Asymmetric hydrogenation of γ‐branched allylamines for the efficient synthesis of γ‐chirogenic amines

Abstract

The efficient construction of γ‐chirogenic amines has been realized via asymmetric hydrogenation of γ‐branched N‐phthaloyl allylamines by using a bisphosphine‐Rh catalyst bearing a large bite angle. The desired products possessing different γ‐substituents were obtained in quantitative yields and with excellent enantioselectivities (up to >99% ee). This protocol provides a practical method for the preparation of γ‐chirogenic amine derivatives such as the famous antidepressant drug Fluoxetine (up to 50000 S/C). The mechanistic calculations show an unusual P‐Rh‐P trans‐chelating pattern and a weak interaction‐promoted activation mode which are completely different from the traditional cis‐chelating pattern and coordination‐promoted activation mode in metal‐catalyzed hydrogenations. Key points Novel methodology of asymmetric hydrogenation was developed for efficient synthesis of γ‐chirogenic amines. New synthetic route was developed for the well‐known antidepressant drug Fluoxetine. Unusual mechanism information was found in the bidentate bisphosphine‐Rh‐catalyzed hydrogenation.

Synthesis of α,γ-Chiral Trifluoromethylated Amines through the Stereospecific Isomerization of α-Chiral Allylic Amines

“…Other examples reported in literature include the synthesis of protected γ-chiral substituted aliphatic amines through enantioselective Pd-catalyzed fluoroarylation, 9 or direct hydrogenation of allyl amines. 10 However, none of these methods tolerate further substitution at Cα or encompass primary amines.…”

“…In this case, the product of the redox-neutral isomerization process, a chiral enamine, reacts with amines in the presence of a reducing agent (NaBH 4 or HCO 2 H) to give γ-chiral primary and secondary amine products with high enantioselectivities. Other examples reported in literature include the synthesis of protected γ-chiral substituted aliphatic amines through enantioselective Pd-catalyzed fluoroarylation, or direct hydrogenation of allyl amines . However, none of these methods tolerate further substitution at Cα or encompass primary amines.…”

“…Other examples reported in literature include the synthesis of protected γ-chiral substituted aliphatic amines through enantioselective Pd-catalyzed fluoroarylation, 9 or direct hydrogenation of allyl amines. 10 However, none of these methods tolerate further substitution at Cα or encompass primary amines. The transition-metal-catalyzed isomerization of allylic alcohols or amines has been widely used to access γ-chiral carbonyl compounds and enamines (i.e., as in step 1 in Scheme 1b), respectively.…”