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Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions

Abstract

The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C–H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si–H bonds to yield an oxophilic silylium (R3Si+) equivalent along with a reducing (H) equivalent. Together, these reactive intermediates enable the reduction of multiple functional groups. Exogenous phosphine Lewis bases further modify the catalyst speciation and attenuate aggressive silylium ions for the selective modification of complex natural products. Manipulation of the catalyst, silane reagent and the reaction conditions provides experimental control over which site is modified (and how). Applying this catalytic method to complex bioactive compounds (natural products or drugs) provides a powerful tool for studying structure–activity relationships.

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Figure 1: Natural products display diverse structures and bioactivity.
Figure 2: Fluoroarylborane catalysts can use the Piers silane-activation mechanism to activate C–O bonds and enable the functionalization of complex natural products.
Figure 3: Chemoselective amide reductions in complex environments are enabled by mixed fluoroarylalkylborane catalysts.
Figure 4: To test the fluoroarylborane methodology on a new natural product class, several selective modifications of 10-deacetoxybaccatin III were demonstrated.

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Acknowledgements

This work was exclusively supported by the Department of Energy (Basic Energy Sciences, DE-FG02-05ER15630). T.A.B. is grateful for a University of North Carolina Dissertation Completion Fellowship.

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T.A.B. and M.R.G. conceived and designed the experiments; T.A.B. performed the experiments; P.R.P. prepared Lewis acid catalysts; T.A.B. and M.R.G. participated in the process of data analysis and the writing of the paper.

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Correspondence to Michel R. Gagné.

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The authors declare no competing financial interests.

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Bender, T., Payne, P. & Gagné, M. Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions. Nature Chem 10, 85–90 (2018). https://doi.org/10.1038/nchem.2863

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