Studies On Asymmetric Synthesis Of Hyacinthacine A₂ And Hyacinthacine A₃

Pyrrolizidine alkaloids occur widespread in nature and many of them possess a variety of important biological activities. Due to their interesting structural features and pharmacological properties, much effort has been directed towards the stereoselective synthesis of these natural products.In this dissertation, the D-O,O'-dibenzyltartaimide-based synthetic methodology, developed from our laboratory, was improved and used for the total synthesis of hyacinthacine A₂ and hyacinthacine A₃. The main results and observations from these studies are listed as follows:Partâ… Studies on the Asymmetric Synthesis of Hyacinthacine A₂ and Hyacinthacine A₃.Polyhydroxylated pyrrolizidine alkaloids are naturally occurring compounds with a substantial interest as inhibitors of glycosidases and glycosyltransferases. Like other polyhydroxylated alkaloids, they may lead to potential therapeutic drugs against diabetesâ…¡, cancer and viral infections including HIV. Among the polyhydroxylated pyrrolizidine alkaloids, those possessing a hydroxymethyl substituent at C-3 are relatively rare in nature. Hyacinthacines are this kind of compounds, which have been recently isolated from the bulbs of Muscari armeniacum (Hyacinthaceae) and demonstrated to be good inhibitors against rat intestinal lactase, rat epididymis a-(?)-fucosidase, and amyloglucosidase from Arpergillus niger. Consequently, these compounds became attractive synthetic targets and their high potential for therapeutic applications has prompted many efforts for devising general strategies for accessing them and their congeners.One aim of this thesis is to accomplish the asymmetric synthesis of hyacinthacine A₂ and hyacinthacine A₃, exploring a new strategy for the synthesis of hyacinthacines. The requisite D-O.O'-dibenzyltartarimide 71 was prepared from D-tartaric acid by modification of a known method, which allows using cheaper reagents and affords higher yields. For the introduction of the benzyloxymethyl group, we also investigated a variant featuring thesamarium diiodide-mediated benzyloxymethylation. The subsequent reductive dehydroxylation led to trans-diastereomer 73h in a ratio of 6:1 from 71.After changing the N-protection group to -Boc, we introduced the TBS-protected propanol group. And then a second reductive dehydroxylation followed, which afforded, in one-pot, the reductive dehydroxylation/ N-deprotection anti product as main product 77h (7.3:1). Finally hyacinthacine A₂ was obtained via two steps with a total yield of 16%.A 1-butene group was introduced to 73h in the synthesis of hyacinthacine A₃. 80h was obtained via the same procedure mentioned before in a ratio of 8:1. The following oxidation and reductive-cyclization afforded hyacinthacine A₃ with a total yield of 15%.Partâ…¡Synthesis of Cytosporone B Analogues with One Hydroxyl Group Malignant tumor disease threatens human life and health seriously. In the near future, it would become the number one killer followed by cardio-cerebral vascular diseases. Recently, researches on antitumor drugs have acheived much progress. Among them, small organic molecule drugs are receiving more and more attention.Cytosporone B, a polyketides compound which was isolated from endophytic fungi dothiorella sp. (HTF3), exhibited great antifungal and cytotoxin activities with the potential of pharmaceutic value. In this dissertation, the synthsis of cytosporone B analogues with one hydroxyl group were investigated. The main results are listed as follows:Starting from phenol, 7-hydroxy-2,3-dihydroinden-1-one 113 was synthesized in a known three steps-two ports reaction. Treated with different Grignard reagents, compound 113 was converted to 1H-indene 115 with different carbon chains on C-3. The following oxidation, esterification and deprotection gave the target molecule 118a and 118b in total yield of 5% and 6%. This approach is cheap and flexible, and is suitable for the synthesis of other compounds with similar structures.