Summary of Efforts toward a Loline Synthesis

This summer I have been attempting a total synthesis of the natural compound loline. The summer commenced with running familiar reactions at larger scales to move more material forward in the route. We were able to improve the yield of the RCM (ring closing metathesis) to an impressive 89%, but this was coupled with continually inconsistent results with the preceding acylation. I then ran three new reactions to make the methyl ester carbamate that was critical to our 2011 synthesis. After some initial troubleshooting, I was able to produce the desired product in good yield. Unfortunately, the following reduction with Dibal-H had a negligible yield despite several revisions to the reaction and work up conditions. There are about four remaining steps to loline past this point, so it would be a futile pursuit to continue running this reaction.

My adviser, Professor Scheerer, is considering a new synthetic route that will bypass the troublesome acylation and reduction reactions. We have recently sent about half a gram of the acylation precursor to Professor Amir Hoyveda at Boston College for a catalyst screening. This is an interesting turn in our research; the Hoyveda-Grubbs catalyst that we’ve used for the RCM reaction is his namesake, so his direct contribution to the project will be greatly appreciated.

In all, the summer underscored some important aspects of organic synthesis. I consider running a new reaction as a challenge to tackling a process that actually entails three primary steps:  reaction, workup, and purification. Each step can present it’s own requirements and challenges, and this truth became more evident with time.

It was an enjoyable summer, though, and I look forward to meeting with Professor Scheerer soon and discussing our new synthetic route toward loline.