[phth]

Wondering if anyone is interested in going through a total synthesis challenge because Merck is about to announce their total synthesis competition (prize 10K EUR). Thought it would be fun to go through some exercises, and I remember that the topic used to be popular here. learn more: https://www.emdgroup.com/en/research/open-innovation/350anniversaryactivities/350compoundchallenge/compound-synthesis.html

I picked two natural products from the literature that may have a solved synthesis (I haven't checked). Included one beginner and one advanced compound. Please post your route! Before there was one week to complete the challenge.

[rolnor]

To draw some schemes how to make these is hard but the real challenge is to draw schemes and test this chemistry so that it actually works, that can take years.

[phth]

To draw some schemes how to make these is hard but the real challenge is to draw schemes and test this chemistry so that it actually works, that can take years.

People used to post pen and paper pictures too.

[phth]

a solution to the challenging one.. 16 steps

[rolnor]

Its very fun that you make this scheme, its a lot to discuss!
I think the first step is very problematic, if you look at the product, it has very acidic protons and a aldehyde in the same molecule and you use basic conditions for the reaction, I think you will get a lot of ringclosure/polymerisation sidereactions. If this reaction is not published I doubt that it is possible.

[phth]

Rolnor, I agree with the first step. I revised the synthesis with photocatalytic enolate chemistry. An alternative would be acrylonitrile if the acetal protection becomes a problem. The next key steps are the enone condensation which I think should be selective due to baldwin's rules. 5 membered transition states are faster with the carboxylate directing deprotonation of the enamine. Next the diels alder reaction may require re-protection of the methoxy group, so I took that into account. After that, the ketone shift requires acid to hydrolyze an enamine, so it is probably higher yield to add the glucose moeity after that step. Finally, the radical cyclization proceeds following baldwin's rules, and the benzylic position epimerizes to give the correct product.

Anyone have another solution??

[rolnor]

I think the first step is not working, the BuLi will attack the carbonyls. The chloro-ketone you make can be reported in the litterature so if whe go to step two I think, again, that you have very acidic protons, base and an aldehyde so the problem with aldol is still there.

[sjb]

Typically for the first step I think you form the first enolate with 1 eq NaH, then the dianion with 1 eq BuLi.

[rolnor]

But you did say 2*BuLi? So, still the problem with the second step, base, acidic protons and aldehyde, its a recipe for disaster (or at least polymer/dimer/oligomer etc.). The chemistry would be completely different but I think you need to work  with a protected aldehyde group from the start. The  molecule you make in the second step is very, very sensitive to basic conditions. With that said I think your project is very ambitious.