Desymmetrization of meso-bisphosphates using copper catalysis and alkylzirconocene nucleophiles

Reece Jacques, Robert D. C. Pullin and Stephen P. Fletcher ()
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Reece Jacques: Department of Chemistry, Chemistry Research Laboratory, University of Oxford
Robert D. C. Pullin: Vertex Pharmaceuticals (Europe) Ltd.
Stephen P. Fletcher: Department of Chemistry, Chemistry Research Laboratory, University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-6

Abstract: Abstract The desymmetrization of meso-compounds is a useful synthetic method, as illustrated by numerous applications of this strategy in natural product synthesis. Cu-catalyzed allylic desymmetrizations enable the enantioselective formation of carbon-carbon bonds, but these transformations are limited in substrate scope and by the use of highly reactive premade organometallic reagents at cryogenic temperatures. Here we show that diverse meso-bisphosphates in combination with alkylzirconium nucleophiles undergo highly regio-, diastereo- and enantio-selective Cu-catalyzed desymmetrization reactions. In addition, C2-symmetric chiral bisphosphates undergo stereospecific reactions and a racemic substrate undergoes a Cu-catalyzed kinetic resolution. The reaction tolerates functional groups incompatible with many common organometallic reagents and provides access to a broad range of functionalized carbo- and hetero-cyclic structures. The products bear up to three contiguous stereogenic centers, including quaternary centers and spirocyclic ring systems. We anticipate that the method will be a useful complement to existing catalytic enantioselective reactions.

Date: 2019
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DOI: 10.1038/s41467-018-07871-x

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