Catalytic Enantioselective Synthesis of α-Difunctionalized Cyclic Sulfones

Abstract

As saturated heterocyclic building blocks become increasingly popular in medicinal chemistry and drug discovery programs, expansion of the synthetic toolkit to novel stereofunctionalized heterocycles is a priority. Herein, we report the development of a palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction to access a broad range of enantioenriched α-difunctionalized 5- and 6-membered sulfones from easily accessible racemic starting materials. The allylic alkylation step was found to occur with high levels of enantioselectivity as a result of a palladium-mediated dynamic kinetic resolution of E / Z enolate intermediates. This methodology paves the way to hitherto unexplored stereodefined cyclic sulfones for medicinal chemistry applications.

Pd-Catalysed asymmetric allylic alkylation of heterocycles: a user's guide

“…In a subsequent report, Franckevičius and co-workers extended their method to sulfolanes, thiane 1,1-dioxides and thiomorpholine 1,1-dioxides. 109 Interestingly, some similar trends were observed. Hence, only L3 gave high levels of enantioselectivity.…”

Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-β-Ketosulfones

“…Encouragingly, the desired ternary ring product 3a was obtained in 16% isolated yield (entry 1); meanwhile, 3a ′ was observed as a byproduct. Subsequent screening of diverse solvents confirmed chlorobenzene as the optimal choice, such as 1,4-dioxane, trichloromethane, DMSO, toluene, acetone, and o-dichlorobenzene (entries [2][3][4][5][6][7][8]. Further experimentation focusing on the base confirmed 2,6-lutidine as the most effective medium for this transformation (entries [9][10][11][12][13].…”

“…5,192.0,169.4,169.3,167.5,167.2,166.2 (d,J = 258.2 Hz),137.0,136.5,134.3,134.3,132.7,132.7,132.6,132.6,132.3 (d,J = 3.2 Hz), 132.1 (d, J = 3.2 Hz), 129. 1,128.9,128.9,116.2 (d,J = 22.9 Hz),69.3,68.4,62.1,61.7,61.6,34.5,34.0,28.2,27.7,24.7,24.3,20.5,20.2,14.1,14.1,14.0,13.9 7.32 (s,0.4 H),3.7 Hz,0.6 H),5.24 (dd,J = 11.5,3.5 Hz,0.4 H),2.6 H),0.4 H),1.4 H),2.39 (s,6.0 H), 2.30 NMR (126 MHz, CDCl3): δc 198.9, 198.7, 190.2, 190.0, 144.1, 144.0, 144. 136.4, 136.3, 135.6, 134.9, 134.2, 134.1, 134.1, 129.6, 129.5, 129.3, 129.3 128.3, 128.1, 128.1, 128.0, 124.4, 124.0, 63.9, 61.5, 35.4, 35.4, 35.0, 34.0, 21.7, 21.6, 21.5;IR: ῡ = 1674...…”

“…Organosulfones, exemplified by compounds such as Adociaquinones and Boehringer Ingelheim, serve as versatile components in pharmaceutical molecules, finely modulating drug metabolism and biotransformation, and have been extensively utilized in clinical trials [1][2][3][4][5]. Notably, functionalized organosulfones exhibited diverse reactivity at α-methylene/arene positions and facile sulfonyl group removal, enabling their valuable role in synthesizing biologically active compounds, pharmaceuticals, intermediates, and natural products [6,7].…”

The Catalytic Asymmetric Allylic Alkylation of Acyclic Enolates for the Construction of Quaternary and Tetrasubstituted Stereogenic Centres

“…The Franckevičius group further expanded the substrate scope of this methodology to 5‐ and 6‐membered cyclic sulfones 260 (D, Scheme 53). [82] The analogous dynamic kinetic resolution was also found to operate, affording high levels of enantioselectivity for a range of 2,2‐disubstituted α‐sulfonyl‐containing ketone and ester products 261 with up to 95 % ee.…”