Collective total synthesis of Grayananes and Kalmanes – SynCol

This project aims at developping a divergent synthetic strategy to access the diversity of Grayanane and Kalmane structures. This strategy will rely on late stage regio- and stereoselective oxidation from two common synthetic scaffolds, one for each family, having the complete carbon skeleton. These two synthetic scaffolds will originate from a common intermediate, having the 6-membered ring characteristic of Grayananes, which will be converted into a 5,5-bicycle characteristic of Kalmane structures through a ring contraction - cyclization cascade.
Thise work will be organized in 4 objectives:
1. Synthesis of the common intermediate
2. Development of the ring contraction - cyclization cascade
3. Synthesis of Grayananes
4 Synthesis of Kalmanes

To this day, the first objective was reached. The common intermediate was obtained through an Ireland-Claisen key rearrangement.
For the second objective, our first approach was to develop a Wolff rearrangement - Prins cyclization cascade. However, this approach proved unsuccessful. We are now exploring an alternative route involving Sakurai cyclization - semi pinacol rearrangement. The alpha oxidation reaction to prepare the substrate for this reaction is currently under study and promising results were obtained using molybdenum oxide.

The next months will be dedicated to objectives 2, 3 and 4. The common intermediate will serve as a synthetic platform to access Grayananes and Kalmanes natural products.

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Grayananes and kalmanes are two families of diterpenoids displaying promising bioactivities. Each family includes many molecules with a same carbon skeleton, and various oxidation levels. The project aims at developing a flexible "collective total synthesis" strategy to access a great number of natural products from these two families in an efficient way. For this, the strategy will rely on a key intermediate common to both families. The differentiation between the two families will arise from a key step featuring a cascade Wolff rearrangement - Prins cyclization, which will be developed as part of the project. The diversity in each family will be introduced in the las steps through directed chemo- and stereoselective oxidations. Through this approach, we plan to synthesize the most recently discovered molecules from the two families of grayananes and kalmanes, in order to study in depth their biological activities.