Efficient and stereodivergent synthesis of unsaturated acyclic fragments bearing contiguous stereogenic elements

Abstract

Synthetic organic strategies that enable the catalytic and rapid assembly of a large array of organic compounds that possess multiple stereocentres in acyclic systems are somewhat rare, especially when it comes to reaching today’s high standards of efficiency and selectivity. In particular, the catalytic preparation of a three-dimensional molecular layout of a simple acyclic hydrocarbon skeleton that possesses several stereocentres from simple and readily available reagents still represents a vastly uncharted domain. Here we report a rapid, modular, stereodivergent and diversity-oriented unified strategy to construct acyclic molecular frameworks that bear up to four contiguous and congested stereogenic elements, with remarkably high levels of stereocontrol and in only three catalytic steps from commercially available alkynes. A regio- and diastereoselective catalytic Heck migratory insertion reaction of alkenylcyclopropyl carbinols that merges selective C–C bond cleavage of a cyclopropane represents the key step.

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Fig. 1: Challenges for the easily diversifiable and stereoselective preparation of acyclic hydrocarbon motifs.
Fig. 2: Stereoselective preparation of polysubstituted alkenylcyclopropyl carbinols 3a–3v.
Fig. 3: Oxidative Pd-catalysed Heck coupling of aryl boronic acids with alkenylcyclopropyl carbinols.
Fig. 4: Stereodivergent and selective construction of four stereoisomers of a similar scaffold.
Fig. 5: Oxidative Pd-catalysed Heck coupling of other nucleophiles with alkenylcyclopropyl carbinols and a proposed rationale as to the stereoselective migratory insertion.

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Acknowledgements

This research was supported by the Israel Science Foundation administrated by the Israel Academy of Sciences and Humanities (330/17) and by the European Research Council under the European Community’s Seventh Framework Program (ERC grant agreement no. 338912). I.M. is holder of the Sir Michael and Lady Sobell Academic Chair.

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J.B., D.P. and I.M. planned the research. J.B. and D.P. conducted and analysed experiments. I.M. directed the project, and wrote the manuscript with contributions from J.B. and D.P. All the authors discussed the results and commented on the manuscript.

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Correspondence to Ilan Marek.

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Supplementary information

Supplementary Information

Detailed experimental procedures with full descriptions of all molecules and complete NMR data of all new compounds

Crystallographic data

CIF for compound 6a; CCDC reference: 1813305

Crystallographic data

CIF for compound 6b; CCDC reference: 1813312

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Bruffaerts, J., Pierrot, D. & Marek, I. Efficient and stereodivergent synthesis of unsaturated acyclic fragments bearing contiguous stereogenic elements. Nature Chem 10, 1164–1170 (2018). https://doi.org/10.1038/s41557-018-0123-7

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