Ynthetic Studies Towards The Lycopodium Alkaloid Palhinine A

The Lycopodium alkaloids are unique polycyclic natural products possessing high structural diversity and significant pharmaceutical potential, and many of them have attracted great interests from medicinal and synthetic chemists. In2010. Palhinine A as a novel C10N-type Lycopodium alkaloid was first isolated by Chinese organic chemists. This tetracyclic alkaloid has an unprecedented isotwistane core, to some extent, demonstrating a challenge from a synthetic point of view. Presently, there was no report on its total synthesis in the literature. This thesis mainly aims at the synthetic study of Lycopodium alkaloid Palhinine A, in which the intramolecular Diels-Alder reaction as a key step was strategically applied to the effective construction of the crucial isotwistane core of Palhinine A. The following three parts are mainly included in this thesis.Part I:Focusing on the Diels-Alder reaction, this chapter gave a brief introduction on its discovery, development as well as synthetic applications in organic synthesis. Since its first report in organic chemistry, the Diels-Alder cycloaddition as one of the classic organic reactions has been well developed experimentally and theoretically in intramolecular or intermolecular fashion, and the deep insight to its chemoselectivity and stereoselectivity has been achieved. Currently, the Diels-Alder reaction has become one of the most powerful reactions in organic synthesis.Part II:Aiming at the construction of the isotwistane skeleton in the Lycopodium alkaloid Palhinine A, we designed the first generation synthetic route featuring an intramolecular Diels-Alder reaction as the key step. Commencing with the readily available1,3-cyclohexanedione, a three-step transformation delivered the cycloaddition precursor, which was subsequently subjected to the thermal conditions of intramolecular Diels-Alder reaction, affording the desired isotwistane skeleton of Palhinine A. This synthetic achievement strategically provides a substantial possibility for the development of routes to Palhinine A in the late stage.Part III:Despite the fact that the isotwistane core could be accessed by using Diels-Alder strategy, the post-synthetic functionalization in our first generation route proved to be problematic. To address the above problems, we designed the second generation synthetic route towards the total synthesis of Palhinine A. According to our revised consideration, an alternative cycloaddition precursor was then designed for the key intramolecular Diels-Alder reaction, and the multi-functionalized tricyclic synthon with the crucial isotwistane core was effectively achieved, laying a basis for the final establishment of nine-membered azonane ring in the total synthesis of Palhinine A.