Problem of the Week - 10/26/09

[azmanam]

This time, I'm not going to answer after every guess.  The community can discuss and combine and come back with a consensus answer.  I like that better than the 'is this right?' 'no.' 'how bout this?' 'sorta, think about it this way.' ... approach to problems.  So discuss and argue and debate amongst yourselves and let me know when you think you've got the answer.

QUESTION: Provide a complete, arrow pushing mechanism for the following transformation and predict the product:

[Heory]

No stereoselectivity in the reaction?

[Heory]

I prefer the old way of discussing, for few people are willing to post their viewpoints.

[azmanam]

It looks like you're right, no one wants to play my way.  Oh well.

There will be stereoselectivity issues to discuss later, but first we'll focus on just the arrow pushing.  You have chosen the wrong nucleophile after L.A. activation, and as a result, the rest of the mechanism is off track.  Reassess with a different nucleophile and see what else looks interesting.

[Dan]

This one's tough. I got to a tricyclic intermediate but I'm not sure where to go from there, or even whether I'm in the right place anyway...

[azmanam]

Diels Alder.  Interesting, but no.  (plus, I think the bottom face opposite the isopropyl group would be more accessible if that were to occur )

[nj_bartel]

For the first mechanism proposed - are there any mechanisms involving vinylic carbocations that are generally accepted?

[azmanam]

addition of HX to alkynes

http://www.chemistry.ccsu.edu/glagovich/teaching/311/content/alkyne/reactions/alkynerxn2.html

[Heory]

 

[Heory]

I'm really very sorry. Your drawing always looks rather beautiful and I just want mine to be better. Well, I will use the ACS style.

[nj_bartel]

addition of HX to alkynes

http://www.chemistry.ccsu.edu/glagovich/teaching/311/content/alkyne/reactions/alkynerxn2.html

Ah alright.  When I took organic I, that mechanism was presented to me as still pretty widely disputed due to the instability of that cation.  An alternative possibility presented was an X'onium intermediate.

Edit:  I like your new one Heory.

[azmanam]

I had no idea this question would be this intriguing.  Three completely different guesses with three completely different modes of activity, yet none of them get to the product of the reaction.  Very fun

Perhaps it would be useful to think about and list in words what the various functionalities of the two reagents are.  Then maybe try to think about how they might react with each other under lewis acidic conditions.  Look for best nucleophiles, best electrophiles and see if we can talk through it that way?

Heory: not sure what you're talking about.  Your schemes are nice and quite easy to follow.  Keep up the good work. (btw, I don't use ACS, I use TotSyn style, downloaded from here:  http://totallysynthetic.com/blog/?page_id=287)

[Heory]

I am totally confused...
OH is not a good nuleophilic reagent in the presence of LA
i need more clues
now it is 0:30 here and i must go to sleep
see you tomorrow

[azmanam]

  see you tomorrow.  Let visions of terpenes dance in your dreams

[Dan]

Diels Alder.  Interesting, but no.  (plus, I think the bottom face opposite the isopropyl group would be more accessible if that were to occur )

My structure also breaks Bredt's rule... Schoolboy error...

This is tough, I need more time to think about it. I'm liking Heory's diene nucleophile though.

[Heory]

the diene nucleophile is just like that in Prinse reaction, but here it may be a side reaction. if the answer was as simple as the acetal, i would be crazy

[azmanam]

couldn't sleep?

haha.  all that functionality just for an acetal formation?  that would be an awesome trick question.  The acetal is the initial product of the diol/aldehyde/L.A.  Once formed, the diol will continue to react.  We're on the right track now.

[nj_bartel]

The acetal formation in this case is allowed to proceed to an appreciable extent due to the carbonyl oxygen coordination to the boron complex, yes?

[azmanam]

yup, lewis acid activation lowers the activation energy for addition to oxonium ions.  loss of water gets us to the acetal

[Heory]

another guess:

[nj_bartel]

What's the leaving group in that last step?

O⁺-B^--F₃?

[Heory]

something was wrong and i'll think of it for some time

[Heory]

q

[azmanam]

nope . my hint for the second step of the mechanism: remember that acetals are in equilibrium

[Heory]

It's quite a difficult work to predict the product, because many paths exist for the reaction. If this is still not right, I'd like you to tell me more information about it.

