Take Time to Unplug Occasionally

I know I spend way too much time surfing the internet. It is a good idea to go unplugged every now and then in order to really get things done. I was reminded of this when I saw 10 Ways to Ungeek for Productivity Just the other day I took one of my classes to the library, so I could really relate to #5:

5. Do Research at the library

Despite what I’d like to think, Google can’t find me every detail on every topic. Depending on what I’m researching, I often go to the public library. Many libraries maintain subscriptions to databases that cost quite a bit to access, but they also have plenty of offline information. I make a habit of chatting to one of the librarians about what I’m working on. They can often point me to references that I might not have thought of or show me connections between my topic and another that I never would have found searching for keywords on the web.

And there are times when a change of scenery can do wonders for your attitude - get out of your room / office and go somewhere else to work. Besides, I like books.  

Finally an Unplugged interlude with Eric Clapton from back when MTV had music.

See if you can spot this one.

Cool Three-In-One Reaction

Since I teach sophomore organic chemistry, I'm always interested to see new research that involves basic organic reactions that I cover in class.  A new reaction using alkynyl halides produces alkynyl epoxides in a one pot procedure as a result of three different reactions.  At first glance, this looks like a complicated reaction, but everything involved is routinely taught in standard organic chem classes.  And it works well, this example gave 92% yield.

In a recent paper Trofimov, Chernyak and Gevorgyan describe their work with this reaction.  They report that it works quite well for aromatic ketones with a tertiary alpha-hydrogen, while other ketones give mixtures of products.  

The reaction starts with a deprotonation of the ketone to form the enolate, which performs nucleophilic attack on the alkynyl Bromine.  To a beginning student of organic chemistry this might look like a strange version of bromine, but mechanistically it is similar to brominating with Br2.  Next, the alkynyl anion attacks the carbonyl carbon.  This produces a halohydrin that simply closes to form the final epoxide product.  Pretty slick - three reactions all in one go.

Alexander Trofimov, Natalia Chernyak, Vladimir Gevorgyan (2008). Dual Role of Alkynyl Halides in One-Step Synthesis of Alkynyl Epoxides Journal of the American Chemical Society, 130 (41), 13538-13539 DOI: 10.1021/ja806178r

Cyclobutanones and Antibiotic Resistance

Antibiotic resistance is a growing problem.  One way in which bacterial are able to resist antibiotics like penicillin is to use an enzyme called a beta-lactamase to react with the antibiotic and convert it into a form that does not work.

One strategy to overcome this is to inhibit the beta-lactamase before it gets a chance to deactivate the antibiotic molecule.  Compounds such as clavulanic acid have been used for just this purpose, but the bugs are starting to become resistant to this approach.  Beta-lactamases are not going away, so new compounds will need to be developed that inhibit them.

The center of activity in an enzyme is its active site - an openning in the enzyme where the substrate that is modified by the enzyme gets bound.  Typically the active site has a shape that complements the substrate, and has a number of catalytic groups inside which account for the chemical reaction that it catalyzes.  An inhibitor often binds to the active site of the enzyme and prevents the enzyme from binding to any of its "real" substrate.

When designing an inhibitor for an enzyme there are two things the molecule has to do.  First it has to have a shape that matches the active site.  Often enzymes are described as having a lock-and-key relationship with the substrate (or with an inhibitor).  Only a key with the right size and shape will fit into the keyhole of the lock.  Likewise, only a compound with the right shape will fit into the active site of the enzyme.  Secondly, the inhibitor should interact strongly with the catalytic groups inside the enzyme to help keep it lodged in the active site.  If the inhibitor comes out of the active site, the enzyme will no longer be inhibited.

A recent paper looks at a series of cyclobutanone-containing compounds as potential beta-lactamase inhibitors.  Beta-lactam antibiotics like penicillin , as well as the beta-lacatamse inhibitors clavulanic acid, sulbactam and tazobactam all contain the amide functionality.  Replacing the beta-lactam with a cyclobutanone is really interesting - it preserves the carbonyl and four-membered ring of the usual beta-lactamase substrates, and at the same time a ketone is very different from an amide.

