Asymmetric reductive amination:: Convenient access to enantioenriched alkyl-alkyl or aryl-alkyl substituted α-chiral primary amines

A two-step procedure for producing optically active, high value primary amines has been developed. The first and key step is the asymmetric reductive amination of a prochiral alkyl alkyl (acyclic or cyclic) or aryl alkyl (acyclic or cyclic) ketone with (R)- or (S)-alpha-methylbenzylamine (alpha-MBA). The normally stepwise excessive procedures of chiral auxiliary approaches are avoided by simultaneously incorporating the auxiliary and a new stereogenic center at the former carbonyl carbon of the ketone during step one. Specifically, step one is the hydrogenation (4-8 bar) of a prochiral ketone substrate in the presence of a-MBA, a Lewis acid [Ti(O-i-Pr)(4), B(O-i-Pr)(3), Al(O-i-Pr)(3), or Zr(O-i-Pr)(4)], and a heterogeneous hydrogenation catalyst (Raney-Ni, Pt-C, Pd-C, Ru-C, or Rh-C), providing the amine diastereomers 2 in good to excellent yield and diastereoselectivity. Depending on the ketone examined (acyclic vs. cyclic, alkyl alkyl vs. aryl alkyl, sterically encumbered vs. unencumbered), the correct combination of heterogeneous hydrogenation catalyst, solvent, and temperature is crucial for allowing high yield and de with practical reaction times (generally 6-20 h). Performing the reaction in the absence of one of the indicated Lewis acids results in the formation of large amounts of alcohol by-product (> 25 %). Step two, hydrogenolysis, allows smooth removal of the chiral auxiliary providing a-chiral primary amines in good overall yield (5 examples 71-78%, 1 example 64%) and in 66-98% enantiomeric excess. This two-step strategy is noteworthy because: 1) it is yield and stepwise efficient; 2) all the reagents are inexpensive and already used by the pharmaceutical industry; 3) a broad range of ketone substrates are suitable; 4) either enantiomeric form of the a-chiral amine product can be produced; 5) the reaction conditions are mild; and 6) the process is amenable to scale-up.