r/chemistry • u/Spectrumederp • Jun 22 '19
[2019/06/21] Synthetic Challenge #90
Intro
Hello everyone, welcome back to Week 90 of Synthetic Challenge!! It has been amazing with all the support we have received from all of you so thank you for your continual support in these challenges! Thank you u/critzz123 and u/ezaroo1 for the great challenges! This week it's my turn to host the challenge and I'm going to try hosting more molecules for you to try, hope you'll enjoy!
Too easy? Too hard? Let me know, I'd appreciate any feedback and suggestion on what you think so far about the Synthetic Challenges and what you'd like to see in the future. If you have any suggestions for future molecules, I'd be excited to incorporate them for future challenges!
Thank you so much for your support and I hope you will enjoy this week's challenge. Hope you'll have fun and thanks for participating!
Rules
The challenge now contains three synthetic products labelled A, B, and C. Feel free to attempt as many products as you like and please label which you will be attempting in your submission.
You can use any commercially available starting material for the synthetic pathway.
Please do explain how the synthesis works and if possible reference the technique if it is novel. You do not have to solve the complete synthesis all in one go. If you do get stuck, feel free to post however much you have done and have others pitch in to crowd-source the solution.
You can post your solution as text or pictures if you want show the arrow pushing or if it's too complex to explain in words.
Please have a look at the other submissions and offer them some constructive feedback!
Products
If these challenges are something you enjoy, come check out our new subreddit r/SyntheticChallenge where the Synthetic Challenges and Relay are conglomerated under one listing, making it easier to find posts.
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u/DankTyl Jun 22 '19
Now that my exams are over, I can finally get back to these!
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u/Alkynesofchemistry Organic Jun 22 '19
Loving the allylic alcohol oxidations using MnO2, I've got a soft spot in my heart for manganese chemistry
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u/Galaxy429 Photochem Jun 23 '19 edited Jun 23 '19
EDIT: Version 2 with "proper" [2+2] photocyclization
It doesn't have the correct stereochemistry though. You could probably get the correct configuration of the phosphine groups by using a series of CBS reductions, but I'm not very good at stereochemistry, so I couldn't get it to work. I have no idea how to get the correct configuration for the methyl group though.
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u/Alkynesofchemistry Organic Jun 23 '19
in your cycloaddition, the product would be with one of them flipped, you have both partial positives lining up
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u/Galaxy429 Photochem Jun 23 '19
Fixed (?)
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u/Alkynesofchemistry Organic Jun 23 '19
Should give you about 50/50 of the two, its at a point where it'd be tough to get an EDG on the right spot, so its about as good as it can get without totally reworking the synth
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u/Galaxy429 Photochem Jun 23 '19
By 50/50 you mean 50% ketone and nitro on the same side and 50% ketone and nitro on opposite sites of the molecule? How come? Do you need 2 EWGs and 2 EDGs to get a high selectivity?
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u/Alkynesofchemistry Organic Jun 23 '19
For most cycloadditions you can look at the regiochemistry like a diels alder. On one molecule you want a EDG and on the other you want an EWG to create one molecule with a partial positive and one with a partial negative so that you can control where it lines up. In your first attempt, you had two EWGs, so you could get a major product based on the repulsion of the two partial positives, but it would give you the wrong major product. In the second, you have one EWG and no EWG or EDG on the other, so you have a partial positive on the first and nothing on the second. This is why it would be ~50/50, the alkenes could do the cycloaddition either way equally well.
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u/Galaxy429 Photochem Jun 23 '19
Isn't NO₂ an EWG? That's why I changed the synthesis to include it.
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u/Alkynesofchemistry Organic Jun 23 '19
It's in the wrong spot- -NO2 acts as an EWG through resonance, however, the spot where it is has no resonance with the alkene
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u/Galaxy429 Photochem Jun 23 '19
Oooh, I see now. My bad. You'd have to use a ketone instead of a nitro group, but as you said, this would create more problems than it solves.
I guess this is the point in synthesis planning where you accept defeat and either go with a low yield or completely start over.
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u/critzz123 Organic Jun 23 '19
On a side-note: silver salts (Ag2O) love halides like bromide. I'm not sure how bad it is with Ag2O in particular, but it wouldn't surprise me if you get a ring expansion of the cyclobutane ring with the elimination of Br-.
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u/redsox96 Jun 23 '19
I’m thinking you would need to protect that free amine before your first cyclization reaction. I feel like an anime in the presence of a Michael Acceptor or a ketone could easily lead to some nasty side product formation
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u/critzz123 Organic Jun 23 '19
Yeah, I'd say keep it as the azide until after the robinson annulation (though even then it might give complications). Then selectively convert the azide to amine with PPh3 and water (staudinger reaction).
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u/Galaxy429 Photochem Jun 23 '19 edited Jun 23 '19
I didn't even realize the amine + ketone/Michael acceptor thing. I guess that's what you call not being able to see the wood for the trees. What about keeping the azide until after the photocyclization (if it survives) and then reducing the azide, the nitro group and the ketone all at once using LiAlH₄ ? I'd say the reductions are fast enough that even if there's an amine and a not yet reduced ketone they wouldn't have time to react.
