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. 2019 Jun 21;55(49):7013-7016.
doi: 10.1039/c9cc03775f. Epub 2019 May 31.

Synthesis of bicyclic ethers by a palladium-catalyzed oxidative cyclization-redox relay-π-allyl-Pd cyclization cascade reaction

Michaelyn C Lux  1 , Melissa L Boby  2 , Joshua L Brooks  3 , Derek S Tan  4
Affiliations

Synthesis of bicyclic ethers by a palladium-catalyzed oxidative cyclization-redox relay-π-allyl-Pd cyclization cascade reaction

Michaelyn C Lux et al. Chem Commun (Camb). .

Abstract

Bicyclic ether scaffolds are found in a variety of natural products and are of interest in probe and drug discovery. A palladium-catalyzed cascade reaction has been developed to provide efficient access to these scaffolds from readily available linear diene-diol substrates. A Pd redox-relay process is used strategically to transmit reactivity between an initial oxypalladative cyclization and a subsequent π-allyl-Pd cyclization at remote sites. The reaction affords a variety of bicyclic ether scaffolds with complete diastereoselectivity for cis-ring fusion.

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Conflict of interest statement

Conflicts of interest

There are no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
(a) Bicyclic ether scaffolds (blue) are found in a variety of natural products. (b) Proposed Pd-catalyzed tandem oxidative cyclization–redox relay–π-allyl-Pd cyclization cascade transmits reactivity tracelessly between two remote cyclization reactions to generate bicyclic ether scaffolds.
Fig. 2
Fig. 2
(a) Substrate scope of the Pd-catalyzed bicyclization cascade reaction. Yields reported are an average of two independent experiments on ≈40-mg scale. dr values are reported for crude reaction products based on 1H-NMR analysis. All products are racemic. Reaction conditions: 9 mol% Pd(OTs)2(MeCN)2, 12 mol% 12, 3 equiv benzoquinone, 1 equiv Ca(OH)2, 300 mg/mmol 3 Å MS, CPME, 80 °C, 16 h. aDiastereomers separable by column chromatography, combined yield shown. bAlso prepared on 1-mmol scale (42%) and 1-g scale (38%). cReaction time 40 h. (b) Functionalization of the vinyl side chain allows epimerization to major diastereomer.
Fig. 3
Fig. 3
Extension of bicyclization cascade to [5,5]- and [5,7]-ring systems. Reaction conditions: 9 mol% Pd(OTs)2(MeCN)2, 12 mol% 12, 3 equiv benzoquinone, 1 equiv Ca(OH)2, 3 Å MS, CPME, 80 °C, 16 h. Yields reported are an average of two independent experiments on ≈40-mg scale. All products are racemic.
See this image and copyright information in PMC

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