Week 2: Continuation of the [2.2.2] monomer synthesis

This week, I continued my synthesis of the [2.2.2] monomer. 1H NMR analysis of the Aldol reaction from last week confirmed that product 1 formed (see Scheme 1). However, unknown impurities were also present. Therefore, after running various Thin-Layer Chromatography (TLC) plates in multiple solvents, I discovered that I needed to purify the mixture via flash column chromatography on silica gel (5% to 40% EtOAc in hexanes). To do this, I used the lab Biotage which was a very convenient way to perform this purification – this bypassed the tedious work of manually collecting individual fractions.

I subsequently ran multiple TLC plates to determine which fractions to combine. I used 1H NMR analysis to confirm which sample was the desired aldol product. Unfortunately, this reaction was only carried out with a 20% yield. This could be an issue resulting from workup, ineffective reaction conditions, and/or loss of desired product during purification. I will discuss this with my professor and determine how to optimize conditions in a future study.

I then completed an acetylation of the free hydroxyl group in 1 (Scheme 1). TLC and 1H NMR analysis showed this reaction was successful.

Blog 2 Scheme 1 (Pic)

I then treated 2 with DBU and norbornadiene to complete an elimination of the Acetoxy group, alkene isomerization, and Diels Alder to finalize the completed monomer 3 (Scheme 2). Norbornadiene acts as an inert co-solvent during the elimination. Once isomerization occurs affording a reactive diene, norbornadiene immediately reacts as the dienophile in this [4+2] cycloaddition. Over the weekend, I will work up this reaction and perform TLC and 1H NMR analysis to see if this reaction was successful.

Blog 2 Scheme 2 (Pic)

Additionally, I have continued the synthesis of Diketopiperazine (DKP) 4 (Scheme 3). This week, I performed a successful azide displacement and am currently finalizing this process with a Staudinger reduction. This will then be purified via flash column chromatography early next week to afford DKP 4.

Blog 2 Scheme 3 (Pic)