Abstract:
The cephalosporolides are a family of natural products containing a small but interesting β,γ-fused-5,5- spiroacetal-γ-lactone moiety 23. There are seven members of this family which differ in the stereochemistry about the spirocentre at C-6 and the side-chain attached to C-9. The simplest members of this family are cephalosporolides E 24 and F 25, which only differ in the stereochemistry at C-6. The first section of this thesis describes the synthesis of cephalosporolides E 24 and F 25. The key step of the synthesis is the chelation-controlled Mukaiyama aldol reaction between silyl enol ether 234 and aldehyde 162 using MgBr2·OEt2 in CH2Cl2 to form the cyclisation precursor β-hydroxyketone 160 with the required syn selectivity at C-3 and C-4. Double deprotection of the benzyl groups followed by acid-catalysed lactonisation afforded cephalosporolides E and F as a 3:2 separable mixture. Chapter three of this thesis reports synthetic studies towards several other members of the cephalosporolide family, namely cephalosporolides H 28 and I 29, and penisporolides A 26 and B 27. These natural products differ from cephalosporolides E and F by the presence of a gem-dimethyl group α to the γ-lactone and the long alkyl substituent attached to C-9. The synthesis of four possible stereoisomers of the spiroacetal core of the natural products penisporolides A and B and cephalosporolides H and I is described. Despite the various attempts to synthesise the key β-hydroxyketone 247 via an aldol reaction, a cycloaddition reaction, a dithiane coupling or an allylation reaction, the results were disappointing. The final reaction sequence involved the cross metathesis coupling of alkene 347 and alkene 354 to afford alkene 360. The desired stereochemistry of the γ-lactone was installed by employing a Sharpless asymmetric dihydroxylation of alkene 360. The (DHQD)2PHAL ligand was used to install the (3R,4R) stereochemistry of cephalosporolides H and I and the (DHQ)2PHAL ligand afforded the (3S,4S) stereochemistry at C-3 and C-4 of penisporolides A and B. Oxidative radical cyclisation of the newly formed lactones 345a, 345b, 380 and 381 afforded the spiroacetal core of the natural products. The final section of this thesis is the biological evaluation of analogues of (2”S)-spirolaxine methyl ether 455 against Helicobacter pylori. Helicobacter pylori is the bacterium responsible for stomach ulcers and gastritis and was classified as a class 1 carcinogen in 1994. (2”S)-Spirolaxine methyl ether 455 was synthesised by Brimble et al. in 2007 and exhibits potent activity against H. pylori. In addition to spirolaxine, a series of analogues 462-469 were also prepared by Brimble et al. and these were all evaluated for their anti-Helicobacter pylori activity.