Intramolecular [4+2] cycloaddition reactions :: influence of ring size on endo/exo ratios

Thumbnail Image



Journal Title

Journal ISSN

Volume Title


University of New Brunswick


Natural products have contributed to health care and prevention of diseases for thousands of years. One family of bioactive compounds that is of particular interest to the MaGee group is the manzamine alkaloids and their derivatives. During their studies on the synthesis of the ABC-tricyclic core targeted for manzamine A and B, an intramolecular Diels-Alder reaction was used that resulted in a 25:1 ratio of endo to exo selectivity. This contrasted other results where a similar substrate resulted in a 2:1 ratio of endo to exo stereoisomers. Therefore a study was initiated to look at the influence of the ring size, where the dienonphile is contained, on endo/exo ratio’s in the intramolecular Diels-Alder reaction. The intramolecular Diels-Alder reaction was examined where the dienophile was embedded in 5, 7, 9 and 11-membered C-rings. While the 5- and 7-membered keto-acids were known compounds, synthetic routes had to be designed to make the other homologues. Once these were made and coupled with dieneamine, it was discovered that depending on ring size different endo/exo ratio’s were obtained. The five and sevenmembered C-rings produced a ratio of 2:1 endo:exo, in contrast to the nine-membered C-ring, which produced an 18:1 endo:exo. The eleven-membered C-ring produced a ratio of only 5.4:1 endo:exo. Although the exact reasons for the differences are not completely known, it is clear that the conformational flexibility of the rings plays a major role.