An ab initio mechanistic understanding of the regioselective acetylation of 8,11-dihydroxy-pentacyclo[5.4.0.0^2,6.0^3,10.0 ^5,9] undecane-8,11-lactam

The regioselective acetylation of 8,11-dihydroxy-pentacyclo[5.4.0.0 2,6.03,10.05,9]undecane-8,11-lactam with acetic anhydride was investigated. Only one of four possible structural isomers, namely 8-hydroxy-11-acetoxy-pentacyclo[5.4.0.02,6.0 3,10.05,9]undecane-8,11-lactam, was obtained. Ab initio [RHF/6-31+G(d)] and DFT [B3LYP/6-31+G(d)] calculations were employed to obtain the optimised geometries and corresponding energies of the different possible structural isomers, precomplexes and corresponding transition states. A six-membered cyclic transition state of acetic anhydride with the reagent was found. The computational model correctly predicts which isomer would preferentially form and suggests that the product obtained is both thermodynamically and kinetically preferred. The computational results were verified using a kinetically controlled experiment and 2D NMR techniques. © 2003 Elsevier B.V. All rights reserved.