Enzymes derive some of their effectiveness by orienting substrates into reactive conformations. This technique can be challenging to mimic using small molecule catalysts, which lack the structural complexity of a protein. However, hydrogen bonding has recently shown promise in achieving enzyme-like directing effects with a simpler scaffold, and Rajaram and Sigman have developed chiral oxazoline-derived catalysts with two proximal hydrogen bond donor sites: a hydroxyl group and a secondary amine. The catalysts are efficiently prepared from amino acids and feature tunable donor strength through variation of the nitrogen substituent. Initial work has produced an optimized structure for the catalytic asymmetric hetero Diels-Alder addition of aryl aldehydes to substituted dienes. Appending a camphor sulfonyl group to the amine drives the reaction with enantiomeric excesses up to 92%. Products of this reaction can then be efficiently elaborated to useful pyranone intermediates. The dual hydrogen-bonding sites proved crucial for grasping the substrates, because catalysts lacking either the hydroxyl or the amine group afforded significantly diminished yields and selectivities. -- JSY
Org. Lett.10.1021/ol052300x (2005).
