We report an efficient and practical strategy for the synthesis of bromo-substituted 2-azetines bearing a β-naphthol moiety. The reaction proceeds via the formation of highly reactive vinylidene ortho-quinone methide (VQM) intermediates, followed by intramolecular bromocyclization to afford highly strained 2-azetines under mild conditions. Notably, the cyclization step is significantly facilitated by catalytic Schreiner’s urea. This protocol is readily scalable, and the strategically incorporated bromo group in the product provides a convenient handle for further derivatization.

In recent years, deuterated pharmaceuticals (heavy drugs) have attracted significant attention as novel drug discovery modalities. While the stronger C–D bonds, as compared to C–H bonds, result in improved metabolic stability, the introduction of multiple deuterium atoms alters the physicochemical properties. Among the various methods developed for the synthesis of deuterated compounds, H/D exchange reactions are regarded as the most straightforward and useful. Herein, we developed a direct method for the multiple deuteration (H/D exchange reactions) of sodium cycloalkanecarboxylates bearing cyclopentane and cyclobutane rings using deuterium oxide, the most inexpensive deuterium source, in the presence of a Pt/C catalyst. Furthermore, deuterated cycrimine was synthesized from the deuterated sodium cyclopentanecarboxylate, and the effect of deuteration on lipophilicity was evaluated by a parallel artificial membrane permeability assay. Although no significant difference in lipophilicity was observed between the deuterated and hydrogenated forms, this study provides a useful method for the synthesis of deuterated compounds and a new synthetic approach to deuterated pharmaceuticals.

Camptothecin (CPT) is a monoterpenoid indole alkaloid produced in several plants and is a clinically important natural resource that serves as the precursor for the semi-synthetic anticancer drugs such as topotecan and irinotecan. CPT possesses a characteristic quinoline-containing scaffold; however, the molecular mechanisms underlying the downstream steps of its biosynthetic pathway remain unclear. In this study, we identified 17-O-acetylcamptothecinic acid (1) in hairy roots of Ophiorrhiza pumila. The abundance of compound 1 was markedly reduced following methyl jasmonate treatment, concomitant with increased accumulation of CPT. Metabolite profiling of CPT-producing plants revealed that compound 1 predominantly accumulates in the roots of O. pumila, O. kuroiwai, and Nothapodytes nimmoniana, but was not detected in Camptotheca acuminata. Clear conversion of compound 1 into CPT was observed upon incubation with cell lysates prepared from O. pumila hairy roots as well as under chemical deacetylation conditions. These findings suggest that 17-O-acetylcamptothecinic acid is a plausible final biosynthetic intermediate of CPT in O. pumila and that a protection–deprotection strategy may operate in CPT biosynthesis, similar to those reported for other alkaloid pathways. Furthermore, the absence of this acetylated intermediate in C. acuminata suggests possible convergent evolution of CPT biosynthetic mechanisms among distinct plant lineages.