Synthesis of symmetrical and non-symmetrical bivalent neurotransmitter ligands

Nicolai Stuhr-Hansen; Jacob Andersen; Mikkel Boas Thygesen; Kristian Strømgaard

doi:10.1002/slct.201600116

Synthesis of symmetrical and non-symmetrical bivalent neurotransmitter ligands

Nicolai Stuhr-Hansen, Jacob Andersen, Mikkel Boas Thygesen, Kristian Strømgaard

Department of Chemistry

1 Citation (Scopus)

Abstract

A novel procedure for synthesis of bivalent neurotransmitter ligands was developed by reacting O-benzyl protected N-nosylated dopamine and serotonin with alkyl- or PEG-linked diols under Fukuyama-Mitsunobu conditions in the presence of DIAD/PPh₃ generating three different bivalent neurotransmitter ligands in a one-pot reaction. The methodology establishes a facile route towards bivalent neurotransmitter ligands, and libraries of in total 40 symmetrical and non-symmetrical bivalent and monovalent dopamine and serotonin compounds linked through alkyl or PEG spacers of varying length were prepared. Interestingly, attempted synthesis of an O-tert-butyl analogue of the N-nosylated serotonin precursor resulted in unexpected tert-butylations at the 1-, 2- and 6-positions of the indole skeleton. We found that upscaling of selected bivalent serotonin ligands was most efficiently performed via N,O-bis-nosyl-serotonin since global de-nosylation was carried out as a final step after Fukuyama-Mitsunobu dimerization.

Original language	English
Journal	ChemistrySelect
Volume	1
Issue number	3
Pages (from-to)	407-413
Number of pages	7
ISSN	2365-6549
DOIs	https://doi.org/10.1002/slct.201600116
Publication status	Published - Mar 2016

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title = "Synthesis of symmetrical and non-symmetrical bivalent neurotransmitter ligands",

abstract = "A novel procedure for synthesis of bivalent neurotransmitter ligands was developed by reacting O-benzyl protected N-nosylated dopamine and serotonin with alkyl- or PEG-linked diols under Fukuyama-Mitsunobu conditions in the presence of DIAD/PPh3 generating three different bivalent neurotransmitter ligands in a one-pot reaction. The methodology establishes a facile route towards bivalent neurotransmitter ligands, and libraries of in total 40 symmetrical and non-symmetrical bivalent and monovalent dopamine and serotonin compounds linked through alkyl or PEG spacers of varying length were prepared. Interestingly, attempted synthesis of an O-tert-butyl analogue of the N-nosylated serotonin precursor resulted in unexpected tert-butylations at the 1-, 2- and 6-positions of the indole skeleton. We found that upscaling of selected bivalent serotonin ligands was most efficiently performed via N,O-bis-nosyl-serotonin since global de-nosylation was carried out as a final step after Fukuyama-Mitsunobu dimerization.",

author = "Nicolai Stuhr-Hansen and Jacob Andersen and Thygesen, {Mikkel Boas} and Kristian Str{\o}mgaard",

year = "2016",

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doi = "10.1002/slct.201600116",

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T1 - Synthesis of symmetrical and non-symmetrical bivalent neurotransmitter ligands

AU - Stuhr-Hansen, Nicolai

AU - Andersen, Jacob

AU - Thygesen, Mikkel Boas

AU - Strømgaard, Kristian

PY - 2016/3

Y1 - 2016/3

N2 - A novel procedure for synthesis of bivalent neurotransmitter ligands was developed by reacting O-benzyl protected N-nosylated dopamine and serotonin with alkyl- or PEG-linked diols under Fukuyama-Mitsunobu conditions in the presence of DIAD/PPh3 generating three different bivalent neurotransmitter ligands in a one-pot reaction. The methodology establishes a facile route towards bivalent neurotransmitter ligands, and libraries of in total 40 symmetrical and non-symmetrical bivalent and monovalent dopamine and serotonin compounds linked through alkyl or PEG spacers of varying length were prepared. Interestingly, attempted synthesis of an O-tert-butyl analogue of the N-nosylated serotonin precursor resulted in unexpected tert-butylations at the 1-, 2- and 6-positions of the indole skeleton. We found that upscaling of selected bivalent serotonin ligands was most efficiently performed via N,O-bis-nosyl-serotonin since global de-nosylation was carried out as a final step after Fukuyama-Mitsunobu dimerization.

AB - A novel procedure for synthesis of bivalent neurotransmitter ligands was developed by reacting O-benzyl protected N-nosylated dopamine and serotonin with alkyl- or PEG-linked diols under Fukuyama-Mitsunobu conditions in the presence of DIAD/PPh3 generating three different bivalent neurotransmitter ligands in a one-pot reaction. The methodology establishes a facile route towards bivalent neurotransmitter ligands, and libraries of in total 40 symmetrical and non-symmetrical bivalent and monovalent dopamine and serotonin compounds linked through alkyl or PEG spacers of varying length were prepared. Interestingly, attempted synthesis of an O-tert-butyl analogue of the N-nosylated serotonin precursor resulted in unexpected tert-butylations at the 1-, 2- and 6-positions of the indole skeleton. We found that upscaling of selected bivalent serotonin ligands was most efficiently performed via N,O-bis-nosyl-serotonin since global de-nosylation was carried out as a final step after Fukuyama-Mitsunobu dimerization.

U2 - 10.1002/slct.201600116

DO - 10.1002/slct.201600116

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Synthesis of symmetrical and non-symmetrical bivalent neurotransmitter ligands

Abstract

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