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The Choice of Phosphane Reagent in Fukuyama−Mitsunobu Alkylation: Intramolecular Selectivity Between Primary and Secondary Alcohols in the Preparation of Asymmetric Tetraamine Building Blocks for Synthesis of Philanthotoxins
Author(s) -
Olsen Christian A.,
Jørgensen Malene R.,
Witt Matthias,
Mellor Ian R.,
Usherwood Peter N. R.,
Jaroszewski Jerzy W.,
Franzyk Henrik
Publication year - 2003
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200300186
Subject(s) - chemistry , reagent , intramolecular force , selectivity , alkylation , polyamine , ionotropic effect , mitsunobu reaction , stereochemistry , combinatorial chemistry , primary alcohol , primary (astronomy) , receptor , organic chemistry , biochemistry , glutamate receptor , physics , astronomy , catalysis
Philanthotoxin‐433 (PhTX‐433) is a polyamine wasp toxin that antagonizes certain ionotropic receptors noncompetitively. Four analogues of PhTX‐433, C ‐methylated in the polyamine chain, were synthesized from ( RS )‐1,3‐butanediol, two diamine building blocks, and an activated/protected tyrosine derivative. Use of a phosphane reagent more bulky than trimethylphosphane gave a high intramolecular selectivity between primary and secondary hydroxy groups in the Fukuyama−Mitsunobu reaction. Thus, trimethylphosphane proved to be the only phosphane reagent that enabled alkylation of 2‐nitrobenzenesulfonamides with a wide range of secondary alcohols, whereas tributylphosphane was selective for primary alcohol groups. This selectivity was utilized to obtain orthogonally protected, asymmetric, branched tetraamines, employed for solution‐phase synthesis of philanthotoxin analogues. The branched philanthotoxin analogues thus obtained were tested in an electrophysiological assay using rat brain ionotropic glutamate receptors expressed in Xenopus laevis oocytes. Their potencies proved to be similar to the corresponding nonbranched analogues. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)