Towards a general diastereoselective route to oxabicyclo[3.2.1]octanes via a gold-catalysed cascade reaction

Junkai Fu,Jianxian Gong,Yu Lan,Tuoping Luo,Yueqing Gu,Hao Yuan,Zhen Yang,Song Liu

doi:10.1038/ncomms9617

Abstract

The development of an efficient diastereoselective synthesis of the oxabicyclo[3.2.1]octane ring system bearing two oxygenated quaternary chiral centres represents a significant challenge. This motif can be found in a wide range of natural products with significant biological activities. Here we report the synthesis of such kind of scaffold using a cyclohexane-trans-1,4-diol with an alkyne side chain in the presence of Au(I) catalyst. This is a domino process in which two C–H, two C–O and one C–C bond is assembled through a sequence of cyclization/semi-pinacol rearrangements. This strategy has been successfully applied to the asymmetric formal total synthesis of (+)-cortistatins.

Highlights

The development of an efficient diastereoselective synthesis of the oxabicyclo[3.2.1]octane ring system bearing two oxygenated quaternary chiral centres represents a significant challenge
We report a general strategy using a semi-pinacol rearrangement cascade reaction of substituted 1-ethynylcyclohexane-trans-1,4-diols. This goes via a highly strained oxonium ion generated in situ and is derived from nucleophilic addition of a hydroxyl group onto a gold-activated alkyne. This chemistry has been successfully applied to the asymmetric formal total synthesis of ( þ )-cortistatins
In summary, a novel strategy for the diastereoselective synthesis of structurally diverse oxabicyclo[3.2.1]octane scaffolds has been achieved via a gold-catalysed cascade reaction, which is consisted of three individual reactions, featuring (1) a gold-catalysed intramolecular nucleophilic addition of the OH group onto the carbon–carbon triple bond; (2) a gold-catalysed isomerization of exo-cyclic enol ether to a highly strained oxonium ion; (3) the oxonium-induced semi-pinacol rearrangement

Summary

Results

Tests revealed Ph3PAuNTf2 (5 mol%) to be the optimum gold catalyst when used at room temperature for 2 h and gave 10 in 72% yield (entries 3–6; Table 1). A control experiment in the absence of gold catalyst gave no desired product, indicating that Ph3PAuNTf2 is essential (entry 14) In light of these results, the optimized conditions for this reaction are Ph3PAuNTf2 (2.5 mol%) in DCM at room temperature. The Au-catalysed sequential reaction of monocyclic diol substrates were tested (Table 3) for the synthesis of 8-oxabicyclo[3.2.1]octane derivatives equipped with several functional groups. Substrates bearing a terminal alkyne and those substituted with halogen atoms or an ester tolerated the reaction conditions These groups allow further functional group manipulation (entries 1–4; Table 3).

H Ph3PAuNTf2

Discussion

Methods