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Happily Ever After March 8, 2007

Posted by thwalls in Synthetic Chemistry.


 You’ll have to excuse my prolonged hiatus from the blogging world since immediately after my exam, which I passed (woot.), I got two projects dropped on top of me which I’ve been working on now for the past month or so.  I appreciate the interest in how my exam went though. 

As for my exam, I know that some people have different experiences so I thought I’d share how it’s done at UVA.  You walk in, there are 3 professors on your board plus your PI who sits there and shakes his head when you say something wrong.  There are two parts to the exam.  The first part involves the 10 min. presentation of your work then 25-10000 min. of questions then the second part which is the critique of a scholarly article which is chosen by your PI which is also 10 min…followed by more questions.  So the first part goes all right, a lot of pKa questions and of course them wanting me to explain the ins and outs of all the stereospecific reactions that I did.  The second part involved more of the same but one question did hit me and I felt absolutely retarded for missing it.  I know that may offend someone, but I did feel like I just fell off the “short” bus. 


Dr. So-and-So: “I see that you’ve drawn in your stetter reaction an equillibrium between two different structures, one with the proton on the carbon and one with the proton on the oxygen.  So the reaction could proceed in two different ways depending on which side of the equillibrium dominates, what’s that called?

Tom: Well it could have to do with…(I’ll save you the time of listening to the BS that I came up with and just jump to the point…)

 Dr. So-and-So:  The answer I was looking for was the Curtin-Hammett principle.

 Tom: Oh yes, I understand what you mean. (Are you kidding Tom, you studied that a thousand times, you had a demonstration of it with the substitution of butadiene.  You are truly an idiot.)

 But to make a long story short, it wasn’t as bad as I thought it would be and the studying did help make life in the lab a lot easier.  I’m going to try to put more of my nonsense out there, especially since I do have a little bit more down time on my hands.  Even though I’ve discovered the excitement of the Daphniphyllum alkaloids and their fused hexacyclic nature.  Nice.

The Day is Upon Us January 18, 2007

Posted by thwalls in Synthetic Chemistry.

So you’re a second year.  You read that extra journal article, you study that extra hour, you draw that transition state just in case your committee asks why you chose that specific diastereomer.  The words of Tetrahedron: Asymmetry begin to blur…at least more than usual…and you have to read that paragraph at least two more times because you read it…you just didn’t READ it. 

 The papers are finished 13-15 drafts later, and you think you might be ready for the presentation.  You added enough animations and structures to make your talk interesting and short…yet held back so that you don’t run over your time limit.  Ah, the day is almost upon us. 

I have my candidacy/proposal oral exam in three weeks and I’m starting to feel the pinch.  Even though I think I’m alright for the exam, there’s always going to be that question you don’t expect…and that’s what keeps me up at night.  I spent tonight examining the asymmetric applications of sulfinyl chiral auxillaries and trying to draw the transition states for my proposed molecules. 

I can’t wait to start reading some interesting articles for fun rather then just reading as if it was an easter egg hunt, searching for that last egg to bolster my hypothesis.  But either way, I think we’ll all be ready, you just have to deal with the drudgery for 3 or so more weeks. 

Other than that, I hope everyone is well, and if your a second year…give em’ hell.

Or at least try not to fall on your face and fail out, because that would suck.

Corey, Aflatoxin, and Cycloaddition…sounds adventurous November 22, 2006

Posted by thwalls in Synthetic Chemistry.
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In keeping with my previous topic of cycloaddition I’ll throw something else out there that might peek an interest or two.  In the Corey lab at Harvard they very recently (by which I mean 2005) published only the second, stereoselective, total synthesis of Aflatoxin B2 (J. Am. Chem. Soc. 2005, 127, 11958-11959).  It’s true that the Trost and Toste duo did work up a synthesis prior to this (J. Am. Chem. Soc. 2003, 125, 3090-3100) but not with the same “elegance” of the new procedure.  I hate to throw that word around since it is already over used in the Chemistry world, especially concerning total synthesis, but if you look at the pathway the word fits. 


So as you can see, the only two stereocenters to be set are those in the furan rings at the bottom.  The manner in which they are set, is what makes this paper a little more interesting.


At this point in the synthesis it is really all down hill.  You will notice that from the paper it is approximately 8 or so steps to product with this being the first and most crucial since there are no stereocenters to be set after this.  Also one should take note of the oxazaborolidinium complex that is used  in this [3+2]-Cycloaddition reaction which  appears in one form or another in many of Corey’s synthetic routes and turns out to be very useful and pragmatic in its own right.  That by itself would add a bit of “elegence” to the routine. 

I would draw the proposed transition state that leads to product, but I don’t think I’m that good with chemdraw, and if you’re really hankering for it, I suggest you look up the paper.  The more interesting question to me is why do you get this product over the other regioisomer and the possible [2+2] product? 

Regioisomer preference can be explained by the coordination of the catalyst in the transition state.  One quinone oxygen has the donating alpha-methoxy group which allows it to be more basic and thus a better site of coordination for the catalyst which mitigates the endo attack of alpha, beta-unsaturated furan.  Incidentally, 32% of the lost yield is made up of this other regioisomer.


So then, why not the [2+2] product either? You can get the [2+2] product with the S-catalyst rather then the R-catalyst which was used in the previous experiment.  The S-catalyst in combination with the addition of an isopropyl and methyl group prevents the quinone from undergoing a 1,3-dipolar transition state which is nescessitated for product to form.  


This dipolar intermediate was later trapped and crystallized.

 So all in all the solution is not as elaborate as it may seem and the process goes to product in good yield, excellent regio- and stereocontrol, and with great haste.  All the things that go into an elegant solution. 

 Well actually, if he catalyzed it with mud and could run it in water, then I guess it could be a little more elegant…


Interesting Inter/Intramolecular Cycloadditions November 21, 2006

Posted by thwalls in Synthetic Chemistry.

 I’m sure that most of you are aware of the [4+2] cycloaddition known as the Diels Alder reaction and if you’re not then you should probably pick up that Organic I textbook and turn to the chapter on pericyclic reactions for dummies.  Well, some interesting work caught my eye (mostly because I was trying to figure out some problems of my own)  from the Boger Lab at Scripps.  For several years now he and his have been working on the preparation of vinca alkaloids by way of an intramolecular Diels-Alder/1,3-Dipolar Cycloaddition cascade.  A good discussion of this work was published very recently in JACS (J. Am. chem. Soc. 2006, 128, 10589-10595) and i suggest thatif your not living under a rock you should check it out.

[4+2]/[3+2] Tandemicity

  Anyway, in the aformentioned article it discusses the use of this [4+2]/[3+2] tandem reaction to set 6, count em, 6 stereocenters in one step.  Well, actually there are two steps but the intermediate is so strained that it does not exist for very long.  The reaction starts with a 1,3,4-oxadiazole and is electron deficient which sets up the first step of running the inverse electron demand DA reaction by using an electron rich dienophile.  The product of this step being a strained cycloadduct that imediately loses Nitrogen and leaves a carbonyl ylide.  This undergoes a 1,3-dipolar addition with a second mole of olefin (which is either electron rich or strained and can be cyclic) to form the oxa-bicyclo-[2.2.1]-heptane product.   


Regardless of its usefulness for anything other than alkaloid products, such as Vindoline (J. Am. Chem. Soc. 2002, 124, 11292-11294), it makes me smile because six stereocenters, controlling stereo- and regiochemistry, is always something to dance to. 

 So there you go, my first donation to the land of the chemically inclined.  But I won’t rant and rave about all the chemistry involved, if you want to know more, open Scifinder Scholar and pretend its reading rainbow.