Diastereomer resolution

Classic resolution was exemplified earlier (section 7.5.3) with the Syntex process for 5-naproxen. A relatively new technique described as resolution of racemate by distillation with inclusion compounds has been reported [24]. This method seems particularly attractive from an environmental perspective. As an example, racemic a-methylbenzyl alcohol was stirred in hexane with a tartaric acid derivative RR) for 1 hour at room temperature and the mixture subsequently distilled. The (—) alcohol could be distilled out at 150°C, in 69% yield with 97% ee (equation 7.3). 

This technique has great potential for industrial scale resolution, and may in the future find increased use. 

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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) . 

SCHEME 7.1 The synthetic sequence to reach ebalzotan in 13 linear steps incorporating a de novo assembly of the chroman nucleus and a diastereomer resolution (abbreviations DMF = Ai,Ai-dimethylformamide p-TSA = para-toluenesulfonic acid). 

SCHEME 7.4 Second generation synthesis of robaizotan comprised of 13 steps. Key features are the presence of the fluorine substituent in the starting material, a de novo construction of the chroman skeleton, and a late stage diastereomer resolution. 

SCHEME 7.12 Successful telescoping of two steps—a nitro group reduction and a diastereomer resolution—into one. 

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. 

The development of liquid chromatography on a chiral support gave a decisive impulse to the study of atropisomerism since resolution can be quantitatively performed under very mild conditions without derivatiza-tion. The analytical methods can be easily extrapolated to preparative scale. Several atropisomeric systems, which do not present suitable functional groups to perform classical resolution through diastereomer resolution, can be readily separated into optically pure enantiomers. Dynamic chiral HPLC fills the gap between barriers attainable by DNMR and by thermal racemization of pure enantiomers. Chiral HPLC opens the way to several unexplored domains in the field of atropisomerism. We have... 

Although diastereomer resolution has a low technology image it is widely used industrially, and there are many instances where it is the method of choice and is economical. The technique is often considered to be empirical, however, Collet et ai, [12] have described guidelines which permit a more scientific approach. 

The knots based on neutral, purely organic molecules are obviously not prone to classical diastereomer resolution, and, while chromatographic methods were not suitable for the separation of the two enantiomers of the metal-templated trefoil knot, they have been proved successful in the amide-containing knots. As far as these knotted molecules are concerned, it must be noted that they incorporate classical stereogenic centers (carbon atoms), which makes them very different from the copper-based systems in terms of chirality. In the first instance, the separation of the two enantiomers of six different knots was achieved with a colunm that was not conunercially available (chiral-AD type). Trichloromethane was needed to obtain an optimal separation. The silica gel and the chiral stationary phase were covalently bound so that the material did not bleed out when the lipophilic eluent was used. Moreover, comparison of the experimental CD of the pure enantiomers of a knot with a theoretically calculated CD (based on X-ray structure and a fiiUy optimized AMI geometry) permitted assignment of the absolute configuration of this knot. The latter preparation of soluble knots based on substitution of the 5-position of the pyridine moieties in 13 afforded molecules that were soluble in solvents which could be used in commercially available chiral columns." On the other hand, the substitution of a racemic mixture of knots with chiral auxiliaries allows the separation of the diastereomeric product." ... 

Physical Properties of DIastereomers Resolution, a Method of Separating Enantiomers from Each Other... 

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... 

This method is widely used for the resolution of chiral amines and carboxylic acids Analogous methods based on the formation and separation of diastereomers have been developed for other functional groups the precise approach depends on the kind of chem ical reactivity associated with the functional groups present m the molecule... 

Section 7 14 Resolution is the separation of a racemic mixture into its enantiomers It IS normally carried out by converting the mixture of enantiomers to a mixture of diastereomers separating the diastereomers then regenerating the enantiomers... 

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Based on chiral functional monomers such as (15), MICSPs can be prepared using a racemic template. Thus, using racemic A-(3,5-dinitrobenzoyl)-a-methylbenzy-lamine (16) as template, a polymer capable of racemic resolution of the template was obtained [67]. Another chiral monomer based on L-valine (17), was used to prepare MIPS for the separation of dipeptide diastereomers [68]. In these cases the configu-... 

With the new very high resolution NMR spectra, it should be a simple matter to assign configurations to other difficult cyclitols or carbohydrates, for example, the numerous still undiscovered isomers of 6-bromo, 6-chloro, and 6-iodoquercitol (20 diastereomers predicted for each). 

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. 

The reported preparations of enantiomerically pure chiral iron-acyl complexes have relied upon resolutions of diastereomers. One route1415 (see also Houben-Weyl, Vol. 13/9 a, p 421) employs a resolution of the diastereomeric acylmenlhyloxy complexes (Fe/ )-3 and (FeS )-3 prepared via nucleophilic attack of the chiral menlhyloxide ion of 2 at a carbon monoxide of the iron cation of 1. Subsequent nucleophilic displacement of menthyloxide occurs with inversion at iron to generate the enantiomerically pure iron-acyl complexes (i>)-4 and (f )-4. 

Another route to enantiomcrically pure iron-acyl complexes depends on a resolution of diastereomeric substituted iron-alkyl complexes16,17. Reaction of enantiomerically pure chloromethyl menthyl ether (6) with the anion of 5 provides the menthyloxymethyl complex 7. Photolysis of 7 in the presence of triphenylphosphane induces migratory insertion of carbon monoxide to provide a racemic mixture of the diastereomeric phosphane-substituted menthyloxymethyl complexes (-)-(/ )-8 and ( + )-( )-8 which are resolved by fractional crystallization. Treatment of either diastereomer (—)-(/J)-8 or ( I )-(.V)-8 with gaseous hydrogen chloride (see also Houben-Weyl, Vol 13/9a, p437) affords the enantiomeric chloromethyl complexes (-)-(R)-9 or (+ )-(S)-9 without epimerization of the iron center. 

Figure 10.47 Dynamic kinetic resolution ofThrA generated diastereomers by enantioselective decarboxylation (a).

Conventional kinetic resolution of diastereomer mixtures by retroaldolization for preparation of enantiopure arylserines and for a synthetic intermediate of an antiparkinsonism drug (b). 

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