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Synthesis of Symmetrical and Non‐Symmetrical Bivalent Neurotransmitter Ligands
Author(s) -
StuhrHansen Nicolai,
Andersen Jacob,
Thygesen Mikkel B.,
Strømgaard Kristian
Publication year - 2016
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201600116
Subject(s) - bivalent (engine) , chemistry , neurotransmitter , serotonin , neurotransmitter systems , stereochemistry , dopamine , combinatorial chemistry , biochemistry , biology , organic chemistry , receptor , neuroscience , metal
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/PPh 3 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.