Mohamed Mahmoud El-Shazly

• The importance of α-chiral amines as building blocks in pharmaceutical drugs, natural products, fine chemicals and agrochemicals have encouraged scientists to develop different methodologies for their preparation. Their main goal was to develop a step wise efficient and low waste production methodology which utilizes inexpensive starting material for the synthesis of α-chiral amines in high yields and enantioselectivity. Different methodologies have been developed aiming to meet these criteria. These strategies are discussed and their importance and limitations are critically analyzed. Reductive amination is a powerful methodology for the synthesis of chiral amines in high yields and enantioselectivity. It is a two step strategy beginning from the prochiral carbonyl compound to the primary chiral amine. The historical development and the latest milestones in this field are discussed in chapter three. Different drugs and natural products which are prepared utilizing reductive amination as a key step in their synthesis are summarized in chapter four. Reductive amination utilizing chiral auxiliary/Lewis acid/ heterogeneous catalyst/ molecular hydrogen has been investigated in our group over the last five years. This combination allowed the preparation of alkyl-alkyl’ α-chiral amines in mediocre to good yields and enantioselectivities. This group of amines is known historically to be difficult synthetic task. We developed a new asymmetric reductive amination procedure using Yb(OAc)3 (50-110 mol %) that allows increased diastereoselectivity (6-15% units) for alkyl-alkyl’ α-chiral amines that previously only provided mediocre to good diastereoselectivity. Different Lewis acids were tested under different reaction conditions of temperature, pressure and solvents and the results of these experiments are discussed in chapter five. The use of catalytic Lewis acids in reductive amination has never been reported in literatures. We demonstrated the beneficial use of 10-15 mol % of Yb(OAc)3 or Ce(OAc)3 or Y(OAc)3 in suppressing alcohol formation and promoting reductive amination in good yield but without enhanced stereoselectivity. Despite the fact that the use of Brønsted acids in reductive amination is well established no literature reports are available. We have performed and extensive study on the use of commercially available Brønsted and mineral acids in reductive amination. The scope of the reaction and the substrate categories are summarized in chapter six. A mechanism for the reaction has been proposed and the basic mechanistic experiments have been performed. An in situ cis- to trans-ketimine isomerization mechanism, promoted by Yb(OAc)3, has been proposed to account for the observed increase in diastereoselectivity. The experiments and the proposed mechanism are summarized in chapter seven.