Enantioselective synthesis of tetrahydrofurans by permanganate-mediated oxidative cyclisation of 1,5-dienes using chiral phase-transfer catalysis

Abstract

Permanganate-mediated oxidative cyclisation of 1,5-dienes under chiral phase transfer catalysis (CPTC) conditions provides 2,5-dihydroxyalkyl substituted tetrahydrofurans (THF-diols) wherein four new C–O bonds are established with excellent control of relative and absolute stereochemistry. Structurally complex THF-containing motifs found in a host of bioactive natural products are accessible by oxidative transformation of simple dienes, which is exemplified by formal syntheses of cis-solamin A. Electron-withdrawing ester or ketone groups in the substrates – conjugated to one alkene of the 1,5-diene system – direct the initial manganation reaction to the electron-deficient alkene, which proceeds with enantiofacial selectivity in the presence of the CPTC. Cinchona alkaloid scaffolds are a convenient platform for chiral quaternary ammoniums with short synthetic routes to anthracenylmethyl and 3,5-bis(trifluoromethylbenzyl) CPTC derivatives realising enantioselectivities up to 89–94% ee for structurally distinct 1,5-diene systems using a readily-available and inexpensive oxidant. DFT calculations provide significant new mechanistic insight into the permanganate-mediated reaction supporting the involvement of a protonated Mn(V) glycolate in THF ring-formation through enhanced electrophilicity of the metal oxo intermediate. Furthermore, calculations identify the interplay between dipole-driven electrostatic stabilisation and cooperative noncovalent interactions in the transition state complex for manganation in the first reaction step, leading to the observed facial selectivity in this powerful synthetic reaction.