Enantiomeric selection screening

The screening was performed in a way similar to that of Welch, except that it involved the use of a spectropolarimeter instead of chiral chromatography to determine the selectivity. Equal amounts of the target racemate 17 were added into each of the 16 wells containing beads and the ellipticity of the supernatant liquid in each well was measured after equilibrating for 24 h at the wavelength of the maximum adsorption (260 nm). Knowing the specific ellipticity of one enantiomerically pure... 

Our group also demonstrated another combinatorial approach in which a CSP carrying a library of enantiomerically pure potential selectors was used directly to screen for enantioselectivity in the HPLC separation of target analytes [93, 94]. The best selector of the bound mixture for the desired separation was then identified in a few deconvolution steps. As a result of the parallelism advantage , the number of columns that had to be screened in this deconvolution process to identify the single most selective selector CSP was much smaller than the number of actual selectors in the library. 

The original library of 10 000 clones used in the Baeyer-Villiger reaction [89] was screened for performance as potential catalysts in the sulfoxidation [32]. This led to the discovery of at least 20 mutants having enantiomeric excess values in the range of 85-99%, some being (R) selective and others being (S) selective. Five mutants resulting in enantiomeric excess values of >95% were sequenced (Table 2.2) [32]. 

Several other enantiomeric ally pure bidentate ligands have been screened using [Ir (cod)Cl]2, including bis-oxazolines [48,49], amino oxazolines [50],Ai-heterocyclic carbenes [51], and diamines [52, 53]. Examples where the enantioselectivity was in excess of 90% ee include the use of ligands 45,46, and 47 [54-56]. Selected examples of the use of these ligands with [Ir(cod)Cl]2 are given in Scheme 12 for the reduction of ketones 48, 50, and 52. 

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. 

A similar approach was reported by Lygo and co-workers who applied comparable anthracenylmethyl-based ammonium salts of type 26 in combination with 50% aqueous potassium hydroxide as a basic system at room temperature [26, 27a], Under these conditions the required O-alkylation at the alkaloid catalyst s hydroxyl group occurs in situ. The enantioselective alkylation reactions proceeded with somewhat lower enantioselectivity (up to 91% ee) compared with the results obtained with the Corey catalyst 25. The overall yields of esters of type 27 (obtained after imine hydrolysis) were in the range 40 to 86% [26]. A selected example is shown in Scheme 3.7. Because the pseudo-enantiomeric catalyst pairs 25 and 26 led to opposite enantiomers with comparable enantioselectivity, this procedure enables convenient access to both enantiomers. Recently, the Lygo group reported an in situ-preparation of the alkaloid-based phase transfer catalyst [27b] as well as the application of a new, highly effective phase-transfer catalyst derived from a-methyl-naphthylamine, which was found by screening of a catalyst library [27c],... 

By screening in solution Miller et al. identified the pentapeptide 32 as a catalyst for kinetic resolution of the alcohol roc-33 (selectivity factor 27, Scheme 12.17). roc-33 was an intermediate in their synthesis of enantiomerically pure mitosane 34 [37]. 

For all the substrates discussed so far the peptide catalysts employed had to differentiate between enantiomeric substrate molecules. Miller et al. subsequently screened peptide libraries for members able to selectively functionalize enantio-topic hydroxyl groups of meso inositols. In particular, they were able to convert myo-inositol 35 to either monophosphorylated D-myo-inositol-l-phosphate 37 or d-myo-inositol-3-phosphate ent-37 in high yield and excellent ee (98% Scheme 12.18) [38, 39], This remarkable result was achieved by use of either of the penta-... 

The rapid development of combinatorial screening methods has been accompanied by the development of ever more efficient high-throughput analysis technologies. These not only enable analysis of catalytic activity but also the determination of enantiomeric excess [2, 21]. Taking these developments together, research in this field can be expected to yield highly active and selective catalysts with structures that could have not been predicted by conventional means. 

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