Chiral metal complexes optical purity

Enantiometrically pure alcohols are important and valuable intermediates in the synthesis of pharmaceuticals and other fine chemicals. A variety of synthetic methods have been developed to obtain optically pure alcohols. Among these methods, a straightforward approach is the reduction of prochiral ketones to chiral alcohols. In this context, varieties of chiral metal complexes have been developed as catalysts in asymmetric ketone reductions [ 1-3]. However, in many cases, difficulties remain in the process operation, and in obtaining sufficient enantiomeric purity and productivity [2,3]. In addition, residual metal in the products originating from the metal catalyst presents another challenge because of the ever more stringent regulatory restrictions on the level of metals allowed in pharmaceutical products [4]. An alternative to the chemical asymmetric reduction processes is biocatalytic transformation, which offers... 

In ordinary reagent- or catalyst-based enantioselective reactions of prochiral substrates (equations 4 and 5, respectively), 100% enantiomeric purity of the chiral source is assumed, and the major concern is the efficiency of the chirality transfer from the chiral source to the substrate, namely, optical yield. In some special cases, however, a chiral metal complex can even amplify chirality (equation 6). A catalyst that is itself only partially resolved may form a chiral product with very high enantiomeric purity (24) (Chapter 5). 

Since Evans s initial report, several chiral Lewis acids with copper as the central metal have been reported. Davies et al. and Ghosh et al. independently developed a bis(oxazoline) ligand prepared from aminoindanol, and applied the copper complex of this ligand to the asymmetric Diels-Alder reaction. Davies varied the link between the two oxazolines and found that cyclopropyl is the best connector (see catalyst 26), giving the cycloadduct of acryloyloxazolidinone and cyclopentadiene in high optical purity (98.4% ee) [35] (Scheme 1.45). Ghosh et al., on the other hand, obtained the same cycloadduct in 99% ee by the use of unsubstituted ligand (see catalyst 27) [36] (Scheme 1.46, Table 1.19). 

Figure 8-1 depicts the relationship between the optical purity of the chiral catalyst and the ee of the product. In a simplified case, when two enantiomeric chiral ligands (LR or Ls) are attached to a metal center (M), complexes ML2 may be formed as the reactive species. Three complexes are possible MLRLS, MLrLr, and MLsLs. Supposing that LR is in excess and the stability constant for the muw-complex MLRLS is greater than that of the chiral complexes, if mt, w-MLR Ls is the more active catalyst, a lower than expected ee will be obtained [(—)-NLEs, curve 3 in Fig. 8-7], The ee will be higher than expected if the me.w-catalyst is less reactive than MLRLR or MLSLS [(+)-NLEs, curve 2 in Fig. 8-7],...

A group at the Academy of Sciences in Moscow 197) has synthesized chiral threonine. Derivatives of cyclic imino acids form copper complexes with glacine and carbonyl compounds. Hydroxyethylation with acetaldehyde and decomposition of the resulting complexes produced threonine with an optical purity of up to 97-100% and with threo/allo ratios of up to 19 1 197). The chiral reagents could be recovered and re-used without loss of stereoselectivity. The mechanism of this asymmetric synthesis of amino acids via glacine Schiff base/metal complexes was also discussed 197). 

The general synthesis of the Daniphos ligands starting from enantiomerically pure [(R)-l-(phenylethyl)dimethylamine]chromiumtricarbonyl 1, is depicted in Scheme 1.4.1 [15]. A directed ortho-metallation (DOM) and subsequent quench with a chlorophosphine leads to an enantiomerically pure planar-chiral complex, which after chlorination using ACE chloride (1-chloroethyl chloroformate) is transformed into the desired diphosphine by a nucleophilic substitution without any loss of optical purity (Scheme 1.4.1) [6, 10]. 

Asymmetric synthesis (i) has gained new momentum with the potential k use of homogeneous catalysts. The use of a transition metal complex with chiral ligands to catalyze a synthesis asymmetrically from a prochiral substrate is beneficial in that resolution of a normally obtained racemate product may be avoided. In certain catalytic hydrogenations of olefinic bonds, optical purities approaching 100% have been attained (2,3,4,5) hydrogenations of ketones (6,... 

Allylic double bonds can be isomerized by some transition metal complexes. Isomerization of alkyl allyl ethers 480 to vinyl ethers 481 is catalysed by Pd on carbon [205] and the Wilkinson complex [206], and the vinyl ethers are hydrolysed to aldehydes. Isomerization of the allylic amines to enamines is catalysed by Rh complexes [207]. The asymmetric isomerization of A jV-diethylgeranylamine (483), catalysed by Rh-(5)-BINAP (XXXI) complex to produce the (f )-enaminc 484 with high optical purity, has been achieved with a 300 000 turnover of the Rh catalyst, and citronellal (485) with nearly 100% ee is obtained by the hydrolysis of the enamine 484 [208]. Now optically pure /-menthol (486) is commerically produced in five steps from myrcene (482) via citronellal (485) by Takasago International Corporation. This is the largest industrial process of asymmetric synthesis in the world [209]. The following stereochemical corelation between the stereochemistries of the chiral Rh catalysts, diethylgeranylamine (483), diethylnerylamine (487) and the (R)- and (5)-enamines 484... 

