Synthetic approaches to polyoxygenated chromone and chromanome natural products

The work described in this thesis is concerned with the chemistry ofpolymethoxylated aromatic carbonyl compounds bearing a 2,6-dioxygenatedsubstitution pattern, with particular regard to establishing synthetic routes tobiologically active chromone and chromanone systems. Syntheses of keyintermediates in the approaches to the natural products stigmatellin, baicalein andLL-D253(x (and related products) were undertaken.In chapter one the reactions of nucleophiles at the carbonyl moieties of 2,6-dioxygenated benzene carbonyl compounds are reviewed. This type of processocan present special difficulties and was to prove particularly significant at variousstageso f the work describedi n subsequenct hapters.Chapter two is a review of the provenance, abundance, biosynthesis, and previoussyntheses of the natural products stigmatellin, baicalein and LL-D253(x, thesebeing the targets of the synthetic work undertaken in the course of the project.Chapter three is concerned with an approach to a fragment of the stigmatellinmolecule (referred to as stigmatellin fragment A) using the Vilsmeier formylationreaction, while chapter four is concerned with an alternative approach tostigmatellin fragment A using Friedel-Crafts acylation methodology. Thestrategies and the results obtained are described and analysed in detail.In chapter five a strategy for the synthesis of baicalein trimethyl ether is describedand the results obtained are discussed

High response speed microfluidic ice valves with enhanced thermal conductivity and a movable refrigeration source

Due to their ease of fabrication, facile use and low cost, ice valves have great potential for use in microfluidic platforms. For this to be possible, a rapid response speed is key and hence there is still much scope for improvement in current ice valve technology. Therefore, in this study, an ice valve with enhanced thermal conductivity and a movable refrigeration source has been developed. An embedded aluminium cylinder is used to dramatically enhance the heat conduction performance of the microfluidic platform and a movable thermoelectric unit eliminates the thermal inertia, resulting in a faster cooling process. The proposed ice valve achieves very short closing times (0.37 s at 10 μL/min) and also operates at high flow rates (1150 μL/min). Furthermore, the response time of the valve decreased by a factor of 8 when compared to current state of the art technology

Photochemical synthesis

Photochemical reactions are generally easily carried out, at least in laboratory scale, and require no expensive apparatus. Some general reactions, e.g. the cycloaddition of enones to alkenes and various oxygenations have been extensively investigated and represent an excellent choice for preparative applications. Many other possibilities are known-and a few are presented below. This suggests that photochemical steps should be considered more often in synthetic planning

Non-monotonic dynamics and crosstalk in signaling pathways and their implications for pharmacology

Currently, drug discovery approaches commonly assume a monotonic dose-response relationship. However, the assumption of monotonicity is increasingly being challenged. Here we show that for two simple interacting linear signaling pathways that carry two different signals with different physiological responses, a non-monotonic input-output relation can arise with simple network topologies including coherent and incoherent feed-forward loops. We show that non-monotonicity of the response functions has severe implications for pharmacological treatment. Fundamental constraints are imposed on the effectiveness and toxicity of any drug independent of its chemical nature and selectivity due to the specific network structure