A tandem one-pot Friedel–Crafts alkylation/double cyclization process to conveniently assemble diaryl-fused 2,8-dioxabicyclo[3.3.1]nonanes with aryl substituents at the C-1 position was developed. 2-Hydroxychalcones and naphthol derivatives reacted in refluxing toluene with (D,L)-10-camphorsulfonic acid (CSA) as the catalyst. The transformation conveniently provided the corresponding 2,8-dioxabicyclo[3.3.1]nonanes fused with one phenyl and one naphthyl group in moderate to good yields, and various substitutions on both reaction partners were tolerated. More importantly, aryl- and aza-aryl-fused 2,8-dioxabicyclo[3.3.1]nonanes were prepared for the first time using this procedure.

Natural product mayamycin is the first example in the angucycline class featuring a C-glycoside linkage at the C5-position of the benz[a]anthracenone core with remarkable biological activities. We successfully synthesized the two retrosynthetic fragments, but found that the final C-glycosylation did not occur. Alternatively, an A-ring saturated aglycon was prepared, but the proposed C-glycosylation still did not proceed. Finally, a simplified substrate was used and the subsequent C-glycosylation went through smoothly, giving a two-ring less analogue of mayamycin.

A three-step, one-pot tandem reaction including radical nucleophilic alkylation/cyclization/aromatization was developed using 0.3 equivalents of silver(I) acetate (AgOAc) as the catalyst and 2 equivalents of ammonium persulfate [(NH₄)₂S₂O₈] as the oxidant. This strategy is highly efficient for the assembly of pentacyclic complex carbazoles from aryl-fused bromobenzoquinones and indol-3-ylpropanoic acid acids in 52–72% overall yields (three steps). This new approach provides a significant improvement over the previously reported methods and would greatly facilitate analog library construction of pentacyclic complex carbazoles and benefit further biological evaluation of these compounds.

Mono- and bis-indolomorphinans were synthesized through a multi-step synthetic approach from the alkaloid, thebaine, to further explore the C-ring SAR (structure-activity relationship) of morphinan scaffold. Both mono-indoles displayed good binding affinity and selectivity for the δ receptor, with compound 6b possessed the highest K_i value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both δ and κ receptors, but moderate binding at the μ receptor was observed. Functional assays indicated that the newly synthesized mono-indole 6b was δ-agonist, opposite to the δ-antagonist profile of naltrindole. Bisindoles 7a,b were μ-agonists. This work further confirms that the phenol component in opioids is essential for higher binding to the opioid receptors. The different binding ability, receptor selectivity, and the functional activity profiles of naltrindole 2, monoindole 6b, and bisindole 7b clearly indicated that they interact with the opioid receptors in different modes.

A series of new 14-hydroxymorphinan analogues with a thiazole or imidazo[2,1-b]thiazole fragment as the heterocyclic function fused to ring C were designed and synthesized. These compounds can be viewed as the result of a direct modification at ring C of the 14-hydroxymorphinan scaffold. Among these compounds, three were identified as having potent binding affinity (∼1 nM) at both κ and μ receptors, and acting as agonists at κ and partial agonists or antagonists at μ receptors. In view of the promising results from studies on compounds with mixed κ and μ receptor activities, these new compounds warrant further investigation.