New Developments in EnantioselectiveBrønsted Acid Catalysis
213
3
The First Enantioselective Brønsted Acid Catalyzed
Transfer Hydrogenation of Ketimines:
Chiral Phosphates Are Efficient Metal-Free Catalysts
The development of the new DPP catalyzed transfer hydrogenation encouraged us to explore a catalytic enantioselective variant of this transformation, as it would not only be the first example of an enantioselective organocatalytic hydrogenation of ketimines but would, additionally, provide a new approach and access to chiral amines. Initial
experiments focused therefore on the application of various Brønsted
acids (Schreiner 2003; Pihko 2004; Bolm et al. 2005), including chiral thiourea-, diol-, amidinium-catalysts as well as chiral sulfonic acids.
However, none of these catalysts afforded satisfactory yields and selectivities. Therefore, we decided to prepare chiral phosphoric acid catalysts 5 and 6 which are based on the BINOL core structure (Rueping
et al. 2006a). These catalysts had previously been used for resolutions
of racemic amines, as ligand in metal catalyzed transformations and,
more recently, in metal-free catalysis. Starting from the protected (R)3,3
-dibromo-1,1
-binaphthyl-2,2
-diol or the octahydro derivative 4 the
corresponding 3,3-aryl substituted catalysts were readily prepared by
Suzuki coupling, followed by deprotection and phosphorylation
(Scheme 1). Alternatively, the silylated BINOL-derivatives 4b were subjected to a Brook-type rearrangement using t-BuLi, and subsequent
phosphorylation resulted in the chiral Brønsted acids 6.
With the chiral BINOL-phosphates in hand we started to examine
the enantioselective transferhydrogenation of ketimines 1. After reaction optimization, including a survey of different solvents, temperatures,
BINOL-phosphates, and Hantzsch dihydropyridines, we found that indeed enantioselectivities are observed and the best selectivities are obtained with Brønsted acid 5a and Hantzsch ester 2a (Table 2). In general, for the first time, high enantioselectivities and good yields are observed in this newly developed metal-free reduction procedure (Rueping
et al. 2005b; Hofmann et al. 2005; Storer et al. 2006).
With regard to the mechanism we assume that, similar to the dehydrogenase (Fig. 1), the ketimine 1 will be activated by protonation
through Brønsted acid 5 which results in the formation of a chiral ionpair, an iminium ion A. Subsequent hydrogen transfer from the dihy-
213
3
The First Enantioselective Brønsted Acid Catalyzed
Transfer Hydrogenation of Ketimines:
Chiral Phosphates Are Efficient Metal-Free Catalysts
The development of the new DPP catalyzed transfer hydrogenation encouraged us to explore a catalytic enantioselective variant of this transformation, as it would not only be the first example of an enantioselective organocatalytic hydrogenation of ketimines but would, additionally, provide a new approach and access to chiral amines. Initial
experiments focused therefore on the application of various Brønsted
acids (Schreiner 2003; Pihko 2004; Bolm et al. 2005), including chiral thiourea-, diol-, amidinium-catalysts as well as chiral sulfonic acids.
However, none of these catalysts afforded satisfactory yields and selectivities. Therefore, we decided to prepare chiral phosphoric acid catalysts 5 and 6 which are based on the BINOL core structure (Rueping
et al. 2006a). These catalysts had previously been used for resolutions
of racemic amines, as ligand in metal catalyzed transformations and,
more recently, in metal-free catalysis. Starting from the protected (R)3,3
-dibromo-1,1
-binaphthyl-2,2
-diol or the octahydro derivative 4 the
corresponding 3,3-aryl substituted catalysts were readily prepared by
Suzuki coupling, followed by deprotection and phosphorylation
(Scheme 1). Alternatively, the silylated BINOL-derivatives 4b were subjected to a Brook-type rearrangement using t-BuLi, and subsequent
phosphorylation resulted in the chiral Brønsted acids 6.
With the chiral BINOL-phosphates in hand we started to examine
the enantioselective transferhydrogenation of ketimines 1. After reaction optimization, including a survey of different solvents, temperatures,
BINOL-phosphates, and Hantzsch dihydropyridines, we found that indeed enantioselectivities are observed and the best selectivities are obtained with Brønsted acid 5a and Hantzsch ester 2a (Table 2). In general, for the first time, high enantioselectivities and good yields are observed in this newly developed metal-free reduction procedure (Rueping
et al. 2005b; Hofmann et al. 2005; Storer et al. 2006).
With regard to the mechanism we assume that, similar to the dehydrogenase (Fig. 1), the ketimine 1 will be activated by protonation
through Brønsted acid 5 which results in the formation of a chiral ionpair, an iminium ion A. Subsequent hydrogen transfer from the dihy-