Saturday, September 02, 2006

Ugi Reaction in Water

In our lab group meeting on Friday Sept 1, 2006 with Khalid, James and Lin, we discussed the status of our effort to use the Ugi reaction to synthesize a library of potential anti-malarial compounds.

Lin's attempt to synthesize a diketopiperazine with piperonal, 5-methylfurfurylamine, Boc-glycine and benzyl isocyanide yielded a fraction 19D-F4B that is consistent with the desired product but still has too many impurities after two attempts at chromatography. We'll have to see if it is worth one more column or starting again and separating the Ugi condensation from the cyclization step.

James has tried to isolate the Ugi product before cyclization, using 3,4-dihydroxybenzaldehyde, 5-methylfurfurylamine, Boc-glycine and benzylisocyanide. We discussed his NMR for 21B-F1 at length. The point of contention was whether the peaks between 5-6 ppm could correspond to the furan ring. Unfortunately we probably won't be able to do C NMR or MS for a few weeks as the instruments are repaired. Khalid will try to run a COSY to clarify this. James's attempt to cyclize the putative Ugi product 21B-F1 did not result in a diketopiperazine.

One of my concerns was that Chris Hulme has already stated that the Ugi reaction works well for aliphatic aldehydes so it may be that James's attempt with the aromatic aldehyde was doomed to failure. The presence of phenols has also been brought up as a potential problem.

At this point I suggested that we go back to doing a simpler, preferably published synthesis of a specific Ugi product for practice. We talked about using acetaldehyde, which is usually available as an aqueous solution. Khalid thought that water should accelerate the Ugi reaction. It turns out that this morning I was checking the Sitemeter hits to UsefulChem and someone from Hungary had tried searching for Ugi and water. Following this search on Google quickly pulled up the Wikipedia entry for the Ugi reaction and Khalid's hypothesis was indeed confirmed. There are some nice links in that summary that I think our group needs to invest some time reading.

It turns out that one of the authors on that Ugi in water article is Mike Pirrung, one of my postdoc supervisors in the early 90s. Small chemical world.


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