Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines Using Asymmetric Protonation: A Method Development and Mechanistic Study

Abstract

<div> <div> <div> <p>A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C–F stereocenter in high enantioselectivity, and is also amenable to stereogenic C–CF3 bonds. Extensive DFT calculations have provided insight into the reaction mechanism and the origin of catalyst selectivity. Crystal structure data shows the dominance of non-covalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and protein data bank mining has indicated benzylic fluorination using this approach has potential for improved potency in several marketed drugs. </p> </div> </div> </div>

Asymmetric synthesis of heterocyclic chloroamines and aziridines by enantioselective protonation of catalytically generated enamines

“…Benchmark substrate 1 preferentially adopts the lower energy s-trans conformation (2.2 kcal/mol preferred vs. s-cis; Figure S2). Consistent with our previous model, 17,18 the reaction proceeds through (1) complexation of 1 with 3 via a hydrogen bond to give 61, (2) nucleophilic addition of aniline, via 62, to the catalyst-substrate complex and proton transfer back to the catalyst to yield 63 (3) protonation of this prochiral enamine by the catalyst via 64, and (4) product dissociation. From a free energy perspective, the aniline addition and proton transfer to the catalyst form a concerted process leading to 63.…”

“…24 Calculations were performed using Gaussian09 (see SI). 17,18,25 A reaction profile for TRIP catalyst (3) is shown in Figure 1 (for full analysis, see SI). Benchmark substrate 1 preferentially adopts the lower energy s-trans conformation (2.2 kcal/mol preferred vs. s-cis; Figure S2).…”

“…An initial screening campaign identified promising conditions using 20 mol% catalyst 3 at -20 ºC in CPME (Entry 1; for full screening details, see Tables S1-S6). 17,18 However, further attempts at reaction optimization did not improve asymmetric induction. We therefore conducted an extensive catalyst screen (see Table S1), which, in combination with DFT analysis (vide infra), allowed catalyst SAR to be rationalized and provided insight into substituent effects more broadly.…”