As noted by Poree and Schoenebeck : "Computationally driven evolution of catalysts is an exciting prospect because it would allow us to break free of the limitations of our ideas and preconceptions." However, it is not clear that this prospect can be achieved by screening userdefined libraries. In this paper, we present a de novo discovery of a new tertiary amine catalyst for the methanol-mediated Morita-Baylis-Hillman (MBH) reaction using GA searches of the entire chemical space of tertiary amines, with synthetic accessibility as the only constraint. The GA searches discover that azetidines are likely to be potent catalysts despite the fact that this moiety is not in the starting population of most of the searches. One of the molecules was successfully synthesized and is indeed more active than DABCO with an eight-fold increase in the rate-constant corresponding to a roughly 1 kcal/mol lower barrier, in good agreement with the predictions.