Field of Science

Smith's Interestingolide is wrong


* Incorrect prediction:

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* Correct prediction:

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* Sharpless mnemonic device:

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* Reference:

It's the simple things that...

I learnt my lesson. The problematic molecule for which our NMR data was not making sense turned out to have some protons with really long relaxation times. I had read a line in some well known NMR book which said "For any detailed study, it's best to measure T1 relaxation times before the experiment". I read it, and I forgot it. Well, not forgot it entirely, but it's still true that for most molecules, relaxation times are similar for all the protons and not doing a T1 does not really make a difference. In our case unfortunately, it were the reference protons for the NOESY distance calculation that turned out to have loooong T1s. Simple solution: measure T1, and then set the relaxation delay (d1 for Varian spectrometers) equal to 5T1. I am in the process of rerunning the NOESY. But from next time, I am never going to forget doing a T1 measurement before anything else, even for simple and 'obvious' moelcules. It's a humbling lesson well learnt for me.

Beyond the rhetoric

I have been reading George Olah's 'Beyond Oil and Gas: The Methanol Economy' and even without having gotten to the part about the methanol economy, I can heartily recommend the book. At first sight, the book looks technical, but it is actually extremely accessible to the layman. The first half of the book is an extremely lucid and comprehensive account of the history, geopolitics, technology and future, of oil, natural gas, and coal, and also discusses the hydrogen economy and alternative fuel sources including atomic energy. The book is very much worth reading and buying for this half alone. All three of these commodities have become the Big Brothers of our lives, seemingly munificent, indispensable, and revolutionary. Yet all three, and especially oil, have made us utterly dependent on them in morbid manner. This is true in the many obvious ways in which we use oil in transportation and electricity and heating, but also in the not so obvious and yet ubiquitous ways in which oil based products are the basis of every part of modern life; from plastics to pharmaceuticals. Our dependence on them is appalling indeed, as demonstrated in the book.

These three commodities are like some of the thieves in movie scenes; the moment the thieves run in some direction where they think that have a safe haven, some insurmountable obstacle materializes. And so it is for fossil fuels. Whatever optimistic estimates and facts we discover about them are almost immediately thwarted by serious problems. Oil is convenient for transportation, is in large reserves, and is the most versatile fossil fuel. Yet, it is riddled by exponentially increasing demand and production costs, locations in regions of political instability, and most importantly, environmental problems. Wars and political regimes are made and broken over oil, and leaders will go to any lengths to disguise their aspirations for oil and the actions resulting from them. Non-conventional sources of oil need much energy input from natural gas, and again contribute to environmental CO2 levels. This last problem is gigantic for coal. Natural gas has momentous transportation and safety problems. So does the much touted Hydrogen Economy of Bush. Ethanol from corn seemingly needs more energy from fossil fuels than it actually saves and produces, and may not be worth it. The bottom line is, any fossil fuel source and many non-conventional energy sources that we can consider have such intractable problems that we cannot think of depending upon them for eternity or even in the comfortable future. Put the rhetoric aside and focus on the facts. Any decision about energy has already been made very difficult because of our aspiration to a high standard of living, our reluctance to give up creature comforts, and because of political lobbying which traps decisions in a cycle of profit and oneupmanship, and the last thing we need is trendy slogans about unlikely energy sources.

It does not matter what the reserves are; after all, predictions about oil reserves have always turned out to be underestimates and false alarms until now. But current predictions seem more true, and in the end, what will be the last straw would be the simple dominance of demand over supply. It would not matter if we have reserves then, but the production costs and the resulting oil price due to demand will be so high, that they would lead to a virtual breakdown in social infrastructure. If oil prices become 150$ a barrel, nobody would care how much proven reserves we have. And it is likely that it will happen very soon, with much of the developing world aspiring to US SUV standards of existence. What's important is that because of our utter dependence on it, such a situation will entail a fundamental shift in our standard of living, especially in the US, and we simply lack the social and mental capacity to make this shift overnight.

