Successful control of spatial configurations of molecules using a new reagent with a cage-shaped structure

A research group from the University of Osaka, made up of Doctoral Student Yuya Tsutsui (at the time of the research) from the Graduate School of Engineering, Undergraduate Student Kokoro Shiga (fourth year) from the Division of Applied Science, School of Engineering, and Assistant Professor Akihito Konishi and Professor Makoto Yasuda, has developed and synthesized a new allylation reagent (allylatrane) with a unique cage-shaped structure centered on group-14 elements. The group has for the first time in the world demonstrated that reaction control via a pathway different from conventional methods is possible. Their findings were published in Nature Communications.

In organic synthetic chemistry, controlling stereoselectivity in nucleophilic addition reactions to carbonyl compounds is a critical challenge that determines the function of molecules. In particular, α-oxy carbonyl compounds, which carry an oxygen atom at the α-position, are widely used as important building blocks in natural-product synthesis and pharmaceutical synthesis.

In allylation reactions of α-oxy carbonyl compounds, chelation control-in which the oxygen atom strongly coordinates to the metal-has been the dominant factor, and the reaction has been understood to yield a single spatial configuration (the syn product). As a result, selectively obtaining the opposite spatial configuration (the anti product) through a metal-coordination-independent pathway (non-chelation pathway) has been extremely difficult, and has remained an unsolved challenge for many years.

The research group developed and synthesized new allylatranes centered on group-14 elements (silicon, germanium, and tin) and demonstrated that using these reagents enables non-chelation-type reaction control that does not rely on metal coordination.

These allylatranes are characterized by their unique intramolecular cage-shaped structure, which allows them to exhibit high nucleophilicity while simultaneously suppressing the Lewis acidity of the metal center.

Furthermore, through a combined analysis using both experiments and theoretical calculations, the group clarified that the allylation of α-oxy ketones proceeds with high anti-selectivity via a reaction pathway distinct from conventional chelation control. This method is applicable to a wide range of substrates, and the researchers successfully produced spatial configurations that were difficult to achieve by conventional methods, with high yield and high selectivity.

This work has achieved non-chelation-type stereocontrol of α-oxy carbonyl compounds, something that had previously been considered impossible. It represents a significant advancement that extends the fundamental concepts of stereoselectivity control in organic synthesis. The approach is expected to serve as a new synthetic strategy, different from conventional techniques, for the precise production of distinct stereoisomers in the synthesis of pharmaceuticals and biologically active compounds, where three-dimensional structure is directly linked to biological activity. Researchers also anticipate that it will find wide future applications as a foundational technology in drug discovery research and the design of high-performance molecules.

Yasuda commented: "In organic synthetic chemistry, reactions that form carbon-carbon bonds are the most fundamental technology and controlling which spatial configuration the molecules adopt when bonding is essential. For α-oxy carbonyl compounds, a method for selectively obtaining only one of the products through metal-based chelation control had been established, but obtaining the product linked in the opposite orientation was considered impossible. In our many years of trial and error in pursuit of non-chelation control, we faced numerous obstacles, including the instability of reagents. However, by discovering the reagent with a cage-shaped structure described in this study, we were able to overcome this long-standing challenge."

Journal Information
Publication: Nature Communications
Title: Non-chelation control in allylations of αα-oxy ketones using group-14 allylatranes
DOI: 10.1038/s41467-026-69732-2