Ligand Fine Tuning

As described above, the Ir-xyliphos catalysts showed extremely high catalyst activities and productivities. On the other hand, the enantioselectivity to the desired S-enantiomer just barely met the requirements. Therefore, we tried to improve the ee values by tuning of the electronic and steric properties of the new ferrocenyl ligands. As shown in Tab. 2, it was indeed possible to increase the selectivity of the catalyst, however, as observed earlier with other ligands, any gain in selectivity was always offset by a loss in catalyst activity and often productivity. In the end, xyliphos was the best compromise as regards activity and selectivity for a technical process. 

Once a catalyst system with the required performance had been found and confirmed, the attention turned to finding a technically feasible overall process. The technical preparation of methoxyacetone and 2-methyl-6-ethyl-aniline as well as the chloroacetylation step had already been established in the existing process for racemic metolachlor. 

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A technical process was developed by Lonza for the Ir-catalyzed hydrogenation of an intermediate of dextromethorphan (Fig. 34.9) which was carried out on a > 100-kg scale [70]. Important success factors were ligand fine tuning and the use of a biphasic system chemoselectivity with respect to C=C hydrogenation was high, but catalyst productivity rather low for an economical technical application. Satoh et al. reported up to 90% ee for the hydrogenation of an intermediate of the antibiotic levofloxacin using Ir-diphosphine complexes. Best results were obtained with bppm and a modified diop in the presence of bismuth iodide at low temperature [71]. 

An Ir-catalyzed hydrogenation developed by Lonza for an intermediate of dextromethorphan was carried out on >100kg scale [29]. Here, the important success factors were the ligand fine tuning and the use of a biphasic system. The... 

Roche [54] described a very efficient hydrogenation of keto pantolactone, an intermediate for pantothenic acid, carried out on multi-100-kg scale also using a Rh/bpm complex (Scheme 19). Success factors were the careful ligand fine tuning and the selection of the right anion which had an unusually strong effect both oti enantioselectivity and catalytic activity. 

After this success, Ir catalysts were employed more often, and it was shown that besides imines, C=0 as well as C=C btmds could be hydrogenated with good success. The hydrogenation depicted in Scheme 47 was developed by Lonza [38] for an intermediate of dextromethorphan and carried out on >100-kg scale. Important success factors were the ligand fine tuning and the use of a biphasic system. Chemoselectivity is high but catalyst productivity rather low for an economical technical application. Bristol-Meyers Squibb [111] achieved the first case of Ir diphosphine-catalyzed hydrogenation of a C=C bond to prepare a lactam pharmacaphore on a 20-kg scale (Scheme 48). DSM [112] in collaboration with Solvias developed a new route for biotin, based on the unprecedented reduction of... 

Ligand fine-tuning continues to provide an important possibility to alter the individual product formation in the aerobic aza-Wacker reaction. For example, Zhang could show that phenanthroHne also constitutes a suitable ligand for this type of reaction, surpassing the more common pyridine in the transformations of alkene 37 to allylamine 38 (Scheme 16.9). 

Based on the above results they have concluded that the ligand groups circularly arranged on the lower rim of the calixarene cavity construct a novel cyclic metal receptor for selective extraction of transition metal cations. Results suggest that the fine tuning in molecular... 

Comparison of our results with those of Tanner et al. demonstrate that fine-tuning of the chiral ligands leads to remarkable improvements in the enantio-selectivity. 

Streptavidin-single-stranded DNA covalent conjugates were described as the building blocks for assembling nanostructured scaffolds [31], The amount and type of biotinylated ligands were used to modulate the affinity of duplex formation between solid-phase-bound nucleic acid templates and DNA-streptavidin conjugates. This system has been proposed for the design of fine-tuned sequence detection systems. 

When the target enzyme is difficult to obtain, related enzymes could be used to provide insights in the design of novel ligands. For example, papain was used to design a class of potent cathepsin K inhibitors [33] spanning both sides of the papain active site. However, fine-tuning these inhibitors to produce more potent ones required the use of the crystal structure of cathepsin K itself [34],... 

The unique suitability of iron comes from the extreme variability of the Fe2+/Fe3+ redox potential, which can be fine tuned by well-chosen ligands, so that iron sites can encompass almost the entire biologically significant range of redox potentials, from about —0.5 V to about +0.6 V. 

A range of bis(tetrachlorocatecholato)spirophosphoranides 91 and 92 have been prepared from diones <2002EJ03580>. Careful fine-tuning of the polarity of the solvent mixture was required for the precipitation of the dimethylammonium salts of the spirophosphoranides. A Cj-symmetric spirophosphoranide 93 with three different bidentate ligands was also prepared. The synthesis required the addition of the dione to a phosphoramidite generated... 

Palladium(0)-catalyzed coupling reactions - i. e. the Heck and Sonogashira reactions, the carbonylative coupling reactions, the Suzuki and Stille cross-coupling reactions, and allylic substitutions (Fig. 11.1) - have enabled the formation of many kinds of carbon-carbon attachments that were previously very difficult to make. These reactions are usually robust and occur in the presence of a wide variety of functional groups. The reactions are, furthermore, autocatalytic (i.e. the substrate regenerates the required oxidation state of the palladium) and a vast number of different ligands can be used to fine-tune the reactivity and selectivity of the reactions. 

It was found by Trost that the low reactivity could be circumvented by the employment of labile ligands, such as the propionitrile in the Mo(CO)3(EtCN)3 precatalyst [57]. Instead of directly transferring this procedure to microwave heating applications, a useful and easily handled microwave procedure was developed for rapid and selective molybdenum-catalyzed allylic alkylations under noninert conditions (Eq. 11.39) [12]. The former, more sensitive, two-step reaction was fine-tuned into a robust one-step procedure employing the inexpensive and stable precatalyst Mo(CO)6, used in low concentrations. The alkylations were conducted in air and resulted in complete conversions, high yields, and an impressive enantiomeric excess (98%) in only 5-6 min. Despite the daunting temperatures, up to 250°C with THF... 

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