Asymmetric Hydrogenation of Protected Allylic Amines

Abstract

A general method for the enantioselective hydrogenation of protected allylic amine derivatives is described. This procedure relies on the generation of a cationic ruthenium complex with the axially chiral ligand (-)-TMBTP. The utility is highlighted by the highly enantioselective hydrogenation of a diene substrate that can then be elaborated to prepare Telcagepant, a compound currently in Phase III clinical trials. The scope of the hydrogenation reaction was studied, and a variety of substituted allylic amine derivatives could be hydrogenated with enantiomeric ratios of 92:8 or higher.

Asymmetric Organocatalysis at the Service of Medicinal Chemistry

“…To this end, an organocatalytic approach, namely, an iminium ion catalysed conjugate addition of nitromethane to a proper cinnamaldehyde [113], was judged as more promising than other asymmetric preparations based on transition metal catalysed reactions, such as ruthenium-catalysed hydrogenation [114] and rhodium based Hayashi-Miyaura addition [115]. Although previously reported with related substrates [116, 117] the organocatalytic step required a careful optimisation for its large scale implementation, as the formation of several by-products was observed under the reported conditions.…”

Enantioselective Synthesis of β‐Methyl Amines via Iridium‐Catalyzed Asymmetric Hydrogenation of N‐Sulfonyl Allyl Amines

“…However, hydrogenation of the only example of 2‐aryl allylphthalimide described in the paper took place with low enantiomeric excess (55% ee). The hydrogenation of N ‐acetamido 2‐phenyl allylamine using a cationic Ru complex bearing the axially chiral ligand (−)‐TMBTP gave an ee of 80% . However, in this case, the hydrogenation occurred after partial isomerization to the enamide.…”

“…The hydrogenation of N-acetamido 2-phenyl allylamine using a cationic Ru complex bearing the axially chiral ligand (À )-TMBTP gave an ee of 80%. [11] However, in this case, the hydrogenation occurred after partial isomerization to the enamide. Therefore, to the best of our knowledge, there are no precedents of Ir-catalyzed asymmetric hydrogenation of N-sulfonyl 2-aryl allylamines.…”

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

“…The most representative research is the enantioselective synthesis of α ‐chirogenic amines by the catalytic AH 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 [14–18]. By contrast, there are few studies concerning the hydrogenative synthesis of β ‐chirogenic amines (Scheme 1b) [19–23]. One approach via the AH of β ‐branched allylic amines is difficult, most likely due to the relatively low forming ability of the chelating intermediate (Scheme 1b up).…”

“…According to statistics, more than 40% of the top 200 listed small molecule drugs contain at least one chiral amine subunit in their [14][15][16][17][18]. By contrast, there are few studies concerning the hydrogenative synthesis of β-chirogenic amines (Scheme 1b) [19][20][21][22][23]. One approach via the AH of β-branched allylic amines is difficult, most likely due to the relatively low forming ability of the chelating intermediate (Scheme 1b up).…”