A multi-substrate screening approach for the identification of a broadly applicable Diels-Alder catalyst

Abstract

When developing a synthetic methodology, chemists generally optimize a single substrate and then explore the substrate scope of their method. This approach has led to innumerable and widely-used chemical reactions. However, it frequently provides methods that only work on model substrate-like compounds. Perhaps worse, reaction conditions that would enable the conversion of other substrates may be missed. We now show that a different approach, originally proposed by Kagan, in which a collection of structurally distinct substrates are evaluated in a single reaction vessel, can not only provide information on the substrate scope at a much earlier stage in methodology development, but even lead to a broadly applicable synthetic methodology. Using this multi-substrate screening approach, we have identified an efficient and stereoselective imidodiphosphorimidate organocatalyst for scalable Diels-Alder reactions of cyclopentadiene with different classes of α,β-unsaturated aldehydes.

Fig. 1

Two approaches to identify a selective catalyst. a Model substrate approach vs. b multi-substrate screening approach

Fig. 2

Multi-substrate screening of Diels–Alder reactions of α,β-unsaturated aldehydes and cyclopentadiene. a Investigated reactions. b GC chromatogram of the stereoisomeric product mixture. c Chromatogram of the product mixture using catalyst 4h. d Graphical representation of a subset of the multi-substrate screening. *Reactions at room temperature. **Reactions at −100 °C. For detailed reaction conditions and results, see Supplementary Note 2

Fig. 3

Large scale experiments. Two gram scale experiments were conducted with each cyclopentadiene and aldehyde 1b and aldehyde 1c, respectively. 21.2 g of pure product 3b was obtained

Fig. 4

The solution structure of catalyst 4g. Structural characteristics of our catalysts were revealed by using NMR-based models