Gold(I) catalysts are ideal for the activation of alkynes under very mild conditions. However, unlike allenes or alkenes, the triple bond of alkynes cannot be prochiral. In addition, the linear coordination displayed by gold(I) complexes places the chiral ligand far away from the substrate resulting in an inefficient transfer of chiral information. This poses a significant challenge for the achievement of high enantiocontrol in gold(I)‐catalyzed reactions of alkynes. Although considerable progress on enantioselective gold(I)‐catalyzed transformations has recently been achieved, the asymmetric activation of non‐prochiral alkyne‐containing small molecules still represents a great challenge. Herein we summarize recent advances in intra‐ and intermolecular enantioselective gold(I)‐catalyzed reactions involving alkynes, discussing new chiral ligand designs that lie at the basis of these developments. We also focus on the mode of action of these catalysts, their possible limitations towards a next‐generation of more efficient ligand designs. Finally, square planar chiral gold(III) complexes, which offer an alternative to chiral gold(I) complexes, are also discussed.
Planar chiral monodentate 1,3-disubstituted ferrocene phosphines inspired on JohnPhos-type ligands have been synthesized and applied to the enantioselective gold(I) catalyzed [4 + 2] cycloaddition of 1,6-arylenynes. Computational studies rationalized the working mode of the catalyst on the folding of the substrate in the chiral environment of the ligand involving attractive noncovalent interactions.
A new generation of chiral gold(I) catalysts based on variations of complexes with JohnPhos-type ligands with a remote C 2-symmetric 2,5-diarylpyrrolidine have been synthesized with different substitutions at the top and bottom aryl rings: from replacing the phosphine by a N-heterocyclic carbene (NHC) to increasing the steric hindrance with bis- or tris-biphenylphosphine scaffolds, or by directly attaching the C 2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine. The new chiral gold(I) catalysts have been tested in the intramolecular [4+2] cycloaddition of arylalkynes with alkenes and in the atroposelective synthesis of 2-arylindoles. Interestingly, simpler catalysts with the C 2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine led to the formation of opposite enantiomers. The chiral binding pockets of the new catalysts have been analyzed by DFT calculations. As revealed by non-covalent interaction plots, attractive non-covalent interactions between substrates and catalysts direct specific enantioselective folding. Furthermore, we have introduced the open-source tool NEST, specifically designed to account for steric effects in cylindrical-shaped complexes, which allows predicting experimental enantioselectivities in our systems.
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