QUESTION: This article does clearly present data and analysis supporting the anti-bacterial capacity of compound 6j in comparison to retapamulin, but it doesn't answer the question: what are the pharmacokinetic properties of compound 6j and how do they compare to the established drug, retapamulin? This is such a critical question when discussing a compounds potential for drug development because while the anti-bacterial capacity may be great and cytotoxicity data compelling as well, if the absorbance, metabolism, distribution, and/or excretion of 6j is/are not good then it is not a viable option for anti-MRSA drug development for humans. However, data in that type of study may show that compound 6j in fact has a better overall pharmacokinetic profile in comparison to retapamulin, and this would lend greater support to the idea of using 6j for further drug development. That key question just hasn't been answered yet and so it's difficult to say whether this compound is actual a good reference for the development of anti-MRSA drugs.

FACT: Intermediate 3 forms in two stages. The hydroxyl is activated to obtain the tosylate intermediate because on its own the hydroxyl is not a good enough leaving group. After activation, it forms a better leaving group that is ready for a classic SN2 reaction. We know the second stage is an SN2 reaction because we have a substitution with 6-thiguanine occurring with TEA (a base) in DMF (an aprotic solvent). These are reaction conditions associated with an SN2 nucleophilic substitution reaction. In this case, the nucleophile would be the thiol group and we can see that it replaces the tosyl group.

CONNECT: This concept of intermediate three being combined with other materials to form carbamate, amide, and urea derivatives connects with our learning of parallel synthesis. Following a parallel synthesis, where intermediates are formed and reacted together concurrently, can help to maximize the overall yield of the experiment and helps with the efficiency of the reaction. By contrast, a linear reaction would take a much longer time and result in more waste in this case, since it would require converting intermediate 3 in a series of steps to all of those derivatives rather than taking portions of intermediate 3 to react in parallel.

CONNECT: We had a discussion on ortho/para and meta directors, and how ortho/para directors were preferred because of steric preference generally speaking. But we learned that para is superior to ortho in most cases because para means opposite to the directing group - the least sterically hindered location and best place for further reactions. So, this idea that the methoxy substitution is an example of the para substitution derivative and consequently had higher activity connects well to that in-class learning objective.