Novel synthetic routes towards the anti-inflammatory mediator resolvin E1, and methodology development

2015-11-23T16:12:03Z (GMT) by Natalie J. Brown
The benefits of fish oil supplementation for inflammation based disorders has been well-documented,[1] prompting investigations into the pathways through which these benefits are achieved. This led Serhan et al. to the discovery of a new class of pro-resolution lipid mediators, termed resolvins .[2][3] There has subsequently been much research into their being a potential treatment for chronic inflammatory diseases such as asthma,[4] diabetes,[5] and arthritis.[6] The aim of this research was to study the bioactivity of resolvin E1 (RvE1) and its analogues; to do this a flexible and versatile route towards the chemical synthesis of RvE1 had to be developed, which would allow for easy modification of the stereochemistry of the C-C double bonds and hydroxyl groups, as well as producing fragments containing key functional groups. The first proposed route synthesised RvE1 from two key fragments termed the lactone and epoxide fragments. RvE1 contains three stereogenic hydroxyl groups, one with S configuration and two with R configuration. The epoxide fragment was to be converted into two adjacent sections of the RvE1 chain. The S-stereocentre was introduced via hydrolytic kinetic resolution using a Jacobsen s catalyst.[7] The two R-stereocentres were introduced via the chiral pool originating from 1,2:5,6-di-O-isopropylidene-D-mannitol. Unfortunately, problems were encountered late on in the synthesis of both fragments and therefore a new synthetic route had to be devised. The second proposed route synthesised RvE1 from two key fragments termed the alkyne and halide fragments. The S-stereocentre and one R-stereocentre were proposed to be introduced via asymmetric reduction of a ketone group. The other R-stereocentre was proposed to be synthesised with the use of chiral additives during an indium-mediated coupling reaction.[8] As work progressed on the halide fragment, the Lewis acid catalysed thermodynamic conversion of a branched chain homoallylic alcohol to its linear counterpart was trialled in order to obtain one of the conjugated diene system in RvE1. Using literature conditions for a similar system[9] this reaction was unsuccessful. The reaction mechanism was studied and a hypothesis was put forward that adding a catalytic amount of the aldehyde that the branched chain homoallylic alcohol was synthesised from to the reaction mixture would promote the thermodynamic conversion to the linear chain. These conditions were trialled on a number of different starting materials, leading to either an improvement in yield for the thermodynamic conversion, or the success of a previously unsuccessful conversion.