Firstly, the membership costs come out of my pocket. Which is fine, since it’s not yet over $100. Local dues and whatnot, it’s about $75 or something, roughly the cost of GROCERIES. And since student stipends are approximately $1000 more a year than the average cost of living (if you pretend the average cost of living was $2000 less than it is) then you can imagine how I might want that week’s worth of food for myself and the lovely Mrs. Finchsigmate.

But, what I’m actually protesting, is not the cost of the dues but that the society doesn’t give a fuck about students. For instance, I myself like to read Org Lett, JACS, JOC and Chem Rev. A year’s worth of subscription to those four mags would cost, with my “awesome” member discount, around $2000 a year. WOW. THX ACS! And it isn’t like they aren’t banking off my goddamn name. I’ve been getting offers from Chase credit cards for “Dr. Finchsigmate.” Which is funny, since I’ve never put “Dr.” on any application in my life. I also get “member only” offers for life insurance, banking, etc etc. Coincidently the same offers my wife, who is an elementary school teacher, gets. Hmmm… They sold my name and address to banks to get some scratch, they put ads in everything and fill each conference up with vendors (and charge you to get in).

So, fuck ‘em. I don’t want to be a part of any club that I can’t afford to be a member of, even if boss were to pay for it. I don’t really see why I should be bent over and fucked sideways just so I can get a print edition of JACS. I can get SIX subscriptions to the journal Science for the same price.

So, if I were you, I’d spread the word of a goddamn ACS boycot until they lower the student cost of print journals. I like to read on the shitter but I’m not going to pay $550 a year for the pleasure.

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You can imagine columns are worthless, as all the compounds fly right off in pure hexanes, pentanes, pet ethers… nothing works for column conditions. One thing I did try, however, was our Kugelrohr. Now that fucker is sweet (unless you’re trying to purify 17 mL… but whatever).

The idea behind the Kugelrohr is that it very quickly (and quite nicely) distills high boiling shit. It does not do so in a manner that is more efficacious than fractional distillation. Don’t let people tell you that. (This being my own limited observation. I was able to get nicer separation on a fractional column filled with glass loops - it just took 6 hours. This did a little worse, but not much, in 30 minutes.) Nevertheless, it does a pretty goddamn good job. Just outside of the picture is a tubing that runs to my pump, so this whole thing is done at high temperatures and under high vacuum. It’s really not so bad. The way the bulbs are arranged is visible to the side there. I fill the bottom one up with about 2 mL of my sample and place it inside that metal cylinder (which is why you only see two bulbs in the picture) to distill the high boiling stuff, leaving the tar that will never come out no matter how hot you get it. Then I drop the temp of the silver cylinder heating element and just shove the second bulb into the heater to distill off the lighter boiling material. This way, I don’t have to break the vacuum and take apart the glassware - I just have to lower the temp, which is nice, but I don’t know if I actually saved myself time doing it that way.

So, if you’re ever in a pinch with a vacuum distillation of high temperature oils and need something a little better than a short path and don’t want to sit around for hours while it refluxes you should get yourself a Kugelrohr.

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First: DOI: 10.1126/science.1152692. Fucking brilliant piece from the Baker lab representing state of the art fuckability of proteins. The title: “De Novo Computational Design of Retro-Aldol Enzymes” gives you a half assed idea of what’s actually going on. Where the typical “state of the art” to select for proteins that do specific chemistry is to essentially make a fuck-ton of proteins and run them on a specially designed column or do some Systematic evolution of ligands by exponential enrichment. The idea is NOT to go and design an active site of a protein and then cut out the active site of another protein and stick your active site in it to do the chemistry you want it to do. My brief description trivializes the difficulty inherent here and may overstate the utility, but it’s a monumental push forward for protein engeneering that relies not upon random insertions or specific point mutations but de novo design of an active site and then finding a protein that is compatible with it.

