Chiral Dice

Recent visitors to my office have been confronted with this on the white board:

How many stereoisomers of a die?

I want to clean it off, so I’m posting it here. It dates from a visit we had from Ben Davis last year as the Cornforth Lecturer. He was telling me that Ken Izumori from Kagawa has a collection (in, I think, wood) of all the possible stereoisomers of a die. This got me thinking about how many there are, and the picture’s the analysis. There’s probably a way of using this to cheat in a casino. Which would make one enantioenriched I guess.

Academic Family Trees

My former colleague Chris Richards alerted me to this “Chemical Genealogy” page from Professor Ged Parkin’s webpage. It’s a neat idea – tracing the influence of academics on their students over time, allowing you to say “you know, my great, great, grand-supervisor was Lavoisier.” The page is from a large collection of such information created by Vera Mainz at Illinois. The emphasis throughout is obviously supervisor-PhD relationships, but there is an ‘influence’ category that I guess concerns postdocs etc, which I think is right. My postdoc advisor (Paul Bartlett) certainly influenced my academic development (for the better!). It would be great to have an interactive wiki version that people could insert themselves into such that the filigree of entries grows and can be navigated.

Puzzle of Tangential Relevance to Organic Chemistry

One of my Honours students, Victor, set me a logic problem yesterday. He’s noticed that I’m always busy, rarely around, and have a month-old baby, so I guess he thought I needed something to do. He said “Imagine you have 12 bags of marbles, and each bag has 100 marbles in it. All the marbles look identical. The marbles in 11 of the bags each weigh 10 g, but one of the bag contains all 9 g marbles.”

I was thinking “what’s this got to do with the extremely interesting experiments you need to be doing right now to complete your Honours thesis?” and he enlightened me: “You have an electronic balance,” (that’s the Chemistry relevance right there) “so how many weight measurements do you need to make to identify the bag with the light marbles?” I said “the obvious answer is four” and he said “No, way too many” and left my office.

How many measurements to detect the light bag?

I worked on setting a tute quiz, then something in the back of my brain squeezed out the answer. Would be nice to do a supramolecular host/guest version of this with mass spec somehow.

Heterocyclic Mechanisms – Isopyrodysinoic acid

Every Thursday morning at Sydney we have a problem session attended by all organic chemistry staff, PhD and Honours students. Part of these sessions always involves running through mechanisms and syntheses on our perpetually spotless blackboards. This is a useful exercise, and usually the simplest questions bring up the most interesting points for discussion.

Recently, one of our graduate students, Kaitlin, challenged the other teams to devise a synthesis of a recently-isolated natural product isopyrodysinoic acid. (One of the reasons Kaitlin chose a “new” molecule is that the question circumvents the repetition of a literature answer. Incredibly “isopyrodysinoic” is a one-word Googlewhack, or at least it was until this post.)

Another of our students, Fargol, wrote up a synthesis on the board for about an hour, and towards the end got to a molecule containing fragment 1. She suggested that in the presence of heat and acid this molecule would cyclise to 2, which is probably true. There was some discussion of how this transformation is possible – Fargol drew the direct displacement of the protonated alcohol by the amide, which probably would not happen. This is quite an interesting step, requiring a different mechanism. I know how I would do it. Suggestions? This would make a good advanced chem question for next year.

Chemspider and Structure of Digitonin

Antony Williams of Chemspider posted an interesting challenge for the community to work out, and decide upon, the structure of digitonin. This molecule is a “saponin” meaning a steroid with sugars attached. The details are on the Chemspider blog and there is a discussion on Friendfeed.

The structure was reported (in German) in Tetrahedron in 1963, with an NMR spectroscopy study being published some years later. This latter paper gives the structure as this:

Published digitoninstructure

I have not gone through the NMR reasoning to check the conclusions. It sounds like they analysed a pure compound, not a mixture: “The seed of Digitalis purpurea L. contain ca. 2% of a saponin mixture whose main component is digitonin. With preparative distribution chromatography on formamide-saturated cellulose, it was possible to obtain 1 in pure form.” The paper’s been cited 12 times, and from the titles it doesn’t look as though there has been a structure revision. Chemspider lists three structures at the moment, which all differ in some aspect of the stereochemistry:

Chemspider structures

Circled are a few anomalies. These structures are actually rotated through 180 degrees to depict the steroid skeleton in (approximately) the usual sense. It’s nice to be proper about these things.

To make the comparison between CS and the literature  easier, we can number the structure and redraw the literature structure in this orientation. It turns out that the Chemspider structures have the steroid ring flipped, so we can flip that too:

Lit structure (top), Chemspider orientation (bottom left) and lit structure redrawn (bottom right)

So, which is right? It looks like none of them. Structure 4976216 is close, but the stereochemistry at position 20 (red methyl) looks to be inverted (in all structures). The literature paper is unequivocal about the stereochemistry there.

Digitonin fragment from paper - stereochem at position 20

Interestingly the varied depictions of the spiro moiety can make a comparison confusing. I included two representations in the above figure, but the Chemspider structures have three different depictions of this. They’re all the same, in fact.

Same stereocentre, different spiro drawing

So I’d suggest “digitonin” means a pure compound, with the literature structure as shown above.

The question that’s interesting is why do the CS structures (which are derived from other sources, clearly, and is no fault of CS) differ? Where do the anomalies creep in? If you look at the Wikipedia structure, that stereocentre is also wrong.

Digitonin Structure from Wikipedia

This picture was drawn using “http://www.commonchemistry.org” as source, but I haven’t gone back to check for sources for that. I’m guessing it’s a chemical case of what we used to call ‘Chinese Whispers’ where what starts out as one thing becomes something subtly different after being passed between people. I asked my wife about this, and she thinks it’s a virus (Epimerizer) that’s sweeping the web, randomly inverting stereocentres in chemical databases. (She’s an anthropologist, so doesn’t understand what a nightmare this idea is.)