Towards the total synthesis of stemona alkaloids oxyprotostemonine and 1-hydroxystemonine



Towards the total synthesis of stemona alkaloids oxyprotostemonine and 1-hydroxystemonine

Introduction

The deep knowledge of plant curative properties acquired by traditional folk medicine has motivated the scientific community towards the isolation and characterization of their bioactive components and the development of new drugs. The extracts of several plants of the Stemonaceae family (Stemona, Croomia, and Stichoneuron genera) have long been used in China, Japan, and other Asian countries for the treatment of respiratory disorders, as antihelmintics, and also as domestic insecticides. Significant constituents of these extracts are a series of structurally related alkaloids that may be responsible for their medicinal and antiparasitic properties, although studies on the specific biological activities of individual members of this alkaloid family are quite limited. Around one hundred Stemona alkaloids are currently known, but in the literature there is a continuous flow of new reports describing the isolation of previously unknown members of the family. The structures of thirty of them have been elucidated by X-ray analyses, whereas those of the remainder were determined from their spectroscopic data and/or by chemical correlation.

All the Stemona alkaloids are polycyclic and most of them possess a central pyrrolo azepine system as a characteristic structural feature, although a few contain a pyrido azepine core instead. The majority also incorporate at least one -methyl- -butyrolactone substructure, which can be linked to the azabicyclic core variously in a spiro or a fused manner or as a substituent. Considering their structural diversity, Pilli and co-workers have recently classified the Stemona alkaloids into eight groups. The common structural motif within each group, along with its most representative member, are shown in Figure 1. The stenine, stemoamide, tuberostemospironine, stemonamine, parvistemoline, and stemofoline groups each have the characteristic pyrrolo azepine nucleus, whereas the stemocurtisine group possesses the less usual pyrido azepine core, and a further, miscellaneous group includes those alkaloids either lacking any of these azabicyclic systems or featuring a hidden pyrrolo azepine moiety. From their biosynthetic connections, Greger has suggested an alternative classification into three skeletal types, which are distinguished by the carbon chains attached to C-9 of the azabicyclic core.

Figure 1. Representative members and characteristic structural feature of the Stemona alkaloid groups according to Pilli's classification.The challenging molecular architectures of the Stemona alkaloids have motivated the development of new strategies for the construction of their skeletons. However, only a small number of total syntheses have been published and they are still limited to quite a small number of targets.This microreview briefly examines most of the synthetic approaches to these alkaloids, according to the strategies devised to assemble their intricate structures. The major difficulties encountered in developing the synthetic plans, including the proper installation of their multiple stereocenters, are addressed. It is not intended to summarize comprehensively or to discuss in detail all the syntheses that have appeared in the literature, but to stress the main similarities and differences encountered in the work developed by different laboratories, as well as the variations introduced along synthetic routes in ...