Stereoselective synthesis of (±)-veadeiroic acid and (±)-veadeirol by cyclisation of a 2-(2-arylethyl)-1,3,3-trimethylcyclohexyl cation: mechanism and stereochemistry of related cycloalkylation reactions

Abstract

(±)-Veadeiroic acid 1 and (±)-veadeirol 2, two new cleistanthoid diterpenes, have been synthesized by stereoselective cyclisation of the carbocation 5 generated from the cyclohexanol 26. The latter is prepared from 2-ethyl-3-formylbenzoic acid (with CO₂H masked as an oxazoline ring) by successive reaction with 3-methylbutan-2-one, Robinson annutation, and reduction of the styrylcyclohexenone 24. The stereochemistry of cycloalkylation of the carbocations A, which ranges from 100%trans to 50 : 50 cis-trans ring-fusion as a non-activated aryl ring becomes activated by substitution, has been rationalised on the basis of the shift of the rate-determining step from the formation of σ-complexes to that of π-complexes and the steric interactions therein.