Desymmetrization of meso-bisphosphates using copper catalysis and alkylzirconocene nucleophiles

Reece Jacques,Robert D C Pullin,Stephen P Fletcher

doi:10.1038/s41467-018-07871-x

Reece Jacques, Robert D C Pullin + Show 1 more

Open Access

https://doi.org/10.1038/s41467-018-07871-x

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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.

Highlights

The desymmetrization of meso-compounds is a useful synthetic method, as illustrated by numerous applications of this strategy in natural product synthesis
The catalytic desymmetrization of meso-compounds is a powerful method of preparing chiral molecules. This strategy allows stereogenic features already present in symmetrical molecules to be unmasked, giving chiral molecules with multiple stereogenic centers in a single step[1,2,3]. These desymmetrizations have been used in the synthesis of enantiomerically enriched cyclic molecules, with metal-catalyzed asymmetric allylic addition (AAA) a proven strategy in C–C and C–X bond forming desymmetrizations[4,5,6,7]
Several natural product syntheses rely on a key desymmetrizing Pd-catalyzed AAA stage[8,9,10,11,12]

Summary

Introduction

The desymmetrization of meso-compounds is a useful synthetic method, as illustrated by numerous applications of this strategy in natural product synthesis. These desymmetrizations have been used in the synthesis of enantiomerically enriched cyclic molecules, with metal-catalyzed asymmetric allylic addition (AAA) a proven strategy in C–C and C–X bond forming desymmetrizations[4,5,6,7]. Cu-catalyzed AAAs enable use of nonstabilized carbon nucleophiles[13,14,15,16,17,18,19], but Cu-catalyzed C–C bond forming allylic desymmetrizations are rare and have only been reported using simple unfunctionalized nucleophiles (Fig. 1a).

Results

Conclusion