OK…. I have a soft spot for tandem (cascade or domino) reactions. Seems everyone always talks about how we have to have this sense of urgency for making molecules, drugs, analogs, new crystal materials at the speed of light. The “speed is of the essense” is not the reason I have an appreciation for these little buggers, nor is my taste for atom economy or saving the last bit of my reagent bottle. I like these mainly because of their artistic value or elegance — since I haven’t been in a situation where I can tank through a 45 step natural product synthesis. These look and feel like that, but I can celebrate the thinking which goes into these without unpacking the thesis that goes into a natural product JACS article (take a look at a recent post from In the Pipeline to see what I mean).

If interested you will be able to return here for a number of these approaches. If you ever want some fun light reading on the subject, I recommend Tse-Lok Ho’s Tandem Organic Reactions book. It makes great material for staying sharp — it isn’t often where one gets an opportunity to use these approaches in the medicinal chemistry world — but hey you never know.

Back to the start — starting simple. Fustero utilized a tandem cross-metathesis with an intramolecular aza-michael reaction for the formation of substituted pyrrolidines and piperidines. They went on to compare conventional and microwave-enhanced approaches to the target compounds. The vinyl ketone and substituted amine were reacted with Hoveyda-Grubbs (1st Gen) catalyst and BF3.OEt2 as an additive in CH2Cl2 at 100C for 20 min under MW irradiation, while the conventional approach at 45C took 4 days for completion.

Tandem Cross-metathesis Aza-Michael Reaction

Tandem Cross-metathesis Aza-Michael Reaction

Hoyveda-Grubbs, 1st Gen

Hoveyda-Grubbs, 1st Gen

 

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