Desymmetrization of meso-bisphosphates using copper catalysis and alkylzirconocene nucleophiles

• Published in: Nature communications Vol. 10; no. 1; pp. 21 - 6
• Main Authors: Jacques, Reece, Pullin, Robert D. C., Fletcher, Stephen P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-01-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/403/933; 639/638/77/883; 639/638/77/888; Carbon; Catalysis; Chemical reactions; Chemical synthesis; Copper; Copper compounds; Cryogenic temperature; Enantiomers; Functional groups; Humanities and Social Sciences; Ligands; multidisciplinary; Natural products; Nucleophiles; Reagents; Science; Science (multidisciplinary); Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07871-x

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,
C
2
-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.
Copper-catalyzed allylic desymmetrizations are, so far, limited to carbocyclic products with two tertiary stereocenters. Here, the authors report a highly enantioselective Cu-catalyzed desymmetrization of
meso
carbo- and hetero-cyclic bisphosphates to give products with up to three contiguous stereocenters.