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New Methods for SImple and Selective Tritium Labelling of Drug Candidates & Synthetic Studies towards Crisamicin A

Uffe Sognstrup Larsen

The current PhD thesis gives an Introduction to the two major areas under investigation in the presented PhD work. First, the fundamentals of radioisotopes and the applications and synthesis of radiotracers are introduced. Secondly, cross-coupling synthesis in general is briefly presented followed by a more detailed survey of cross-coupling reactions involving enol phosphates.

Subsequently Tritium Labelling of Drug Candidates describes the development of new methods for simple and selective tritium labelling of drug candidates. Four different areas have been investigated. Synthesis of 1,4- and 1,5-Substituted Tetrahydropyridines describes the synthesis of precursors for tritium labelling of 1,3- and 1,4-disubstituted piperidines. This part includes the development of new Suzuki and Kumada-Tamao cross-coupling syntheses with enol phosphates of 3- and 4-piperidone. In example the highly active catalyst 2-(di-tert-butylphosphino)-biphenyl palladium has proven to promote Suzuki cross-coupling reactions with non-activated enol phosphates which otherwise fail to react. One of the synthesised precursors was subject for further investigation leading to tritium labelling of a Haloperidol analogue. The tritium labelling of the 1,4-disubstituted piperidine was effected in the final step of an efficient six step synthesis starting from 4-piperidone. Isotope Effect in Asymmetric Hydrogenation describes efforts to establish if an isotope effect influences the enantioselectivity in asymmetric hydrogenations. Labelling of Amines by Reduction of Amides provides studies of amide reduction as a strategy for tritium labelling of amines. This work leads to an efficient tritium labelling of bromhexine from the corresponding amide with LiBT4. Finally, Tritium Labelling of Peptides describes efforts to develop a new method for tritium labelling of proteins and peptides employing tributyltin tritide.

Synthetic Studies towards Crisamicin A presents the work performed at The University of Auckland. The significance and previous work dealing with Crisamicin A will be described within the chapter, followed by the development of an efficient eight step synthesis providing a key bis-cyanophthalide intermediate from 3,5-dihydroxy-benzoic acid. The synthetic sequence encloses the development of an efficient Suzuki cross-coupling reaction for a biaryl linkage.

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