Iron outperforms rare metals in stunning chemistry advance

Many widely used photocatalyst metals, including ruthenium and iridium, are scarce and expensive. Researchers at Nagoya University in Japan previously introduced an iron based substitute, but that earlier version depended on large quantities of costly chiral ligands. These ligands act as spatial guides, determining the three dimensional arrangement of the final chemical products.

In a study published in the Journal of the American Chemical Society, the team unveiled a redesigned iron catalyst that cuts chiral ligand use by two thirds. The system also works under energy efficient blue LED light, making the reaction conditions more practical and potentially more sustainable.

With this improved catalyst, the scientists completed the asymmetric total synthesis of (+)-heitziamide A. This natural compound, found in medicinal plants, is known to suppress respiratory bursts. The research was carried out by Professor Kazuaki Ishihara, Assistant Professor Shuhei Ohmura, and graduate student Hayato Akao at Nagoya University’s Graduate School of Engineering.

Smarter Iron Catalyst Design Improves Efficiency

In their 2023 work, the researchers created an iron photocatalyst that incorporated three chiral ligands per iron atom. However, only one of those ligands actually contributed to enantioselectivity, which made the approach inefficient.

The newly developed catalyst uses a more strategic design. It combines affordable achiral bidentate ligands with chiral ligands to form a specific iron(III) salt structure. The chiral ligand directs the three dimensional configuration of the product, while the achiral bidentate ligand enhances catalytic performance.

Using this system, the team achieved a highly controlled radical cation (4 + 2) cyclization. In this reaction, two molecular components join together to form a six membered ring. The process allows for the creation of 1,2,3,5-substituted adducts, structural motifs commonly found in natural products such as heitziamide A.

“The new catalyst design represents the definitive form of chiral iron(III) photoredox catalysts,” stated Ohmura, one of the study’s corresponding authors. “We believe this achievement marks a significant milestone in advancing iron-based photocatalysis.”

First Total Asymmetric Synthesis of (+)-Heitziamide A

Although researchers have previously reported laboratory synthesis of heitziamide A, they had not accomplished the total asymmetric synthesis of its naturally occurring enantiomer.

By carefully controlling six membered ring formation with a blue light activated iron photocatalyst, the team achieved the first total asymmetric synthesis of (+)-heitziamide A. The findings suggest that using the mirror image version of the catalyst would also make it possible to produce (-)-heitziamide A, allowing selective access to both enantiomers.

Implications for Pharmaceutical Chemistry

The new iron photocatalyst makes it possible to construct complex molecules, including pharmaceutical precursors, using abundant iron and blue LEDs instead of rare metals.

“Achieving the first-ever asymmetric total synthesis of (+)-heitziamide A using this catalytic reaction is a remarkable accomplishment,” stated Ishihara, the study’s other corresponding author. “Several additional bioactive substances can be accessed through total synthesis, with enantioselective radical cation (4 + 2) cycloaddition serving as a key step. We intend to publish follow-up papers on the asymmetric total synthesis of these compounds in the near future.”