Manganese catalyzed fluorination and fluorine-18 labeling

Abstract

Fluorinated organic molecules are important in modern chemistry, affording pharmaceuticals, agrochemicals, materials and radioactive tracers for PET imaging. Nevertheless, approaches to incorporate fluorine into organic molecules are limited either in nature or in chemist’s toolbox. Moreover, few of them have been further translated to practical use for PET tracer production. Though enzymatic fluorination via a metal-oxo intermediate has yet been found, other non-oxygen transfer processes have inspired us to explore fluorination via such an oxidative strategy in synthetic models. In the past few years, several fluorination methods catalyzed by manganese catalysts have been discovered in our group. The use of simple fluoride ion in these reactions facilitated their adaption to 18F chemistry using [18F]fluoride. In this dissertation, this manganese-catalyzed strategy has been further developed, poised to the clinical implementation of 18F PET.

In chapter 2, We describe a successful translation of manganese catalyzed decarboxylative 18F-fluorination to a radioactive scalable and automated robotic procedure for the preparation of clinical doses. This protocol provides access to tertiary carbon-[18F]fluorine bonds that are hard to synthesize via conventional methods. It also offers a more efficient approach to prepare tracer molecules containing a 18F-fluoromethoxy group than current strategies. Two tracer candidates have been synthesized in this way, showing the utility of this method in drug development and PET imaging.

Inspired by a redirected heteroatom rebound process in SyrB2 enzyme, in chapter 3, we have evaluated the possibility of evolving an oxidative fluorination strategy in a non-heme coordination scaffold. A cis-difluoromanganese(III) complex has been synthesized, characterized and demonstrated fluorine transfer activity to alkyl radicals. Oxo-manganese(IV) intermediates have been accessed. Additionally, fluorinated products from simple alkanes was observed in the catalytic conditions. These results have shown the mechanistic feasibility of this manganese catalyst platform to fluorination.

In the last chapter, we have explored the reaction further using [18F]fluoride and presented a novel, late-stage C-H 18F labeling chemistry. A variety of building blocks and bioactive molecules have been successfully labeled with moderate radiochemical conversions. Operational simplicity of this labeling method will empower its application in automated radio-syntheses and high throughput screening of radiotracer candidates.