When the beta-lactamase binds to penicillin it hydrolyzes the amide bond which leaves penicillin unable to act as an antibiotic.  Most beta-lactamases have a serine at the active site wich reacts with the beta lactam carbonyl.  After the serine OH attaches to the carbonyl carbon, the amide bond is broken to produce an acyl intermediate in which the penicillin molecule is covalently bound to the enzyme.  This is followed by a hydrolysis 

step which releases the resulting penicilloic acid.  

Currently used beta-lactam inhibitors do the same thing, except they get stuck at the acyl intermediate step.  With the inhibitors, the final hydrolysis step does not happen so the inhibitor remains covalently attached to the enzyme in its active site.  This prevents the enzyme from binding to penicillin and inactivating it.

The cyclobutanone analogs should also able to bind in the active site of the beta-lactamase enzymes.  Initially, the serine at the active site can attack the cyclobutanone carbonyl, which forms a hemi-ketal.  However, no further reaction can take place - there is amide group which can be broken to form the acyl intermediate.

Some beta-lactamases work through a different mechanism which involves two zinc ions at the active site.  Instead of a nucleophilic attack by serine, these metallo-enzymes use a hydroxide ion bound to one of the zinc ions as a nucleophile.  The substrate is never bound covalently to the enzyme and the acyl intermediate does not form.  Currently used beta-lactamase inhibitors are inactive against these metallo-enzymes.  The cyclobutanone analog can still react at the active site, forming a hydrate.  The hydrate can't react further, since there is no amide bond to be hydrolized.  In principle, the hydrate could remain bound to the zinc ions in the active site, and so inhibit the enzyme.

Since bacteria are developing resistance to beta-lactamase inhibitors, new strategies to counteract them are necessary.  Cyclobutanone-containing analogs show promise - since  they do not form a covalently bound acyl intermediate, they could inhibit the beta-lacatamase by a different mechanism than compounds like clavulanic acid and could be effective even in bacteria with resistance to clavulanic acid.  Furthermore, they could also be effective against metallo-enzymes which are not inhibited by the current crop of beta-lacatamase inhibitors.

Leo Kottke - Taxco Steps

I'm always amazed at how much sound Leo gets out of a single guitar.  And here he's only playing a six string.

An Interesting Stable Oxonium Ion

The textbooks all say that hydronium ion is a strong acid, and the alkyl analog should also be very reactive. However, oxatriquinane turns out to be quite stable. One might think that it should be a powerful electrophile and react with even weak nucleophiles like water, but when boiled in water for 72 hours there was still no sign of decomposition.

Another thing I found rather satisfying is that all the chemistry used to prepare this compound is routine for a sophomore organic chemistry class. It starts with treating cyclonona-1,4,7-triene with MCPBA to form an epoxide. The epoxide is opened by reacting with LiAlH4 ( a nucleophilic hydride ion) . Reacting the resulting alcohol with iodine (I2) leads to an intramolecular halohydrin reaction. The iodine is removed with Raney Nickel. Finally, the compound is treated with HBr which protonates the remaining alkene. The oxygen bonds to the resulting carbocation to give the bromide salt of oxatriquinane.

The bromide salt could not be crystallized, so they used simple ion exchange to replace it with hexafluorophosphate ion or hexafluoroantimonate. The ion proved quite stable - they were able to measure the NMR in D2O, and even recrystallize from water. Weak nucleophiles such as water, alcohols or iodide ion did not react with oxatriquinane. On the other hand, nucleophiles like hydroxide, cyanide and azide quickly reacted.

Mark Mascal, Nema Hafezi, Nabin K Meher, James C Fettinger(2008) Oxatriquinane and Oxatriquinacene: Extraordinary Oxonium Ions J. Am. Chem. Soc., 130(41), 13532-13533. DOI: 10.1021/ja805686u

Exercise and Your Brain

It seems as if I have seen several news reports in the last year that show how exercise benefits the brain.  Now here are two more via Research Blogging.

In the first article, Neurotopia discusses a new paper that documents how exercise helps the brain recover from brain cancer.

But exercise is not just for stress relief. There are several studies out there which imply that exercise can make you THINK better, too. And this paper goes one step further, and implicates exercise in helping young animals recover from brain cancer.

The second article is discussed by Dr. Shock, and it describes the benefits of walking regularly for elderly women who are either overweight  or moderately depressed.  

Exercise isn't just for athletes.  

Midterm Break