Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy

Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy

Substituted Diazatetracyclo[4.4.0.1^3,10.1^5,8]dodecanes as Stable Caged Proton Sponges

Herein, we report a molecular framework design differing significantly from the traditional topology of proton sponges. We developed a synthetic approach to the preparation of caged secondary amines by acid-catalyzed rearrangement of fused tetracyclic heterocycles synthesized by intramolecular criss-cross cycloaddition. Alkylation of amines led to air nonsensitive diazatetracyclo­[4.4.0.1^3,10.1^5,8]­dodecanes (DTDs) with rare alicyclic scaffolding in high overall yields. Their p<i>K</i>_BH+ values were determined by transprotonation experiments as well as their sensitivity toward nucleophiles, acids and bases. Crystal structures of free base and monoprotonated form are discussed

Substituted Diazatetracyclo[4.4.0.1^3,10.1^5,8]dodecanes as Stable Caged Proton Sponges

Herein, we report a molecular framework design differing significantly from the traditional topology of proton sponges. We developed a synthetic approach to the preparation of caged secondary amines by acid-catalyzed rearrangement of fused tetracyclic heterocycles synthesized by intramolecular criss-cross cycloaddition. Alkylation of amines led to air nonsensitive diazatetracyclo­[4.4.0.1^3,10.1^5,8]­dodecanes (DTDs) with rare alicyclic scaffolding in high overall yields. Their p<i>K</i>_BH+ values were determined by transprotonation experiments as well as their sensitivity toward nucleophiles, acids and bases. Crystal structures of free base and monoprotonated form are discussed

Substituted Diazatetracyclo[4.4.0.1^3,10.1^5,8]dodecanes as Stable Caged Proton Sponges

Herein, we report a molecular framework design differing significantly from the traditional topology of proton sponges. We developed a synthetic approach to the preparation of caged secondary amines by acid-catalyzed rearrangement of fused tetracyclic heterocycles synthesized by intramolecular criss-cross cycloaddition. Alkylation of amines led to air nonsensitive diazatetracyclo­[4.4.0.1^3,10.1^5,8]­dodecanes (DTDs) with rare alicyclic scaffolding in high overall yields. Their p<i>K</i>_BH+ values were determined by transprotonation experiments as well as their sensitivity toward nucleophiles, acids and bases. Crystal structures of free base and monoprotonated form are discussed

Unexpected Heterocyclic Products from Cycloaddition Reactions of Nonsymmetrical Allenyl Aldoketazines with Substituted Alkynes

International audienc

Combined intra-intermolecular criss-cross cycloaddition reactions leading to perfluoroalkylated fused tricyclic nitrogen heterocycles

International audiencePerfluoroalkylated hydrazones 1a–ewere preparedfrom diethyl hydrazinophosphate andwere engaged in the reaction with 3-substitutedhomoallenyl aldehydes according to Zwierzak’smethod. The resulting non-symmetrical perfluoroalkyl-derived azines reacted in combined intra-intermolecular criss-cross cycloaddition with phenyl isocyanate, phenyl isothiocyanate and dimethyl acetylenedicarboxylate producing fused tricyclic heterocycles. Besides, the thermal cyclization of perfluoroalkylated non- symmetrical azines, without added dipolarophile, was carried out providing fused bicyclic systems