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Synthesis 2005(16): 2687-2694  
DOI: 10.1055/s-2005-872118
PAPER
© Georg Thieme Verlag Stuttgart · New York

On-Resin Carboxy Group Activation of ω-Amino Acids in Solid-Phase Synthesis­ of Philanthotoxin Analogues

Malene R. Jørgensena, Jerzy W. Jaroszewskia, Matthias Wittb, Henrik Franzyk*a
a Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark
b Bruker Daltonik GmbH, Fahrenheitstrasse 4, 28359 Bremen, Germany
Fax: +4535306041; e-Mail: hf@dfuni.dk;
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Publication History

Received 20 April 2005
Publication Date:
04 August 2005 (online)

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Abstract

A protocol for parallel solid-phase synthesis of ω-amino acid-elongated philanthotoxins was developed for exploration of structure-activity relationships for unnatural wasp toxin analogues. Several methods for on-resin activation of N-trityl-linked ω-amino acids were investigated, and the influence of chain length upon activation as pentafluorophenyl (Pfp) esters was examined. Comparison of Pfp-ester activation with phosphonium- and aminium/uronium-promoted coupling without pre-activation of the resin-bound carboxylic acids showed that only benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) exhibited a comparable efficiency. The present Pfp ester protocol gave high yields and purities of the resulting philanthotoxin analogues; however, in the case of γ-aminobutyric acid (GABA), use of PyBOP was required in order to avoid lactamization to 2-pyrrolidone.

Key words

amino acids - amides - coupling - solid-phase synthesis - philanthotoxins

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21

BOP: Benzotriazol-1-yloxytris(dimethylamino)phos­-phonium hexafluorophosphate; DCC: N,N′-dicyclo­-hexylcarbodiimide; DIC: N,N′-diisopropylcarbodiimide; GABA: γ-amino butyric acid; HATU: O-(7-azabenzo­-triazol-1-yl)-1,1,3,3-tetramethyl­uronium hexafluorophos­-phate; HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra­-methyluronium hexafluorophosphate; HOAt: 7-aza-1-hydroxybenzotriazole; HOBt: 1-hydroxybenzotriazole; PyAOP: 7-azabenzotriazol-1-yloxytris(pyrrolidino)phos­-phonium hexafluorophosphate; PyBOP: (tris)pyrrolidino­-phosphonium hexafluorophosphate; PyBroP: bromo­-tris(pyrrolidino)phosphonium hexafluoro­phosphate; TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; TCTU: 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; TFFH: tetramethylfluoroformamidinium hexafluorophosphate; TSTU: O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate.