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Synthesis 2001(6): 0877-0884
DOI: 10.1055/s-2001-13410
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Versatile Method for Solid-Phase Synthesis of Polyamines: Neuroactive Polyamine Toxins as Example

Kristian Strømgaarda, Kim Andersenb, Thomas Ruhlandb, Povl Krogsgaard-Larsena, Jerzy W. Jaroszewski*a
a Department of Medicinal Chemistry and NeuroScience PharmaBiotec Research Center, Royal Danish School of Pharmacy, Universitetsparken 2, 2100 Copenhagen, Denmark
Fax: (+45)35306040; e-Mail: jj@dfh.dk;
b Department of Combinatorial Chemistry, Medicinal Chemistry Research, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
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Publication History

Received 29 December 2000
Publication Date:
24 September 2004 (online)

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Abstract

A general method for sequential synthesis of polyamines on solid-phase is described. Each polyamine chain elongation step is based on alkylation under Mitsunobu conditions of resin-bound amine, activated with a 2-nitrobenzenesulfonyl group. The Mitsunobu reaction was accomplished with 1,1’-(azadicarbonyl)dipiperidine and tributylphosphine, using 2-(trimethylsilyl)ethoxy-carbonyl-protected amino alcohols as the chain extension elements. The yield of the Mitsunobu reaction was optimized with respect to reaction time, reagent ratio and concentration, order of addition of the reagents, and temperature; the optimized yield approached 100%. The method was used for synthesis of philanthotoxin-433, a natural polyamine wasp toxin, and of its seven analogs, with all possible combinations of trimethylene and tetramethylene units separating the nitrogen atoms of the polyamine chain. The yields of purified end products were 23-40%.

Key words

amines - philanthotoxins - parallel synthesis - solid-phase synthesis - Mitsunobu reaction