Molecule of the Day

While not wildly complex for a drug, it does have a number of what are called “chiral centers,” which haven’t been covered here before. A good explanation is given at Wikipedia here. If you are baffled and not too proud to be caught playing a kid’s game to understand (I did!), the Nobel Foundation has one here.In brief, though, chirality is “handedness.” A chiral molecule will have two nonsuperimposable versions. Two classic examples of chiral objects are shoes and hands. You can’t orient your left and right hand in a way that they overlap. You can put the two back sides together, as when they clasp, but you can’t match up each fingernail with its mate on the other hand. Make sense?Another good example that is a bit easier to understand but harder to visualize is a screw. The reason we have “righty-tighty, lefty-loosey” is because screws are made that way; they are chiral objects too. Left handed screws actually exist; one example is in a centrifuge rotor. The centrifuge’s rapid spinning would cause a right handed screw to come loose, so we use a screw that tightens when turned left to put in the rotor (holds whatever you’re centrifuging).It gets worse. The three triangular/wedged bonds coming out of the six-membered (hexagonal) ring on the right side there are attached to “chiral centers.” EACH of those has a left- and right-handed version. So we have 2*2*2=8 different stereoisomers. Only the one shown above is right. It turns out that chirality begets chirality; as a rule, you need something chiral to make a new chiral object. (Back to hands: punch a piece of clay with your left hand and right hand. You can’t fit the “wrong” fist in the other’s imprint. Chiral synthesis through clay-bashin’!)So, it turns out that EVERYTHING that is alive has left-handed amino acids making up its proteins. True to form, living things merrily make chiral molecules all day, while the chemists trying to make Tamiflu either a) suffer and get, at most, 12.5% of the right thing or b) use expensive and temperamental “chiral ligands”, improving the situation with varying degrees of efficacy and expense. Chirality is a big problem for organic chemists; Nobel Prizes have been awarded for this stuff.It turns out, though, that sometimes it’s easier to just throw in the towel and let the plants do your bidding.

Enter Star Anise, the exotically-named unsung hero of the bird flu circus. While we fret about bird flu, star anise calmly, methodically, and homochirally puts out buckets (well, on the order of 5% by weight. relative buckets.) of shikimic acid like so.

What does this have to do with Tamiflu? Take a closer look. Shikimic acid has the proper chirality, and it is appropriate to use in preparing Tamiflu - the 1 in 8 stereoisomers of Tamiflu that is correct! Easy, huh?

(Image from Tamiflu Wikipedia article, public domain).

Hard. This is one of a few routes from shikimate to oseltamivir. This actually isn’t where any potential Tamiflu shortage results, though. Nobody is jumping up and down over a fifteen-plus-step synthesis route, but a lot of those steps are not-so-bad, and this is the kind of stuff process chemists know how to gear up and do. It turns out that the really hard part is getting enough shikimic acid! Some estimates have Roche using up to 90% of the star anise harvest, just to make Tamiflu. If you’ve tried to get a script for it filled lately, you know that it’s not enough.

If you have ever had the bizzare liqueur Galliano, you have drunk some star anise. I can only imagine the market will end up curtailing or making prohibitively expensive such frivolous uses, so if you’re a Harvey Wallbanger fan, stock up? Ew.

You may have wondered above where the first chiral stuff came from, if we need chirality to get there. Other people do, too. This is called the homochirality problem. This is an important part of the origin of life puzzle.

Shikimic acid is an example of a natural product precursor. Lots of natural products turn up in pharmaceutical design (penicillin was one, for example). Derek Lowe had a good post about them today. As he put it:

The famous natural product drugs - the taxanes, vinblastines, penicillins, quinines, and erythromycins of the world - hit specific biochemical targets like the ones the synthetic molecules are aimed at. They’ve had untold millions of years of optimization, and what we see are the variants that have been best at keeping other bacteria away, for example, or keeping insects from stripping the leaves. It’s often impossible to improve on the potency of a natural product for its target. The best chances for that are when you can optimize for the human forms of the enzyme or receptor that the compounds are hitting, as opposed to the ones its been honing itself against all these years, or to improve its characteristics in the human digestive and circulatory system, which it probably also hasn’t been under pressure to do anything about.

Structurally, they get lots worse. Here (PDF) are some examples of some natural products grad students gave up the better part of their twenties for.

Another recent discussion over at Nature’s blog, The Sceptical Chymist. From their entry:

[…] both syntheses avoid using either (-)-shikimic or (-)-quinic acid as starting materials: Corey’s synthesis starts with 1,3-butadiene and trifluoroethyl acrylate and Shibasaki’s synthesis starts with the asymmetric ring-opening reaction of a meso-aziridine with TMSN3. If these syntheses could be scaled up and optimized further, it might be possible to reduce the cost of oseltamivir/Tamiflu and pharmaceutical companies (or paranoid graduate students) could make plenty of the compound, which could be stockpiled and used if a human pandemic occurs.

The only catch: oseltamivir-resistant virus has already been reported in Vietnam…

The Corey in question is EJ Corey, yet another Nobel laureate and godfather of “retrosynthetic analysis.” If you are an undergrad in organic chemistry, this is close to your heart (or other vital organ). For the uninitiated, this is essentially the principle of working backwards from a desired product (Tamiflu, here) using a known structure (shikimic acid, or butadiene (!) in the case of Corey’s lab). While this might sound obvious, it’s only because it’s one of those brilliant ideas that sounds obvious after the fact. If you’ve ever looked at a synthetic scheme and thought, “hey, it’s kind of like Lego,” you owe a debt to Corey. We will no doubt talk about him another time.

Update 5/4: Take a look at the good folks at Totally Synthetic. They just did a two part series on the Corey synthesis of Tamiflu if you enjoy the organic synthesis side of things (Part One, Part Two).

Tomorrow: The biochemistry of Tamiflu. Have a good night, thanks for reading.