Introduction
As versatile building blocks and synthetic intermediates, chiral amines play important roles in the construction of numerous valuable molecules. According to statistics, more than 40% of the top 200 listed small molecule drugs contain at least one chiral amine subunit in their structures. Therefore, the development of general and efficient methods to prepare chiral amines has been a major focus in both academia and industry.[1] In the process of pursuing this goal, catalytic asymmetric hydrogenation (AH) has gradually emerged as the most industrially feasible option due to its high efficiency, cost competitiveness and environmental friendliness.[2,3] Until now, hundreds of chiral transition metal catalysts have been developed and successfully applied in the asymmetric hydrogenation of thousands of structurally differentN -containing substrates. The most representative research is the enantioselective synthesis of α -chirogenic amines by the catalytic asymmetric hydrogenation of enamines and imines (Scheme 1A), which was awarded the Nobel Prize in Chemistry of 2001 and has been used in several impressive industrial productions.[3]By contrast, the number of studies on the hydrogenative synthesis ofβ -chirogenic amines decreases significantly. One route via the asymmetric hydrogenation of β -branched allylic amines is difficult due to the relatively low stability of the macrocyclic chelating intermediate.[4] Another route via the asymmetric hydrogenation of β -branched enamines is also difficult due to a relatively poor stereocontrol for the distinct substituted environment (Scheme 1B).[5] Therefore, it can be envisaged that the construction of γ -chirogenic amines via the asymmetric hydrogenation of γ -branched allylamines, which contains either of the above-mentioned difficulties for remote control, is a greater challenge (Scheme 1C). Until now, there have been no universal solutions with regards to this topic,[6]in spite of γ -chirogenic amines being required for the synthesis of important pharmaceuticals such as the antidepressant drugs Atomoxetine, Fluoxetine and Duloxetine, and the anti-muscarinic drug Tolterodine (Figure 1).
Scheme 1. Asymmetric hydrogenation for the synthesis of chiral amines.
Figure 1. The importance of γ -chirogenic amines.