Resolution of Racemic Carbonyl Compounds

The asymmetric olefination of the racemic ketone 111 with the anion of the phosphinothioic amide 15 can be regarded as an example of kinetic resolution  

the method of kinetic resolution was extended to aldehyde substrates [79, 

In a similar way, racemic 3-substituted cyclohexanones 121 were reacted with the anion of the chiral phosphoamidate reagent 18a to give two isomeric optically active alkenes, that is (S, ) and (i , Z)-alkenes possessing the opposite absolute configuration at the homoallylic carbon centers, with high enantiomeric excess [55]. 

Base KHMDS / 18-crown-6 KHMDS / 18-crown-6 NaHMDS KHMDS 

Asymmetric olefination based on kinetic resolution was then directed to the use 

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Related to this is the use of amino acid derived reagents for resolution of racemic carbonyl compounds and determination of absolute configurations by X-ray analysis at the imine stage. This is exemplified by the L-valinol derived imine of tricarboxyl (l-formyl-2-methoxyphenyl) chromium (see p 417)88. 

Optical resolution of racemic carbonyl compounds is catalyzed by several microorganisms as well as isolated enzymes (Figure 27). Various compounds including organometallic compounds (Figure 27(d))28d were resolved successfully. 

The utility of bifunctional reagents such as oxalic acid monohydrazide for the resolution of racemic carbonyl compounds has been reported. Glyoxal reacts with ethyl carbamate under acid catalysis to give 1,1,2,2-tetra-(ethoxycarbonylamino)ethane (46) and not, as previously reported, glyoxal bis(ethoxycarbonylimide) (47). 

A method for the resolution of racemic carbonyl compounds, by separation of the diastereomeric mixtures of dithioketals formed with L(+)-2,3-butanedithiol, has been described [96]. 

Another chiral aldehyde suitable for such transformations is the recently prepared pyridoxal derivative (121).323 Even more recent examples of chiral carbonyl compounds (122) have been used for the partial resolution of amino acids. The enantiomers of compounds (122) undergo reaction with racemic a-amino acids and copper(II) ions to give preferential formation of enantiomeric copper complexes. The ( -enantiomers of (122) preferentially form complexes containing the... 

Although about 20 polysaccharide-based CSPs have been commercialized and much work on enantioresolution has been carried out on these phases, it remains very difficult to predict the best CSP for the chiral resolution of a particular compound. It has been observed that most of the resolved racemic compounds contain aromatic rings or groups such as carbonyl, sulfinyl, nitro, amino, and benzoyl. However, some reports have been published on the chiral resolution of nonaromatic racemates on polysaccharide CSPs [61]. As in the case of other CSPs, polysaccharide-based CSPs do not require a certain combination of functional groups. However, only one group can afford a satisfactory separation. Presumably some chiral space (e.g., a concavity or ravine existing on a polysaccharide derivative) could enable such a separation [62],... 

It is not easy to determine the differences in structural selectivity among all possible derivatives. A rationalization based on an electronic effect [18] and the length of the acyl substituent on cellulose were attempted [42]. CTA-I (micro-crystalline cellulose triacetate) is very specific and can be used for resolution of racemic compounds both having aromatic rings and carbonyl groups. On the other hand, a CTA-II (cellulose triacetate) CSP has a different selectivity. Both... 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

The late 1990s saw the development of an alternative methodology for the enzymatic resolution of racemic amines using transaminases. Transaminases are pyridoxal phosphate 50 dependent enzymes that catalyze the transfer of an amine group to a carbonyl compound (amine group acceptor), such as a ketone, aldehyde, or keto add (Figure 14.19). 

As noted for amino acids, the addition of a carbonyl compound to a primary amino group at an appropriate pH can trigger the formation of the corresponding imine, which greatly enhances the acidity of the a-carbon, thus stabilizing the enolate and favoring racemization. In this context, studies of the racemization of amino esters in the presence of various aldehydes have been performed [43], and this phenomenon has been exploited by coupling the racemization with enzymatic hydrolysis to initiate resolution under DKR conditions (Scheme 8.5) [44]. 

It is generally beheved that selectivity of hydrolytic enzymes strongly depends on the proximity of the chiral center to the reacting carbonyl group, and only a few examples of successful resolutions exist for compounds that have the chiral center removed by more than three bonds. A noticeable exception to this rule is the enantioselective hydrolysis by Pseudomonasfluorescens Hpase (PEL) of racemic dithioacetal (5) that has a prochiral center four bonds away from the reactive carboxylate (24). The monoester (6) is obtained in 89% yield and 98% ee. 

CSPs (CTA-I and CTA-II) have inverse selectivity for Troger s base and trans-1,2-diphenyloxirane racemates. These characteristics of CTA CSPs are responsible for good chiral resolution of small cychc carbonyl compounds [42]. In 2001 Aboul-Enein and Ah [63] observed the reversed order of elution of nebivolol on a Chiralpak AD column when ethanol and 2-propanol were used separately as the mobile phases. Table 1 presents selectivity data for the polysaccharide-based CSPs. Okamoto et al. [42] observed that the introduction of a methyl group at the para position of cellulose tribenzoate results in a dramatic shift of the structural selectivity toward aromatic compounds with larger skeletons, and its selectivity was rather similar to that of cellulose tricinnamate. 

Because the steric effect contributes to the complex formation between guest and host, the chiral resolution on these CSPs is affected by the structures of the analytes. Amino acids, amino alcohols, and derivatives of amines are the best classes for studying the effect of analyte structures on the chiral resolution. The effect of analyte structures on the chiral resolution may be obtained from the work of Hyun et al. [47,48]. The authors studied the chiral resolution of amino alcohols, amides, amino esters, and amino carbonyls. The effects of the substituents on the chiral resolution of some racemic compounds are shown in Table 6. A perusal of this table indicates the dominant effect of steric interactions on chiral resolution. Furthermore, an improved resolution of the racemic compounds, having phenyl moieties as the substituents, may be observed from this Table 6. ft may be the result of the presence of n—n interactions between the CCE and racemates. Generally, the resolution decreases with the addition of bulky groups, which may be caused by the steric effects. In addition, some anions have been used as the mobile phase additives for the improvement of the chiral resolution of amino acids [76]. Recently, Machida et al. [69] reported the use of some mobile phase additives for the improvement of chiral resolution. They observed an improvement in the chiral resolution of some hydrophobic amino compound using cyclodextrins and cations as mobile phase additives. 

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