I haven't gotten to the part about methanol yet, so I will refrain from commenting on it until later, but what is clear is that oil and fossil fuels have to go, in some way or the other. I have said it before and I say it again, that nuclear energy is the cheapest, safest, and most efficient energy source that we can use in the near future. What to do about terrorists hitting a nuclear power plant is a complex problem, but surely Bush can take care of that, with all the extreme measures he takes for enforcing national security.

In any case, it is eminently worth taking a look at 'Beyond Oil and Gas' if you get a chance.

The same and the not same

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One of the most important questions that someone in the early stages of drug discovery can ask is: Do similar ligands bind in a similar manner? Ambiguities riddle this seemingly commonsense question, right from the definition of 'similar'. Countless drug discovery projects must have been made or broken because of attention or lack of attention to this central principle.

If I had to give a one word answer to the question, it would be no, not because it's the right answer, but I would be playing safe by saying that. It can be a very big mistake to assume that similar ligands will bind to the same way in a protein binding pocket, or even in the same pocket, and medicinal chemists both on the experimental and computational sides are aware what a wide and disparate range of SAR relationships similar ligands can have. This extends very much to similar binding too.

Not on one occasion have medicinal chemists taken the known binding conformation of a ligand, and then twisted and turned another 'similar' ligand into that same conformation. The two structures are then superimposed. They look so similar, with the hydrophobic and polar groups in the same places. Ergo, they must be overlapping in their binding mode. Big mistake. While this can turn out to be the case many times, it's just wrong on a philosophical basis to assume it. That's because ligands have their own personalities, and each one of them can prefer to act quite differently with a protein binding pocket. The problem is; superposition of ligands can always be justified in retrospect if your ligand shows activity. But that does not make your assumption true.

One of the better known cases concerns the search for a 'common pharmacophore' for Taxol, Epothilone, and other ligands which bind to the same pocket in tubulin. A common pharmacophore is a minimal set of common structural features which will cause bioactivity. In typical fashion, researchers compared the various parts of the molecules and twisted them to overlap with each other (PNAS paper). Based on this superposition, they then designed analogs. Result: most of the analogs turned out to be inactive. Thus, there was no 'common pharmacophore'. In this context, Snyder and others published a model (SCIENCE paper) in which, doing meticulous electron density fitting for Taxol and Epothilone, they demonstrated that each one of these molecules explores the binding pocket of tubulin in a unique way, utilizing unique interactions. Thus, the ligands are 'promiscuous'.

Many times, modeling may assume that similar ligands are binding in the same conformation. Docking programs dock them in the same conformation. What docking programs fail to take into account is mainly protein flexibility, which accounts as much for ligand binding as ligand flexibility. Then, when X-ray structures of those 'similar' ligands bound to the same protein are obtained, they reveal that either the protein underwent a conformational change and changed the binding modes of the ligands, or that even without this, the ligands bound in a dissimillar manner. Ligand binding is a 1 kcal/mol energy window game, and there's no telling how each ligand will exploit this window.

So it's timely that a Swedish team has published a paper in J. Med. Chem that tries to tackle the question: Do similar ligands bind in the same way? The team has used the Tanimoto index to measure similarity of ligands, and then has looked at many samples from the PDB to guage the binding of similar ligands to the same protein. They try to use three main criteria of difference:
1. The position of water molecules
2. The movement of backbone atoms
3. The movement of protein sidechain atoms.

The first factor significantly turned out to be the most different for their examined cases, and one which is not always paid attention to. Water is a fickle guest for a protein host, and it can mediate interactions differently even in ligands with slight structural differences. The second factor is also significant, as side chain conformational differences induced by particular ligand features can greatly change the electrostatic environment of the protein; as illustrated above from the paper, the conformation of a single Met residue changes the electrostatics. The third factor, backbone movements, is relatively unchanged and a benign variable.

The bottom line is, it may be an ok working hypothesis to assume that because your known ligand binds in a known conformation, other very similar ligands or even known actives will bind the same way. But start taking it as an obvious rule, and you can always expect trouble.

