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[Abstract]

Development of Methods for Solid-Phase Synthesis of Neuroactive Polyamine Derivatives

Christian Adam Olsen

Philanthotoxin-433 (PhTX-433) is a polyamine wasp toxin that antagonizes certain ionotropic receptors non-competitively. In this dissertation the development of solid-phase synthesis (SPS) strategies for the preparation of such polyamine toxins is described.

Monoprotected primary diols were used as building blocks in Fukuyama-Mitsunobu SPS of polyamine toxins extending the scope of this strategy, due to the availability of a variety of diols. Attempts to introduce secondary alcohols in this solid-phase sequence failed. Four analogues of PhTX-433, C-methylated in the polyamine chain, were synthesized in solution from four building blocks in 11-17 % overall yield (6 steps). These philanthotoxins were tested for antagonistic effect on AMPA receptors, and all showed potencies within two-fold of the reference compound PhTX-343.

SN2 displacement of resin-bound sulfonates was then investigated, and preparation of analogues of PhTX-83 proved to be feasible when having a mesylate on the solid support. The overall yield (24 %) was comparable to the yields obtained using Fukuyama-Mitsunobu alkylation. However, on-resin halide formation/displacement proved to represents a more efficient protocol for preparation of secondary and tertiary amines. Although no polyamine toxins were prepared, good yields and high purities were obtained for single alkylations.

For alkylation of resin-bound secondary amines the use of readily prepared 2-nitrobenzenesulfonates proved to represent a relatively mild and efficient protocol. Also, these conditions were applied for synthesis of polyamine amides containing piperidine and piperazine residues in the polyamine chain. Only formation of tertiary amino groups were possible using this strategy, however, and in order to obtain a more diverse pool of compounds for SAR studies a borane-reduction strategy was extended with respect to the availability of building blocks. This was achieved as the use of Dmt as a temporary N-protection group in preparative SPS was demonstrated on trityl and 2-chlorotrityl resin linkers.

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