Synthesis Of Some Gem-Difluoromethylenated Analogues Of Natural Products

Currently more than half of the prescription drugs derive from natural products, or natural product analogues. Therefore, the natural product-inspired drug discovery and development has become one of the most efficient strategies to explore new drugs in recent years. It's well known that fluorinated compounds play an important role in life sciences due to the introduction of one or a few fluorine atoms into an organic compound showing profound changes in its chemical and biological nature, so the interest of fluorinated analogues of natural products is increasing continuously. As we known,α,β-unsaturatedδ-lactone is a common structural unit of natural products with medicinal interest. In this dissertation, we designed and synthesized some potentially bioactive gem-difluoromethylenated natural products withα,β-unsaturated 8-lactones from readily available materials in the hope of exploring a new compound, which shows excellent bioactivity and lower toxicity. The dissertation is divided into following two parts:Part I:Gem-difluoromethylenated analogues of Pironetin, which exhibits significant activity were syntheiszed. Firstly two key segments 3 and 30 have been synthesized after several trials. However, the coupling of the two segments was unsuccessful, which made us adjust our synthetic strategy. The straightforward synthesis of four gem-difluoromethylenated analogues of Pironetin 79,80,81,82 began with available 1,3-propanediol. This approach included the use of two efficient Evans oxazolidinone-mediated syn-aldol condensations to establish the four contiguous stereogenic centers, the highly efficient Wittig reaction to install double bond and the indium-mediated gem-difluoropropargylation of aldehydes 67 and 68 with the fluorine-containing building block 10 to afford compounds 69,70, respectively, then the selective hydrogenation and deprotection of the primary tert-butyldimethylsilyl group to construct gem-difluoromethylenatedα,β-unsaturatedδ-lactones. The biological evaluation of these synthetic analogues was assayed.PartⅡ:Starting from available D-gluconoδ-lactone, we have synthesized two totally deacetylated gem-difluoromethylenated analogues of boronolide 99,100 and two gem-difluoromethylenated analogues of boronolide 101,102. Our synthesis features the efficient construction of the key intermediates 91 and 92 through the indium-mediated gem-difluoropropargylation of aldehyde 90 with the fluorine-containing building block 10. Beginning with the initial synthesized intermediate 87, we also have synthesized two gem-difluoromethylenated analogues of anamarine 133 and 134. The E configuration of the double bond segments in compounds 133 and 134 was constructed by means of the typical Horner-Wadsworth-Emmons reaction and the lactone was obtained by the oxidation of 1,5-diols spontaneously ring closure.