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Highly efficient molybdenum-based catalysts for enantioselective alkene metathesis

Abstract

Discovery of efficient catalysts is one of the most compelling objectives of modern chemistry. Chiral catalysts are in particularly high demand, as they facilitate synthesis of enantiomerically enriched small molecules that are critical to developments in medicine, biology and materials science1. Especially noteworthy are catalysts that promote—with otherwise inaccessible efficiency and selectivity levels—reactions demonstrated to be of great utility in chemical synthesis. Here we report a class of chiral catalysts that initiate alkene metathesis1 with very high efficiency and enantioselectivity. Such attributes arise from structural fluxionality of the chiral catalysts and the central role that enhanced electronic factors have in the catalytic cycle. The new catalysts have a stereogenic metal centre and carry only monodentate ligands; the molybdenum-based complexes are prepared stereoselectively by a ligand exchange process involving an enantiomerically pure aryloxide, a class of ligands scarcely used in enantioselective catalysis2,3. We demonstrate the application of the new catalysts in an enantioselective synthesis of the Aspidosperma alkaloid, quebrachamine, through an alkene metathesis reaction that cannot be promoted by any of the previously reported chiral catalysts.

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Figure 1: Catalytic ring-closing metathesis of triene 1.
Figure 2: Stereoelectronic effects have a critical role in alkene metathesis reactions promoted by a molybdenum complex that bears a donor and an acceptor ligand.
Figure 3: Diastereoselective synthesis of stereogenic-at-Mo complexes.
Figure 4: Efficient and highly enantioselective synthesis of (+)-quebrachamine.

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Acknowledgements

This research was supported by the US National Institutes of Health, Institute of General Medical Sciences (grant GM-59426 to A.H.H. and R.R.S.). We are grateful to B. C. Bailey and K. Wampler for assistance in obtaining the X-ray structure of the major diastereomer of molybdenum complex 13b. We thank A. R. Zhugralin for numerous discussions regarding the mechanistic aspects of these investigations and R. Singh for experimental suggestions. Mass spectrometry facilities at Boston College are supported by the US National Science Foundation (grant DBI-0619576).

Author Contributions S. J. Malcolmson and S. J. Meek were involved in the discovery and development of the new catalysts. E.S.S. designed and developed the synthesis route to racemic quebrachamine. A.H.H. and R.R.S. designed and directed the research program. A.H.H. wrote the manuscript.

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Correspondence to Amir H. Hoveyda.

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X-ray crystallographic data have been deposited at the Cambridge Crystallographic Data Centre, UK; CCDC 703841 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk/data_request/cif).

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Malcolmson, S., Meek, S., Sattely, E. et al. Highly efficient molybdenum-based catalysts for enantioselective alkene metathesis. Nature 456, 933–937 (2008). https://doi.org/10.1038/nature07594

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