Organocatalytic reductive amination

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... 

Based on the above activation mechanism we wondered whether it would be possible to develop a biomimetic, organocatalytic reductive amination or transfer hydrogenation of ketimines. We reasoned that the activation of the imine by catalytic protonation through the Brpnsted acid should enable the hydrogen transfer from a suitable NADH mimic to yield the corresponding amine (Fig. 2). Hence, initial experiments focused on the examination of various Brpnsted acids in combination with different hydride sources (Rueping et al. 2005a). 

Figure 7.3 Organocatalytic reductive amination product examples.

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... 

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... 

Scheme 14. Organocatalytic asymmetric reductive amination of ketones...

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... 

Scheme 7.5 Organocatalytic cascade featuring reductive amination with TRIP.

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

Since these seminal organocatalytic reports, other groups have used the same strategy for the reduction of different interesting imine derivatives such as MacMillan [62] [It is important to remark that as declared by the authors, the complete details of MacMillan s group concerning reductive amination were first... 

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. 

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... 

The C=N double-bond reduction is the most examined and hence the most developed of all organocatalytic reductions. The great importance of chiral amines for natural product and drug synthesis (Figure 32.4) certainly triggers this research. The depicted drugs will be briefly discussed for further information, please consult the corresponding literature. 

In 2010, Enders et al. reported on an organocatalytic, one-pot, three-component reductive amination/aza-Michael sequence. They used bis(2,4,6-triisopropyl-phenyl)-l,l -binaphthyl-2,2 -diyl hydrogenphosphate (TRIP) 319 as the organocatalyst and 2-binaphthyl substituted benzathioazole derivatives 320 as the reducing agent and t-BuOH was used as the base. After alkylative cyclization, substituted tetrahydroisoquinoline derivatives 318 were formed in high yields with excellent stereoselectivity (Scheme 40.69). 

Enders D, Liebich JX, Raabe G. Organocatalytic asymmetric s3mthesis of tra j-l,3-disubstituted tetrahydroisoquinolines via a reductive amination/aza-Michael sequence. Chem. Eur. J. 2010 16(32) 9763 9766. 

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