The Diels-Alder reaction is one of the most powerful construction processes in organic synthesis, especially for the formation of molecules containing quaternary carbon stereocenters. [1] For this reason there has been much research on the development of enantioselective versions using chiral Lewis acid catalysis. [2] While various kinds of chiral Lewis acid promoted reactions have been developed, these reactions must be carried out under strictly anhydrous conditions. The presence of even a small amount of water stops the reaction because most Lewis acids react immediately with water rather than with the substrate, and decompose or are deactivated. [3] This turns out to be a serious problem when using chiral Lewis acid catalyst in organic synthesis since a large quantity of optically active product is expected to be obtained with a very small amount (> 1 mol %) of enantiopure catalyst.
Among the most useful and reactive enantioselective Diels-Alder catalysts are those reported by Corey that employ an oxazaborolidine catalyst in the presence of a Brønsted acid [4] : this is an excellent example of a Brønsted acid assisted Lewis acid catalyst (BLA). [5] Since we have been interested in combined acid catalysis systems for several years, [5-7] the activity of the corresponding Lewis acid assisted Lewis acid catalyst (LLA) system [6] -an l-proline derived oxazaborolidine as a precatalyst combined with a Lewis acid as an activator-was examined for Diels-Alder reactions. However, the resulting LLA was much less efficient (62 % ee) than the original BLA catalyst. Surprisingly, a simple monocyclic oxazaborolidine 1 derived from l-valine (Scheme 1) was found to be a promising chiral precatalyst for the LLA system. [8] The resulting LLA was not only found to be a highly potent and stable chiral catalyst for the Diels-Alder reaction but it is also unusually resistant to moisture, oxygen, and Lewis bases, [9, 10] which we believe has wide implications for versatile catalyst designs in the future.
Our study commenced with a search for the most effective Lewis acid activator for the Diels-Alder reaction of 1,3cyclopentadiene and methacrolein with the oxazaborolidine 1 a as precatalyst. LLA catalysts were typically prepared by