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. 2022 Aug 5;87(15):10256-10276.
doi: 10.1021/acs.joc.2c01240. Epub 2022 Jul 8.

Catalytic Enantioselective Synthesis of α-Difunctionalized Cyclic Sulfones

Eleanor Bowen  1 , Gillian Laidlaw  1 , Bethany C Atkinson  1 , Timur A McArdle-Ismaguilov  1 , Vilius Franckevičius  1
Affiliations

Catalytic Enantioselective Synthesis of α-Difunctionalized Cyclic Sulfones

Eleanor Bowen et al. J Org Chem. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Enantioenriched α-disubstituted cyclic sulfones.
Scheme 1
Scheme 1. Pd-Catalyzed DAAA of Enolates
Scheme 2
Scheme 2. Substrate Synthesis
Scheme 3
Scheme 3. Substrate Scope Investigation,,
Reactions performed on a 0.09–0.29 mmol scale with [Pd2(dba)3] (2.5 mol % for esters and 5 mol % for ketones) and (S,S)-L4 (6.5 mol % for esters and 13 mol % for ketones) in 1,4-dioxane (0.1 M). All yields are of the isolated product after purification by chromatography. All ee values were determined by chiral HPLC. Catalyst loading: [Pd2(dba)3] (5 mol %) and (S,S)-L4 (13 mol %).
Scheme 4
Scheme 4. Mechanistic Study
Scheme 5
Scheme 5. Proposed Catalytic Cycle
See this image and copyright information in PMC

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