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. 2012 Jul 25;134(29):12149-56.
doi: 10.1021/ja3034075. Epub 2012 Jul 5.

Copper-catalyzed intramolecular alkene carboetherification: synthesis of fused-ring and bridged-ring tetrahydrofurans

Yan Miller  1 , Lei Miao, Azade S Hosseini, Sherry R Chemler
Affiliations

Copper-catalyzed intramolecular alkene carboetherification: synthesis of fused-ring and bridged-ring tetrahydrofurans

Yan Miller et al. J Am Chem Soc. .

Abstract

Fused-ring and bridged-ring tetrahydrofuran scaffolds are found in a number of natural products and biologically active compounds. A new copper-catalyzed intramolecular carboetherification of alkenes for the synthesis of bicyclic tetrahydrofurans is reported herein. The reaction involves Cu-catalyzed intramolecular addition of alcohols to unactivated alkenes and subsequent aryl C-H functionalization provides the C-C bond. Mechanistic studies indicate a primary carbon radical intermediate is involved and radical addition to the aryl ring is the likely C-C bond-forming mechanism. Preliminary catalytic enantioselective reactions are promising (up to 75% ee) and provide evidence that copper is involved in the alkene addition step, likely through a cis-oxycupration mechanism. Catalytic enantioselective alkene carboetherification reactions are rare and future development of this new method into a highly enantioselective process is promising. During the course of the mechanistic studies a protocol for alkene hydroetherification was also developed.

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Figures

Figure 1
Figure 1
Bioactive fused-ring and bridged-ring tetrahydrofurans
Scheme 1
Scheme 1
Copper-facilitated alkene carboetherifications
Scheme 2
Scheme 2
Rationale for regioisomer formation
Scheme 3
Scheme 3
Enantioselective transannular carboetherification and hydroetherification
Scheme 4
Scheme 4
Proposed carboetherification catalytic cycle
See this image and copyright information in PMC

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