Asymmetric Catalysis in Propargylic Substitution Reactions

The field of asymmetric catalysis in propargylic substitution has advanced rapidly in recent years, offering powerful strategies for constructing stereochemically complex alkynes. Propargylic substitution transforms propargylic alcohols or carbonates into a wide range of functionalised alkynes by nucleophilic attack at the carbon adjacent to an alkyne. Chiral catalysts—often based on transition metals such as copper, nickel, palladium or indium—enable precise control over enantioselectivity and diastereoselectivity, forging quaternary and tertiary stereogenic centres under mild conditions. Dual catalytic systems, merging photoredox activation with a chiral metal core, have extended the scope to involve free‐radical intermediates. Concurrently, stereoconvergent approaches allow racemic mixtures of electrophiles and nucleophiles to funnel into a single enantiomeric product. These developments not only enrich the synthetic toolbox for natural product synthesis and pharmaceutical discovery but also demonstrate routes to complex acetylenic scaffolds with high atom economy and environmental benignity.

Research from Nature Portfolio

Recent studies have demonstrated the power of dual photoredox and transition‐metal catalysis for enantioselective propargylic alkylation. A diruthenium–photoredox system generates alkyl radicals from dihydropyridines under visible light, with a chiral ruthenium core guiding radical addition to propargylic alcohols and delivering quaternary stereocentres in high yield and enantioselectivity. Complementing this, a copper/magnesium dual catalytic platform achieves doubly stereoconvergent coupling of racemic propargylic substrates and nucleophiles to afford vicinal tertiary and quaternary stereocentres with excellent diastereo‐ and enantioselectivity. More recently, cationic indium catalysts have enabled dehydrative SN1 propargylation of α-alkyl propargyl alcohols under mild, open-air conditions. This approach generates propargyl cations in situ, which react with a diverse set of nucleophiles to furnish α-aryl and heteroaryl propargyl compounds with broad functional group tolerance and potential applications in the synthesis of colchicine analogues.

Asymmetric Catalysis in Propargylic Substitution Reactions publication trend

The graph below shows the total number of articles in asymmetric catalysis in propargylic substitution reactions across all publications each year (not limited to Nature Index journals).

Technical terms

Asymmetric catalysis: Use of a chiral catalyst to induce enantioselectivity in a chemical reaction.

Propargylic substitution: Nucleophilic attack at the carbon adjacent to an alkyne (the propargylic position) resulting in substitution.

Enantioselectivity: Preference for formation of one enantiomer over the other in a chiral reaction.

Photoredox catalysis: Catalytic cycle where light-excited species enable single-electron transfer to generate reactive radicals.

Stereoconvergence: Conversion of racemic starting materials into a single enantiomeric product.

Allenylidene: Reactive intermediate featuring a metal-bound cumulated diene (–C=C=CH–) engaged in nucleophilic attack.

References

1. Interplay of diruthenium catalyst in controlling enantioselective propargylic substitution reactions with visible light-generated alkyl radicals. Nature Communications (2023).
2. Doubly stereoconvergent construction of vicinal all-carbon quaternary and tertiary stereocenters by Cu/Mg-catalyzed propargylic substitution. Nature Communications (2022).
3. Cationic indium catalysis as a powerful tool for generating α-alkyl propargyl cations for SN1 reactions. Communications Chemistry (2023).
4. Enantioselective propargylic [1,3]-rearrangements: copper-catalyzed O -to- N migrations toward C–N bond formation. Chemical Science (2017).
5. Copper-catalyzed yne-allylic substitutions: concept and recent developments. Beilstein Journal of Organic Chemistry (2024).
6. Gold-catalyzed propargylic substitutions: Scope and synthetic developments. Beilstein Journal of Organic Chemistry (2011).