Second: DOI: 10.1088/1468-6996/9/1/014104. Sir Fraser Stoddart and Bill Goddard collaborated to create one of the most awesome ideas in supramolecular chemistry , which I’ve gushed over here. The paper details the attempt and successful creation of the “quasi-tristable [2]catenane.” Limitations exist in the system and it’s apparent that the design, as it stands, is unlikely to produce the desired results as an unfortunate overlap appears to exist between the absorption and CT bands of the various colored bits, but I’m still undaunted in my interest of a system like this.

Finally: DOI: 10.1002/anie.200800891. The prior post makes this next post a bit more apropos. Design of rotaxanes with strong binding interactions necessarily makes “shuttling” them around rather difficult but the synthesis of interlocked molecules nearly necessitates strong interaction between thread and macrocycle to assemble. A Catch 22, as it were. Leigh and Zerbetto have a rather clever hack which is slightly reminiscent of some of Vogtle’s (and Leigh’s own) work, where the macrocycle is used to direct the chemistry that is going to make the rotaxane in the first place, though they use it in a distinctly clever way by exploiting the copper mediated Cadiot–Chodkiewicz reaction. I have pretty high hopes for this sort of thinking in the design of molecular shuttles.

These are just a few of the articles I read and found very interesting. If I weren’t so goddamn busy I’d give literature more treatment and limit my fluff posts. But, it’s my blog, so blah.

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Q: How many grams can you load?
A: As many as you wish. It becomes cumbersome above 10 grams and hardly worth it below 40 mg. I’ve run as little as 10 mg, however, and gotten pretty good separation.

Q: Can you do gradients?
A: Yes. As stated, the gradients are fully adjustable since it’s very, very ghetto. You have two bottles and one is pulling solvent out of the other. It’s pretty easy math to do on a spreadsheet.

Q: How much does it cost, seriously?
A: If you buy all new parts (and I mean all new parts, including a brand new fraction collector) you can get away with about $5,000 - half that cost being the fraction collector. Generally you can skimp and save a few here and there and pull it off for about $1500. When I wrote that post, I was referencing prices from two years ago when I built it, so things have naturally gone up.

Q: Does it save solvent or silica?
A: Not really a solvent saver. I guess, if you’re into recycling solvent it’s easier to do. I do not recycle my solvent, so it saves me nothing in that regard. It obviously saves a shit load of free silica, since I don’t pack my own columns. If you were to, and you packed them correctly, you could run the same columns over and over again saving yourself a lot of silica gel.

Q: How do you load?
A: Loading is easy. Dissolve your shit up into a syringe and inject it onto the loading column. If your sample is fully dissolved it shouldn’t plug the column up but the beauty of working with this ghetto system, is you can load your sample into the guard column and if you include a bit of dead space above the silica, it doesn’t have to even be soluble in your mobile phase. I.E. dry packing is usually not needed. Not only that, but the guard column keeps nasty shit like dirty used Grubb’s catalyst off your nice column, so it’s a must have.

Q:What about air?
A: In the solvent? That’s no problem. But in the column, you’ll want to avoid it, but it’s not the end of the world. The pressure will usually squish the air into the solvent but you’ll want to pump all the air out before you begin. That’s pretty intuitive, I’d think.

Q: What kind of columns do you recommend?
A: I whole heartedly endorse the use of RT Scientific’s packed glass columns. The inital cost is about $100-$200 for smallish columns but the repacking service is cheap and you can run gallons of chloroform and gallons of methanol through them without doing much damage to them. Eventually, even the best packed column dies (especially if you make a habit of cleaning it with methanol). The problem with RT Scientific is that they’re scatterbrained so, while they offer a superior product, they’re not the best at customer service. Otherwise I use ana logix columns (35 micron pore size silica) since they’re consistently well packed and we get a great deal on them.

