The synthesis of fluorinated natural products.

  • J. A. Wright

Student thesis: Doctoral ThesisPhD


In the Introduction, synthetic and structural aspects of fluorocarbobydrates and fluoronucleosides are reviewed, and it is pointed out that, in the case of carbohydrates, the available synthetic methods are largely limited to the introduction of fluorine into primary or anomeric positions. A few compounds related to carbohydrates, such as fluorotetritols and fluoropentitols are available by total synthesis, but those methods are restricted by stereochemical complications. In the nucleoside fluid, it is shown that until the present time, synthesis of nucleosides fluorinated in secondary positions of the carbohydrate as limited to pyrimidine nucleosides with an oxygen function at position 2 of the base. A few nucleosides containing fluorine in the heterocycle portion are also available, such as 2-floroadenosine and 5-fluorouridine. The biological effects brought about by the introduction of the C-F group to various types of natural product are discussed, and it is seen that replacement of H by F in many such compounds leads to interesting consequences, including inhibition, lethal synthesis, and incorporation of the fluorine-containing molecule into macro-molecules such as nucleic acids. It is proposed that replacement of hydroxyl by fluorine, particularly in important metabolites such as carbohydrates nucleosides, should lead to biologically interesting compounds. Part 1 is concerned with the synthesis of fluoropentoses. The action of hydrogen fluoride in dioxan on the fully-blocked pentose epoxides, methyl 2,3-anhydro-5-0-benzl- and -D-lyxofuranosides (107a & b), is discussed, and it is shown that, in contrast to the known behaviour of this reagent with steroid epoxides and folly-blocked 2,3-anhydropentopyranosides, a complex mixture of approximately eight products is obtained, and the isolation of useful quantities of pure products is difficult. Consequently, the use of HF/dioxan to open pentofuranoside epoxides is considered unsuccessful. Evidence is presented for the formation of 2,3-anhydro-5-0-bunzy1- -D-lyxofuranosyl fluoride (113) by HF/dioxan treatment of methyl 2,3-anhydro-5-0-benzy -D-lyxofuranoside (107b). The use of KHF2, in ethane-diol is discussed, and the action of this fluorinating agent on a number of pentose epoxides is examined. Thus it is shown that treatment of methyl 2,3-anhydro-4-0-benzyl--D-ribopyranoside (117) with KHF2 leads to a secondary fluorosugar which is identified as methyl 4-0-benzy1-3-deoxy-3-fluoro--D-xylopyranoside (118). This structure is assigned on the basis of catalytic hydrogenation, which removes the benzyl group to give the glycoside, methyl 3-deoxy-3-fluoro--D-xylopyranoside (119). The absence of vicinal hydroxyl groups in this glycoside, shown by its failure to react with sodium metaperiodate, Indicates the 3-deoxy-3-fluoro structure, and assuming the normal trans-scission of the epoxide, the xylo-configuration is the most likely structure. Acid hydrolysis of methyl 3-deoxy-3-fluoro--D-xylopyranoside (119) gives 3-deoxy-3-fluoro-D-xylose (121), which crystallizes in the -configuration, 128°. The free sugar is further characterized as the 2,5-dichlorophenylhydrazone, 75°, and the glycoside as the 2,4-di-0-toluene-p-sulphonyl ester (120) 138°. Extension of the use of KHF2 for the synthesis of secondary fluorosugars in the furanose form is next described. Treatment of methyl 2,3-anhydro-5-0-benzyl--D-lyxofuranoside (107s) with KHF2 leads to a mixture of products from which a 30% yield of methyl 5-0-benzy1-3-deoxy-3-fluoro--D-arabinoitiranoside (122) is isolated by preparative thin-layer chromatography. The structure of this fluorosugar was established by acid hydrolysis to the reducing sugar, 5-0-benzyl-3-deoxy-3-fluoro-D-arabinose (126). On treatment with periodate, this consumes 1 mole of the oxidant, and liberates 1 mole of formic acid, indicating the