Insight and scope of cis-selectivity of Wittig reaction for the synthesis of mono and multi-substituted stilbenes

Combretastatin A-1 and A-4, cis -stilbenes, have been involved in numerous anticancer clinical trials and have received orphan drug designation from the FDA. The Wittig synthesis yielded 90 % of the cis -isomer of A-1. This study examines the cis -selectivity of stilbenes observed with mono-, di-, and trisubstituted benzaldehydes and phosphonium bromides. Substituents considered include alkoxy, alkyl, halo, and trifluoromethyls. In mono-substituted systems, a C-2 methoxy or C-2 bromo-benzaldehyde combined with an unsubstituted phosphorane typically results in approximately 70 % cis -stilbene, while bulky alkoxy groups reverses the selectivity. The 2,2′-disubstituted stilbene system, featuring C-2 substituents on both the benzaldehyde and the benzyl phosphorane, achieves 90–96 % cis -selectivity, with steric bulk at C-2 on either or both reactants increases selectivity, even at ambient temperature. These findings indicate that steric factors primarily influence the high selectivity, not the electronic effects. For highly substituted combretastatin-type stilbene systems, 2,3,4-trialkoxybenzaldehyde determines cis -selectivity, and symmetrical 3,4,5-trimethoxy benzyl phosphorane enhances this effect. Additionally, 2-methoxy-5-iodo benzaldehyde alone governs the cis -selectivity regardless of benzyl phosphoranes used. In this case, the high cis -selectivity appears to result mainly from the iodo group, although the specific mechanism is not fully understood. These results are exemplified with 54 examples.