Studies towards the total synthesis of DEM30355/A and related polyketides

PhD ThesisDEM30355/A 1 is a novel bioactive natural product polyketide isolated from an Amycolatopsis bacteria. 1 shows antibacterial activity against several pathogenic Gram positive bacteria, including methicillin-resistant Staphylococcus aureus. Thus we have explored the total synthesis of 1 and a number of related polyketide natural products (Figure 1). Figure 1: Structure of DEM30355A 1. In our first attempts towards the synthesis of target molecule 1 we examined several synthetic routes towards a key intermediate 2. These routes included: (a) the synthesis of Wittig product 3, followed by an unsuccessful attempt at a sterically challenging Baylis- Hillman reaction with diethyl ketomalonate 4; (b) following the synthesis of 5, an attempted Lewis acid catalysed Friedel-Crafts reaction between 1,4-dimethoxybenzene 6 and 5; and (c) Heck coupling of 2-bromo-1,4-dimethoxybenzene 8 with 5. The best results were obtained via route (c) although the yields from the Heck coupling were low, prompting us to examine an alternative route (Scheme 1). Scheme 1: Examined routes to key synthetic intermediate 2. Abstract iii We then examined alternative synthetic approaches towards the aromatic ring A of target molecule 1, based on the formation of the synthetic intermediate 9. Compound 11, which contains the core substitution pattern needed to create ring A, was successfully produced via an unusual bromination of 2,5-dihydroxybenzaldehdye 10. After considerable optimisation we developed a method for the di-methylation of 11. Reduction of aldehyde 12 into corresponding alcohol 13 and subsequent protection of 13 with TBDMSCl gave 14 in a high yield. The synthesis of 9 was completed via a halogen-metal exchange reaction of 14 followed by trapping with DMF (Scheme 2). Scheme 2: Synthesis of ring A. Alongside our work towards the synthesis of 1, we have examined the total synthesis of the polyketide natural product (-)-(3R)-5-hydroxymellein 15, starting from the previously synthesised common intermediate 13. We have successfully synthesised 18, the deoxy-analogue of 15, via a halogen-metal exchange reaction of 16 followed by ring opening of propylene oxide and followed by deprotection and cyclisationUmm Al-Qura Universit