CATSYNCAL · New Organocatalytic Malononitrile Michael Addition Methodology for the Enantioselective Synthesis of Calyciphylline K

New Organocatalytic Malononitrile Michael Addition Methodology for the Enantioselective Synthesis of Calyciphylline K

Calyciphylline K is a complex natural product belonging to the Daphnezomine L-type family of alkaloids, which consists of six compounds isolated from different genera of the Daphniphyllum flowering plant; these compounds represent potential pharmaceutical targets owing to their unique bioactivities. Specifically, Calyciphylline has shown promising activity in the expression of nerve growth factor (NGF)1 and Daphnezomine L (4) has been found to exhibit cytotoxicity against mouse lymphoma cells using in vitro experiments. These compounds may be promising starting points for the development of central nervous system or anticancer pharmaceuticals. During the course of this project, we have developed several synthetic approaches toward the core of the Daphnezomine L alkaloids, along with significant progress towards the completion of these synthetically challenging natural products. Although we initially planned to develop an enantioselective asymmetric Michael addition to construct these compounds, early model studies did not show any evidence for the desired reactivity, and we therefore modified our synthetic approach to overcome this obstacle. Specifically, we have developed a working synthetic route to the tricyclic core of the Daphnezomine L alkaloids which incorporates all of the correct relative and absolute stereochemistry. Key synthetic transformations include a Pd(0) catalysed coupling between an alpha-iodo enone and a vinyl stannane, followed by a diastereoselective Michael addition and a Tsuji-Trost allylation reaction to install the pendant side chain. We also demonstrated the successful transformation of this side chain into either the desired methyl ester or carboxylic acid side chains found in the Daphnezomine L alkaloid family. At the time of writing, our efforts to convert this advanced tricyclic core into the target natural products are still ongoing. As part of these efforts, we also investigated several other synthetic approaches to the Daphnezomine L alkaloids. Several months were spent to develop of a Samarium Iodide promoted radical-type Michael addition to construct the central seven membered ring, however it was later discovered that this reaction provided the incorrect stereochemical configuration for the completion of the Daphnezomine L family of natural products. Other synthetic approaches are still under investigation. In summary, we have successfully demonstrated the synthesis of the core structure of the Daphnezomine L alkaloids which incorporates useful functionality for the completion of this class of natural products. This research should be of great interest to the organic synthetic community as it demonstrates and advances the state of the art in natural product synthesis and applied synthetic methodology. Given the intriguing bioactivities of the Daphnezomine L alkaloids, this work should also find impact within the field of pharmacology and these compounds may provide starting points for central nervous system or anticancer drug development.

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