presence of a -CHOH-CHO residue, and thereby showing that the fluorine is at C3. On the basis of trans-scission of the epoxide, therefore, this series of fluorosugars is assigned the 3-deoxy-3-flaoro-D-arabinose configuration. Catalytic hydrogenation of methyl 5-0-benzl-3-deoxy-3-fluoro--D-arabinofuranoside (122) results in a quantitative yield of methyl 3-deoxy-3-fluoro--D-arabinofuranoside (127), characterized as the syrupy 2,5-di-0-acutate (129) and the crystalline 2,5-di-O-benzoate (130), 82°. Acid hydrolysis of the glycoside (127) using 0.1N aqueous sulphuric acid leads to the free sugar, 3-deoxy-3-fluoro-D-arabinose (128), which is readily induced to crystallize ( 120°) in the -configuration by seeding with -D-arabinose. Further characterization of the free sugar is obtained by preparation of the 2,5-dichlorophenylhydrazono, 120°. The preponderance of the 3-deoxy-3-fluoro-D-arabinose isomer produced by fluorination of the 2,3-anhydrolyxofuranoside is explained in terms of the conformational stabilities of the transition states arising from the two possible mods of SN2 opening of the epoxides. On the same basis, products obtained from fluorination of methyl 2,3-anhydro-5-0-benzyl--and --D-ribofuranosides (142a & b) are expected to be principally 2-deoxy-2-fluoro-D-arabinose and 3-deoxy-3-fluoro-D-xylose derivatives and experimentally this is found to be the case. Thus, KHF2 treatment of methyl 2,3-anhydro-5-0-benzyl--D-ribofuranoside (142b) gives methyl 5-0-benzyl-3-deoxy-3-fluoro--D-xylofuranoside (143), whose structure is determined by periodate oxidation of the 5-o-benzyl reducing sugar (144) as in the 3-deoxy-3-fluoro-D-arabinose series. Catalytic hydrogenation of methl 5-0-benzyl-3-deoxy-3-fluoro--D-xylofuranoside applicability. In Part 2, the synthesis of fluoronucleosides, using the fluoropentoses discussed in Part 1, is described. This method of synthesizing nucleosides fluorinated in the sugar moiety is considered to be less limited than previously-described syntheses. Two well-established procedures are investigated, (a) the chloromercuri procedure, and (b) a direct condensation method, and the latter is shown to give better yields of nucleosides. Methyl 3-deoxy-3-fluoro- -D-xylofuranoside (145) is converted to the crystalline 2,5-di-o-benzoyl ester (148), 67°. Treatment with hydrogen bromide in glacial acetic acid then gives 2,5-di-o-benzoyl-3-deoxy-3-fluoro-D-xylofuranosyl bromide (157), which is immediately condensed under appropriate conditions with 6+benzamidopurine or chloromercuri-6-benzamidopurine to yield 6-benzamido-9-(2,5-di-o-benzoyl-3-deoxy-3-fluoro--D-xylofuranosyl)purine (164). Removal of the benzoyl blocking groups is effected by treatment with methanolic sodium methoxide to give 9-(3-deoxy-3-fluoro--D-xylofuranosyl)adenine (165). The 9--glycosyl configuration is assigned on the basis of the trans-rule, analogy with data. Confirmation of the 9- -configuration is obtained by preparation of 9-(3-deoxy-3-fluoro-5-o-tosyl--D-xylofuranosyl)adenine (168), and its subsequent cyclization to 3,5'-cyclo-9-(3-deoxy-3-fluoro--D-xylo-furanosyl)adenine toluene-p-sulphonate (169). In the arabinose series, methyl 3-deoxy-3-fluoro--D-arabinofurano-side (127) is converted through the 2,5-di-o-benzoyl ester (130) to 2,5-di-o-benzoyl-3-fluoro-D-arbinofuranosyl bromide (158). Condensation the gives 6-benzamido-9(2,5-di-o-benzoyl-3-deoxy-3-fluoro--D-arabinofuranosyl)purine (170). Hydrolysis to the unblocked nucleoside, 9-(3-deoxy-3-fluoro--D-arabinofuranosy)adenine (171) is effected as in the case of the xylofuranosyl analogue. The 9--glycosyl configuration is assigned using the same procedures as for the xylose isomer. Thus, 9-(3_deoxy-3-fluoro-5-o-tosyl--D-arabinofuranosyl)adenine (172), prepared from (171), fails to cyclize upon refluxing in dioxan.
Date of Award1967
Original languageEnglish
Awarding Institution
  • University of Bath

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