Cobalt-Catalyzed Hartung-Mukaiyama Cyclization of γ-Hydroxy Olefins: Stereocontrolled Synthesis of the Tetrahydrofuran Moiety of Amphidinolide N

Cobalt-catalyzed Mukaiyama-type cyclization of gamma-hydroxy olefins is known as an atom- and step-economical means for stereoselective synthesis of 2,5-trans-substituted tetrahydrofuran derivatives. In this study, we investigated the synthesis of a series of 2,5-substituted tetrahydrofuran derivatives by means of a cobalt-catalyzed Hartung-Mukaiyama cyclization. The stereochemical consequence of the reaction was found to be largely dependent on the substitution pattern and relative configuration of gamma-hydroxy olefins. 2,5-cis-Substituted tetrahydrofuran derivatives could be obtained diastereoselectively from appropriately substituted gamma-hydroxy olefins. Additionally, relatively bulky olefin substituents and unprotected hydroxy groups at non-interfering positions (e.g., alpha and delta) were well tolerated in the reaction. Finally, the synthetic versatility of the Hartung-Mukaiyama cyclization was demonstrated through a stereocontrolled synthesis of the tetrahydrofuran moiety of amphidinolide N, a potent cytotoxic macrolide of marine origin. This study expands the capacity of Mukaiyama-type cyclization in that it can be used in convergent assembly of complex tetrahydrofuran motifs from internal olefins.

Automated summary

The study investigates the synthesis of a series of 2,5-substituted tetrahydrofuran derivatives through cobalt-catalyzed Hartung-Mukaiyama cyclization. The stereochemical outcome of the reaction is dependent on the substitution pattern and relative configuration of gamma-hydroxy olefins. Appropriately substituted gamma-hydroxy olefins can result in diastereoselective formation of 2,5-trans-substituted tetrahydrofuran derivatives.