New Developments in EnantioselectiveBrønsted Acid Catalysis
209
1
Development of the First Highly Enantioselective
Organocatalytic Reduction of Ketimines
The hydrogenation of unsaturated organic compounds, such as olefins,
carbonyls and imines is one of the most important and utilized transformation in both academia and in the chemical industry. With the ever increasing number of biologically active substances with hydrogen as part
of the stereocenter, it is not surprising that the development of efficient
asymmetric reductions has become a central research area in enantioselective catalysis. So far, most of these enantioselective reductions rely
on chiral transition metal catalysts, and highly enantioselective hydrogenations of ketones and alkenes are known. However, the asymmetric hydrogenation of ketimines to obtain chiral amines still represents
a challenge and only less effective and selective reductions are available. Current methods include transition metal catalyzed high pressure
hydrogenations (Blaser et al. 2003; Tang and Zhang 2003), hydrosilylations (Riant et al. 2004; Carpentier and Bette 2002; organocatalytic
hydrosilylation: Malkov et al. 2004), or transfer hydrogenations (Kadyrov and Riermeier 2003), using a variety of chiral transition metals,
such Pd, Ti, Rh, Ru, and Ir-complexes. While almost all of these metal
catalyzed transformations show high reactivities and selectivities none
proved to have a broad substrate scope. Hence, so far exclusively enzymatic resolutions are applied for the large-scale production of chiral
amines, with the typical disadvantage of biocatalytic resolutions, limited substrate scope and recycling of the undesired byproducts. Given
the above limitations we decided to develop a new biomimetic enantioselective reductive amination or transfer hydrogenation of ketimines
using nature as the role model.
2
Biomimetic Reductions: Amino Acid Dehydrogenases
as the Role Model for the Brønsted Acid Catalyzed
Transfer Hydrogenation of Ketimines
Dehydrogenases are important enzymes involved in the assimilation
or dissimilation of ammonia. For instance, glutamate dehydrogenase
(GDH) catalyzes the reductive amination of 2-ketogluterate to gluta-
209
1
Development of the First Highly Enantioselective
Organocatalytic Reduction of Ketimines
The hydrogenation of unsaturated organic compounds, such as olefins,
carbonyls and imines is one of the most important and utilized transformation in both academia and in the chemical industry. With the ever increasing number of biologically active substances with hydrogen as part
of the stereocenter, it is not surprising that the development of efficient
asymmetric reductions has become a central research area in enantioselective catalysis. So far, most of these enantioselective reductions rely
on chiral transition metal catalysts, and highly enantioselective hydrogenations of ketones and alkenes are known. However, the asymmetric hydrogenation of ketimines to obtain chiral amines still represents
a challenge and only less effective and selective reductions are available. Current methods include transition metal catalyzed high pressure
hydrogenations (Blaser et al. 2003; Tang and Zhang 2003), hydrosilylations (Riant et al. 2004; Carpentier and Bette 2002; organocatalytic
hydrosilylation: Malkov et al. 2004), or transfer hydrogenations (Kadyrov and Riermeier 2003), using a variety of chiral transition metals,
such Pd, Ti, Rh, Ru, and Ir-complexes. While almost all of these metal
catalyzed transformations show high reactivities and selectivities none
proved to have a broad substrate scope. Hence, so far exclusively enzymatic resolutions are applied for the large-scale production of chiral
amines, with the typical disadvantage of biocatalytic resolutions, limited substrate scope and recycling of the undesired byproducts. Given
the above limitations we decided to develop a new biomimetic enantioselective reductive amination or transfer hydrogenation of ketimines
using nature as the role model.
2
Biomimetic Reductions: Amino Acid Dehydrogenases
as the Role Model for the Brønsted Acid Catalyzed
Transfer Hydrogenation of Ketimines
Dehydrogenases are important enzymes involved in the assimilation
or dissimilation of ammonia. For instance, glutamate dehydrogenase
(GDH) catalyzes the reductive amination of 2-ketogluterate to gluta-