Catalytic carbozincation of diazoesters and development of probes for F-18 imaging based on rapid bioorthogonal reactivity.

摘要

This dissertation has been focused on the development of new synthetic methods for carbometallation and in the use of rapid bioorthgonal chemistry to construct 18F-PET probes for nuclear medicine.;While the canon of Rh(II)-catalyzed reactions with diazo compounds is extensive, there were no reports in which organometallic compounds have been engaged as substrates. Organozinc reagents have been employed in a variety of transition-metal catalyzed coupling reactions, and have been shown to display a wide range of functional group tolerance. In Chapter 1, it is shown that organozinc reagents may participate in reactions with diazo compounds by two distinct, catalyst-dependent mechanisms. With Rh2(DIEA)4, the likely reaction mechanism initial formation of a Rh-carbene and subsequent carbozincation to give a zinc enolate. With Rh2(OAc)4, initial formation of an azine preceeds a subsequent 1,2-addition reaction with an organozinc reagent. This straightforward route to the hydrazone products provides a useful method for preparing chiral quaternary alpha-aminoesters or pyrazoles via the Knorr condensation with 1,3-diketones. Crossover and deuterium labeling experiments provide evidence for the mechanisms proposed.;1,2,4,5-Tetrazines, or s-tetrazines, have a rich history that bridges applications in synthesis, energetic materials, supramolecular chemistry and bioorthogonal chemistry. Tetrazines are almost always prepared through the initial formation and then oxidation of 1,4-dihydro-s -tetrazines. Nitrous reagents are commonly used as the oxidant for 1,4-dihydro-s-tetrazine oxidation. The advantage of using nitrous acid is the low cost of the reagent. A disadvantage of nitrous acid is that of functional group tolerance due to the acidic and harshly oxidizing conditions. In Chapter 2, it is described that phenyliodonium diacetate serves as a mild and efficient reagent for converting dihydro-s-tetrazines to s-tetrazine derivatives. This oxidant provided an efficient, large-scale synthesis of an s-tetrazine derivative that is used in various applications in nuclear medicine and cell labeling. Exploration of substrate scope showed that heterocycles like furan and pyridine are tolerated, and that dialkyl and diphenyl substitutions are also tolerated.;In Chapter 3, it is shown that tetrazine-trans-cycloctene ligation can be used efficiently for Positron Emission Tomography (PET) probe construction. The fast reaction rate for the tetrazine-trans-cycloctene ligation is shown to be advantageous for achieving labeling at low concentration and with a minimal excess of substrate, reducing the effects of competitive inhibition from the unlabeled substrate. An initially developed system based on dipyridyl-s-tetrazine was successfully used for rapid construction of an 18F-labeled cRGD conjugate that could be used for in vivo imaging in a mouse tumor model. However, metabolic stability studies showed that the probe stability was only modest. A CF3-substituted 3,6-diphenyl-s-tetrazine derivative displays fast conjugation rates toward an 18F-labeled TCO, providing nearly quantitative 18F labeling within minutes at low micromolar concentrations. This bioorthogonal ligation reaction was used to construct an 18F-cRGD conjugate, which was evaluated for integrin alpha