The idea of ligand efficiency as a metric for comparing new heterocyclic motifs has always intrigued me. Things get particularly interesting when heterocyles are combined with the elements of reversible covalent inhibition. In his 2013 paper in JACS, Taunton and colleagues described a series of reversible covalent inhibitors of MSK/RSK-family kinases that contain noncatalytic cysteine residue close to the active site. In fact, C436 is found in only 11 of 518 human kinases (so there are reasons to go after this cysteine). The acrylamide fragments described in the Taunton paper were later used to develop potent kinase inhibitors, underscoring the fact that ligand efficiency of reversible covalent fragments was sufficient for further elaboration. Below you see a view I created using PyMol, showing how the indazole scaffold of the acrylamide inhibitor forms the expected hydrogen bond pattern with the hinge region. The authors point out that the indazole core does not extend beyond the gatekeeper T493. Interestingly, unfolding of the indazole fragment/RSK2 adduct with guanidinium-HCl resulted in quantitative recovery of the fragment, indicating that the covalent bond was formed reversibly. It will be interesting to see if good levels of kinetic discrimination can be achieved with reversible covalent inhibitors. From my point of view, one of the most interesting lessons offered by this study is that potency is not solely driven by the free energy of covalent bond formation.
I am sitting on my Oakville-bound train that is about to depart Union Station in Toronto. This winter has been super cold in our part of the country. It’s kind of funny because I have been hearing way less about global warming on the news. Weird, eh? I guess we’ll wait for a couple of months for people to start complaining. OK, I am being a troll.
Tonight I want to talk about the venerable Diels-Alder reaction. There is no need to praise it beyond the superstar status it already has. Instead of empty accolades, I will pay a facts-based tribute to this process and, in the spirit of recent discussions, try to poke at it.
Are there 6-membered rings that cannot be made using this reaction? I can’t think of too many. The classroom value of Diels-Alder reaction is also undisputed: we beat this reaction to death when we teach frontier molecular orbitals (FMO) method, to the extent that some students leave our classes with an impression that this cycloaddition (and perhaps some electrocyclizations and sigmatropic reactions) defines the FMO theory in its entirety, which is not true at all. Nonetheless, this is still one of the most awe-inspiring reactions out there. To challenge its bulletproof status, one might want to subject Diels-Alder reaction to the limits of angular strain, hoping that that the cycloaddition might “crack”. Time and again, though, this resilient reaction has surprised us in most admirable ways. Take a look at one of my favorite papers on this subject. This is a study published by Dirk Trauner and Ken Houk some years ago. I would not have expected that imposing such severe strain on the 6-membered transition state would deliver any reasonable outcome. But the reaction works at 30 oC. There are some other interesting insights offered by this paper, so check it out. I think the lesson here might be that no matter how strain-crazy your idea might be, you should just give it a shot if it involves the magical 6p-electron transition state.
Now… Keeping up with the flavor of my recent post on heteroatom-heteroatom bonds, here is another viewpoint from my “vault of near-impossibles.” While there are countless examples of C-C and C-heteroatom bond formations using Diels-Alder reaction, it is interesting to note that heteroatom-heteroatom connections aren’t really made using this process. If you have a good example – please let me know. There is probably a fairly decent energetic argument against the transition state that produces a link between two heteroatoms (I should ask Ken Houk about this). Overall, I feel a bit better about showing that not everything is hunky-dory in the Diels-Alder bag of tricks. I will feel this way until you guys show me that I am wrong (or will you?).
Tandem cyclizations that result in rapid formation of complex molecular skeletons have always attracted my attention, especially when fairly unusual intermediates are implicated in the corresponding reactions. Below you see a really cool sequence recently reported by Jennifer Stockdill of Wayne State University. The reaction targets the tricyclic system of daphniyunnine (what a mouthful…). The first step is N-chlorination, which is achieved by the use of NCS (N-chlorosuccinimide). N-chloroamines are interesting synthetic intermediates that can get tantalizingly close to losing the elements of HCl upon treatment with base, yet are often surprisingly stable and isolable. Upon alcohol oxidation in the example below, the tricyclic system is set up by way of a tandem radical cyclization, which starts off the aminyl radical. The authors highlight the neutral nature of the aminyl radical undergoing 6-exo cyclization in their sequence. It will be interesting to see a completed synthesis (hopefully some time soon).