Diels-Alder has got to be one of my favorite reactions of all time. Everything happens in one step, attached groups have intriguing (but predictable) effects on the rate, stereochemistry, and regiochemistry of the reaction, and, last but not least, it makes rings…which I find cool…which may make me sound a little nerdy…although apparently listening to video game music remixes also makes me nerdy. But that’s another story. 🙂 Today’s story stems from this JOC paper, which describes the enantioselective synthesis of bridged bicyclic ring systems via an (here comes the good part!) intramolecular Diels-Alder reaction!
There are two kinds of intramolecular Diels-Alder (IMDA). In type 1 substrates, the diene is connected to the dienophile at carbon 1, and in type two substrates, carbon 2. See below.
You’ll notice that type 2 substrates are particularly well-suited for forming bridged bicylic ring systems with bridgehead double bonds via the IMDA. Bear, Sparks and Shea have written a nice Angewandte Chemie review with some of the history of this reaction. To give you an idea of how unstable bridgehead double bonds actually are, the bridgehead double bond in bicyclo[3.3.1]nonene has been shown to be a million times as nucleophilic as an unstrained double bond! A one-step synthesis of something that reactive? Pure gold! If you read the Angew. Chem. paper, check out the intruiging rearrangement of methylene bicyclo[3.3.1]nonene (5) to dimethylene bicyclo[2.2.2]octane (3). Crazy stuff!
In the old days, temperatures for the type 2 IMDA were in the hundreds of degrees. Lewis acid catalysts have rendered these harsh conditions obsolete, although the reactions take longer when run at room temperature (hours and minutes, compared to seconds for the gas-phase reactions that were done originally). Dimethylaluminum chloride seems to work well as a catalyst. Developments since then have focused on applying the reaction to organic synthesis.
The late 1970’s is “the old days”…wow, I’m getting old. 🙂