Three-Component, Diastereoselective Prins–Ritter Reaction for cis-Fused 4-Amidotetrahydropyrans toward a Precursor for Possible Neuronal Receptor Ligands

Abstract

Here, we report an unprecedented, highly diastereoselective Prins-Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the synthesis of tetra-cis-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles but also for more complex heterotricycles, showing acceptable levels of conversion yield (42-97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure-activity relationships of biologically active small molecules.

Menthyl esterification allows chiral resolution for the synthesis of artificial glutamate analogs

“…Finally, the hydrolytic removal of the menthyl, methyl, and TFA groups was attempted towards both enantiomers of TKM-38, 3 and 3* (Scheme 6). A preliminary study with 21* (2S) showed the low reactivity under acidic conditions (6 M aq HCl, MeOH, 65 °C) [5,24], which resulted in the quantitative recovery of the substrate 21* (2S). We then examined an alkaline hydrolysis (KOH, MeOH, H 2 O, 40 °C) [25,26], which gratifyingly furnished (2S)-TKM-38 (3*) in a good yield (77%) after ion-exchange chromatography (Dowex ® 50W x8-200, H + form).…”

The Potential of β‐Hydroxy‐γ‐vinyl‐γ‐lactone in the Synthesis of Natural Products and Beyond

“…An interesting three‐component Prins‐Ritter reaction of lactone 1 with benzaldehyde, acrolein or cinnamaldehyde and acetonitrile or benzonitrile to obtain 4‐amidotetrahydropyrans 94a‐f diastereoselectively was disclosed by Oikawa and co‐workers (Scheme ). [51a] The Prins‐Ritter reaction of the lactone 1 was further extended to the reaction with 1,3,5‐trioxane in presence of AlCl 3 , p TsOH or MsOH to deliver the Cl, OTs or OMs substituted tetrahydropyrans 95a‐c in moderate yields. [51b]…”

“…[51a] The Prins‐Ritter reaction of the lactone 1 was further extended to the reaction with 1,3,5‐trioxane in presence of AlCl 3 , p TsOH or MsOH to deliver the Cl, OTs or OMs substituted tetrahydropyrans 95a‐c in moderate yields. [51b]…”

Menthyl esterification allows chiral resolution for synthesis of artificial glutamate analogs

“…Finally, hydrolytic removal of menthyl, methyl, and TFA groups were attempted toward both enantiomers of TKM-38 (3/3*, Scheme 6). Preliminary study with 21* (2S) showed the low reactivity under acidic conditions (6 M aq HCl, MeOH, 65 °C) [5,21], which resulted in quantitative recovery of the substrate 21* (2S). We then examined alkaline hydrolysis (KOH, MeOH, H2O, 40 °C) [22,23]…”