Samarium (II) iodine-mediated organic synthesis.

The aim of this project was the synthesis a range of carbocycles from carbohydrates using SmI2 as the key reagent. Carbocycles derived from functionalised cyclopentanes form important substructures in many natural compounds, many of which are biologically active. This therefore provides a route to many highly desirable biologically active analogues. The project was initiated with the selective preparation of a variety of substituted g- butyrolactone dimers. To the end of preparing the dimers, we foresaw that g-ketoesters would be ideal substrates: pinacolisation to the corresponding bis-Sm-alkoxide, followed by intramolecular cyclisation onto esters, was anticipated to afford the corresponding g- butyrolactone dimers. The requisite g-ketoester starting materials were readily available via the Stetter reaction of a variety of aryl aldehydes with some a,b-unsaturated esters. A range of g-butyrolactone dimers was prepared. In keeping with the pinacol type reaction, the second section of work investigated focussed on the pinacol coupling of a variety of 1,4-diketone analogues with SmI2. The primary substrate on which the study began was 2,3,5-tris-O-phenylmethyl-D-arabinose. A variety of functionalities was introduced at the anomeric position and pinacol coupling attempted. It was interesting to see the crucial role that the radical acceptor played in the success of the transformation. These functionalities include an O- methyl oxime, nitrile, butyl group and the thiophene. The O-methyl oxime proved to be a poor radical acceptor and after several attempts no success was attained. This therefore initiated a new study to find an improved radical acceptor. Both the butyl and thiophene groups successfully gave the desired cyclobutanol analogues. In addition to the pinacol reactions attempted with 2,3,5-tris-O-phenylmethyl-Darabinose analogues, pinacol coupling reactions were attempted with deoxy-analogues of D-ribose. Once again a variety of substitutions at the anomeric position were looked at. These include the phenyl, butyl and furan groups. Both the phenyl and butyl containing deoxy-analogues were successfully converted into cyclobutanol products. The first work described in this thesis focussed upon the pinacol cyclisation of chiral 1,4- diketone derivatives. The second section of work relied on a keto-olefin cyclisation reaction to afford the cyclobutane product. The first part of this aspect of the work looked at the construction of functionalised cyclobutanols from carbohydrate precursors via 4-exo-trig cyclisations. The work was initiated with a D-arabinose derived substrate, a sugar having trans stereochemistry at positions 2 and 3. The work was then extended to sugars having cis stereochemistry at position 2 and 3. 2,3:5,6-Di-O-isopropylidene-Dmannofuranose successfully gave three of the desired monomers. Due to the large protective groups at positions 5 and 6, dimer formation was not possible. Ultimately, success was obtained using D- lyxose as a starting substrate. After transforming the starting sugar to a substrate suitable to attempt a 4-exo-trig cyclisation on, four cyclobutane monomer products, along with a single dimer product, were obtained. The latter set of reactions was based on a defined reaction sequence revolving around a Wittig reaction and in situ oxidation sequence to set up the desired precursor for the SmI2-mediated cyclisation. It was desirous to probe the possibility of employing a different approach to setting up the direct precursor to the cyclisation reaction, one that did not rely on the Wittig-oxidation sequence. This new approach delineates a new methodology towards the formation of cyclobutanes, involving the SmI2-mediated cyclisation between an aldehyde and an activated alkene. In addition to the new route to cyclobutanes, a novel approach making use of an elimination reaction to form the desired enal is described. The synthesis of the desired analogue proved to be quite problematic but with very interesting conclusions being derived from varying various func tionalities on the precursor carbohydrate. The desired substrate containing an aldehyde and an a,b- unsaturated nitrile was finally synthesised and the well developed samarium diiodide methodology tested. The desired cyclobutanol analogue was obtained, along with a mixture of dimeric products.Prof. D.B.G. William