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The Synthesis of Gem-Difluoromethylenated Analogues of Natural Products

Author: DengXiangJun
Tutor: QingFengZuo
School: Donghua University
Course: Organic Chemistry
Keywords: α,β-Unsaturated-δ-lactone gem-Difluoromethylenated Dodoneine Evans Aldol reaction Wittig reaction Discodermolide
CLC: O621.3
Type: Master's thesis
Year: 2009
Downloads: 18
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Abstract


This dissertation focused on the synthesis of fluorinated analogues of natural product with potential bioactivity by using novel fluorine-containing building blocks. Asα,β-unsaturatedδ-lactone is a common structural unit of natural products with medicinal interests and is also a versatile building block for synthesis of complex natural products, we designed and tried to synthesize potentially bioactive molecules:fluorinated analogues of Dodoneine and Discodermolide containing y,γ-gem-difluoromethylene-α,β-unsaturatedδ-lactones structure. The dissertation is divided into two parts:Part I:The total synthesis of fluorinated analogs of DodoneineDodoneine was isolated from Tapinanthus dodoneifolius, a hemiplant parasite, and was found to exhibit relaxation effects on preconstricted rat aortic rings. The structure of dodoneine contains a aromatic ring and a a,(3-unsaturated-8-lactone ring. We designed and tried to synthesize difluoromethylated dodoneine analogue la.Starting from cheap and readily available L-malic acid, alcohol 12 was prepared via ester 11 through a reaction sequence comprising selective reduction, TBS, MOM protection. Unfortuanately, the oxidation of alcohol 12 to aldehyde 13 was failed. so the synthetic route was modified, alcohol 15 was synthesized and which can be oxidized to aldehyde 16. Aldehyde 16 was then subjected to the Wittig reaction with 2 to form 18 which is supposed to react with the fluorine-containing building block 4 after the cleavage of benzyl group, reduction of C=C, and oxidation of alcohol. Difluorinated analogs of dodoneine la can be conveniently prepared from homopropargyl alcohol 7 by syn-reduction, deprotection, oxidative cyclization, and finally removal of the protection group. We only finished the synthesis of 18 so far due to time limitation.Part II:The synthesis of B Unit (C9-C14) of analogues of DiscodermolideDiscodermolide was isolated from the deep-sea sponge. Its highly encouraging biological profile makes it a promising candidate for clinical development as an anticancer drug. Discodermolide was usually cut into three fragments in its total synthesis, and the uint B(C9-C14) of discodermolide was synthesized in this dissertation.Starting from (S)-(+)-3-hydroxy-2-methylpropionate, aldehyde 28 was prepared by PMB protection of hydroxyl group, reduction of the ester group, Swern oxidation of hydroxyl group. And the triad of contiguous stereogenic centers was orchestrated through Evans syn-aldol reaction The auxiliary group was directly removed after the MOM protection of alcohol 25, A new method for preparing Z vinyl iodide 21 through dibromodiene 30 was tried and failed. The aim compound 21 was finally abtained by Zhao-wittig reaction according to literature method. The synthesis of unit B (C9-C14) took 8 steps in a total yield of 23%.

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CLC: > Mathematical sciences and chemical > Chemistry > Organic Chemistry > Organic Chemistry general issues > Synthetic organic chemistry
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