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Abstract
Total synthesis of novel structures from Mother Nature inspires organic chemists to develop new methods and tactics. It also shapes the new discipline of synthetic chemistry. In this dissertation, we will introduce our recent total synthesis of several annotinolides, which belong to a new family of Lycopodium alkaloids discovered by the Hu group in 2016. The inspiration of new transformations and strategies during the synthesis of annotinolides will be illustrated. Also, our exploration of the transformation between annotinolides provides some insight to their potential biosynthetic pathway. First, we will analyze the novel structures of annotinolides. We are particularly interested in the cage-shaped molecules within this family. Then we will introduce the inspiring biosynthetic pathway proposed by the Hu group and the synthetic efforts from the She group and the Tu group.
Next, we will discuss our synthetic effort towards annotinolide B in Chapter 2. Based on the four-membered ring within the molecule, we envisioned an intramolecularly [2+2] reaction as the key reaction. We successfully constructed the C ring system, featuring a Michael addition/triflation sequence and the Mitsunobu reaction or oxidation/reduction sequence to install the desired stereochemistry. However, the key [2+2] reaction failed in multiple substrates due to the potential ring strain.
In Chapter 3, our synthesis of 4-epi-annotinolide C, 4-epi-annotinolide D, annotinolide C, annotinolide D and annotinolide E will be introduced. We first attempted to use the intramolecular oxidative coupling reaction to construct the key [3.2.1] bicycle but only led to an unexpected [3.3.1] hemiketal. Based on this result, we used a Conia-ene reaction and iodolactonization to introduce the key caged structure moiety. The stereochemistry was controlled by the tactical application of a nitrile group and the detailed analysis of the conformations for the advanced intermediates. Deiodination on different substrates could lead to different diastereomers, and we were able to access 3 natural products and 2 natural product epimers. The transformations between annotinolide C, D, and E were also explored, which delivered interesting results compared to the proposed biosynthetic pathway.
The asymmetric solution for our total synthesis will be discussed in Chapter 4. We developed an enzymatic resolution approach, which highlights the recovery of the undesired enantiomer. The ee erosion was observed in the following steps, but we could still get 79% ee with detailed optimization.
Finally, we will summary the discoveries and conclusions in Chapter 5. Those results would be inspiring for the synthesis of similar systems.