This study focuses on developing functional "molecules" and "reactions" aimed at controlling biomolecular functions. In the aspect of molecules, the asymmetric total syntheses of (-)-stemonamine and (-)-isostemonamine, which are stemona alkaloids isolated from Stemona japonica, were achieved. The strategy featured an intramolecular acylation to construct a seven-membered lactam and a tandem 2+2 cycloaddition/Dieckmann condensation to build the cyclopentenone ring, yielding the stemona alkaloids with high optical purity. Detailed kinetic analyses experimentally revealed, for the first time, the details of racemization and epimerization of/between stemonamine and isostemonamine. Biological assays demonstrated that (-)-isostemonamine exhibited potent antiproliferative activity against ERα-negative breast cancer cells. This synthetic methodology paves the way for the supply of stemona alkaloids whose biological activities are unknown and which have not yet been synthesized, and it is expected to greatly contribute to elucidating the biological functions hidden within their unique structures. In the aspect of reaction, a highly acid-sensitive Nazarov reaction proceeding under weakly acidic or even neutral conditions was developed. Key to this unprecedented reaction was the synergistic combination of (i) enhanced Lewis basicity of the carbonyl group, (ii) promotion of cyclization, and (iii) irreversible phenol elimination that shifts the reversible cyclization equilibrium toward the product. This system was further extended to a "molecular release reaction," enabling fluorescent dye liberation in aqueous media. While further development is still required, the methodology offers a basis for future exploration of biocompatible acid-responsive reactions and the establishment of new biochemical tools that releases molecules targeting the acidic environment within living systems.
Takayuki Iwata (Sun,) studied this question.