Metal complexes, enantiomeric 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... 

A tremendous number of transformations of allenes have been reported owing to their high jt-coordination ability towards transition metals. Among them, intramolecular cycloaddition reactions of allenes, in particular, appear to be a practical means of carbon-carbon bond formation in a complicated system. The allenic moiety, however, should be precisely designed for the synthetic purpose of more complex frameworks. A formidable challenge is the synthesis of diversely functionalized allenes of high chemical and/or enantiomerical purity. 

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). 

When 1 is added to a solution of a mixture of enantiomers, A and A, it associates differently with each of the two components to produce the diastereo-meric complexes A+ 1 and A 1. The nmr spectrum of the mixture then shows shift differences that are large compared to the uncomplexed enantiomers (because of the paramagnetic effect of the europium) and normally the resonances of the A+ 1 complex will be distinct from those of the A 1 complex. An example of the behavior to be expected is shown in the proton nmr spectrum (Figure 19-4) of the enantiomers of 1-phenylethanamine in the presence of 1. Although not all of the resonances are separated equally, the resolution is good for the resonances of nuclei closest to the metal atom and permits an estimate of the ratio of enantiomers as about 2 1 and the enantiomeric purity as 33%. 

The salen-Ni(II) complex 39a derived from (lR,2R)-[N,N -bis(2 -hydroxybenzyl-idene)]-l,2-diaminocyclohexane was also equally effective (Table 7.3, entry 4). In contrast to earlier reports on salen-metal complexes, where the introduction of a bulky tert- butyl substituent increased enantioselectivity [31], the use of complex 39b exhibited a significant decrease in enantioselectivity (entry 5). The presence of a bulky tert-butyl group obstructed the chelation of alkali metal ions by phenolic oxygen atoms. A dramatic increase in selectivity could be achieved when nickel was replaced with copper, and a salen-Cu(II) complex 39c afforded 85% ee (entry 6). Although screening of other bases or 50% NaOH were not advantageous, the use of 3 equiv. NaOH improved the enantiomeric excess to 92% (entry 9) and after recrystallization of a-methylphenylalanine optical purity was increased to 98% ee. 

In 1989, Brown et al. [15] suggested that since B-O and B-N bonds are shorter than metal-oxygen and metal-nitrogen bonds, there is a greater chance that boron complex will be a more effective catalyst. In order to substantiate this hypothesis, they carried out enantioselective addition of diethyl zinc to several aldehydes using (45,5/ )-3,4-dimethyl-5-phenyl-1,3,2-oxazaborolidine as catalyst and achieved very high yield and enantiomeric purity (upto 96 % ee) of secondary alcohols. 

FIGURE 9.2 General schematic for studying enantioselective discrimination using the KM. A metal (M) is mixed in solution with a chiral reference compound (CR) and an analyte of interest (A ). A ternary complex is isolated in the gas phase and induced to fragment. The logarithm of the ratio of product ion channels is measured and can be correlated with the enantiomeric purity of A. ... 

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