Bizarre halloween paper of the year

If there was a prize for "Bizarre paper published to celebrate halloween", this paper may get it. On a more serious note, it's an interesting paper published in this week's ACIE that tackles a very common phenomenon- the metallic odor of iron that we all perceive. As the authors demonstrate, the odor is more likely to be from carbonyl compounds produced by the reduction of lipoperoxides in the skin by Fe2+. They also analyze the garlicky odor produced when iron is 'pickled' with phosphorus, commonly attributed to phosphine (PH3) and argue that this odor too is due to organophosphines rather than phosphine itself. Some of their statements and conlcusions (not to mention the title: The Two Odors of Iron when Touched or Pickled: (Skin) Carbonyl Compounds and Organophosphines) really merit Transylvanian attention:
"Humans are perplexed by the metallic odor from touching iron metal objects, such as tools, cutlery, railings, door handles, firearms, jewelry, and coins. Phosphorus-containing iron which is under acid attack gives rise to a different carbide or garlic odor which metallurgists have attributed to the gas phosphine (PH3); however, we found that purified PH3 at breathable dilution has hardly any odor. The aim of our research is to understand the chemical causes of these two iron smells in our engineered metal environment."

"1) Ironically, the iron odor on skin contact is a type of human body odor"

"Blood iron: Blood of one of the authors rubbed onto his own skin resulted in similar metallic odor and the same odorants (78±7 nmol dm-2, 4 repetitions) as in the above experiments. Controls by addition of FerroZine which is a blood-iron chelator suppressed the reaction (4±0.4). Aerated and homogenized blood also developed metallic odor on its own. There are reports that blood iron[10] can decompose blood lipidperoxides and that FerroZine inhibits this reaction.[11] This finding confirms that blood iron can trigger the metallic odor on skin or in blood itself."

"Sweaty skin corrodes iron metal to form reactive Fe2+ ions that are oxidized within seconds to Fe3+ ions while simultaneously reducing and decomposing existing skin lipidperoxides to odorous carbonyl hydrocarbons that are perceived as a metallic odor. This fast reaction creates the sensory illusion that it is the metal in itself that we smell right after touching it."

Several of the experiments made me a little edgy; breathing phosphine to detect its odor (I have always been looking for a reference to the man/woman who first described the taste of KCN) and blood rubbed on to skin. These guys' work sure is interesting; what I am not sure of is whether I want to do a postdoc with them. Interestingly, pure phosphine, just like pure methane, is odorless.

Cholesterol in plants fun fact

One of the questions I have always asked myself is "Do plants contain cholesterol?". I was under the impression that they don't and that this is precisely the difference between the cholesterol pathway in plants in animals; lanosterol to cholesterol in animals, and to stigmasterol or ergosterol etc. in plants and fungi. Interestingly, none of the 'popular' biochem books I read elaborated on this question or answered in the affirmative.

So it was interesting when I came across this J. Chem. Ed. article which talked about the existence of cholesterol in plants. Apparently, the amount as expected is quite low. But what is more interesting is the authors' study of popular biochem books (Lehninger, Stryer, Garrett and Grisham, Voet etc.) in which they certify that this fact is not mentioned.

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But the most interesting fact may be that the USDA does not state the existence of cholesterol when it is less than 2 mg/serving, which is the case with plant products. I wonder what other product labels Uncle Sam dispenses with when they refer to compounds which are less than a certain percentage. Or maybe they should at least state what upper limits can do, as is the case of that compound in Chicken McNuggets, which can kill you when it's more than 1g.


Real life haas finally intervened, and I have been busy with it for the past couple of days. The hiatus will continue till the weekend after which I hopefully should fill in a backlog.

'But is it chemistry?' hits Nature

There it is. Nature has picked up on the 'Is it chemistry' thread. Awareness and contrbutions from the good folks at the Skeptical Chymist were no doubt responsible for the article. The article does not echo bloggers' views directly, but echoes the views of previous Nobelists which in turn echo bloggers' views. There's the one that thinks (like I and some others do) that they should have a separate award for biology. There are those who point to the disparate majority of bioscientists on the Nobel chemistry committee, and there are those who think that such biology oriented chemistry awards are inevitable in the future. Like it or not, I think we have to agree with this last prediction. This year's Nobel makes no major advances in fundamental understanding of structure, reactivity, or synthesis. But then, are many such advances possible in the near future? And in the absence of such advances, awards such as the one given this year are inevitable.

