From mannose to morphan analogues: methyl α-d-mannoside as chiral building block for the synthesis of mono- and bicyclic σ receptor ligands Original Research Article

Previously the synthesis and high σ1 receptor affinity of mannose derived pyrans 3–5 with equatorially oriented amino groups have been reported. Herein the synthesis and receptor affinities of the corresponding axially substituted pyrans and oxa-morphans are described. Key step in the diastereoselective synthesis was an SN2 substitution of tosylate 10 with NaN3. Heating of the azide 6 with acid led unexpectedly to the oxa-morphan 13, which showed remarkable affinity toward the σ1 receptor (Ki = 860 nM). The benzylamine 15α and the dimethylamine 16α were obtained by reduction of the azide 6 and subsequent reductive alkylation. In contrast to the equatorial amines 3–5, the axial amines 15α and 16α did not interact with the σ1 receptor or another investigated receptor system.