Trialkylstannylation of Aryl and Vinyl Halides with a Fluorous Distannane

Abstract

<p> The development of a convenient route for the preparation of fluorous-tagged compounds for use with the fluorous labeling strategy (FLS) is described in this thesis. The FLS is a new and convenient method for the preparation of radiotracers and therapeutics in high effective specific activity (HESA) without the use of preparative HPLC. The objective of this thesis was to expand the general utility of the FLS by enabling the introduction of fluorous tags into molecules using a palladium-catalyzed cross-coupling reaction. To this end, a fluorous distannane, hexa(1H,1H,2H,2Hperfluorooctyl) distannane, was prepared from the corresponding fluorous tin hydride and used to produce trialkylarylstannanes from aryl and vinyl halides. Using the developed methodology, fluorous precursors for two radiopharmaceuticals, fialuridine (FIAU) and idoxuridine (IUdR), were prepared. The fluorous-tagged products were radiolabeled with iodine-125 to afford the desired compounds in high effective specific activity and in good radiochemical yield. </p> <p> Hexa(1H,1H,2H,2H perfluorooctyl)distannane was prepared from the corresponding tin hydride in nearly quantitative yield in the presence of Pd(PPh3)4. The distannane was combined with a series of seventeen aryl bromides and iodides and the appropriate palladium catalyst to afford trialkylarylstannanes in 15-59% isolated yield. </p> <p> The use of a phosphaadamantane ligand reported by Capretta et al. in the cross-coupling was also investigated, and the yields for the model compounds ranged from 13-67% Although no substantial change in yields was observed for aryl halides compared to the traditional catalyst Pd(PPh3)4, the phosphaadamantane ligands were more effective for the synthesis of precursors to [125I]fialuridine (FIAU) and [125I]idoxuridine (IUdR). Using this ligand system, the FIAU precursor was prepared in 38% overall yield from a dibenzoyl-protected vinyl bromide, and the IUdR precursor was prepared in 21% yield from a vinyl iodide. </p> <p> Following preparation of the FIAU and IUdR precursors, direct iodinolysis using a sub-stoichiometric amount of iodine was performed and the products isolated in excellent yield and purity using fluorous solid-phase extraction (FSPE). Following these experiments, the precursors were radiolabeled with [125I]NaI (50 – 500 μCi, 1.9 – 19 MBq) in the presence of Iodo-Gen® as an oxidant. Average radiochemical yields for three trials were 88% for FIAU and 94% for IUdR. The precursor was not observed in the FSPE-purified reaction mixture by UV-HPLC within the instrument’s detection limit. </p> <p> The fluorous labeling strategy allows molecular imaging and associated therapy agents to be produced in high effective specific activity in a rapid and convenient manner. With the development of the fluorous distannane and the associated coupling reactions reported here, the general utility of the fluorous labeling strategy has been greatly expanded. </p>