A novel synthesis of bacterial autoinducer DPD and approaches towards its fluoro-analogues

Abstract

(S)-4,5-Dihydroxypentane-2,3-dione ((S)-DPD) is a signaling molecule for the inter- and intra-species bacterial communication called quorum sensing. Although DPD is a simple molecule, it is highly reactive and functionalized, and therefore complicated to synthesize. The aims of this research were to develop a novel synthesis of (S)-DPD, and to synthesize the fluoro-analogues of (S)-DPD, with the replacement of one or both of the hydroxyl groups with fluorine. (S)-DPD and its fluoro-analogues will be of use in microbiology studies to investigate their biological activities and potentially find a lead for the development of novel anti-bacterials.A novel synthesis of (S)-DPD was developed, starting from a commercially available chemical, L-gulonic acid-γ-lactone, which underwent protection and oxidation, followed by a Wittig reaction, dihydroxylation and oxidation to give (S)-DPD.In an attempt to prepare the fluoro-analogues of DPD, three pathways were designed. Pathway 1 started from D-mannitol using a Wittig reaction to give an alkene diol, (S, E)-Pent-3-ene-1,2-diol, which was the precursor for the fluorination steps. Fluorination of the alkene diol with XtalFluor-E failed to give the desired compounds and pathway 1 was discontinued.Pathway 2 was developed to produce an alkyne diol, (S)-Pent-3-yne-1,2-diol, from D-mannitol, the key step involving a Corey-Fuchs reaction. The very low yield of the alkyne diol led to the termination of the pathway 2.Pathway 3 started from L-gulonic acid-γ-lactone protected by the cyclohexylidene protecting group. The alkyne diol, (R, E)-Pent-3-ene-1,2-diol, was formed in a moderate yield, but its fluorination with XtalFluor-E to make the corresponding fluoro-alkyne (S)-4,5-difluoropent-2-yne failed. Although the syntheses of the fluoro-analogues of DPD have not been achieved, several novel precursors have been prepared and modification of their fluorinating conditions may yield these analogues.

Date of Award	31 Dec 2011
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Sally Freeman (Supervisor) & Andrew Mcbain (Supervisor)