Q: Do you really run one column a month?
A: One FLASH COLUMN. I run about two columns a day, sometimes more, depending on what I’m doing. I like to have a full bench. That being said, I take my sweet time running columns. Usually run one during the day and run the other over night. Since it’s automated (with a fraction collector) I’m not really hurried into forcing the shit through the column unless I have to. Most compounds I’ve encountered prefer to take their time on the column and a slow drip produces great separation. That being said, I can crank it up and be done in half an hour - if needed. Obviously, if my ghetto column is running, I can always pack a flash column and run it, so it’s quite possible to separate two things at once.

Q: Does it save you time?
A: Fuck yeah. Why you would run a flash column when you could do it automated is beyond me. And, even though I like to toot my own horn a bit, I’m not as good at flash columns as my MPLC and I’m not very patient with collecting the test tubes. If I had an auto-TLCer that would be great.

Q: What about a UV detector?
A: That might be nice and I’ve got the general electronics figured out if I wanted to make one in the machine shop, but I don’t. The UV detector can’t tell me anything about coeluting shit anyway, which is really more important to me, so I’d have to run a TLC anyway. I guess I could rig up a photo diode array… that would be pretty pimp. But that’s just retarded.

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An MPLC is the “medium pressure” variant of an HPLC, but they really couldn’t be further from HPLCs. Whereas HPLCs are unmistakably scientific instrumentation, MPLCs never are. They’re simple purification machines and, as such, they shouldn’t cost $6000. (a bargain when you consider the $40,000 an HPLC costs) I provide here the means for you to build your own MPLC for purifying organic goodies for under $1500. If you can’t swing that, you should get another lab. Since I’ve run all kinds of things on this set up, I can promise you that if you can separate it on a flash column, you can separate it better on an MPLC. I list vendors here, but you can buy from anyone. These are just the guys I buy from and I’m not getting any money by mentioning their names (though I should) so I can be candidly honest about all of them.

MPLCs can be divided up into 3 parts: The part that runs the solvent, the place where your shit is separated and the part that collects the solvent as it comes off the column. The first thing you need to consider is a pump and a solvent system. I run a lot of binary gradients, but that doesn’t mean I need to buy two pumps. All it means is I need to buy two bottles, one of which has an awesome screwcap top. The pump I have connected it to is an FMI “Q” Pump. You can find out more about these guys here at their website. The pumps can produce a lot of pulsation, but that’s taken care of down the line. This pump is a cheap one and I’ve let it run dry over a weekend and it still keeps chugging. It’s grade A good shit. The whole thing is about $500. You can control the flow rate by twisting a little knob. It not only gets pretty fast, but you can even make it go backwards, which I have yet to find a use for. That bottle is obviously from an Acros bottle and that PFTE cap was purchased from RT Scientific. Essentially, as a vacuum is created in the brown bottle, it pulls solvent from the clear bottle. This is how I get my gradient. It’s very much a true gradient - as much so as a 50mL prep HPLC binary system can produce. That silver thing the brown bottle is sitting on is an old shitty stir plate, of which most labs have a shitty one lying around.

That’s the first part. The second part involves the actual purification and sample introduction. That’s actually even cheaper. As you need to purchase an $8 disposable column from Ana-logix (you can ask for a free sample pack from a sales rep), a $30 gas tight syringe, a $70 3-way lure lock and a small glass loading column, also available from RT Scientific for something like $100.

The whole assembly is connected with about $20 worth of tubing and I’ve run more than 300 liters of chloroform (seriously) through this set up. Nothing will touch it. The pulse suppressor is probably necessary. You can buy it from FMI (see that link above) for something like $250. That’s a lot of money, but separation is generally unaffected if you keep the pump speed low. If you can afford it, get it. So, that’s pretty much all you need if you want to collect by hand and you’re still under $1000. Collecting by hand is awfully gay and sort of defeats the point of “automation” since I find nothing more enjoyable than setting up my MPLC and going out to lunch or writing a blog post (the MPLC is indeed pumping as I write this). But this isn’t such a big deal. While fraction collectors are notoriously over priced, Ebay always has good deals on them. Indeed, a quick search turned up 66 different items. The best part is, if you pay for it with your own money you can tell people to fuck off if they want to use it and you can take it with you to your next job/postdoc/whatever. I didn’t have to buy my own, but life without it would be the sucks. Indeed, here is an Ebay store selling the older version of what I’m using right now for only $250.

