Just this morning after listening to Nick Terrett on the C&EN’s virtual symposium, I was intrigued by his statements on macrocyle available space and added protein interaction potential — it provided a glimpse on how complex and how one would differentiate added interactions when we are so used to directed targeted small binding sites using traditional approaches. Drug designers are starting to wrap their heads around these approaches as we move away from the small chemical space available – considering this, there is going to have to be a needed relationship built between synthetic chemistry and macrocylic targeted design to take advantage of the potential of the availability of the good protein-compound interaction over the bad…something challenging for today’s crop of medicinal chemists.

Moving into some chemistry

Although the research done toward the synthesis of complex macrocyles using microwave irradiation is a small percentage of overall strategies, there are examples when needed where improvements have been made. Clearly C-C forming reactions dominate the effective transformations, some out of the box thinking has resulted in progress (search the blog for examples).

One of the recent examples (Org Lett 2014) involves an unexpected subsstitution pattern in the synthesis of oligophenyl systems with a diyne-ethylene glycol macrocyles. In performing their research, some surprising results provided a change in the mechanism for the cycloadditions providing a different relief of induced-strain to provide products from a [2+1+2+1] over a [2+2+2] cycloadduct. A schematic of the forward approach is shown below:

Screen Shot 2014-09-24 at 10.21.40 AM

Design of reaction process

So rather than the expected para-terphenylene systems the ortho-substitution pattern resulted in all cases. From catalyst to solvent experimentation provided the same result….classical heating compared with microwave heating also gave the same result. Fortunately, the microwave process reduced decomposition and reaction times from 40 hrs to 6 hrs without refreshing catalyst or high loading. The table below illustrates the applicability of the process:

Screen Shot 2014-09-24 at 10.25.45 AM

And while this is a worthwhile transformation, it does provide a look into the possibilities of going after the desired products through a different approach. For all of you mechanistic chemists, I have included the thought process around this transformation. Happy reading — hope this gives you some thought for additional approaches.

Screen Shot 2014-09-24 at 10.26.02 AM

[2+1+2+1] process

Advertisements