Pergamon Tetrahedron: Asymmetry 10 (1999) 265–279 TETRAHEDRON: ASYMMETRY Computational study of solvation and stereoselectivity in deprotonation of cyclohexene oxide by a chiral lithium amide Sten O. Nilsson Lill, Per I. Arvidsson and Per Ahlberg ∗ Organic Chemistry, Department of Chemistry, Göteborg University, SE-412 96, Göteborg, Sweden Received 10 November 1998; accepted 14 December 1998 Abstract A detailed computational investigation of possible activated complexes in the epoxide opening of cyclohexene oxide by a chiral lithium amide is presented. Transition states for the two routes giving (S)- and (R)-alkoxides with and without solvent have been calculated. Geometry optimizations at PM3 and HF/3-21G levels of theory, and single point calculations at B3LYP/6-31+G(d) level have been used. The experimentally obtained stereoselectivity is semi-quantitatively reproduced at all levels except PM3//PM3. The factors found to control the stereoselectivity are solvation and some non-bonded interactions other than those previously proposed. © 1999 Elsevier Science Ltd. All rights reserved. 1. Introduction Enantioselective deprotonation of meso-epoxides by chiral lithium amides yielding chiral allylic alcohols in high yield and enantiomeric excess (e.e.) is of increasing importance in synthesis. There are many recent reports on improvement of the stereoselectivity and yield obtained by trial and error structural changes of the amides. 1–26 Surprisingly, no thorough experimental or theoretical studies of the epoxide opening mechanism and initial- and transition-state structures can be found in the literature. Thus the basis for rational design of effective stereoselective amides is lacking. The challenge to predict and interpret the stereoselectivity in lithium organic chemistry computatio- nally has recently been accepted by a few groups. 27–30 Major questions to be answered concern the structures and energies of transition states (TS) and the role of solvation. However, the task is difficult due to the complexity of the systems. Following our previous reports, 19,31–34 which include solvent effects on enantioselective deprotona- tion of epoxide and solvent induced isomerization of allylic alcohol to homoallylic alcohol, we now ∗ Corresponding author. Tel: +46-31-772-2899; fax: +46-31-772-2908; e-mail: per.ahlberg@oc.chalmers.se 0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0957-4166(98)00501-1 tetasy 2648 Article