Strategies for the Catalytic Enantioselective Synthesis of α-Trifluoromethyl Amines

Abstract

The exploitation of the α-trifluoromethylamino group as an amide surrogate in peptidomimetics and drug candidates has been on the rise. In a large number of these cases, this moiety bears stereochemistry with the stereochemical identity having important consequences on numerous molecular properties, such as the potency of the compound. Yet, the majority of stereoselective syntheses of α-CF 3 amines rely on diastereoselective couplings with chiral reagents. Concurrent with the rapid expansion of fluorine into pharmaceuticals has been the development of catalytic enantioselective means of preparing α-trifluoromethyl amines. In this work, we outline the strategies that have been employed for accessing these enantioenriched amines, including normal polarity approaches and several recent developments in imine umpolung transformations.

Enantioselective Synthesis of α-Trifluoromethyl Amines via Biocatalytic N–H Bond Insertion with Acceptor-Acceptor Carbene Donors

“…To further demonstrate the synthetic value of the present biocatalytic strategy, asymmetric Ht-Cc552 -catalyzed N–H carbene insertion with DTPs was leveraged to enable the chemoenzymatic synthesis of various α-trifluoromethylated amine derivatives ( Scheme 5 ), which are highly sought after motifs for medicinal chemistry and drug discovery. 56 For example, benzyl-protected α-trifluoromethylamino acid 7 was synthesized in high yields and in a highly enantioenriched form (86% yield, 90:10 er) by treating enzymatically produced 3c with ceric ammonium nitrate (CAN) ( Scheme 5 ). α-Trifluoromethylated amino acids are valuable noncanonical amino acids 8 , 9 that find applications in the design of peptidomimetics and peptide-based drugs.…”

Regio- and enantioselective umpolung gem-difluoroallylation of hydrazones via palladium catalysis enabled by N-heterocyclic carbene ligand

“…7a ). Since these products such as fluorinated amino alcohols have important applications in medicinal chemistry 47 – 49 , this protocol provides an efficient route for applications in drug discovery and development. One-mmol scale reaction also proceeded to deliver similar results (Fig.…”

“…A Pd-mediated [3,3]-reductive elimination process (inner-sphere mechanism) is proposed for the high selecitivities 37 – 46 . The resulting products are easily converted into some other chiral fluoro-containing products, including chiral amines, which play an important role in medicinal chemistry 47 – 49 .…”

Leveraging Electron‐Deficient Iminium Intermediates in a General Synthesis of Valuable Amines

“…In particular, at temperatures as low as -10 °C, we observed the combination of A with unactivated alkenes to deliver the desired secondary α-trifluoromethylamines (Scheme 2A; see Supporting Information for the full optimization). As known methods to access α-trifluoromethylamines are often multistep procedures, [24][25][26][27][28][29][30][31][32][33] or rely on unstable reagents under oxidative conditions, [34][35][36] the coupling of A with readily available alkene feedstocks provides a direct solution to this synthetic challenge. The scope of this reaction proved to be…”