Unified retrosynthetic approach for accessing a variety of cytochalasin Kjeld Gerdes, Anton Dieckmann, Markus Kalesse Leibniz Universtiy Hannover Institute of Organic Chemistry, Germany Cytochalasins are renowned for their diverse biological activities, making them attractive for drug development. These compounds have demonstrated promising anticancer [1] , immunomodulatory [2] , and antiviral activities [3] , raising interest in their therapeutic potential for various diseases. To gain access and broaden the scope of the cytochalasin family, a unified retrosynthesis approach is proposed. This strategy streamlines the synthesis process and provides a versatile platform for constructing diverse cytochalasin analogues. The intermediates of important synthetic steps allow us to adapt the approach to synthesise different target cytochalasins. The unified retrosynthetic strategy enables the synthesis of cytochalasins with modified structural features, expanding the chemical diversity of this compound class. Through a late stage Negishi coupling different amino acid derivatives can be mimicked, and many derivatives that could be useful for different applications can be introduced here. With the help of two olefination reactions, many different macrocycles can be constructed by synthesising the side chain in parallel. In addition, access to open-chain cytochalasins can be obtained. In this way, the various cytochalasins can be traced back to the isoindolone motif, which is to be established by a Diels– Alder reaction. This versatility facilitates the optimization of their biological activities, potentially leading to im proved therapeutic applications and a deeper understanding of structure-activity relationships.
A major milestone has been achieved in the synthesis of the isoindolone motif, a crucial structural component that serves as centerpiece of the entire cytochalasin framework. Two potential side chains, which will later function as anchor points in the construction ofthemacrocycle, have also been successfully synthesised.
References 1. M. Trendowski, Anti-Cancer Agents Med. Chem. 2015 , 15 , 327. 2. D. S.Chulpanova, Tissuie Cell, 2021 , 73 , 101664. 3. S. Rochfort, J. Antibiot. Res., 2005 , 58 , 279.
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