Progress on Transition-Metal-Catalyzed Asymmetric Synthesis of Chiral Tertiary Alkyl Ethers via C—O Bond Formation

doi:10.6023/cjoc202604011

Abstract

Chiral tertiary alkyl ethers are important structural motifs widely found in natural products, drug molecules, and biologically active small molecules. Owing to the presence of sterically congested tetrasubstituted carbon stereocenters, the enantioselective synthesis of chiral tertiary alkyl ethers poses a significant challenge. In recent years, driven with the development of novel chiral catalysts and continuous innovation in reaction design, remarkable advances have been made in the asymmetric construction of such structures via C—O formation. In this review, the advances are summarized based on reaction types and the transition-metal catalysts employed, including asymmetric nucleophilic substitution, olefin alkoxylation, cycloaddition/annulation of ketones, C—H bond functionalization and cascade carbene O—H insertion reaction. The review focuses on the design principles, catalyst systems, substrate scope, and proposed mechanisms of the discussed reactions. Furthermore, current challenges and future directions in the field are discussed.

Key words: asymmetric catalysis, transition-metal catalysis, chiral tertiary alkyl ether, tetrasubstituted carbon stereocenter, asymmetric construction of C—O bond

Cite this article

Haoyu Zheng, Chuan-Ying Li, You-Yun Zhou. Progress on Transition-Metal-Catalyzed Asymmetric Synthesis of Chiral Tertiary Alkyl Ethers via C—O Bond Formation[J]. Chinese Journal of Organic Chemistry, 2026, 46(8): 2892-2925.

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Fig. & Tab. 40

Figure 1. Natural products and pharmaceutical molecules containing chiral tertiary ether structures

Scheme 1. Synthesis of chiral chromans by Pd-catalyzed asymmetric intramolecular allylic alkylation

Scheme 2. Gold-catalyzed intramolecular asymmetric allylic substitution to construct chiral tetrasubstituted chromanones

Scheme 3. Palladium/chiral phosphoric acid synergistic catalysis for intramolecular asymmetric allylic substitution of allylic alcohol to construct chiral benzoxazine structures

Scheme 4. Two-component catalyst system for asymmetric allylic alkylations with alcohol pronucleophiles

Scheme 5. Decarboxylative cycloaddition via asymmetric allylic substitution for the construction of chiral tertiary vinyl 1,3-dioxcy- clopentane

Scheme 6. Pd-Catalyzed asymmetric allylic cycloaddition

Scheme 7. Enantioselective construction of tertiary C—O bond via allylic substitution of vinylethylene carbonates with alcohols

Scheme 8. Pd-catalyzed enantioselective synthesis of tertiary allylic aryl ethers

Scheme 9. Asymmetric allylic etherification of vinylethylene carbonates with diols via Pd/B cooperative catalysis

Scheme 10. Copper-catalyzed enantioconvergent O-alkylation of alcohols with racemic α-tertiary haloamides

Scheme 11. Achiral pyridine ligand-enabled enantioselective radical oxytrifluoromethylation of alkenes with alcohols

Scheme 12. Catalytic desymmetrizing functionalization of alkyl radicals via Cu(I)/CPA cooperative catalysis

Scheme 13. Palladium-catalyzed asymmetric alkoxylation-arylation of alkenes for constructing chiral tertiary alkyl ethers

Scheme 14. Synthesis of chiral 1,4-benzodioxanes and chromans by Pd-catalyzed enantioselective aryloxyarylation of alkenes

Scheme 15. Palladium/Xu-Phos-catalyzed enantioselective arylalkoxylation of γ-hydroxyalkenes

Scheme 16. Palladium/Xu-Phos-catalyzed enantioselective alkoxyalkenylation of γ-hydroxyalkenes

Scheme 17. Catalytic asymmetric intermolecular iodoetherification of unfunctionalized alkenes

Scheme 18. Palladium-catalyzed asymmetric Wacker-type cyclization

Scheme 19. Palladium-catalyzed asymmetric tandem Wacker oxidation/Heck reaction

Scheme 20. Copper-catalyzed enantioselective hydroalkoxylation of alkenols for the synthesis of cyclic ethers

Scheme 21. Catalytic asymmetric hetero Diels-Alder reactions of ketones

Scheme 22. Other ligands and transition metal-catalyzed asymmetric hetero Diels-Alder reactions

Scheme 23. Catalytic asymmetric [3＋2] annulation of allylsilanes with isatins

Scheme 24. Palladium-catalyzed enantioselective [3＋2] cycloaddition of trimethylenemethane and fluorinated ketones

Scheme 25. Palladium-catalyzed asymmetric [3＋2] cycloaddition of α-trifluoromethyl carbanions with ketones

Scheme 26. Palladium-catalyzed asymmetric [3＋2] cycloaddition of vinyl cyclopropanes and isatins

Scheme 27. Palladium-catalyzed diastereo-and enantioselective [3＋2] cycloaddition of vinylcyclopropanes with azadienes

Scheme 28. Palladium-catalyzed enantioselective [3＋2] cycloaddition of vinylarylcyclopropanes (VACPs) with photogenerated ketenes to tetrahydrofurans

Scheme 29. Synthesis of chiral tertiary alkyl ethers via one-pot Rh/Pd relay asymmetric catalysis

Scheme 30. Copper-catalyzed formal enantioselective phenoxylation of C—H bond of β-keto esters

Scheme 31. Palladium-catalyzed asymmetric intramolecular allylic C—H oxidation for the synthesis of chromans

Scheme 32. Asymmetric tandem carbene O—H insertion/Mannich-type reaction of diazo compounds and alcohols with imines via Rh/chiral phosphoric acid cooperative catalysis

Scheme 33. Asymmetric catalytic three-component reaction of diazo compounds and alcohols with imines to synthesize tertiary alkyl ethers

Scheme 34. Asymmetric three-component reaction of alcohols and imines with enynal as carbene precursor to synthesize chiral tertiary alkyl ethers

Scheme 35. Asymmetric catalytic three-component reaction of diazo compounds and alcohols with aldehydes to synthesize tertiary alkyl ethers

Scheme 36. Bronsted acid catalyzed enantioselective assembly of spirochroman-3,3-oxindoles

Scheme 37. Cu(I)/chiral bisoxazoline-catalyzed asymmetric annulation of aryldiazoacetates with o-acyl or o-iminyl substituted phenols

Scheme 38. Rh(II)/chiral phosphonic acid co-catalyzed asymmetric Mannich-type reaction of ortho-phenol tethered diazo compounds with imines

Scheme 39. Copper-catalyzed asymmetric cascade diyne cyclization/Meinwald rearrangement for the synthesis of chiral tertiary ethers

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