Methods Development for the Synthesis of Biologically Relevant Porphyrins and Porphyrin Rigid Linker Arrays

Abstract

This research focuses on two main aspects: The synthesis of new derivatives of naturally occurring porphyrins and the preparation of non-natural chromophore-rigid linker conjugates as potential bioisosteres and mimics of photosynthetic systems. While the synthetic accessibility of natural porphyrins is limited there is a demand for new derivatives for biochemical and medicinal applications. A goal of this research was the development of synthetic methods for the functionalisation of protoporphyrin IX dimethyl ester (PPIX-DME) by simple and versatile methodologies. Pd(II)-catalysed cross coupling reactions as well as Cu(I)-catalysed 1,3-dipolar azide-alkyne cycloaddition (?click?) reactions were employed for this purpose. Initially, a procedure for the selective bromination of the vinyl groups of PPIX-DME in up to 84% yield was devised. Suzuki and Sonogashira coupling reactions were successfully performed on the di-brominated porphyrin and the substrate scope was studied. Furthermore, PPIX-DME diyne free base and Zn(II) derivatives, obtained by Sonogashira coupling reaction, were used as precursors for ?click? reactions. The procedures described herein represent robust and versatile methods for the easy functionalisation of PPIX-DME. Following the development of synthetic methods for bromination and coupling reactions on PPIX-DME, the aim was to synthesise PPIX-DME-fluorophore triads as potential theranostic bio-probes with promise for dual therapeutic and imaging applications. Three porphyrin-Bodipy triads were prepared for this purpose: (1) A conjugate consisting of one PPIX-DME und two α-unsubstituted BODIPY units, (2) a Sn(IV)PPIX-DME complex with two axially ligated BODIPY units, and (3) a conjugate composed of one PPIX-DME and two α-distyryl-substituted BODIPY moieties. Preliminary spectroscopic measurements indicated that in the first triad BODIPY-to-porphyrin energy transfer occurred, in the second triad the overall emission of the complex was strongly quenched while in the third triad energy transfer between the porphyrin and BODIPY moieties possibly occurred in both directions. Bicyclo[1.1.1]pentane (BCP) is a rigid hydrocarbon motif which is discussed as a potential bioisostere and as a linker for chromophore arrays. The potential of new synthetic strategies for the preparation of BCP-chromophore conjugates under ?click?-type conditions was studied. 1-Azido-3-iodo-BCP was reacted with different ethynyl-substituted chromophores and small molecules under three different reaction conditions: (1) Standard Cu(I)-catalysed ?click? reaction conditions to form di-substituted BCP-triazoles, (2) Cu(I)-catalysed ?click? reactions in presence of an iodine source and under oxidising conditions to produce tri-substituted BCP-5-iodotriazoles, and (3) Cu(I)/Pd(II)-catalysed cycloaddition-Sonogashira coupling conditions to obtain 5-alkynylated tri-substituted BCP-triazoles. This is the first report of tri-substituted triazoles conjugated to the BCP motif. The obtained products have promise as bioisosteres in medicinal chemistry applications. Furthermore, a variety of BCP-linked chromophore arrays were prepared as potential electron/energy transfer model systems. The BCP motif was incorporated as a rigid, non-conjugated linker unit between different donor and acceptor moieties with the goal of arranging the substituents in a defined spatial manner while preventing any undesired electronic coupling between them. An electron-deficient (15-(pentafluorophenyl)-10,20-diphenylporphyrinato)zinc(II) moiety as the energy acceptor unit was connected via the BCP linker to BODIPY, pyrene and (10,15,20-triphenylporphyrinato)zinc(II) donor units. BCP-linked 15-(pentafluorophenyl)-10,20-diphenylporphyrin dyads with two different metal centres were also prepared. X-ray analysis of some of the prepared arrays gave information about the mutual orientation of donor and acceptor moieties in the solid state.