So, there you have it. Automated for under $1200. You can think of it in terms of saving money in solvent and silica (you won’t) or think of it in terms of saving time.

Now… you could be asking yourself “But Kyle, you’re rich and famous. Why are you using such a ghetto-assed-fuggly MPLC set up like that?” To which I would respond: Because. I built it from NOTHING AND MADE IT PERFECT. And no one will use something that looks like a bunch of shit hobbled together so I pretty much get it 100% of the time, even though it kicks so much ass its feet are forever covered in shit.

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It is frustrating that none of these points were raised in the keyboard gnashing in the last post. A lot was said about the need to “train organic chemists” which isn’t a reason to fund TS but it’s a good reason to do it - a chemist who does nothing but attempts to synthesize the hardest compound they can is likely most qualified to produce compounds for drug testing (though this isn’t necessarily always true.) There was one misguided attempt at claiming certain organometallic reagents originated with TS, but tripping over the first hurdle out of the gate pretty much ends the race. Still I give that person credit for trying. If there is one stereotype about TSers that needs to be addressed it’s that they have no idea why they’re doing what they’re doing. Of all the stereotypes, I encounter that one more often.

On the other hand, there was a lot of name calling and vitriol reserved for TSers, namely for their arrogance. This is a stereotype which lacks true self analysis. I can think of a few of the most arrogant people I know in my department and, to be honest, I can think of only one that I find repulsively arrogant in total synthesis. The rest are in various other groups doing various other things (even BIOCHEMISTRY!). The distribution is pretty broad.

But, as I leave at night, when I look back at the building - most of the labs are dark. The biochemists are clearly gone, the inorganic chemists and computational chemists all have their lights out, indeed, the only lights in the building that remain on are those of the labs that do organic synthesis (including my own). So maybe that sleep depraved determination gives them some legitimacy? I don’t know.

I think my point is, everyone should get out of their labs and walk over to meet other people who do other work or make an effort to read outside your field or go to seminars that aren’t related to what you do. Have the balls to ask a question. I’ll be honest with you I’ve asked some pretty retarded questions in seminar but I don’t give a fuck. They sounded good in my head and I’ve gotten to be WAY too cynical about the notion of “intelligence” to care what other people think of mine. The only way you’ll ever know is if you ask and the only way you’ll ever ask is if you build up the nuts to do so

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If you’ll forgive the gayness of my chart, I pulled that data here, from the very government those drug companies have worked so hard to create for us. The blue line indicates the number of NDAs approved and, apparently, the only people that can really tell the difference between “the good years and the bad years” are John Lechleiter, Richard Clark, Jeff Kindler and/or any other douche bag that is lucky enough to be promoted to “transient CEO of big pharma for a few months.” An average of 90 ± 20. With a huge boom in the late 90’s where, I presume, most of those are still covered by the more realistic “25 year patents”.

I remember back in 2002ish at Lilly when Big Syd Taurel got on the jumbotron in building 78 (there really is a huge screen and projector in the atrium - at least there was at the time) and announced that Lilly was going to enter into a hiring freeze because someone fucked up and lost the patent to Prozac before they could wring a few last good years out of it. Since then, it’s been a litany of unproven excuses like “It costs a BILLION dollars to discover a new drug and the Canadian reimportation/corporate taxes/generic competition/short patent/turrists/life is just draining all our money away and we’re operating on PENNIES, PENNIES I TELL YOU” and so on, yet - we can see from our friend the graph, that apparently some companies are doing just fine.

