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Stereoselective synthesis through remote functionalization

Nature Synthesis volume 1, pages 37–48 (2022)Cite this article

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A Publisher Correction to this article was published on 14 April 2022

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Abstract

Transition-metal-catalysed alkene isomerization is instrumental to remote functionalization processes, in which a chemical transformation is induced at a position remote from the initial reactive site. The dynamic nature of alkene isomerization, which is crucial for such transformations, often leads to substantial difficulties in controlling the stereochemistry of C(sp3) centres along the carbon skeleton. This review features synthetic methods that tackle this issue and strategically leverage alkene isomerization to control C(sp3) stereocentres in complex organic molecules. Stereocentres can be created at either the initiation or termination site of an isomerization process, retained during chain-walking across the molecular backbone or revealed through restructuring of the carbon skeleton by selective ring-opening of a strained ring. As each of these options imposes different mechanistic requirements, the different examples are divided according to the stage in the chain-walking process at which stereochemistry is established and the type of intermediates that lead to stereodefined products.

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Fig. 1: Remote functionalization and general considerations.
Fig. 2: Asymmetric C-H bond formation at the initiation site.
Fig. 3: Asymmetric C–C and C–B bond formation at the initiation site.
Fig. 4: Walking ‘over’ tertiary and quaternary stereocentres.
Fig. 5: Formation of stereocentres at the termination site through allyl- and benzylmetal intermediates.
Fig. 6: Formation of stereocentres at the termination site through alkylmetal intermediates.
Fig. 7: Formation of stereocentres at the termination site through intermolecular reactions of alkene intermediates.
Fig. 8: Accessing sigmatropic rearrangement substrates through alkene isomerization.

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Acknowledgements

This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 786976.

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  1. Schulich Faculty of Chemistry, Technion – Israel Institute of Technology, Haifa, Israel

    Itai Massad, Rahul Suresh, Lucas Segura & Ilan Marek

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  1. Itai Massad
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  2. Rahul Suresh
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  3. Lucas Segura
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  4. Ilan Marek
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I. Massad, R.S., L.S. and I. Marek conceived and wrote the manuscript. All the authors contributed to discussions.

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Correspondence to Ilan Marek.

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Nature Synthesis thanks Guangbin Dong, Wanbin Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Alison Stoddart managed the editorial process and peer review in collaboration with the rest of the editorial team.

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Massad, I., Suresh, R., Segura, L. et al. Stereoselective synthesis through remote functionalization. Nat Synth 1, 37–48 (2022). https://doi.org/10.1038/s44160-021-00002-3

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