Synthesis of phosphonates and organofluorine compounds for bio-organic studies

Abstract

This thesis focuses on two main areas: the synthesis of novel anti-metabolites of 1-deoxy- D-xyulose-5-phosphate (DXP) and the stereoelectronics which influence the conformation of fluoromethyl groups in organic compounds. DXP, a sugar phosphate, has recently been established as a key biosynthetic intermediate to a number of plant and bacterial co-enzymes and vitamins. Chapter 1 describes the role of DXP in three biosynthetic pathways; in the formation of the isoprenoid building block isopentenyl pyrophosphate, and the vitamins B(_1) and B(_6). A new strategy to novel antibiotics and / or herbicides is proposed by the inhibition of DXP metabolism. A description of phosphonates as hydrolytically stable phosphate mimics is presented, including fluorine phosphonates that enable fine tuning of these mimics. Synthetic targets are designed as inhibitors of the DXP reductoisomerase catalysed reaction from DXP to 2-C-methyl-D-erythritol-4-phosphate (MEP). In Chapter 2 the successful synthesis of the CH(_2) phosphonate analogues of DXP and MEP is described. The DXP analogue was initially approached via the diethyl phosphonate ester, however it proved necessary in the end to prepare the dibenzyl ester followed by hydrogenation. Synthesis towards the CF2, and the a-fluorinated ketone, phosphonate analogues of DXP were incomplete due to low yields. Further syntheses is described towards the reduced form of the CH2 phosphonate analogue of DXP, and to a compound related to fosmidomycin. Chapter 3 describes fluorine's stereoelectronic influence in determining the conformations of fluoromethyl containing organic compounds through n/π-σ* conjugation and gauche effects. Solid state evidence for the influence of these effects is presented through the first X-ray crystallographic data of fluoromethylaromatics and β-fiuoroethylamides respectively. Structures of bis-2,6-(fluoromethyl)pyridine and its N-oxide displayed fluoromethyl conformations with the C-F bond co-planar to the aromatic ring whereas benzyl fluoride and 4-bromobenzyl fluoride displayed conformafions with the C-F bond orthogonal to the aromatic ring. Structures of N-(2-fluoroethyl)-3,5-dinitrobenzamide and N-(2-fluoroethyl)-4-nitrobenzamide reveal a fluorine / amide gauche effect.