Studies On Bioinspired Asymmetric Synthesis Of Montanine-type Amaryllidaceae Alkaolids

The natural montanine-type alkaloids exist in many Amaryllidaceae plants, and its unique structure featuring 5,11-methanomorphanthridine nucleus constitutes one of the representative structures of Amaryllidaceae alkaolids. Since the isolation of first montanine-type alkaloid in 1950s, studies on the chemical synthesis of these alkaloids have attracted great interest of the medicinal and synthetic chemists due to their unique polycyclic structure and significant pharmaceutical potential. Despite the substantial progress in the synthetic studies of montanine-type alkaloids in the last two decades, there was no report on their bioinspired asymmetric synthesis in the literature.This thesis mainly aims at the synthetic studies of montanine-type Amaryllidaceae alkaloids along with the related design methodologies, in which the new strategy featuring a bioinspired tandem oxidative dearomatization/intramolecular aza-Michael addition was developed to the effective construction of the crucial 5,11-methanomorphanthridine core of montanine-type alkaloids. The following four parts are mainly included in this thesis:Part 1: The brief introduction to the isolation, structure characteristics and bioactivities of montanine-type Amaryllidaceae alkaloids was presented. With the retrospective analysis for the previous literature reports on the total and formal synthesis of montanine-type alkaloids, some representative achievements were summarized based on the various assemblies of 5,11-methanomorphanthridine skeleton. Five types of advanced synthons were strategically involved, which included the hydroindole-type Ⅰ synthon, the hydroindole-type Ⅱ synthon, the hydroisoquinoline-type synthon, the morphanthridine-type synthon, and the methanobenazapine-type synthon.Part 2:The classification of Amaryllidaceae alkaloids and their possible biogenetic pathways were presented. Focusing on the total synthesis of montanine-type alkaloids, two retrosynthetic analyses were demonstrated, in which a novel bioinspired tandem oxidative dearomatization/intramolecular aza-Michael addition was designed to assemble the unique 5,11-methanomorphanthridine skeleton.Part 3:According to the above retrosynthetic pathway (1) of montanine-type alkaloids, the racemic cherylline-type intermediate with the tetrahydroisoquinoline skelecton was prepared, and then the conditions for the key tandem oxidative dearomatization/intramolecular aza-Michael addition were screened. The possibility of racemic synthesis of montanine-type Amaryllidaceae alkaloids was initially evaluated.Part 4:In terms of the above retrosynthetic pathway (2) of montanine-type alkaloids, two routes for the synthesis of the chiral cherylline-type intermediate bearing the tetrahydroisoquinoline skelecton were firstly developed on the basis of "organocatalytic enantioselective Friedel-Crafts-type conjugate addition of electron-rich phenols with β-aryl-nitro-olefins" and "transition-metal-catalyzed asymmetric conjugate addition of arylboronic acid with β-aryl-nitro-olefins". With the above chiral cherylline-type intermediate in hand, a bioinspired tandem oxidative dearomatization/intramolecular aza-Michael addition was explored as a key reaction, and the detailed investigations on the tolerance of functional groups and the scope of substrates were also conducted. Based on the above methodologies and starting from the common advanced polycyclic intermediate, we developed a diversity-oriented, expeditious asymmetric total synthesis of five montanine-type Amaryllidaceae alkaloids. It is worth mentioning that the current exploration not only synthetically gives a bridge between the tetrahydroisoquinoline skelecton of cherylline-type precursor and the 5,11-methanomorphanthridine core of montanine-type alkaloids, but also manifests the perspective of bioinspired design in the chemical synthesis of other relevant montanine-type alkaloids.