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An efficient stereoselective synthesis of cis-2,6-disubstituted tetrahydropyrans 14a–c has been achieved via gold-catalyzed Meyer–Schuster rearrangement/hydration/oxa-Michael addition sequence from bis-propargylic alcohols 13a–c. The reaction of 13a proceeds via 2,6-disubstituted tetrahydropyran 14′a as an intermediate. [ABSTRACT FROM AUTHOR]

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ 1 receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2 , tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)- 5 leading finally to enantiomerically pure test compounds 3a - g. With respect to σ 1 receptor affinity and selectivity over a broad range of related (σ 2 , PCP binding site) and further targets, the enantiomeric benzylamines 3a and cyclohexylmethylamines 3b represent the most promising drug candidates of this series. However, the eudismic ratio for σ 1 binding is only in the range of 2.5–3.3. Classical molecular dynamics (MD) simulations confirmed the same binding pose for both the tetrahydropyran 3 and cyclohexane derivatives 2 at the σ 1 receptor, according to which: i) the protonated amino moiety of (2 S ,6 R)- 3a engages the same key polar interactions with Glu172 (ionic) and Phe107 (π-cation), ii) the lipophilic parts of (2 S ,6 R)- 3a are hosted in three hydrophobic regions of the σ 1 receptor, and iii) the O-atom of the tetrahydropyran derivatives 3 does not show a relevant interaction with the σ 1 receptor. Further in silico evidences obtained by the application of free energy perturbation and steered MD techniques fully supported the experimentally observed difference in receptor/ligand affinities. Tetrahydropyrans 3 require a lower dissociative force peak than cyclohexane analogs 2. Enantiomeric benzylamines 3a and cyclohexylmethylamines 3b were able to inhibit the growth of the androgen negative human prostate cancer cell line DU145. The cyclohexylmethylamine (2 S ,6 R)- 3b showed the highest σ 1 affinity (K i (σ 1) = 0.95 nM) and the highest analgesic activity in vivo (67%). [Display omitted] • To increase hydrolytic stability and polarity tetrahydropyran derivatives were designed as potent σ 1 receptor ligands. • A chemoezymatic synthesis was performed to obtain the tetrahydropyrans in enantiomerically pure form. • Molecular dynamic simulations were performed to analyze the binding mode and compare the binding with analogous cyclohexanes. • The most potent compounds were able to inhibit the growth of the androgen negative human prostate cancer cell line DU145. • Analgesic activity was observed in the mouse capsaicin assay of neuropathic pain. [ABSTRACT FROM AUTHOR]