Just one problem with the article. Richard Schrock became Robert Schrock.

Overheard from the 2007 But Is It Chemistry (BIIC) Conference at Tierra del Fuego:
* Physicist, biologist, medical researcher and engineer: Hey, chemist...too chicken to compete for the prize?
* Chemist: What are you talking about? You are all doing chemistry.

Well, maybe it's not that simple, but close.

Wrong data makes me happy

Well, it's not that simple, but a couple of months ago, I did a NOESY analysis of an alkaloid. I acquired the spectrum, integrated the peaks, and got the interproton distances, which looked fine. Then I tried to do a similar analysis for the salt. That's it, nothing much different, just the salt. And now, try as I may, I could never get decent distances. Most of my distances seemed too short (<2.4 A) I reran the NOESY with different parameters, integrated the peaks tediously, and everything looked fine. But again, when I calculated the distances from the intensities, everything was messed up. Finally, the cost-benefit analysis of spending the time on the compound and getting it done from an expert was carried out, and it was quickly decided that it would be best to send it to an expert.

A couple of days ago, we got the intensities of the peaks from the expert, and guess what. The distances are still terrible, at least most of them. So that means that maybe it was not my fault. Maybe it wasn't me, it was you (you=the machine, the parameters, the molecule itself). I am not blaming the expert, because there seems to some unique feature of the molecule itself that's causing trouble. So in some ways, I am happy that it wasn't just me. But I am also sad that this means that our analysis is even further prolonged. This is a project which I want to get done with and publish. And it never seems to be getting close to that goal.

But this also is making the situation more chemically interesting. Why would a simple transformation from the alkaloid to its salt make the analysis so much more difficult? The 1D spectra look ok, so we are pretty sure no decomposition/chemical transformation has taken place. And yet the problem suddenly became thorny because of such a simple change. It seems that the vagaries of SAR reflect in SNR (Structure-NMR Relationships) too.

In the beginning...



Here are all the results:

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The Trouble With Everything



Anyway, more after I actually read the book.

Chartelline and copper catalyzed decarboxylation

A former mentor-student duo has published successive papers in JACS.

Total Synthesis of Antheliolide A
Chandra Sekhar Mushti, Jae-Hun Kim, and E. J. Corey

Total Synthesis of (±)-Chartelline C
Phil S. Baran and Ryan A. Shenvi

First, Corey publishes a synthesis of Antheliolide and then Baran publishes Chartelline. Corey uses a several nice transformations including a [2+2] ketene formation. In one step, he uses LiOH/MeOH to deprotect a TMS protected alkyne, instead of TBAF, because TBAF will also protect the TBDPS group. Why does LiOH protect only the TBS and not the TBDPS?

Also, in another step, he wanted to convert a (methylated) lactol to a lactone. But he had a sensitive caryophyllene like moeity in the ring, which would have been notoriously sensitive to acid and oxidants. So he takes the indirect way and first converts the OMe to a phenyl seleno, then turns it into a hydroxyl with AgNO3, and then finally uses mild oxidation with TPAP to oxidise the hydroxyl. Neat.

Baran's synthesis is more elegant, and as usual, based on biosynthetic proposals. He does some neat transformations, including a cascade like reaction to effect a nice ring closure.

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However, it is the last step which I found interesting, in which he was trying to decarboxylate a vinyl carboxylate. Copper catalyzed decarboxylation failed, but it turned out that the carboxylate was quite sensitive and labile to heat, so simple heating worked; the mechanism involved a proton that seemed to be serving a function akin to copper as noted in the reference below. He also suggested transient positive charge stabilization by chlorine. I know fluorine can do it well; chlorine would be less efficient but could still do it I suppose.

