Trimethyl lock

As part of an ongoing study, we recently tried to think of reactions wherein an amide linkage gives way to an ester. It is interesting to note that, when it comes to proteases, there is nothing remarkable about N-to-O replacement. It happens all the time and is controlled by the low pKa of the active site hydroxyl, among other factors. Synthetic chemistry is different in that ground state energies dictate that the reverse (O-to-N) is more likely. Indeed, we typically make amides out of esters, not the other way around. Unless there is a way to change the energy landscape of the reaction, that is… In this regard, the fascinating chemistry of trimethyl lock (TML) comes to mind. It is particularly nice to see how basic ideas of conformational control enable some ideas in drug delivery to come to fruition. An instructive example of “immolation” of a boron-containing therapeutic through the use of TML is described in Ron Raines’ recent work. In this paper, the authors describe molecules with boronic acid appendages and their internalization by mammalian cells. As you might have guessed, reversible interaction with sugars is the driver of this process. Boron aside, what attracted me to the paper is that it puts TML, the tool of physical organic chemistry, to good use.

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http://pubs.acs.org/doi/abs/10.1021/acschembio.5b00966

4 thoughts on “Trimethyl lock

  1. My first project in graduate school was figuring out what mystery isobaric contaminant was present in my once pure cyclic peptide. Ended up being an N to O acyl shift of a threonine sidechain. We found it was highly sequence specific and used MD to rationalize which compounds could and couldn’t access the correct burgi dunitz angle for initial attack of the hydroxyl.

    http://pubs.acs.org/doi/abs/10.1021/ol503170b

    • Wonderful and I am very glad you reminded me about this work from Scott’s lab! Indeed, this is such a remarkable finding. Here too, the reaction shows that conformational constraints can play an important role. Cheers!

  2. I think this classic Thorpe-Ingold effect! This effect has also been brilliantly utilized by people to affect Intramolecular Diels-Alder reactions involving furans!

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