Enantioselectivity imines

The formation of dimers and trimers is a major issue in hydrogenations with iridium catalysts. In the context of developing an industrial process to produce (S)-metolachlor via an enantioselective imine hydrogenation (see Chapters 34 and 37), Blaser et al. investigated the causes of catalyst deactivation in the iri-dium/bisphosphine-catalyzed hydrogenation of DMA imine (Scheme 44.11) [84]. 

Scheme 44.11 Iridium-catalyzed enantioselective imine hydrogenation.

Zr-Catalyzed Enantioselective Imine Alkylations with Alkylzinc Reagents... 

Figure 18 Schematic catalytic cycle proposed for the enantioselective imine hydrogenation.

The reaction is somewhat selective for the cis-diastereomer. The use of chiral additives in this reaction leads to aziridines enantioselectively. " Imines can be formed by the reaction of an aldehyde and an amine, and subsequent treatment with Me3SiI and butyllithium gives an aziridine. " A-Tosyl imines react with diazoalkenes to form A-tosyl aziridines, with good cis-selectivity " and modest enantioselectivity in the presence of a chiral copper catalyst, " but excellent enantioselectivity with a chiral rhodium catalyst. . It is noted that A-tosyl aziridines are formed by the... 

Tab. 3 gives an overview of the timetable and the milestones for the development of a technical process for the production of enriched (S)-metolachlor. It took so many years to reach the ambitious goal because the efforts to find a suitable catalyst system for the enantioselective imine hydrogenation had to start almost from zero. The final result of our efforts can be seen in Fig. 14 which depicts a partial view of the production unit. 

The selection of the catalytic system was especially difficult because the required catalyst performance was very ambitious and very little was known about enantioselective imine hydrogenation. 

For recent overviews on enantioselective imine hydrogenations see H. U. Blaser and F. Spindler, ChimicaOggi, 1995, June, p. 11 H. U. Blaser and F. Spindler, Proceedings of Chiral Europe 94 Synq)osium, Spring Innovations, Stoclqx)rt, UK, 1994, p. 69. 

The time for process development obviously depends very much on the state of the art of a given catalytic technology. When one has to start almost at point zero as for the enantioselective imine hydrogenation, it may take many years to reach the goal. In our experience, an empirical approach is the fastest... 

In a very recent paper, this group has extended this strategy, developing chiral borane catalysts for the enantioselective imine reduction with enantioselectivities as high as 84% [20]. 

Zuend, S. J. Jacobsen, E. N. Mechanism of Amido-Thiourea Catalyzed Enantioselective Imine Hydrocyanation Transition State Stabilization via Multiple Non-Covalent Interactions. ]. Am. Chem. Soc. 2009,131,15358-15374. 

Jacobsen and Fang have synthesized a new family of diphenylpho-sphinoyl imines (217) and used them in the highly enantioselective imine-allene [3 + 2] cycloaddition raction leading to substituted 2-aryl-2,5-dihydropyrroles (218) (Scheme 16) ... 

Mitsukura, K., Suzuki, M Tada, K Yoshida, T., and Nagasawa, T. (2011) Asymmetric synthesis of chiral cyclic amine from cyclic imine by bacterial whole-cell catalyst of enantioselective imine reductase. Org. Biomol. Chem., 8, 4533 535. 

Blaser H-U, Pugin B, Spinder F, Togni A. Enantioselective imine hydrogenation with Ir diphosphine catalysts fighting deactivation. C. R. Chim. 2002 5 379-385. 

The first enantioselective imine reduction using Hantzsch esters as hydride donor was carried our by Singh and Batra in Using cysteine-derived catalysts, only moderate,... 

The first catalytic asymmetric reduction of imines, as summarized in Equation 14, was achieved by Kagan in 1973 [135]. Since then a number of catalytic enantioselective imine reductions involving hydrogenations or hydrosilylations have been developed [20, 33, 36, 37]. 

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