Isomeric interconversions in tamoxifen and related compounds: An AM 1 study

Semiempirical molecular orbital techniques ( AM 1) were applied to the study of cis – trans isomerism in tamoxifen and related compounds. AM 1‐derived structures were in good agreement with X‐ray data. Theoretical evaluation indicated that both cis ‐ and trans ‐tamoxifen as well as the 4‐hydroxytamoxifen isomeric pair were very close in energy, confirming experimental results suggesting nearly equivalent populations of the two isomers under equilibrium conditions. Mechanistic studies included a determination of selected proton affinities to establish the nature and location of compound protonation as well as conformational studies of the formed carbocations. In particular, internal rotation about the incipient olefinic CC bond in the tamoxifen and 4‐hydroxytamoxifen carbocations provided a likely reaction mechanism. There evaluations suggested that the more rapid isomerization of 4‐hydroxytamoxifen as compared to tamoxifen was related to transition‐state stabilization through phenolic oxygen electron donation. © 1995 John Wiley & Sons, Inc.