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 increase selectivity, even at the ambient temperature. These findings indicate that the 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 in not fully understood. These results are exemplified with 54 examples.