The Diels-Alder reaction is a very powerful and selective means for introducing densely packed relative stereochemistry in one synthetic step. The term “relative stereochemistry” is used reiteratively to clearly indicate the typical reaction is not stereoselectively producing one enantiomer over another. Such an outcome would require the transition state taking place in an asymmetric environment. Part One revealed how the reaction is useful in the synthesis of simple six-membered rings, however the synthetic utility spans beyond this.

What happens when a cyclic diene is utilized in a Diels-Alder reaction? A very good example is the reaction of furan, an activated electron rich diene, with diethyl maleate, an activated electron poor dienophile.

The above example “doubly activated” reaction does not require heating at reflux to proceed. In fact, it takes place at low temperature over a period of approximately 36 h. The product mixture favors the endo product over exo even though the exo product is more thermodynamically stable. This is an excellent illustration of just how significant secondary orbital overlap is in stabilizing the transition state of the Diels-Alder reaction.

Low temperature is an effective means in gaining control of stereochemistry in a reaction. Prof. David Evans, et. al.^1,2  illustrated this point in examples of the asymmetric Diels-Alder reaction employing Lewis acid catalysis along with an L-valine-derived chiral auxiliary (X_c), which creates an asymmetric environment in the transition state.

Freshly distilled cyclopentadiene was reacted with an alkene bearing the chiral oxazolidone auxiliary in the presence of Et₂AlCl at -100 °C to obtain the optically active [4+2] cycloadduct in a 48:1 endo/exo ratio. Saponification of the X_c group afforded the chiral endo product in a diastereomeric ratio of 95:5. The rationale for the asymmetric induction is indicated below.

The rigid asymmetric environment imparted by the chelated cationic oxazolidone favors approach of the diene from the least hindered (front) face. The indicated s-cis conformation of the chelated acyl oxazolidone is presumed to be the favored species in solution. Although chiral chelates are not involved in every reaction utilizing an asymmetric induction step, they are an effective recurring theme in Organic Synthesis.

1. Evans, D.A.; Chapman, K.T.; Bisaha, J. J. Am. Chem. Soc. 1984, 106, 4261-4263.

2. Evans, D.A.; Chapman, K.T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238-1256.

© 2011 Joseph Lennox, Ph.D.

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