Bidentate chiral ligands were the rule in metal-catalyzed asymmetric hydrogenation for more than 30 years [1] as chelation was believed to be necessary to impart the necessary rigidity to the metal complex for an efficient transfer of chirality. Recently, however, a few groups have demonstrated that monodentate ligands can also induce high enantioselectivity [2] as long as two of these ligands are present in the active species. Herein, we describe the first example of a highly asymmetric hydrogenation that is induced by a metal catalyst containing only one monodentate ligand. [3] Iridium is an important metal in hydrogenation. The Crabtree catalyst, [4] its enantioselective version, developed by Pfaltz, based on chiral P,N ligands, [5] or the celebrated Metolachlor process catalyst [6] are prime examples of Irbased hydrogenation catalysts (Scheme 1). We were interested in investigating whether iridium complexes of chiral monodentate phosphoramidites could also act as efficient enantioselective hydrogenation catalysts. Although such Ir complexes have already been reported, [7] which has led to the discovery of new cyclometalated species that are active in allylic substitution, [8] there are no reports of their use in enantioselective hydrogenation.Our initial studies were aimed at the preparation of cationic iridium complexes that are analogues of the Crabtree catalyst containing a phosphoramidite ligand L, and either the same phosphoramidite, a phosphine, or pyridine as the secondary ligand L' (Scheme 1). Based on literature precedents, [9] two equivalents of Monophos were treated with [{Ir(cod)Cl} 2 ] to immediately give [Ir(cod)(L)Cl] [7b] which, upon chloride abstraction in the presence of another equivalent of L, should form a cationic complex of the type [Ir(cod)LL'] + . Although we screened several phosphoramidites in combination with different ancillary ligands and counteranions, we did not obtain an efficient hydrogenation catalyst. The breakthrough came with the observation that an active but also enantioselective catalyst is obtained with bulky phosphoramidites based on Binol with substituents in the 3,3' positions without abstraction of the chloride ligand, that is, from the non-cationic catalyst precursor [Ir(cod)(L)Cl] containing only one phosphoramidite ligand per metal. [10] The drastic effect of the substitution in the 3,3' positions of the diol backbone of the ligand can be visualized by comparing the hydrogen uptake curves obtained during the hydrogenation of methyl (Z)-2-acetamidocinnamate (Figure 1). Figure 1 clearly shows that increasing the bulkiness of the chiral backbone in the 3,3' positions leads to a substantial increase not only in activity but also in enantioselectivity (average TOFs of 6, 24, 50, and 150 h À1 and ee values of 28, 67, 93, and 98 % for R 1 = H, Me, Ph, and R 2 = tBu, respectively; see also Scheme 1). For practical reasons, namely that the diol precursor is commercially available, the bulkiest ligand with the tBu substituents is based on biphenol while the other li...
Amadoriases are a class of FAD-dependent enzymes that are found in fungi, yeast and bacteria and that are able to hydrolyze glycated amino acids, cleaving the sugar moiety from the amino acidic portion. So far, engineered Amadoriases have mostly found practical application in the measurement of the concentration of glycated albumin in blood samples. However, these engineered forms of Amadoriases show relatively low absolute activity and stability levels, which affect their conditions of use. Therefore, enzyme stabilization is desirable prior to function-altering molecular engineering. In this work, we describe a rational design strategy based on a computational screening method to evaluate a library of potentially stabilizing disulfide bonds. Our approach allowed the identification of two thermostable Amadoriase I mutants (SS03 and SS17) featuring a significantly higher T50 (55.3 °C and 60.6 °C, respectively) compared to the wild-type enzyme (52.4 °C). Moreover, SS17 shows clear hyperstabilization, with residual activity up to 95 °C, whereas the wild-type enzyme is fully inactive at 55 °C. Our computational screening method can therefore be considered as a promising approach to expedite the design of thermostable enzymes.
Bidentate chiral ligands were the rule in metal-catalyzed asymmetric hydrogenation for more than 30 years [1] as chelation was believed to be necessary to impart the necessary rigidity to the metal complex for an efficient transfer of chirality. Recently, however, a few groups have demonstrated that monodentate ligands can also induce high enantioselectivity [2] as long as two of these ligands are present in the active species. Herein, we describe the first example of a highly asymmetric hydrogenation that is induced by a metal catalyst containing only one monodentate ligand. [3] Iridium is an important metal in hydrogenation. The Crabtree catalyst, [4] its enantioselective version, developed by Pfaltz, based on chiral P,N ligands, [5] or the celebrated Metolachlor process catalyst [6] are prime examples of Irbased hydrogenation catalysts (Scheme 1). We were interested in investigating whether iridium complexes of chiral monodentate phosphoramidites could also act as efficient enantioselective hydrogenation catalysts. Although such Ir complexes have already been reported, [7] which has led to the discovery of new cyclometalated species that are active in allylic substitution, [8] there are no reports of their use in enantioselective hydrogenation.Our initial studies were aimed at the preparation of cationic iridium complexes that are analogues of the Crabtree catalyst containing a phosphoramidite ligand L, and either the same phosphoramidite, a phosphine, or pyridine as the secondary ligand L' (Scheme 1). Based on literature precedents, [9] . Although we screened several phosphoramidites in combination with different ancillary ligands and counteranions, we did not obtain an efficient hydrogenation catalyst. The breakthrough came with the observation that an active but also enantioselective catalyst is obtained with bulky phosphoramidites based on Binol with substituents in the 3,3' positions without abstraction of the chloride ligand, that is, from the non-cationic catalyst precursor [Ir(cod)(L)Cl] containing only one phosphoramidite ligand per metal. [10] The drastic effect of the substitution in the 3,3' positions of the diol backbone of the ligand can be visualized by comparing the hydrogen uptake curves obtained during the hydrogenation of methyl (Z)-2-acetamidocinnamate (Figure 1). Figure 1 clearly shows that increasing the bulkiness of the chiral backbone in the 3,3' positions leads to a substantial increase not only in activity but also in enantioselectivity (average TOFs of 6, 24, 50, and 150 h À1 and ee values of 28, 67, 93, and 98 % for R 1 = H, Me, Ph, and R 2 = tBu, respectively; see also Scheme 1). For practical reasons, namely that the diol precursor is commercially available, the bulkiest ligand with the tBu substituents is based on biphenol while the other ligands are based on binaphthol.[12] Increasing the bulkiness of the phosphoramidite by changing its amino moiety does not, however, produce the same effect, and the catalytic performance of the complex remained poor when the dimethylamino g...
A new approach to highly enantioenriched cyclic compounds (up to 98 % ee) has been developed by using ω-ethylenic allylic substrates in a one-pot asymmetric allylic alkylation and ring-closing metathesis sequence. The starting compounds are synthetic equivalents of cyclic allylic substrates. The method is exemplified with both Cu and Ir catalysts, and chiral phosphoramidite ligands
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