Enantioselective Organocatalytic Reductive Amination

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

Follow up studies regarding the further development of the just noted one pot, 

P chiral amines are not included in this review, but we remind the reader that List has extended his TRIP/p anisidine system to an elegant dynamic kinetic reductive amination protocol for a branched aldehydes, which provides p chiral amines [18]. A computational investigation of the stereochemical pathway for p chiral amine formation has been reported on and is noteworthy [19]. 

Using their earlier developed organocatalytic methods for imine reduction, they 

Some of the a chloroimines were unstable or sensitive to purification, prompting 

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An enantioselective organocatalytic reductive amination has been achieved using Hantzsch ester for hydrogen transfer and compound (21) as catalyst. This mild and operationally simple fragment coupling has been accomplished with a wide range of ketones in combination with aryl and heterocyclic amines.359... 

During the study on enantioselective organocatalytic reductive amination, MacMillan et al. found that the pyruvic acid-derived cyclic imino ester could be efficiently reduced to yield the corresponding alanine amino ester with 97% ee and 82% yield... 

Soon afterward, MacMillan s group properly explored this organocatalytic reductive amination, observing that the ortho-triphenylsilyl phosphoric acid 17n in the presence of 5-A MS facilitates the desired coupling of acetophenone and 4-OMe-aniline in high conversion and with excellent levels of enantiocontrol at 40 C (87% yield, 94% ee) [55]. Authors report also the reduction of the pyruvic acid-derived cyclic imino ester with excellent enantioselectivity. However, implementation of the corresponding ethyl-substituted imine resulted in a dramatic decrease in... 

The same approach was used by Benagha s group for the enantioselective organocatalytic reduction of P-trifluoromethyl nitroaUcenes 73, with the aim of achieving chiral yS-trifluoromethyl amines 75 (Scheme 28) [161]. The authors also performed the organocatalyzed reduction of a-substituted-p-trifluoromethyl nitroalkenes, although with poorer results. The stereochemical result of the reaction and the behavior of thiourea catalyst 74 were discussed based on computational studies and DFT transition-state analysis. 

Although natural amino acids are readily available, there is a continuing need for unnatural amino acids. Jon C. AntiUa of the University of South Florida has described J. Am. Chem. Soc. 2007,129, 5830) a promising approach, based on the enantioselective organocatalytic reduction of imines such as 1 derived from a-keto esters. The aryl group is easily removed to give the primary amine. 

Itoh T, Nagata K, Miyazaki M, Ishikawa H, Kurihara A, Ohsawa A (2004) A selective reductive amination of aldehydes by the use of Hantzsch dihydropy-ridines as reductant. Tetrahedron 60 6649-6655 Jen WS, Wiener JJM, MacMillan DWC (2000) New strategies for organic catalysis The first enantioselective organocatalytic 1,3-dipolar cycloaddition. J Am Chem Soc 122 9874-9875... 

Aspects featured in a review of asymmetric reductive aminations have included transition metal-mediated homogeneous-, enantioselective organocatalytic-. 

As detailed in Sections 42.2 and 42.3, both covalent and non-covalent organocatalytic activation modes have provided efficient strategies to design asymmetric MCRs. A quite recent study by Zhou and list has demonstrated the feasibility of combining asymmetric Bronsted acid catalysis with aminocatalysis to design even more sophisticated reaction sequences toward the synthesis of useful complex molecules. Specifically, they developed a highly enantioselective approach to pharmaceutically relevant 3-substituted cyclohexylamines from 2,6-diketones 223 via an aldolization/dehydration/conjugate reduction/reductive amination domino... 

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