A modular route to the 1-epi-pseudoguaianolide scaffold from abundant starting material classes is reported. Key transformations of the developed sequence are Knoevenagel condensation of sterically congested ketones, diastereoselective deconjugative alkylation including a predictive model and enyne ring-closing metathesis. In few additional steps, the scaffolds can be converted to advanced intermediates having the key functionality (enone and acrylate) responsible for this large family’s biological activity. In the course of these studies, we also uncovered an unusual Pd-catalyzed stereospecific decarboxylative protonation reaction which allows for selective access to different diastereomers of the epi-pseudoguaianolide scaffold.

Strategy for sampling cis-pseudoguaianolide chemical space

2019 Spring National Meeting

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