Wednesday, December 20, 2006

NMR and Whisky

I have a real weakness for single malt whisky so when I started my PhD in Cambridge I was pleasantly surprised to see that the NMR machines were named after Scotch single malt whiskies: Aberlour, Cragganmore, Glengrant, Glenlivet and Laphroaig. At the same time as I started my PhD they began the process of acquiring and installing a 700 MHz Bruker Cryo probe monster. Obviously this new addition to the collection of NMR machines needed a name. I'm a big fan of the Arran single malt whisky which at the time was the youngest Scottish distillery. So I thought that Arran would be an appropriate name for the departments youngest NMR machine and I suggested it to the NMR guys. I even went as far as purchasing them a little box with a selection of Arran malts. Clearly, the guys liked the idea and to my great pleasure the machine was named Arran. Here's a picture of the NMR people (from left: Duncan, Andrew and Brian) with Arran and a selection of miniature Arran bottles:

Not only do they give their NMR machines great names but they also provide a most excellent NMR service. These guys actually like what they do and will go to great lengths to help you out. The best NMR department (by orders of magnitude) that I have experienced so far. Anyway, after Arran was named we obviously had to run some 1 and 2D NMR of the Arran malt on Arran to see what the spectrum of a tasty single malt looks like. Below the HMQC spectrum of the organic phase after an extraction of Arran malt with dichloromethane is shown. We didn't use the regular stuff but a limited edition single cask Arran malt (Bottle no. 125 of 348, 58.7%, distilled 18/7-1997).

Yes a complete waste of time and resources but it was fun. We took the photo above and a bunch of the NMR spectra and sent it to Isle of Arran Distillers with a letter explaining matters and it turned out that the guys at the distillery really liked the story. They showed their appreciation by sending us a bottle of Arran malt each - nice guys! D!

Friday, December 15, 2006

How to make drugs

A couple of months ago I noticed this perspective in OBC (Org. Biomol. Chem., 2006, 4, 2337-234 7, DOI: 10.1039/b602413k). It provides a summery of the reactions used for the preparation of all drug candidates at AstraZeneca, GlaxoSmithKline and Pfizer in the UK.
A nice read to for anyone who wants to know what is actually done on large scale or preparing for a process chemistry interview. A word of warning though, anyone who has spent a significant part of their life developing asymmetric methodology may be somewhat disheartened. It seems buying and resolving are still order of the day.

Tuesday, December 12, 2006

Identifying old NMR solvents (in Cambridge, UK)

When I was still messing around in Cambridge I one day happened to walk into the NMR service room at the perfect time. Dudley Williams had retired and was giving his stuff away and the NMR guys had this big box of NMR stuff they wanted to get rid of. The box was jammed full of deuterated solvents, NMR tubes and shift reagents so I grabbed the whole thing and took it back to the cave. However, not all of the solvents were easily identifiable. There was a large number of ampoule's with no label on them. They did however have some interesting colour codes happening. After a quick trip back to the NMR room it turned out that Cambridge used to have its own colour coding system for deuterated solvents. Here's a selection of ampoule's and what they contain:
The Cambridge NMR service web page used to have a guide to this colour coding. However, not anymore as most of these old ampoule's are gone by now. That was probably a bit premature since there are still quite a few of these ampoule's floating around. I talked the NMR guys into sending me the old colour chart so I could post it here. So to all you Cambridge people scratching your heads in bewilderment here's the answer to all your problems:

