Chiral Tetrahydropyridines via FeCl3-Catalyzed Carbonyl-Olefin Metathesis

Abstract

<div> <div> <p>Herein, we describe the application of Lewis acid-catalyzed carbonyl-olefin metathesis towards the synthesis of chiral, substituted tetrahydropyridines from commercially available amino acids as chiral pool reagents. This strategy relies on FeCl<sub>3</sub> as an inexpensive and environmentally benign catalyst and enables access to a variety of substituted tetrahydropyridines under mild reaction conditions. The reaction proceeds with complete stereoretention and is viable for a variety of natural and unnatural amino acids to provide the corresponding tetrahydropyridines in up to 99% yield.</p> </div> </div> <br>

Expanding the Protecting Group Scope for the Carbonyl Olefin Metathesis Approach to 2,5-Dihydropyrroles

“…1 .03 (dt, J = 15.9, 6.9 Hz, 1H), 4.76 (s, 2H), 4.08 (dd, J = 6.9, 1.3 Hz, 2H), 2.44 (s, 3H). 13 The spectroscopic data matched those reported in the literature. 8 Synthesis of 4 Ts and 4A Ts .…”

“…1 H NMR spectra were recorded at 298 K at 500 or 600 MHz on a Bruker UltraShield 500 spectrometer or a 600 MHz Bruker Avance III NMR spectrometer equipped with a cryogenic QCI-F probe, respectively. 13 C NMR spectra were recorded at 126 or 151 MHz on a Bruker UltraShield 500 spectrometer or a 600 MHz Bruker AvanceIII NMR spectrometer equipped with a cryogenic QCI-F probe, respectively. Chemical shifts of 1 H NMR and 13 C NMR spectra (measured at 298 K) are given in ppm using residual solvent signals as references (CDCl 3 : 7.26 and 77.16 ppm).…”

“…13 C NMR spectra were recorded at 126 or 151 MHz on a Bruker UltraShield 500 spectrometer or a 600 MHz Bruker AvanceIII NMR spectrometer equipped with a cryogenic QCI-F probe, respectively. Chemical shifts of 1 H NMR and 13 C NMR spectra (measured at 298 K) are given in ppm using residual solvent signals as references (CDCl 3 : 7.26 and 77.16 ppm). Coupling constants (J) are reported in hertz (Hz).…”

“…In 2020, the Schindler group was able to expand the substrate scope and access tetrahydropyridines. 13 Recent findings in the Nguyen group demonstrated that other catalysts (I 2 , NIS, ICl) 14,15 are able to convert regular tosyl-protected substrates with substoichiometric amounts of catalyst (Figure 1c). Li and Lin reported the use of AuCl 3 as a catalyst for the COM approach to pyrrolidines (Figure 1d).…”

Tetrahydropyridines via FeCl3-Catalyzed Carbonyl–Olefin Metathesis

“…We recently reported a distinct design principle for catalytic carbonyl–olefin ring-closing metathesis reactions for the synthesis of cyclic systems such as spirocyclic lactones, indenes, polyaromatic hydrocarbons, and 3-pyrrolines. − Upon the reaction with FeCl 3 as a Lewis acid catalyst, aryl ketones bearing prenyl or styrenyl fragments undergo a concerted, asynchronous [2 + 2]-cycloaddition to form intermediate oxetanes. A subsequent Lewis-acid-catalyzed retro [2 + 2]-cycloreversion results in the desired ring-closing metathesis product. , Herein we report the expansion of this robust synthetic strategy toward tetrahydropyridines 4 (Figure B). Our approach relies on readily available amino acids as chiral pool reagents and FeCl 3 as an inexpensive and earth-abundant metal catalyst.…”