Studies in transannular and type V intramolecular (4+3) cycloadditions

Abstract

Extended studies on transannular (4+3) cycloadditions of macrocyclic epoxy ketone s have been done to fully elucidate the mechanistic course of the reaction. The synthetic route towards macrocyclic epoxy ketones was successfully optimized. Six epoxy ketone substrates were synthesized, and each ketone delivered 1,2-geometric isomers of the enolsilane derivatives. In contrast to the one pot reactions done in the preliminary studies, enolsilanes were synthesized then isolated whenever possible, and characte rized, before subjecting them to transannular (4+3) cycloadditions. This in-depth study has allowed us to make correlations between the enolsilane geometry and its effect on the diastereoselection in the subsequent transannular (4+3) cycloadditions. Compared with inter- and intramolecular cycloadditions, transannular cycloadditions were found to be more substrate-controlled because the substrates are less flexible. Each cycloaddition substrate reacted differently due to the differences in ring sizes and the transannular interactions that are experienced by each substrate. Enolsilane (Z)-2.103 derived from epoxy ketone 2.97 underwent predominantly exo cycloaddition to provide cycloadduct 2.110 as a single diastereomer. Similarly, both (Z)-2.102 and (E)-2.102 derived from ketone 2.96 underwent exo-cycloadditions. On the other hand, enolsilanes (Z)-2.106 and (E)-2.106 derived from epoxy ketone 2.97, instead underwent predominantly endo cycloadditions. Enolsilane (Z)-2.106 reacted to give diastereomeric cycloadducts 2.116 and 2.118 in a ratio of 3.8:1, whereas (E)-2.106 underwent endo cycloaddition to provide 2.117. Similarly (Z)-2.104 and (E)-2.104 underwent endo cycloadditions. Notably, the diastereomeric outcomes of the transannular cycloaddition corresponded well to the dr of Z/E enolsilanes. A novel amine-mediated transannular (4+3) cycloaddition of epoxy ketones which directly yielded optically active cycloadducts by kinetic resolution via chiral enamine formation has been investigated. A series of macrocyclic epoxy ketone substrates were investigated, however, not all that underwent cycloadditions via enolsilanes reacted via enamine formation to generate (4+3) cycloadducts. Only epoxy ketones 2.96, 2.98 and 2.99 reacted to generate cycloadducts, which were obtained with up to 39% yield and 87% ee. Unlike the typical low-temperature (4+3) cycloadditions of epoxy enolsilanes, the mechanism of the asymmetric amine-mediated transannular (4+3) cycloadditions could involve allylic cation species due to employing higher temperatures under microwave irradiation. Amine 9-NH2-epiQD was found to be a good mediator leading to enantiodifferentiation and acceptable ee, but enamine formation was extremely inefficient. Interestingly, the diastereomeric outcomes of the asymmetric amine-mediated cycloadditions were different from those of the typical low-temperature (4+3) cycloadditions of enolsilanes. Type-V intramolecular (4+3) cycloadditions of epoxy enolsilanes were investigated for enolsilanes 4.13－4.19. However, no (4+3) cycloaddition was observed, only Friedel-Crafts cyclization products were obtained with yields up to 47%. The results showed that the first C－C bond formation was facile, but the second bond formation culminating in cycloaddition was prohibited due to the rigidity of the intermediate.