The Z-configurated lactam (4a) formed as by-product proved to be stable under the reaction conditions, so a chromatographic separation was necessary. In an attempt to avoid this separation step we have studied the possibilities of E-2 isomerization.
Whereas in the case of unsaturated C'5-unsubstituted lactams [see (3b)] only the desired E-configuration is formed under kinetically controlled and is thermodynamically stable, in the case of the geissoschizine intermediate (3a) competing formation of the Z-isomer (4a) takes place by steric interaction between CH3 and R [see conformation (3')]. This interaction would be minimized in the conformation (.?")-a conformation which however is not populated, unless forcefully so by bonding between R and the indole N-atom. This is achieved by treatment of the lactamic acid (4b) with trifluoroacetic anhydride. This ring closure is in fact accompanied by a spontaneous isomerization of the double bond with formation of the E-configurated dilactam (5). Regioselective ring-opening of the dilactam with sodium methoxide in methanol leads to the lactamate (34 in quantitative yield.
The synthesis becomes stereoconvergent through the intermediate (5). The mixture of the lactamates (3a) and (4a) is hydrolyzed to the mixture of the lactamic acids, which then cyclize to the single dilactam (5) in very high yields. All the steps give excellent yields and can be carried out without resorting to isolation and purification of the intermediates. (3a) is cleanly converted into geissoschizine (1) by "Borch reduction" and formylation (see l'l).