Microwave-accelerated transformations in synthetic organic & medicinal chemistry

Abstract

Microwave assisted organic syntheses have evolved from pioneering work conducted in the 1980's to become a central feature of contemporary organic chemistry. Though initial research was conducted using modified domestic instruments, a variety of sophisticated reactors are now available, and the technology has been adopted widely throughout the pharmaceutical industry. Based on dielectric heating, microwave mediated synthetic transformations exploit the ability to achieve very carefully controlled yet rapid application of thermal energy, which typically results in faster reaction rates and improved product impurity profiles. The research described herein highlights powerful new applications of microwave assisted organic synthesis with particular emphasis on radiolabeling methodologies. In this arena, the full benefits of fast reaction rates are exploited as the methodology can allow practical routes to short half-life radiopharmaceuticals otherwise inaccessible by conventional means. Following a review of the field, Chapter 2 describes microwave mediated fluorodenitration of nitroarenes. In addition to providing access to an array of fluoroarene building blocks for organic and medicinal chemistry, the methodology is extended to the introduction of 18F labeled products. The latter are of importance in the rapidly emerging field of positron emission tomography (PET) imaging, and the reaction times are compatible with the half-life of this positron emitting nuclide, rendering this methodology suitable for adoption in biomedical and clinical imaging. Chapter 3 describes application of microwave mediated cross coupling of substituted arenes with a variety of carbon based electrophiles. Exploiting the power of microwave irradiation in the presence of transition metal catalysts allowed access to products otherwise accessible by conventional methods. Furthermore, by careful choice of substrate, in situ coupling followed by tandem fluorination could be achieved. This one pot, three component methodology provides facile access to libraries of heavily functionalized arene products, including analogs of clinical candidates for PET imaging, where lipophilicity can be readily modulated as desired. In Chapter 4, the application of microwave thermolysis is harnessed in the synthesis of members of the xanthine class of heterocycles. A key feature of the methodology involves a novel catalyzed annulation, and the process provides access to libraries of functionalized xanthines, including inhibitors of the tags, prepared using microwave methodology, for the labeling of peptides, proteins, and antibodies. Applications of these methodologies can be expected through in vivo imaging, allowing biodistribution of the parent biogenic molecule to be studied in real time. Incorporation of aspects of the methodology in the undergraduate chemistry laboratory is also described, together with emerging collaborations with industrial partners.