Synthesis of Chiral β-Fluoroalkyl β-Amino Acid Derivatives via Palladium-Catalyzed Hydrogenation

Abstract

An enantioselective palladium-catalyzed hydrogenation of β-fluoroalkyl β-amino acrylic acid derivatives has been successfully developed, providing the corresponding chiral β-fluoroalkyl β-amino acid derivatives in good yields with excellent enantioselectivities. In addition, chiral γfluoroalkyl γ-amino alcohol could be synthesized by a simple reduction of the corresponding hydrogenated product. The mechanism of the reaction was explored by deuterium-labeling experiments.

Catalytic enantioselective synthesis of fluoromethylated stereocenters by asymmetric hydrogenation

“… 12 Several Ru II , 13 Rh I , 14 and Pd II (ref. 15 ) complexes were found effective for hydrogenation of some specific CF 3 substituted olefins with a coordinating group near the substrate double bond ( Scheme 1C , left). Fortunately, Ir complexes complement the substrate limitations of Rh/Ru catalyzed enantioselective hydrogenation and are efficient catalysts for enantioselective hydrogenation of CF 3 substituted unfunctionalized olefins or CF 3 substituted olefins with the weak chelating group.…”

Strategies for the Catalytic Enantioselective Synthesis of α-Trifluoromethyl Amines

“…Even so, several groups have established various means of accessing α-CF 3 amines by reduction with boranes or silanes, transition-metal-catalyzed hydrogenation, or transfer hydrogenation protocols. Additionally, related hydrogenations of enamines, 20 enamides, 21 or hydrazones 22 have also yielded these chiral amines.…”

Recent Advances in Catalytic Enantioselective Synthesis of Fluorinated α‐ and β‐Amino Acids

“…[87] Recently, a highly efficient Pd-catalyzed enantioselective hydrogenation of β-fluoroalkyl β-enamino esters/ amides 159 was developed by Peng and co-workers (Scheme 35, eq 2). [88] The use of 4 mol% of Ph-BPE/ Pd(OCOCF 3 ) 2 and 20 mol% of p-anisic acid allowed the access of various chiral β-fluoroalkyl β-amino acid derivatives 161 in up to 84% yields with 96% ee. The hydrogenated products are readily elaborated into the chiral γ-fluoroalkyl γ-amino alcohol via reduction with LiAlH 4 or unprotected amino ester via oxidative cleavage with CAN.…”

“…discovered that N ‐aryl β‐CF 3 ‐β‐enamino ester 159 a could also be reduced with H 2 (6 atm) under 1 mol% TangPhos‐Rh complex catalysis to β‐CF 3 ‐β 3 ‐amino ester 161 a with 79% ee and 48% conversion (Scheme 35, eq 1) [87] . Recently, a highly efficient Pd‐catalyzed enantioselective hydrogenation of β‐fluoroalkyl β‐enamino esters/amides 159 was developed by Peng and co‐workers (Scheme 35, eq 2) [88] . The use of 4 mol% of Ph‐BPE/Pd(OCOCF 3 ) 2 and 20 mol% of p ‐anisic acid allowed the access of various chiral β‐fluoroalkyl β‐amino acid derivatives 161 in up to 84% yields with 96% ee.…”