Chiral ligands future developments

Since the discovery and development of highly efficient Rh catalysts with chiral diphosphites and phosphine-phosphites in the 1990s, the enantioselectivity of asymmetric hydroformylation has reached the equivalent level to that of asymmetric hydrogenation for several substrates. Nevertheless, there still exist substrates that require even further development of more efficient chiral ligands, catalyst systems, and reaction conditions. Diastereoselective hydroformylation is expected to find many applications in the total synthesis of complex natural products as well as the syntheses of biologically active compounds of medicinal and agrochemical interests in the near future. Advances in asymmetric hydrocarboxylation has been much slower than that of asymmetric hydroformylation in spite of its high potential in the syntheses of fine chemicals. 

Currently, this area is not as well developed as the use of cinchona alkaloid derivatives or spiro-ammonium salts as asymmetric phase-transfer catalysts, and the key requirements for an effective catalyst are only just becoming apparent. As a result, the enantioselectivities observed using these catalysts rarely compete with those obtainable by ammonium ion-derived phase-transfer catalysts. Nevertheless, the ease with which large numbers of analogues - of Taddol, Nobin, and salen in particular- can be prepared, and the almost infinite variety for the preparation of new, chiral metal(ligand) complexes, bodes well for the future development of more enantioselective versions of these catalysts. 

It is certain that many more applications of catalytic asymmetric intramolecular Mizoroki-Heck reactions will be described in the future. This survey makes apparent the small number of ligands that have been used thus far, with Noyori and coworkers BINAP ligand being the most widely employed [80]. Two future trends are easy to predict a larger variety of chiral ligands [56, 58, 81, 82] will be used in asymmetric Mizoroki-Heck processes and a greater variety of cascade processes involving intramolecular Mizoroki-Heck reactions will be developed. 

In this chapter Lewis-acid-mediated reactions have been summarized. While more than stoichiometric amounts of the Lewis acids were employed in conventional reactions, many efforts have been made to reduce the amounts of Lewis acid needed, and many truly catalytic reactions have been developed. Chiral Lewis-acid catalysis has been of great interest in the 1990s and early 2000s, and various combinations of metals and ligands have been investigated. Importantly, the established understanding that Lewis acids are easily hydrolyzed in water has been exploded. Water-compatible Lewis acids are stable in air and moisture, and are easily recovered and reused in many cases. These Lewis acids may solve recent environmental issues, and will be used further in many reactions in future. 

This includes future potential applications in radiopharmaceuticals. Furthermore, new chiral enantiopure NJ, 0 tripod ligands have been developed starting from cheap compounds of the chiral pool. 

The yields of the allenes and the enantioselectivities are not very high, and the method could possibly be further developed by the use of more rigid, e.g., bidentate ligands. Since no satisfactory reagent-controlled enantioselective synthesis of chiral allenes is known to date, this is a challenge for the future. 

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