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.

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Reductions and Revisions

My most recent work in the lab has been to reduce the an ester to a primary alcohol. In other words, we’re attempting to alter the oxidation state of a particular portion of the compound. To this end, we’re using the reducing agent diisobutylaluminum hydride, or Dibal-H, for the reaction. This reagent is a bit dangerous to work with it, because it is pyrophoric, meaning it spontaneously ignites in air at room temperature. This requires that we make a 1.0 molar solution of Dibal-H in a solvent, which will be added to the starting material.

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Progress and Setbacks in the Lab

My research towards the synthesis of loline alkaloids has had some interesting results this summer. After several unsuccessful attempts, I was able to make the methyl ester carbamate in 72% overall yield. This is an improvement over the 65% yield reported in our 2011 synthesis, so it’s a promising result. Next, I will  need to characterize the substrate, which entails writing a detailed procedure for the reaction, as well as reporting necessary NMR, MS, and IR data. All of this information is useful in affirming the structural identity of the compound, which allows for other researchers and myself to reproduce results and further knowledge of the overall synthesis.  Once you’ve successfully reproduced a reaction, you can scale it up to save time in the future. To that end, I’ve also been reproducing some of the earlier reactions in the synthesis to move more material forward so we can make substantial progress toward the final natural product.

Week 9 update

It’s the end of week 9 and it’s certainly hard to believe how quickly the summer is passing. This research session has certainly had its ups and downs. The saponification/esterification sequence that previously plagued my chemical synthesis has become facile. My latest run had an overall yield of 71% over 3 steps, which is an improvement over the 65% yield that was achieved in the first generation synthesis. The following reduction, though, has proved difficult. After doing the reaction three times, I’ve maintained consistent results but the yields have been very low (20-30%).  it’s been a true test of using all available skills and techniques to learn how to improve a reaction. We’ve currently devised a new plan to circumvent the alcohol with a new scheme. Unfortunately, this new plan somewhat dampens the efforts and progress we made to get to that point, but it appears to be a necessary solution.

Setting a pace

It’s hard to believe that over two whole weeks of summer research are already completed. The pace of the summer is certainly different than that of the academic term. Running multiple reactions and purifying them can be easily accomplished. Idleness, though, is not always inescapable. It’s always prudent to play your day beforehand, a point that my adviser has stressed to his students. A busy or malfunctioning instrument can make you rethink those characterizations you were intending to knock out, the column that needs to be done, etc.

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