But I was discussing the legends of total synthesis contribution to this. Pardon the digression. The problem, as I see it, is that people who work in these labs go on to fill the ranks of big pharma, who have done nothing, while little upstarts, which are filled with people from “lesser groups” at “lesser schools” appear to be doing alright. WTF gives? Is it… possibly… that total synthesis MAY NOT be the best training for drug discovery (heresy!). (Tip: the stock excuse is that you hear more from little companies because they’re more likely to announce their discoveries faster. Apparently, Big Pharma sits on ALL news, not just the bad news.) Or has Big Pharma academically inbred it self into Appalachian style banjo plucking retardation? It could be both, of course.

I don’t think it’s just me, but it could be: does it seem like the groups with the largest anti-bio vibe are either material groups or total synthesis groups? While the obvious pitfalls of not appreciating the delicate biochemistry of the organisms you intend on eradicating may become apparent all too soon to the material folk, being anti-bio in a total synthesis lab is stupid, counter productive, and very prevalent. The new “multidisciplinary” action that compose 30% of Big Pharma powerpoint slides isn’t coming through in their hiring practices as they keep recruiting from labs that wouldn’t be able to find the active site of a protein if it were docked to the fatty part of their ass. It would be more logical to approach people who work in multidisciplinary labs, that make and model enzyme substrates - people who think like a biochemist but are trained as an organic chemist. The target in drug discovery is never known at the onset - if it were, the discovery process would be a lot easier. This is clearly not the case in total synthesis, where the target you’re synthesizing is known from day one and your mission is to make it, live or die trying.

So I dropped these things on her and got back the stock responses which I’ve heard before (she is a proud alumni of the Evan’s lab, unsurprisingly)- “we need people who can think critically about chemistry.” To which I obviously replied, “I would think anyone obtaining a PhD in chemistry should have that ability.”

Her answer was glib. “You’d like to think so…” suggesting, some how biochemists lack a certain part of their brain that performs these advanced critical thinking tasks and are awarded PhDs on the basis of “good, honest hard work if not pointless work.” Or, if I were to be even more cynical, that people who are in these legendary groups are always going to be critical thinkers and everyone else is too questionable to spend time interviewing. Which is bullshit, of course, but I’m just being cynical here.

Obviously, if you want synthetic chemists, you’ll want to hire people with bench experience, but there’s no need to hire people from the same 10 or 15 groups. Apparently, anyone can use SciFinder now, so it’s largely unneeded to get people with broad encyclopedia knowledge of reactions and, at any rate, at some point companies need to look internally to determine why they are failing and, amongst other atrocious practices (including over use of direct-to-consumer marketing, out sourcing R&D and process to developing countries with governments that are blind to intellectual property theft, excessive executive compensation packages and top heavy managment structures… so on and so forth) they need to consider that they’re recruiting researchers poorly and their hiring strategy is pulling a homogenous pool of people and they’re doing it because 1. the people hiring were from those groups and 2. trying new shit is just not something huge, stupid drug companies do well or do quickly.

I’ll end this rather long post with a cautionary disclaimer - I don’t do total synthesis but I’m also not interested in working for Big Pharma. I have no outward interest in these companies suddenly recruiting from… say… oh… some lab at Cal Tech. I also think TS is a great area to prepare chemists for work in drug companies - the issue is homogeneity and inbreeding, not that they’re failing to find quality people.

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I mean, possibly 10% higher, but these polls are horribly inaccurate anyway, so I’ll just call everything even and say, maybe if availability weren’t an issue, But it’s not as high as another number. Apparently, almost 60% of you have already tried a drug for recreational purposes already.

Now… that’s interesting.

