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CoMFA – MFer. March 8, 2007

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 So I’m finishing up some of my work and of course a CoMFA is required since my work centers around the inhibition of a particular transmembrane protein.  Of course, if you’re familiar with medicinal chemistry, you’ll know that every medchem student is entrenched with the thorough understanding that if the computer tells you the analog is good, then obviously…it’s good.  This then leads to your PI telling you to make all 150,000 analogs that could possibly be good since, hey, the in vitro data may be different.

I hate Sybyl, and I think it equally hates me. 

And possibly you too.

Happily Ever After March 8, 2007

Posted by thwalls in Synthetic Chemistry.
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poison-dart-frog2.jpg

 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. 

stuff.GIF

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.
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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.

Where’s the Spin?? December 20, 2006

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Still nothing new unfortunately.  I’m hoping that after this examination that’s coming up in February I’ll devote a bit more time to the endeavor that this is by bringing up some new and novel chemistry…but at the moment I’m trying to make sure that I have enough sources for my Candidacy Research paper.  I’m hoping to get this done by the end of the week so that I can get some people started on my reviews, but we’ll see how that goes. 

Either way, I’ve found some novel Vanadium chemistry that should yield better results for my cyanation of an aryl ketone.  This is some of the work with the Vanadium triflate catalyst that seems like it can do anything but make you a sandwhich while the reaction is running.  Apparantly you just take some oxo-vanadium sulfate, and impregnate it into a dowex ion exchange column.  You then pass through it a solution of hot 1 M triflic acid and presto chango, you get vanadium triflate out the other side which can then be used directly in your reaction that is high yielding and exceptionally easy to work up.  The vanadium catalyst is actually very water soluble and thus can washed out, leaving only your product and any remaining starting material, so hopefully just two spots on the TLC plate…well actually I’m hoping for one…

Our lab also purchased a new 400 MHz Varian NMR which we’ve been using like crazy, especially after not having access to one for over 3 months.  So for some reason you’ll be using it and the guage that measures your NMR tube spin will spontaneously drop to zero and your nice flat base line turns into thick-sliced bacon as your peaks become uber fat…so not too happy about that.

Second Years Unite December 10, 2006

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It has been at least one full moon since I’ve updated this and I think that I’m totally justified in my absence.  I’ve got about two months now until my Candidacy/Proposal Exam and I’m starting to feel the pressure just a little bit.  Since I am a Med/Synthetic Student I have to know the reactions, which aren’t too bad, along with the medicinal reasoning and biological jargon…which sucks.

 I can understand Chemical Experiments where you combine A and B to get C.  You can then go on to explain why you chose A and B as your starting reagents.  But when trying to figure out how a sodium channel works the biologists won’t tell you why exactly they chose Saxamaxaaflaxataxatoxin Q1 to block the sodium channel in it’s resting state by binding to the outer portion of the S1 subunit.  Or why they used the squeezings of a scorpion to effect something or other in the active transporter of the neuron.  So that seems to be the hold up right now.

I can’t wait for March.

C & EN, November, 20…Vol.2 (Kornberg’s Triumph?) November 23, 2006

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You should have also noted the article, “Complexity to live by.” discussing this years Nobel Prize in Chemistry for the ellucidation of the Pol II crystal structure with co-crystallized DNA as it is being transcribed.  I will have to admit that I love a good crystal structure, especially one as magnitudinous as RNA Polymerase II.

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 Sorry for the small pictures (The EMBO Journal (1998) 17, 2353–2358).

Anyway, the article is interesting and I highly suggest that you check it out (Science 2001, 292, 1863-1876) since this kind of work has a tendency to lead to novel drug targets.  Even though SYBYL is excellent if you can’t get the crystal structure, everyone likes to actually see what they’re trying to bind to…not just patches of computationally determined red, green, yellow, and blue space on a screen.  This leads into my complete lack of trust for things such as FlexX and flexible docking in general, but I think that’s a different topic for a different day. 

 More to the point, kudos to the Kornberg lab and all the grad students that slaved over the X-ray crystal data to unlock the first 20% of the structure. 

The one thing that I didn’t like about this article was that it threw a dead rat into the festivities by saying that Robert Roeder at Rockefelller University should have probably shared the award with him – even though it is something that I would whole heartedly agree with.  This is not to say that everyone on your acknowledgements, or everyone who helped advance your research should share in the work, but at least throw in the other guy who “[was] among the first to identify RNA pol II,” and “led the characterization of the activities of the polymerase in regulation of genes for decades.”

This kind of argument is not a new one to say the least, especially in this field.  Everyone should know about the Watson, Crick, and Wilson debacle for their Nobel Prize in “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material” (http://nobelprize.org/nobel_prizes/medicine/laureates/1962/).  Rosalind Franklin, a crystallographer who actually performed the crystallography work and appeared with them in Nature, was never mentioned by the Nobel committee.  It’s also interesting to note that neither Watson nor Crick ever received permission from Franklin to use her crystallographic data from which the elucidation of the alpha helical structure of DNA was made.  So even though this is not exactly the same situation, some can definitely see the parallels…at least I can.

 So, congrats to the Kornberg Lab and my sympathies to the Roeder Lab – better luck next year.

-TW

C & EN, November, 20… Vol. 1 November 23, 2006

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So I assume that all of you opened up your mailbox and with eager fingers began looking through your latest edition of C&EN news this week.  Lately I’ve been finding the business aspects kind of gloomy, what with certain chemical companies cutting back (Merck, the pharmaceutical industry, etc.) but hey, the Japanese market is booming, so I guess I’ll just have to move. 

Two articles made me think, one concerning the shipment of chemicals and the other concerning the passing of a new “Animal Terrorism” Bill. 

The articles one chlorine containment and shipment and the general shipment of hazardous materals was interesting.  I really have never thought about how they bring me my Ethylacetate and as long as they kept it coming, I didn’t care.  But when you think about it, there’s a lot of “stuff” getting moved around that is pretty nasty and oh so unfriendly.  They referenced the derailing of some chlorine containers spilling gaseous chlorine into the open on a metric ton scale.  That would be pretty bad, especially if it happened to my shipment of chlorine that I needed for a reaction. 

Also, the animal terrorism bill leaves something to be desired since it points out that it is illegal to enter a laboratory and set free the animals, nor is it legal to harass a scientist or the family of a scientist because of his or her research.  Hmmm…I thought that this was already illegal.

 On top of that, several animal activist groups (go online and you shall find many) claim that this is infringement of free speech and parts of first ammendment rights.  I’m all about the humane treatment of animals, in and out, of the lab.  But it’s a shame when specific laws like these need to be addressed because some people can’t see the bigger picture.   Though, I will agree that some animal research is useless, but coming from a med lab, it comes with the territory, so bring on the rats baby.

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. 

Aflatoxin

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.

Corey

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.

Corey2

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.  

Corey3

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…

 -TW 

Hello, is this thing on…? November 22, 2006

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Alone

So the holdiay season is upon us and of course, I am alone in the lab.  I don’t know if other people have the same thing happen in there respective laboratories, but it seems that every time there is a holiday weekend, people just take more and more time off around here.  Even the Boss was gone for the entire week. 

Not that I’m at all bothered by it since I get all of the instruments and lab space to myself and can be that guy who plays his music/NPR too loud…hey, I got catch up on my news sometimes.

 Although it is a bit brisk outside today, making the eventual drudge into the outside world an awful thought to think about. I guess it’ll just keep me here longer today.

-TW

Interesting Inter/Intramolecular Cycloadditions November 21, 2006

Posted by thwalls in Synthetic Chemistry.
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 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.   

Vindoline

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. 

-TW

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