Novel linkers for solid phase synthesis

• Main Author: Murdoch, A. M.
• Published: University of Aberdeen 2000
• Subjects: 547
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.593191

This thesis outlines the three-year investigation into novel linkers for solid phase synthesis. Traceless linkers for tethering compounds onto polymer supports are of interest particularly for the discovery of drugs active in the central nervous system, as polar functional groups which are released from many non-traceless linkers can resist penetration of the blood brain barrier. The REM linker reported recently, based on an acrylic ester Michael acceptor, is an example of a traceless linker useful for the synthesis of tertiary amine libraries via a Michael addition of the amine, quaternisation and then cleavage by a Hoffman elimination reaction. An investigation into a number of related linkers, in particular amide and sulfonamide based is reported. These linkers were expected to offer advantages over the ester based REM resin in terms of chemical stability. This would allow a more diverse range of reagents and conditions to be employed in a library synthesis. First is a brief review of the explosion of interest in this fascinating and fast-moving topic. The REM scheme is then described in more depth and some of the inherent problems associated with the ester linker are detailed. An in-depth study into a series of amide linkers was carried out, and their stability compared to that of the ester linker. As expected it was found that the amide linkers showed enhanced stability to a wide variety of reagents. The inherent instability of an ester-based system compared to an amide bond was exploited to create a wider range of possible library syntheses. Sulfone and sulfonamide based linkers were then prepared and compared to the ester and amide systems. Expanding the scope of the original ester REM resin was then investigated. This includes attempted addition of other biologically interesting nucleophiles such as imidazole. All experimental data is included and includes synthesis of the linkers and analytical data of the cleaved tertiary amines. The final chapter is a brief summary of the work carried out, and includes a "linker library" table. It details typical yields of cleaved tertiary amine from each linker, for a quick comparison.