Optimization of total synthesis of indolizidine alkaloids VIA nickel catalyzed (4 + 2) cyclization utilizing silyl and stannyl alkynes

In order to expand the versatility of the synthetic route to naturally occurring indolizidine alkaloids previously developed in the Louie Group, a path was developed using a bicyclic azetidinone to produce indolizidine alkaloids such as (+)-seco-antofine. However, due to the asymmetric nature of the alkynes used in this pathway it was necessary to optimize the (4 + 2) Ni catalyzed cyclization to improve regioselectivity. The product of the cyclization was to be carried on to (+)-seco-antofine as proof of concept for use of this methodology for all indolizidine alkaloids requiring the use of asymmetric alkynes. Two routes were developed, utilizing a silyl or stannyl alkyne. The silyl route found success in the cyclization, but only afforded low yields in the subsequent coupling reaction. P(2-MeOC6H4)3 and the Buchwald ligand S-Phos were found to have the best selectivity for the desired product during cyclization while maintaining an acceptable yield. The stannyl alkyne route was found to be a viable alternative due to its success during the cyclization step and the subsequent coupling reaction. It was determined that PPh3 was the optimal ligand for this route as it afforded only the desired regioisomer. Other parameters such as reaction temperature and equivalents of starting material were also determined. The exploration of these two routes and reaction parameters has been a big step forward in bringing this synthetic pathway closer to viability.