[azmanam]

you've got the right transformation (which named reaction is this?), but the wrong regiochemistry.  why did you choose that c-c bond to make?

[Dan]

Hmmm. Good work on the acetal Heory!

Something like this?

This terpene stuff is making me itch for a hydride shift... but I can't see a good oppertunity.

[azmanam]

that's the right C-C bond formation.  The orientation of the alkene-containing side chain will be dictated by steric clash with the isopropyl group... but the diene-containing 6-membered ring will not adopt a chair conformation, so we'll need to rethink the origin of selectivity in the c-c bond forming step (still need a name for this reaction).

The chemistry after the c-c bond forming step is not correct yet.  different things happening here.  getting closer

[Heory]

 

[azmanam]

you're correct up to your last step.  Still looking for a name for the c-c bond forming step (and there will be a name for the final step).  you've got the right idea, but hydride doesn't transfer.  I think as a result of geometry, but I might have to look at a model.  anyway, we're quite close now.

[Heory]

 

[azmanam]

There is certainly a lot of functionality in this system.  I'd wager the acetal is definitely the fastest process based on relative nucleophilicity of alcohols over alkenes.  From there, the 6-membered transition state in the Prins rxn[1] is fast due to proximity.  The pinacol[2] (good job on the naming, btw) occurs based on the chair geometry of the THP.  I believe only the alkyl group has sufficient overlap with the p-orbital to migrate.  While there is a lot of functionality, Overman sure tames it well, as the product is isolated in near 80% yield as a single isomer.[3]

The Prins-Pinacol is a recurring theme in the Overman lab, as they have numerous papers on the subject[4].  It is certainly a powerful too for building significant molecular complexity (3 new stereocenters and a new ring) on their way to Briarellin E.  Well done.

[1] http://www.organic-chemistry.org/namedreactions/prins-reaction.shtm
[2] http://www.organic-chemistry.org/namedreactions/pinacol-rearrangement.shtm
[3] http://dx.doi.org/10.1021/ja035445c (comm)
     http://dx.doi.org/10.1021/jo9010156 (full paper)
[4] for example:
     http://dx.doi.org/10.1021/jo0522862
     http://dx.doi.org/10.1021/jo034982c

[Heory]

finally work it out! But it's quite a hard work for me to predict the product without any hints. How great overmann's idea is!

[Heory]

BTW, I just started to learn organosilicon in my advanced organic chemistry class, and just after class this problem happened to occur to me, which made me itch for a reaction related to the silyl groups. However, the C≡C-TMS groups didn't react, so I get the concept that C≡C-TMS is not so active as C=C-TMS, which usually acts as a nucleophilic reagent.
I still have some doubt. When the alcohol OH bound to BF₃, which weakened the B-F bond and released F^- (in equilibration), why wasn't the protected alkyne or the hydroxyl deprotected? As we know, Si-F bond is one of the most strongest sigma bond. On the other hand, the resulted water would react with BF₃ thus leading to the formation of HF and B(OH)₃, which undoubtedly would not only make the two groups deprotected but also destroy the catalyst of the reaction. But it seems that water was not removed from the reaction system, why?

[Ulfsaar]

But why does the tow hydroxyl group only one can take part in the reaction?

[Heory]

azmanam, could you please answer my questions? Thanks very much.

[azmanam]

re: heory, I don't have a great answer to your question, but I would not expect the equilibrium with F- to be very favorable.  We don't usually think of F- as a leaving group, at least not in the same way we think of Cl- or Br- or I- as leaving groups. 

Also of interest, I copied the question from Evans' problem database.  In Overman's actual papers, though, the published route uses tin tetrachloride.  so maybe sometime between the posting of the question to the database and the publication they did encounter such problems.  They also preform the acetal with PPTS and MgSO4 (to soak up the water), so the actual prins/pinacol pathway maintains anhydrous conditions.  I think your comments are quite insightful, but Overman does not seem to expand on the point much in either the comm or the full paper.

re: ulfsaar, I don't know.  You can form a diffrent 6-membered TS with the other olefin to give a tertiary carbocation... maybe sterics of that TS preclude that pathway.  Interesting question I don't have a good answer for off the top of my head.