Resolution Of diastereomers

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. 

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

B. Feibush, Interpretation and correlation of bulkiness chirality and separation coefficients in the resolution of diastereomers by gas-chromatography. Anal. Chem. 43 (1971), 1098. 

Tsuda Y, Hosoi S, Ishida K, Sangai M (1994) Chiral Synthesis of Erythrina Alkaloids (2). Synthesis of enantio-Typc Erythrinan Alkaloids Utilizing Asymmetric Acylation and Kinetic Resolution of Diastereomers. Chem Pharm Bull 42 204... 

Suda, Y. T. Hosoi, S. Ishida, K. Sangai, M. Chiral Synthesis of Erythrina Alkaloids. Synthesis of enantio-type Erythrinan alkaloids utilizing asymmetric acylation and kinetic resolution of diastereomers. Chem. Pharm. Bull, 1994, 42, 204-213. 

The substrate is a mixture of only two diastereomers (Scheme 57.1c), the enzyme selectively transforms one of them resolution of diastereomers), while the other one (Sr s) experiments fast epimerization at the stereocenter involved in the enzymatic transformation. 

Figure 32 Preparation of enantiopure phenylserines by resolution of diastereomer mixtures using retroaldolization imder kinetic control [154].

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. 

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-... 

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. 

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. 

Although fractional crystallization has always been the most common method for the separation of diastereomers. When it can be used, binary-phase diagrams for the diastereomeric salts have been used to calculate the efficiency of optical resolution. However, its tediousness and the fact that it is limited to solids prompted a search for other methods. Fractional distillation has given only limited separation, but gas chromatography and preparative liquid chromatography have proved more useful and, in many cases, have supplanted fraetional crystallization, especially where the quantities to be resolved are small. 

Stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on page 132. A method has been developed to evaluate the enantiomeric ratio of kinetic resolution using only the extent of substrate conversion. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane, since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as (56 with one... 

Furthermore, the same methodology was used for an approach towards enantiopure PGFla (2-46) through a catalytic kinetic resolution of racemic 2-43 using (S)-ALB (2-37) (Scheme 2.10) [14]. Reaction of 2-35, 2-36 and 2-43 in the presence of 2-37 led to 2-44 as a 12 1 mixture of diastereomers in 75 % yield (based on malonate 2-36). The transformation proceeds with excellent enantioselectivity thus, the enone 2-45 obtained from 2-44 shows an ee-value of 97 %. 

The use of dissociable diastereomers for enantiomer resolution may be illustrated by the case where racemic mandelic acid is resolved using en-antiomerically pure a-methylbenzylamine. The n and p salts of a-methylbenzyl-amine mandelate have aqueous solubilities of 49.1 and 180 g/L, respectively, at 25°C [153], A more recent example, which focuses on the crystallographic origin of the solubility differences, is provided by the resolution of ( )-mandelic acid with (-)-ephedrine in water or methanol solution [154], In general, the relative solubilities of the n and p salt pairs are strongly influenced by the choice of solvent medium and temperature, which provide considerable flexiblity in optimizing the crystallization conditions and the efficiency of resolution. This process may be facilitated by the development of a full solubility phase diagram. 

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