A team at Nagoya University has built an iron-based photocatalyst that, when activated by blue LED light, can help assemble complex natural molecules while reducing the amount of expensive chiral ligand needed in their reported reaction by about two-thirds. Professor Kazuaki Ishihara, Assistant Professor Shuhei Ohmura, and graduate student Hayato Akao developed the system, which uses abundant iron rather than the rare-metal photocatalysts (such as iridium or ruthenium complexes) often used in related photoredox chemistry. The method delivered what the researchers describe as the first total asymmetric synthesis of (+)-heitziamide A, a plant-derived compound that has shown oxidative-burst inhibitory activity and cytotoxic effects in prior screening reports, suggesting a potentially cheaper and greener route to making scarce natural products for further study.
Iron Replaces Rare Metals in Photocatalysis
Metal-based photocatalysts are widely used in organic synthesis because they absorb light and channel that energy into driving chemical reactions. The dominant systems rely on iridium and ruthenium complexes, metals that are scarce, expensive, and concentrated in geopolitically sensitive supply chains. Swapping them for iron, one of the most abundant elements on Earth, has been a long-standing goal in synthetic chemistry, but iron catalysts historically suffered from short-lived excited states that limited their usefulness. The Nagoya team’s approach overcomes that barrier by pairing an iron(III) salt with energy-efficient blue LEDs, generating radical cations that trigger selective ring-forming reactions in electron-rich alkenes.
What makes this system distinct from earlier iron photocatalysis attempts is its ability to control molecular handedness, or chirality, the left-versus-right mirror-image geometry that can strongly affect a molecule’s biological activity. Conventional routes to chiral molecules require large quantities of chiral ligands, specialized organic structures that steer reactions toward the desired mirror form. These ligands can account for a significant share of synthesis costs. The Nagoya method reduces chiral ligand use by two-thirds while still achieving high selectivity, a combination the team says had been difficult to achieve with iron-based photocatalysis for this class of reactions.
First Total Synthesis of a Bioactive Plant Compound
The researchers chose (+)-heitziamide A as their proof-of-concept target, and the choice was strategic. Heitziamide A and its relative heitziamide B are amides and lignans originally isolated from the stem bark of Fagara heitzii, a tree in the Rutaceae family native to Central Africa. Previous biological screening linked these compounds to oxidative burst inhibitory activity and cytotoxic effects, making them of interest for further anti-inflammatory and anticancer research. Yet the researchers report that no one had completed a full asymmetric synthesis of (+)-heitziamide A in the lab, which can leave studies reliant on isolating small amounts from natural sources.
Using selective six-membered-ring formation driven by the iron photocatalyst under blue light, the Nagoya group completed that synthesis for the first time. The achievement matters beyond a single molecule. It demonstrates that an inexpensive iron-and-light system can handle the kind of stereoselective bond construction that pharmaceutical chemists need when building complex natural product scaffolds. If the method generalizes to related lignans and amides, it could open a practical laboratory route to compounds that are currently bottlenecked by scarce natural supply.
How Radical Cation Chemistry Evolved to This Point
The Nagoya result did not emerge in a vacuum. Radical cation-induced cycloadditions, the broad reaction class at work here, have been studied for decades. A review in Chemistry Letters traces how initiators for [2+2] and [4+2] cycloadditions of electron-rich alkenes progressed from simple chemical oxidants to photoredox catalysts, gradually expanding substrate scope and, more recently, enabling enantioselective variants. Iron(III) salts appeared in that lineage as one of several radical cation initiators, but their use was limited to non-selective transformations that offered little control over chirality.
The iron-and-blue-LED approach described in the recent report represents a departure from that earlier work. By combining iron photocatalysis with a reduced loading of chiral ligands, the Nagoya team achieved something that prior oxidant-based approaches could not: high enantioselectivity under mild, energy-efficient conditions. The study published in the Journal of the American Chemical Society details the catalytic cycle and substrate scope, and the authors compare its performance and practical advantages with established iridium- and ruthenium-based systems. For a field that has long treated rare-metal photocatalysts as the default, the demonstration that iron can match their selectivity while cutting ligand costs is a significant data point.
Cost and Sustainability Pressures on Drug Synthesis
The practical appeal of this work extends well beyond academic elegance. Pharmaceutical companies face mounting pressure to reduce both the financial and environmental costs of synthesizing drug candidates. Iridium is generally far more expensive and less abundant than iron, and chiral ligands designed for iridium or ruthenium systems often require multi-step syntheses of their own. Cutting chiral ligand consumption by two-thirds, as the Nagoya method does, translates directly into lower raw-material bills and less chemical waste per reaction batch. Blue LEDs, meanwhile, consume far less energy than the UV lamps or high-temperature conditions that older photochemical methods demand.
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*This article was researched with the help of AI, with human editors creating the final content.