I wouldn’t do it myself, actually, for a very singular and almost arbitrary reason: I can’t stand stimulants. I suppose Provagil isn’t really a stimulant, but I hate everything that prevents me from getting to sleep. I enjoy the taste of delicious warm coffee, so I do drink caffeine, but never after 4pm. I didn’t use the shit to stay awake as an undergrad and I don’t use it to stay awake now. Sleepiness is God’s gift to you. It means you’ve done a good day’s worth of work. Maybe that’s not a very good reason not to do it. I suppose there are no higher moral reasons in me that would keep me from taking any drugs to accomplish more in the lab, but let’s be frank, most of the problems I have with illegal drugs are non-existent:

1. You’re using your own machinery. “Drugs” advance what you have - they don’t give you more. It’s not like they build gray matter, they just make it more avaliable
2. These are high quality pharmaceuticals, not crack rocks. Quality wouldn’t be an issue
3. Using FDA approved drugs does not perpetuate cross boarder illegal trade and perpetuate street violence
4. I am not providing any more impetus to continue to fund the DEA than I absolutely need to

There you have it. I don’t know if I can condone the use of drugs for performance enhancing purposes, but I don’t think I would mind if someone were using them. Unless someone can point out why I should care.

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The 1 in 5 number is a bit surprising, but it brought up a number of well written and freely accessible deliberations on the use of such drugs here. (Note the persistence of the age old practice of addressing letters to the editor as SIR. I demand righteous indignation be heaped upon them out of fairness for the abuses I’ve taken.)

Whatever. To the chemist, most of these drugs are readily accessible compounds. Only the fear of ingesting stuff you made in the lab must be overcome (which is honestly about as close as “not accessible” as one can come), but, I hypothesize, for most people availability is a major hurdle to doing drugs. So, let me ask you this question: I’ll qualify it by saying that you’d use it only in cases where it is necessary, but, let’s say you had a bottle of Provagil all legally obtained. You needed it to finish up an experiment (which you could do the next day, though that wouldn’t be ideal) would you take a pill to help you finish up your work through the night? I’ll do a follow up in a week or so as the votes trickle in. (I appreciate that this is a bit of a trickier question than, “which way is it spinning” but perhaps I could convince a few hundred of you to vote here. I mean… you’re clicking a button here. JUST VOTE. Don’t think. Pretend this is Chicago or something.)

You know, you could abuse the shit out them too… but the point is, you’ve got the bottle already - why not?

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Very good. Now that we are versed in the plight, we should also be refreshed knowing that the problem is with obtaining Shikimic acid, the material from which Oseltamivir is derived and which has been synthesized in a variety of different ways - and you’re free to read all 8 papers referenced therein. But Bee Emm Tea is a clever old fox, and decided to make Oseltamivir NOT from Shikimic acid but from… errr… 6-oxabicyclo[3.2.1]oct-3-en-7-one which is “commercially available.”

It’s a good synthesis, actually. Not that we needed yet another. But, hilariously, it was made by a person that was riding off another pharma company’s fellowship. Money well spent, Novartis. But let’s look at the awesomeness of this chemistry, mostly the Trosty flavored assymetric shit done using a “Trost Catalyst” (-10 for using your own name to describe your catalyst. Booo.):

The clever transformation here is the decision to use the TMS amide I (incorrectly) drew up above (due to laziness). Experimentally it was determined that the desired nitrogen moiety must approach with a significant bulk of electron density (it must be deprotonated) and it must do so right next to a negatively charged carboxylate (i.e. they couldn’t get the reaction to work under standard conditions). The solution was to use an oxophilic TMS protected amide which would not only provide the amine in the final product, but also entertain the negatively charged oxygen of the carboxylate with some silicon so it wouldn’t interfere with addition. Very Clever! (+20… BILLION. Ohh. Trost wins this round, EJ.) Conversion to the ethyl ester was done in one pot with ethyl alcohol with some pretty decent yields. Awesome.

Wheeler is dead. For a remarkably well written piece describing his life and accomplishments, see here.

Trost, B.M., Zhang, T. (2008). A Concise Synthesis of (−)-Oseltamivir. Angewandte Chemie International Edition DOI: 10.1002/anie.200800282

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