Marchelli used the copper(II) complex of histamine-functionalized P-cy-clodextrin for chiral recognition and separation of amino acids [27]. The best results were obtained for aromatic amino acids (Trp). Enantioselective sensing of amino acids by copper(II) complexes of phenylalanine-based fluorescent P-cyclodextrin has been recently published by the same author [28, 29]. The host containing a metal-binding site and a dansyl fluorophore was shown to form copper(II) complexes with fluorescence quenching. Addition of d- or L-amino acids induced a switch on of the fluorescence, which was enantioselective for Pro, Phe, and Trp. This effect was used for the determination of the optical purity of proline. 

Conversion of the separated diastereoisomers 10a and 10b into the enantiomers +9 and —9 was achieved by treatment with HC1 in benzene solution. In the examples given earlier, to accomplish conversion of diastereoisomers into enantiomers, only those bonds were broken that did not involve the chiral metal atom this was to avoid loss of optical purity through possible change in configuration of the metal atom. In this work, Ti—O bond cleavage had to be used to convert the diastereoisomers (10) to the enantiomers (9). However, HCI cleavage of the Ti—OR bond in compounds of type 10 was shown to be stereospecific with respect to the chiral Ti atom, and to occur with retention of configuration (44-48). Optically active complexes with a chiral Ti atom could also be obtained by asymmetric decomposition (49, 50). 

The most popular methods of preparing optically active l-octyn-3-ol involve asymmetric reduction of l-octyn-3-one with optlcally-active alcohol complexes of lithium aluminum hydride or aluminum hydride. These methods give optical purities and chemical yields similar to the method reported above. A disadvantage of these metal-hydride methods is that some require exotic chiral alcohols that are not readily available in both enantiomeric forms. Other methods include optical resolution of the racemic propargyl alcohol (100 ee) (and Note 11) and microbial asymmetric hydrolysis of the propargyl acetates (-15% ee for l-heptyn-3-ol)... 

After a metal hydride complex was prepared from LAH and quinine (1 1), irradiation of a mixture of the resulting solution containing the above chiral hydride agent and the enamide (133) led to the formation of two optically active lactams 158 [6%, [a]D —63° (c = 0.48, CHC13)] and 155 [ 13%, [a]D — 102° (c = 0.44, CHC13)] with 37% optical purity. Reduction of the lactam 155 with LAH furnished (—)-xylopinine (20) in 48% chemical yield. 

Ito and coworkers found that chiral ferrocenylphosphine-silver(I) complexes also catalyze the asymmetric aldol reaction of isocyanoacetate with aldehydes (Sch. 26) [51]. It is essential to keep the isocyanoacetate at a low concentration to obtain a product with high optical purity. They performed IR studies on the structures of gold(I) and silver(I) complexes with chiral ferrocenylphosphine 86a in the presence of methyl isocyanoacetate (27) and found significant differences between the iso-cyanoacetate-to-metal coordination numbers of these metal complexes (Sch. 27). The gold(I) complex has the tricoordinated structure 100, which results in high ee, whereas for the silver(I) complex there is an equilibrium between the tricoordinated structure 101 and the tetracoordinated structure 102, which results in low enantioselectivity. Slow addition of isocyanoacetate 27 to a solution of the silver(I) catalyst and aldehyde is effective in reducing the undesirable tetracoordinated species and results in high enantioselectivity. 

One means of stereoselective cleavage of biaryl lactones [53] is activation of the carbonyl group with a Lewis acid and subsequent attack with a chiral nucleophile. Conversely, activation can be effected with a chiral Lewis acid followed by attack of an achiral nucleophile. Complexation of a biaryl lactone to the chiral fragment [CpRe (NO)(PPh3)j then reduction with K(s-Bu)3BH (K-selectride) and ring opening of the intermediate rhenium lactolate gives the metalated aldehyde (dr = 75 25) which is converted to the alcohol without essential loss of optical purity (Sch. 6) [54]. 

This process (hetero Diels-Alder reaction leading to a dihydropyran system) may be also conducted in an asymmetric version application of chiral transition-metal catalysts based on BINOL, BDMAP, bisoxazolines, etc. provides adducts in very high optical purity (ee up to 99%) [1,6], In a series of papers Jurczak reported recently a highly enantioselective cycloaddition of 1-methoxy-1,3-butadiene and butyl glyoxylate catalyzed with chiral salen complexes [21],... 

A number of other chiral ligands are available, but have been studied much less extensively. Hie chiral diamines (106) and (107) are reported to mediate the reactions between aryl Grignards and aldehydes (Bgure 22 equation 26). Hie alcohols range in optical purity from 40 to 75% ee selectivities increase with the bulkiness of the aldehyde substituent (see Table 28). Hie use of an aiyloxy metal halide to complex the aldehyde moiety enhances the observed enantioselectivities. °... 

Transition-metal complexes bearing chiral ligands catalyze an asymmetric aldol condensation of isocyanoacetates with aldehydes to afford a mixture of cis- and /rons-4,5-disubstituted-4,5-dihydrooxazoles (188) in high optical purity (Equation (27)). Both gold and silver ferrocenylphos-phine complexes are effective <94TL2713>. 

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