Chase Hop1 possible routes?

[edwintse]

The Chase Hop1 (pictured below) compound was the most popular voted compound during the recent online meeting (#386).

ClC(C=C1)=CC=C1C2=NN=NN2C3=CN=CC(OCCC4=CC(F)=C(F)C=C4)=N3 InChI=1S/C19H13ClF2N6O/c20-14-4-2-13(3-5-14)19-25-26-27-28(19)17-10-23-11-18(24-17)29-8-7-12-1-6-15(21)16(22)9-12/h1-6,9-11H,7-8H2 HHZUPBCYYAXEQO-UHFFFAOYSA-N

I have since found two possible routes to this compound.

Sambaiah, T.; Reddy, K.K. ChemInform. 2010, 23. DOI: 10.1002/chin.199240197

El Kaim, L.; et al. Org. Lett. 2011, 13, 1261-1263. DOI: 10.1021/ol200003u

[MFernflower]

@edwintse Could you chat with me on hangouts laater tonight? I think I may have found a flaw in the first synthetic route...

[mattodd]

@MedChemProf out of interest were the above routes the kind of thing you had in mind?

[MedChemProf]

@mattodd I have certainly taken note of the proposed routes, but do not currently have all of the suggested reagents. I actually have some 4-chlorophenyl-tetrazole and the plan was to simply add that to the dichloropyrazine followed by the addition of the alcohol. I know that the tetrazole addition to the pyrazine will give a mixture of two isomers, but I was of the mindset that as along as we can produce enough to complete the synthesis and test the activity, optimization of the synthesis can follow later. On another note, I had originally proposed a few other scaffold hop analogs along with the tetrazole. Just prior to the meeting, we had already started on another hop that contained a thiadiazole. Since the student had already made some progress on this analog, I thought it would be best to complete its synthesis first and then transition to the tetrazole target. I hope to be able to report on the completion of the first analog in the next week or so. Several of my students attended the online meeting the other day and they now have a better appreciation for the importance of completing their work.

[mattodd]

If you've started on another, then I'd continue as you're doing, yes. Do you have a link to the the thiadiazole work? I think that people liked your scaffold hop idea first, and the specific scaffold was perhaps secondary, so what you're doing is still in the spirit of the vote!

[MedChemProf]

@mattodd There is a few structures shown in thread #352 about 1/3 of the way down from the beginning of the thread.

[MFernflower]

@medchemprof Could try a isoxazole ring?

[MedChemProf]

May be best to wait to see if the proposed shows activity prior to making similar analogs.

[MedChemProf]

@mattodd @edwintse We are still moving slowly on the synthesis of the tetrazole analog. As mentioned in another thread, our synthetic route was chosen based partially on the ready availability of some of the starting materials. The route however, was predicted to possibly give a mixture of isomers that we were planning to separate. There was some literature precedent that indicated that the desired isomer may actually be the dominant product. In practice, we found that one of the isomers was actually favored by approx. 4:1. (See ELN here. Note, I just asked the student to update some of the missing information.)

I did some rudimentary minimizations on the desired product and I found several low energy conformations that should have allowed us to see some nOe interactions. The NOESY experiment showed us strong nOe's on the phenethyl side of the molecule, but not the diagnostic nOe between the chlorophenyl protons and the pyrazine ring. A HSQC followed by an HMBC experiment was hoped to show the long range coupling between the pyrazine proton and the carbon of the tetrazole, but no interaction was found. The negative result cannot be used to confirm that the undesired compound may be the dominant one formed however. Instead of approaching the problem by changing the synthetic route, I was wondering whether it might be just as fruitful to look at a different scaffold hop based on click-chemistry instead. I would like to hear the group's thoughts on focusing on the triazole (via click) versus the tetrazoles. I think @drc007 had suggested a different triazole scaffold in another thread.

[mattodd]

Obviously separating the isomers and then evaluating them separately would be great. Won't you see the same problem for the triazole, particularly given the extent to which the Cu-catalyzed click gives the isomer we (probably) don't want?

[MedChemProf]

With the way things have been going in the lab lately and the time my students can put in, I doubt we will have enough be able to separate the two isomers (we also do not have a prep HPLC would be ideal). My only goal at this point is to send the final product for testing which will have some of the other isomer as an impurity. It is also why I started thinking about the triazole compounds. The stereochemistry of the triazole formation is much easier to control based on the selection of the catalyst.