Copper(i)-catalyzed asymmetric exo-selective [3+2] cycloaddition of azomethine ylides with β-trifluoromethyl β,β-disubstituted enones

Abstract

The employment of β,β-disubstituted enones as dipolarophiles poses a considerable challenge due to their steric hindrance and low reactivity. A copper-catalyzed asymmetric exo-selective dipolar cycloaddition of β-trifluoromethyl β,β-disubstituted enones with azomethine ylides was developed, which provides an efficient access to valuable pyrrolidines bearing a trifluoromethylated all-carbon quaternary stereocenter. Up to quantitative yields with up to >20 : 1 dr and 99% ee were delivered. A broad substrate scope, good functional group tolerance, high stereoselectivity, as well as diverse synthetically valuable transformations of the products make this approach highly attractive.

Catalytic Enantioselective Synthesis of Highly Functionalized Pentafluorosulfanylated Pyrrolidines

“…NMR spectra were recorded on aB ruker DXP 300, 1 HNMR spectra at 300.1 MHz, 13 CNMR spectra at 75.5 MHz, 19 FNMR spectra at 282.4 MHz. Reaction temperatures are reported as the temperature of the bath surrounding the vessel.…”

“…The enantiomeric excesses (ee)were determined by chiral UHPLC analysis performed on ThermoFisher Ultimate 3000 combined with a PDA detector,u sing aD aicel Chiralpak IA, IB, IC or IE column. NMR spectra were recorded on aB ruker DXP 300, 1 HNMR spectra at 300.1 MHz, 13 CNMR spectra at 75.5 MHz, 19 FNMR spectra at 282.4 MHz. Chemical shifts (d)a re quoted in parts per million (ppm) relative to residual solvent peak for CDCl 3 (d H = 7.26; d C = 77.0 ppm;o rr elative to external CFCl 3 d = 0.0 ppm).…”

“…[10] The same group reported, with the same level of enantioselectivity,t he [3+ +2] cycloaddition reaction of Schiff bases of a-aminophosphonates to activated alkenes with total exo or endo selectivity depending on the chiral catalyst (Scheme 1, Eq. [13] Subsequently,o ne of us described the synthesis of aromatic amide-derived nonbiaryl atropisomers (Xing-Phos in particular) and its application to as ilver-catalyzed [3+ +2] cycloaddition of aldiminoesters to nitroalkenes or a,b-unsaturated ketones with high diastereo-and enantioselectivities (Scheme 1, Eq. [11] Another approach, developed by Wang, relying on the Cu I -catalyzed 1,3-dipolar cycloaddition of azomethine ylides with 4,4,4-trifluorocrotonates, using aT F-Biphamphos or BTBM-Biphep-type catalyst, led to CF 3 -substituted pyrrolidines in very good yields and high levels of enantioselectivity (Scheme1,E q.…”

“…(3)). [13] Subsequently,o ne of us described the synthesis of aromatic amide-derived nonbiaryl atropisomers (Xing-Phos in particular) and its application to as ilver-catalyzed [3+ +2] cycloaddition of aldiminoesters to nitroalkenes or a,b-unsaturated ketones with high diastereo-and enantioselectivities (Scheme 1, Eq. (4)).…”

CuI-Catalyzed Asymmetric [3 + 2] Cycloaddition of Azomethine Ylides with Cyclobutenones

“…However, the use of β,β-disubstituted enones, which would enable the preparation of pyrrolidines with a quaternary stereocenter at the C 3 position, remains particularly challenging, because of the high sensitivity of the reaction to steric effects at the dipolarophile. Very recently, Zhang and co-workers have described access to enantioenriched pyrrolidines bearing a quaternary stereocenter at C 3 by a copper­(I)-catalyzed [3 + 2] cycloaddition of azomethine ylides with β-CF 3 -β,β-substituted enones (Scheme , eq 1) . In contrast, to the best of our knowledge, tetrasubstituted or β,β-disubstituted enones lacking an electron-withdrawing group in the beta position have not been reported so far.…”