Synthesis of Spirocyclic Ethers by Enantioselective Copper-Catalyzed Carboetherification of Alkenols

Abstract

Spirocyclic ethers can be found in bioactive compounds. This copper-catalyzed enantioselective alkene carboetherification provides 5,5-, 5,6- and 6,6-spirocyclic products containing fully substituted chiral carbon centers with up to 99 % enantiomeric excess. This reaction features the formation of two rings from acyclic substrates, 1,1-disubstituted alkenols functionalized with either arenes, alkenes, or alkynes, and clearly constitutes a powerful way to synthesize chiral spirocyclic ethers.

Keywords: copper; cyclizations; enantioselectivity; spiro-compounds; synthetic methods.

Figure 1.

Bioactive spirocyclic ethers.

Figure 2.

Proposed transition state consistent with the crystal structure of 2k.^[17]

Scheme 1.

Spirocycle synthesis strategy.

Scheme 2.

Scope of the enantioselective carboetherification. Reaction conditions from Table 1, entry 5 were used. In the reaction leading to 2i, Ag₂CO₃ was used as oxidant instead of MnO₂.

Scheme 3.

Scale-up (1.8 mmol 1d) and regioisomer rationale.

Scheme 4.

Substrates with pendant alkenes and alkyne.

Scheme 5.

Conditions from Table 1, entry 5 were used unless otherwise noted. The reaction to give 2o was run using (S,S)-iPr-Box instead of (S,S)-tBu-Box. Cbz=benzyloxycarbonyl, Ts=4-toluenesulfonyl.