crystallization of the diastereomers is a resolution process. This process is used as base for many other preparations of chiral molecules, such as tartaric acid and under its influence, the kinetic resolution and tme asymmetric synthesis have been developed in modem organic synthesis. The asymmetric synthesis has been redefined by Morrison and Mosher as the reaction by which an achiral unit of the substrate is converted into a chiral unit in such a manner that the two resulting stereoisomers are produced in unequal amounts. ... 

In 1971, an interesting application of the chlorobridged Pd(II) complexes with orthometallated chiral amines was demonstrated by Otsuka and co-workers resolution of racemic chiral phosphincs. The binuclear species reacts with tertiary phosphines or arsines to form two equivalents of mononuclear complexes (Scheme 3). If both the phosphines and the orthometallated palladium complexes were chiral, the mononuclear products could be a mixture of diastereomers. With appropriate combinations of the chiral racemic phosphines and the enantiomerically pure orthometallated palladium species, one of the two enantiomers of the phosphines reacts with the palladium complex selectively to give a specific diastereomer of the mononuclear palladium complexes, leaving the other enantiomer of the phosphine unreacted. 

The most common method of chiral resolution is via the formation and separation of diastereomers. For example, a racemic acid AH may be treated with a chiral base B. 

Probably the most popular and the most preferred method for the resolution of organic acids or bases is a chiral resolution via diastereomeric salt formation. Ionic salts are easily formed and easily crystallized, and after the separation process, an enantiomerically pure separated compound may be easily isolated, and the resolving agent can be recovered and reused (Figure 1.37). Resolution via diastereomeric salt formation involves the acid-base reaction of a racemate with an enantiomerically pure resolving agent. The resulting two diastereomers have different physical properties e.g., the difference in solubility is used to separate them by crystallization. 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

Chiral Recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is caUed chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether (53) partially to resolve the racemic amine salt (54). " When an aqueous solution of 54 was... 

In the kinetic resolution, the yield of desired optically active product cannot exceed 50% based on the racemic substrate, even if the chiral-discriminating ability of the chiral catalyst is extremely high. In order to obtain one diastereomer selectively, the conversion must be suppressed to less than 50%, while in order to obtain one enantiomer of the starting material selectively, a higher than 50% conversion is required. If the stereogenic center is labile in the racemic substrate, one can convert the substrate completely to gain almost 100% yield of the diastereomer formation by utilizing dynamic stereomutation. 

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

The same cyclocarboUthiation reaction, using the corresponding A,A-diisopropylcarba-mate 60 and applying a five-fold excess of the chiral base, has been reported by Nakai and coworkers . Starting with the racemic 4-TBSO-hexenyl carbamate rac-61, a diastereomer resolution takes place The 1,3-cw-compound 62a remains stable until trapped by protonation (40% of 63, d.r. = 95 5), but from 62b the enantiomerically and diastereomerically pure bicyclo[3.1.0]hexane 64 (38%, > 95% ee) results (equation 14) . 

In recent work, Chmielewski and co-workers (174) reported the highly stereoselective reaction of ene-lactones with chiral pyrrolidine nitrone (141) to afford tricyclic adducts (Scheme 1.31). A 1 1 mixture of ene-lactone 142 and nitrone 141 provided adduct 143 with an uncharacterized isomer (97 3) (91%) whUe homo-chiral D-glycero (138) gave the adduct 144 as a single diastereomer (88%). A 2 1 mixture of racemic 138 and nitrone 141 afforded a 91 1 mixture of the two possible adducts, representing an effective kinetic resolution of the racemic lactone. 

Another approach that relies on asymmetric induction from the alkene part, uses chiral auxiliaries of various types, thereby leading to enantiomerically enriched or pure isoxazoline products. The complexity of some of these auxiliaries is high, and more economical solutions are desirable since the competition is the resolution of racemic cycloadducts with an overall efficiency up to 50% yield. With chiral nitrile oxides, the situation is much less satisfactory since asymmetric induction of the 1,4-type (with 1-alkenes) is minimal, and hardly better with a 1,3-relationship of inducing-forming stereocenters, when 1,2-disubstituted alkenes are employed (Scheme 6.22). Upon separation of the two diastereomers, however, another entry to pure optically active isoxazolines is available. 

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. 

The most widely applicable method of optical resolution utilizes a chiral auxiliary, which is taken from either the chiral pool 14 (carbohydrates, terpenes, amino acids etc.) or obtained by previous optical resolution. The auxiliary A, in an optically pure form, combines with the racemic substrate S to form two diastereomers p and n, respectively. 

Optical resolution of the dithiol The problem of optical resolution of racemic disulfides has been successfully tackled (77JOC925). The bis-thiol (128) was reacted with a chiral bis-sulfenyl chloride, the resultant mixture of diastereomers separated, and the product reconverted to the starting material by NaBH4 reduction. Subsequent iodine oxidation gave the chiral epidisulfides (Scheme 40). 

A chiral stereoisomer is not superimposable on its mirror image. It does not possess a plane or center of symmetry. The nonsuperimposable mirror images are called enantiomers. A mixture of equal numbers of molecules of each enantiomer is a racemic form (racemate). The conversion of an enantiomer into a racemic form is called racemization. Resolution is the separation of a racemic form into individual enantiomers. Stereomers which are not mirror images are called diastereomers. 

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