Enantioselective Synthesis of 2-Carboxy Cyclic Ethers

Key words

asymmetric O-H insertion - cyclic ethers - copper

Significance

The formation of new carbon-­heteroatom bonds using transition-metal-­catalyzed carbene insertion reactions into X-H bonds (X = O, N, S) is a useful synthetic tool. While highly enantioselective variants of intermolecular O-H insertions are known, selective intramolecular versions have not been developed. Herein, the authors present the first highly enantio-selective copper-catalyzed O-H insertion approach used for the preparation of chiral 2-carb­oxy cyclic ethers of type 2.

Comment

Starting from readily available ω-­hy­droxy-α-diazo esters 1, a number of chiral cyclic ethers of type 2 with various ring sizes could be prepared in good to excellent yields and high enantioselectivities. The combination of CuOTf and the chiral spiro bisoxazoline ligand (S _a ,S,S)-3 in the presence of catalytic amounts of NaBAr_F in non-coordinating solvents like methylene chloride was found to be crucial to achieve high selectivities. The products formed in this transformation are useful building blocks since the 2-carboxylic cyclic ether substructure can be found in several natural products and pharmaceuticals.