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This led to me look up some back references on vinyl decarboxylation. I found out a reference by Theodore Cohen of Pittsburgh (J. Am. Chem. Soc.; 1970; 92(10); 3189-3190) who proposed the following schematic for explaining stabilization of the TS by copper.

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He was trying to explain some copper catalyzed quinoline decarboxylations that went back to 1930. I also came upon a 1950 paper by Frank Westheimer (J. Am. Chem. Soc.; 1951; 73(1); 429-435) in which he tried to explain the decarboxylation of alpha-keto acids with copper, a classic reaction which he uses as an enzyme model system.

Schrodinger Webinars 2006. And the importance of being polarized


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Whither chemistry?





Chemistry Nobel for Biologist

So there we are; Roger Kornberg following in line behind his father, has won the Nobel for chemistry. This prize also seems to have been a quickie; Kornberg's pivotal papers seem to have been published after 2000. I am sure Kornberg deserved it, but like Paul, who stayed up all night looking at the announcements, I too don't feel really excited about it. I wouldn't have predicted this as I am not so familiar with molecular biologists, but I was surprised to see that absolutely no blog I read had this name in a post or in the comments. No problem of course with molecular biologists getting the chemistry prize. In a way, it's a triumph for chemistry because it shows the vast scope and purview of the science. Maybe the committee decided to balance the 'pure' chemistry that was honoured last year with something more interdisciplinary. But it's always more exciting to see the prize awarded to someone whose work you are familiar with and who is more from your general field, as happened last year.

Nitrone-cyclopropane cycloaddition

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Use of a methodology I haven't really heard about in a long time.; the nitrone-cyclopropane cycloaddition. Kerr and coworkers now use it in the synthesis of one of those indolizidine alkaloids, phyllantidine. Fairly straightforward synthesis, although again, I would always pay attention to forming an N-O bond at an early stage. One of my favourite name reactions is used- the Krapcho decarboxylation, the concomitant hydrolysis and decarboxylation of an ester using LiCl in DMSO.

I am too lazy to look up the literature, but why doesn't the nitrone add to the double bond?

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Also, the nitrone-cyclopropane addition should be nonconcerted, since we have a nicely stabilised ring opened intermediate.

The other interesting thing is the selectivity of the enolate oxidation.

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At first, I was not satisfied, but then I thought that their explanation for it sounds ok. But it looks a little crafty when you draw the vinyl group conveniently pointing in a sterically hindered direction, and make that the only structure with the group in that position! The difference between the group in that position and pointing away from that position is 2 kcal/mol by the way, at least that's what MMFF says for a model compound.

According to Eliel's latest version, the A value for OH ranges from 0.6 to 1.04 for different solvents, while that for CO2CH3 is 1.2-1.3. Also, MMFF gives a difference of 1 kcal/mol for the product with OH axial. So not much difference there, but still worth keeping in mind that the product with the CO2CH3 axial dominates. I wonder how much the reaction is product controlled here though. Such analyses depend on the thermodynamic nature of the reaction; in this case, the fact that the oxaziridine ring opens probably means that the products as a whole are lower in energy. If that is so, then the TS should resemble the reactant, but I would never place my bets on such rationalizing, as subtle effects can change things in the TS. Also there are other factors here, especially the facile nature of topside attack.

Ref: Total Synthesis of (+)-Phyllantidine, Cheryl A. Carson, Michael A. Kerr
Published Online: 13 Sep 2006
DOI: 10.1002/anie.200602569

Corwin Hansch

In the whole Nobel betting, I think we forgot someone significant- Corwin Hansch, whose QSAR has now become ubiquitous in medicinal chemistry and biology, both theoretical and experimental. Also, I think Hansch is one of the first ones, if not the first one, to apply classical physical organic chemistry (Hammett etc.) to medicinal chemistry and bioactivity.

Updates: New thoughts.
Albert Overhauser: Nuclear Overhauser Effect
Norman Allinger: Molecular Mechanics

Solvent assisted olefin epoxidation: fluorine emerges a winner


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