Saturday, December 09, 2006

Adelaide Synthetic Symposium 2006 Part II

As I mentioned previously Professor Mukund Sibi also presented at the symposium. His talk was entitled: "A New Dimension to Enantioselective Catalysis - Templates Come to the Rescue". Sibi is all about developing new methodologies for asymmetric synthesis. However, the approach is different from what other people in the area are doing. Basically, his concept is to attach a template to the molecule you would like to perform your asymmetric chemistry on. To achive asymmetric induction he now chucks some chiral Lewis acid into his flask followed by the reagent that is going to react with his substrate. The result is high yields and excellent ee's. Okay I think it's time for some structures to clarify matters. Sibi has done a whole bunch of asymmetric radical additions that goes along these lines:A very important detail is that the template is a simple, achiral unit. The sole purpose of the template is to coordinate the Lewis acid well, exert rotamer control and as a consequence give good facial selective for the incoming nucleophile. Now as I mentioned before this principal works very well for many reactions. The Lewis acid is used in sub-stoichiometric quantities (generally 10-20 mol%). The radical stuff that I outlined above is okay cool but I personally like his stuff on pericyclic reactions better. Back in 2001 he published a very interesting paper in JACS (DOI: 10.1021/ja016396b) on Diels-Alder reactions:
So this is taking things one step further by using a pyrazolidinone template with a substituted nitrogen. What they are achieving here is what can be described as relay induced enantioselectivity by nitrogen inversion. In other words, you use a achiral pyrazolidinone template and throw your chiral Lewis acid in that upon coordination will favour one asymmetric conformation of the template. Pretty funky stuff. You really need to check this paper out to get all the details. Anyway, it works very well. Here's some numbers:
Notice that template 11 with no relay unit is poor proving their point.
More recently Sibi has done some work on enantioselective [3+2] cycloaddition of nitrile imines (DOI: 10.1021/ja051650b). This time using their basic system with no relay. This stuff also works exceptionally well giving some heterocyclic compounds that might be appealing to people doing a bit of medicinal chemistry:
This time there's also regioselectivity issues. However, they solve this and all other associated problems elegantly producing the desired dihydropyrazoles in excellent yields and ee's.
I recommend reading these two JACS communications. Good thorough science and very well written papers. D!

Friday, December 08, 2006

van Gogh in Angewandte

Recently, a group at the Moscow State University published some synthetic work in Angewandte (DOI: 10.1002/anie.200602190).

It is a quite simply (and high yielding) route to a new funky heterocyclic circulene starting from the commercially available 3,4-dibromothiophene (even though, it doesn't seem clear to me, how they convince four thiophenes to make a macrocycle and not doing a lot of other stuff during the Yamamoto coupling):

The circulene is just as soluble as a brick, though. But if they (or others) can come up with some soluble derivatives or analogues - similar to what was done to kick off the research in hexa-peri-hexabenzocoronenes (HBCs) at the Max Planck Institute in Mainz by Professor Klaus Müllen - then a lot of cool applications are possible, I think...

Monday, December 04, 2006

Adelaide Synthetic Symposium 2006 Part I

They let me out of the lab today. It was time for the annual Synthetic Symposium that was held at Flinders University this year. As usual they fly two big wigs in to present stuff. The remaining talks (6 this time) is given by PhD students. This year the big wigs were Professor Martin Banwell from the Australian National University and Professor Mukund Sibi from North Dakota State University. Both of them gave very interesting talks indeed. Apparently what these guys do is old news. Well It was news to me so here's a brief crackdown on what Banwell had to say. Banwell is a total synthesis man and today he was talking about the synthesis of compounds such as Brunsvigine, Complicatic Acid, 11-O-Debenzoyltashironine etc. The talk was entitled "Chemoenzymatic Methods in Synthesis" and it was the whole chemoenzymatic bit that caught my attention. Basically they are taking simple substituted benzenes and dihydroxylating them. Truly amazing stuff:As Banwell pointed out the example with styrene is unbelievable and the ee's are through the roof! Moreover, the concept isn't limited to monosubstituted systems and more than 250 metabolites of this kind are known by now. So a couple of things immediately spring to mind. What scale can you do this sort of thing on and how do you get the other enantiomer of your product if that is what you are after. Well Banwell was on top of things and addressed these matters during his talk. Firstly, this stuff can be done on big scale. In the case of bromo- and chlorobenzene they obtain 35 grams of stuff per litre of fermentation broth which is pretty damn impressive. If you want the other enantiomer things are a bit trickier. However, Allen et al. have developed a method where the enantioselectivity is switched by introducing an iodine substituent that can be removed after the dihydroxylation:A nice and simple solution to a complex problem that was published in Chemical Communications in 1995 (DOI: 10.1039/C39950000117). Anyway, this was just Banwell's introduction. He went on to talk about the total synthesis of a whole range of natural products starting from these metabolites. Most of it was unpublished stuff so I'll be a good boy and not post it all here just yet. Enough for now. I'll post what Professor Sibi had to say some other day. D!