Solvent-controlled stereoselective formation of a cyclic ether in the Lewis acid-mediated allylation of an α-chloroacetoxy acyclic ether. Very high stereoselectivity in CH₃CN vs low stereoselectivity in CH ₂Cl₂

(Chemical Equation Presented) The MgBr₂·OEt ₂-mediated intramolecular allylation of a 4:1 diastereoisomeric mixture of the α-chloroacetoxyl ether 1a bearing the A-G/JK ring system of brevetoxin B in CH₂Cl₂ gave a 1:1 diastereoisomeric mixture of the trans- and cis-cyclization products 4a and 5a having the A-G/I-K ring system, while that in CH₃CN afforded the trans-isomer 4a nearly as the single product. To help clarify a reason for this marked solvent effect in the cyclization of the brevetoxin B precursor, DFT computations for the starting materials, intermediates, transition states, and products were carried out. The cyclization would proceed through a carbocation intermediate 3a having sp² flat structure (SNI type mechanism) in CH₂Cl ₂, in which the activation energies leading to both diastereoisomers are approximately identical, while in CH₃CN alkylnitrilium salts 6a would be formed through the coordination of CH₃CN to the carbocation leading to an sp³-type intermediate in which sever steric hindrance takes place in the transition state leading to the undesired diastereoisomer. The scope of this novel solvent-controlled stereoselectivity was tested for simple compounds. In small model compounds the marked solvent dependence was absent, but the model bearing two consecutive cyclic ether rings 1b exhibited a remarkable solvent effect similar to that observed in the brevetoxin B system.