A chiral ligand for the rhodium‐catalyzed asymmetric 1,4‐addition of an arylboronic acid to a coumarin substrate that could markedly reduce catalyst loading was developed using interplay between theoretical and experimental approaches. Evaluation of the transition states for insertion and for hydrolysis of intermediate complexes (which were emphasized in response to the experimental results) using DFT calculations at the B97D/6‐31G(d) level with the LANL2DZ basis set for rhodium revealed that: (i) the electron‐poor nature of the ligands and (ii) CH–π interactions between the ligand and coumarin substrates played significant roles in both acceleration of insertion and inhibition of ArB(OH)2 decomposition (protodeboronation). The computationally‐designed ligand, incorporating the above information, enabled a decrease in the catalyst loading to 0.025 mol% (S/C=4,000), which is less than one one‐hundredth relative to past catalyst loadings of typically 3 mol%, with almost complete enantioselectivity. Furthermore, the gram‐scale synthesis of the urological drug, (R)‐tolterodine (l)‐tartrate, was demonstrated without the need of intermediate purification.magnified image
The DIPSkewphos/PICA derivative-Ru(II) complexes catalyzed asymmetric hydrogenation of significantly sterically hindered 2',3',4',5',6'-pentamethylacetophenone, which was not reduced with NaBH 4 at 25 8C, with a substrate-to-catalyst molar ratio (S/ C) of 2000 under 50 atm of H 2 in a base-containing 2-propanol to afford the alcohol in 99 % ee quantitatively. A series of polysubstituted aromatic ketones was smoothly reacted with an S/C of 300-10,000 under 10-50 atm of H 2 , yielding the alcoholic products in up to 99 % ee. The catalyst system achieved an industrial-scale (50 kg) hydrogenation of 2',6'-dichloro-3'-fluoroacetophenone, affording the alcohol in 96 % isolated yield and in 98 % ee. The obtained alcoholic product is known as a key intermediate for the synthesis of the medicine crizotinib.
A convenient
asymmetric reductive amination of benzylic ketones
(α-arylated ketones) catalyzed by newly designed Cp*Ir complexes
bearing a chiral N-(2-picolyl)sulfonamidato ligand
was developed. Using readily available β-amino alcohols as chiral
aminating agents, a range of benzo-fused and acyclic ketones were
successfully reduced with formic acid in methanol at 40 °C to
afford amines with favorable chemo- and diastereoselectivities. The
amino alcohol-derived chiral auxiliary was easily removed by mild
periodic oxidants, leading to optically active primary β-arylamines
without erosion of the optical purity (up to 97% ee). The excellent catalytic performance was retained even upon lowering
the amount of catalyst to a substrate/catalyst (S/C) ratio of 20,000,
and the amination could be performed on a large scale exceeding 100
g. The precise hydride transfer to iminium species generated from
the ketonic substrate and the chiral amine counterpart was suggested
by the mechanistic studies on stoichiometric reactions of isolable
hydridoiridium complexes and model intermediates such as N,O-acetal, enamine, and iminium compounds.
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