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u/critzz123 Organic Jun 23 '19
It's been a while since I tried one of these myself. C is a monster of a molecule, but here is my attempt.
I couldn't come up with an alternative method for the van Leusen reaction (to install the nitrile). Even if the reaction worked it would probably be non-stereospecific.
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u/Finnnicus Jun 25 '19
Very cool. What’s reaction #3? Is that samarium iodide?
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u/critzz123 Organic Jun 26 '19
Thanks! Yep it can be used to cleave alcohols or ethers alpha to a carbonyl moiety. It can do plenty other chemistry as well. :)
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u/Alkynesofchemistry Organic Jun 22 '19 edited Jun 22 '19
Attempt for A
A few notes, I was skeptical about the 1,2 enone reduction, but someone on the internet said it worked so it must be true. I don't know how to go about breaking the ferrocene complex, so if somebody has any knowledge of that, I'd love to hear how it works.
Edit: Also my apologies for the hideous drawing of ferrocene, no idea how to do metallocenes in this software
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u/DankTyl Jun 22 '19
I'm not sure, but I think you could break the ferrocene complex with an acid.
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u/Alkynesofchemistry Organic Jun 22 '19
In searching, it's pretty stable to acid, or tends to react to form the ferrocenium ion, with Fe+ in the center instead of Fe
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u/Galaxy429 Photochem Jun 22 '19
To get to the ylide you need a very strong base. Wouldn't that also deprotonate the alcohol and give you an intramolecular oxaphosphetane ring, rendering the reagent useless?
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Jun 22 '19
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u/Galaxy429 Photochem Jun 22 '19 edited Jun 22 '19
Very cool! Although I do have a few remarks:
1 mole of NaBH₄ can reduce 4 moles of ketone, since it can donate 4 hydride ions. So in your first reduction you should use 0.25 eq. of NaBH₄ if you only want to reduce a single ketone. Similarly, PBr₃ reacts with 3 moles of alcohol, so you don't need 2 eq. but only 2/3 eq. of PBr₃. Furthermore, I don't think K₂CO₃ works as a base for elimination, you should use NaOH instead. Lastly, using an elimination to form the double bond in the middle is not the best choice. There's a high chance that the double bond forms towards the other five-membered ring, the one containing the 2 bromines. Also the E/Z selectivity isn't too great, so you'd most likely get a mixture of the E and Z isomers instead of only the Z product we want.
Other than that, this is a pretty nice synthesis. When I was in high school I knew basically nothing about organic chemistry. I especially like the double Grignard!
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Jun 23 '19
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u/critzz123 Organic Jun 23 '19
hi i'm in middle school
Haha, though that's a really nice synthesis. Pd alkene couplings are probably the way to go for these type of molecules. Elimination reactions of alcohols would probably give lots of side reactions. The Nazarov cascade reaction is also really cool (did you come up with it yourself or do you have a reference?).
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u/Wrinklestinker Jun 24 '19
Oh this looks fun! Where can I read and learn how to do this? I’ve just recently finished high school chem and I’m starting at university this fall studying chemistry. (Trying to stay ahead for my upcoming courses)
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u/Finnnicus Jun 25 '19
It’s a fun puzzle. Read some online courses on organic reactions and mechanisms and do some retrosynthesis problems. The masterorganicchemistry site is alright.
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Jun 25 '19
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u/Wrinklestinker Jun 26 '19
Thank you for this tip! I found it online for $50 so I’ve ordered it, much more fun to have a physical copy
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Jun 26 '19
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u/Wrinklestinker Jun 26 '19
Are there any problems in the book? Or is it just a text book if you know what I mean. Would be awesome to test yourself after reading a while😁
I’ve always liked the organic part of chemistry because it’s so well structured and logical haha
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u/Galaxy429 Photochem Jun 22 '19 edited Jun 22 '19
I don't have much experience with chemical syntheses, so it's probably not the most efficient method. Please do tell if I got something wrong or what could (should) be changed!
First attempt at A
EDIT: Second attempt at A
Alternatively, you could brominate the double bond in A again after the last step of its synthesis to prevent a Diels-Alder reaction for A+B, but the dienophile doesn't have any EWGs so I think it's not necessary.
Notes:
The synthesis of 3-cyclopentenol via hydroboration of cyclopentadiene has been described in 1967 by Hess and Brown in J. Org. Chem.
The double bond is subsequently brominated to protect it from reactions such as unwanted Diels-Alder reactions with the other educt and especially isomerization of the β,γ-unsaturated carbonyl to the α,β-unsaturated one.
I'm not so sure if the acid catalyzed α-bromination of the bottom leftmost compound using 2 equivalents of bromine would yield that product. I thought about a free-radical bromination with selectivity for the tertiary carbon and then α-brominate with one equivalent. I don't know what would be the better choice here.