The future of total synthesis

From structure confirmation to methodology improvements, making complex natural products has driven innovation in organic synthesis for decades. Nina Notman looks at its current state, with threats from funding to academic pressures

Natural products are metabolites produced by living organisms; they are relatively small molecules compared to enzymes and proteins with extremely diverse structures that are typically 3D and very complex. ‘Natural products tend to be polycyclic with lots of stereochemistry,’ says Sarah Reisman from the California Institute of Technology in the US. Complex small molecules can theoretically be deconstructed in a myriad of ways. But turning one of these into a viable synthetic route in the forward direction requires strong problem-solving credentials and an abundance of creativity. Natural product chemists are often compared to mountain climbers plotting the best route to a summit.

An evolution of purpose

Chemists have been trying to synthesise natural products in the lab for around two centuries urea was the first to be made in 1828. Structure confirmation is one reason to attempt a total synthesis, especially so in the early years. ‘Most of the organisms that make these molecules produce them in very, very small quantities,’ explains Nigel Mouncey from Lawrence Berkeley National Laboratory in California, US. This makes elucidating their structures challenging, even more so before the advent of modern spectroscopic and x-ray crystallography techniques. By making a sample of the compound with an assumed structure in the lab and comparing its analytical data with that of the natural compound, its structure can be confirmed or corrected. Chemists still sometimes find errors in long-assumed structures during total synthesis projects, especially at stereocentres.

Performing a total synthesis also provides scientists with enough of a molecule to study its biological function and potential medicinal properties. ‘These molecules are not random they are the result of millions of years of evolution, designed by nature to perform biological processes with incredible precision,’ says Chao Li from the National Institute of Biological Sciences in Beijing, China. It is estimated that around 50% of approved drugs in the EU and US are currently either a natural product or a derivative of one. These include paclitaxel (Taxol), a compound found in the bark of Pacific yew trees that has been extensively used to treat breast, lung, ovarian and other cancers for over 30 years. A more recent example is voclosporin (Lupkynis), derived from cyclosporine A found in the Beauveria nivea fungus; it was approved for use as an immunosuppressant to treat kidney complications from lupus in the US in 2021 and the EU in 2022.




Another common reason academics participate in total synthesis projects is to train the next generation of medicinal chemists. ‘If you talk to any pharma company, the people they want to hire more than anyone else are those trained in the art of total synthesis,’ says Phil Baran, from Scripps Research in La Jolla, California. Problem-solving skills developed during this type of work is one reason, as is the breadth of experience gained each step in a total synthesis typically requires a different type of chemistry. ‘In natural product synthesis, [students] have the chance to experience many different kinds of organic reactions,’ explains Jinghan Gui from the Chinese Academy of Sciences’ Shanghai Institute of Organic Chemistry

Improved route planning

For many organic chemists, however, the main attraction of total synthesis is the opportunity to add more tools to the synthetic chemistry toolbox. For much of the 20th century, the focus was on being the first to make a target molecule of interest. In recent decades, the goal has evolved into trying to make complex molecules using the shortest route possible. Returning to the mountain climber analogy, organic chemists no longer necessarily aim to be the first ever to reach a summit. Rather, they strive to be the fastest and use the fewest steps. ‘The goal should be an organic synthesis where you only make skeletal bonds and nothing else,’ says Baran. This means a route where each reaction builds a bond or two onto the molecule that is still present in the final product, with no detours (such as protecting groups) needed. ‘To achieve that requires that the practitioner become an inventor ,’ he explains.

The desire to make a complex molecule provides the inspiration to develop novel reactions and strategies, says Rebecca Goss, from the University of St Andrews, UK. ‘It’s just like developing new technologies to prepare for an Everest assault. The inspiration, the muse for developing new synthetic methodologies, [is the potential] to take greater strides up the mountain.’

Baran outlines the importance of these technological developments: ‘Those methods that come out as a consequence of coming up with innovative routes to natural products often find their way into the portfolio of methods that people use to design and invent new drugs,’ he says.

Growing the toolbox

New tools can come in many forms. A favourite category from the Baran lab is radical cross-coupling reactions. Radical retrosynthesis is a less common way to think about disconnecting molecules than polar bond analysis. ‘We’ve all been taught how to make molecules by assigning delta plus and delta minus partial charges to functional groups and then disconnecting between them,’ Baran says. Using a radical cross-coupling instead allows unique disconnections to be made and enables rapid access to complex 3D molecular motifs, he adds. In March 2025, Baran reported that sulfonyl hydrazides can be used to forge a wide variety of carbon–carbon bonds through radical pathways. In August, he demonstrated its utility in the synthesis of saxitoxin, a potent shellfish neurotoxin of interest to the pharmaceutical industry.

The Gui group also explores the potential for radical reactions in total synthesis. In February 2024, it reported the first laboratory synthesis of aspersteroids A and B in 15 and 14 steps respectively from commercially available ergosterol. These synthesises had several radical chemistry steps including a diastereoselective radical reduction of an epoxide to install a challenging stereocentre. Earlier attempts at this transformation produced the opposite chirality at this centre to the natural product. ‘It took us over a year to solve that issue,’ says Gui. ‘It was one of the most challenging projects we have worked on.’

Hong-Dong Hao, from Northwest A&F University in Shaanxi, China, also looks to use uncommon disconnection types. In December 2024, his group reported the construction of the four ringed (one six- and three five-membered rings) skeleton of marine cyclopianes with key steps including a gold-catalysed Nazarov cyclisation and Pauson–Khand reaction. Hao completed the asymmetric synthesis of conidiogenones C and K and 12β-hydroxy conidiogenone C, each in around 20 steps. He also collaborated with Houhua Li from Peking university to show that these molecules have anti-inflammatory activity. ‘The Nazarov cyclisation works smoothly on several substrates, and this is a disconnection that is not obvious using retrosynthetic analysis,’ says Hao.

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Fossils Inside Fossils: The Bizarre Discovery Hidden in a Caribbean Cave

Paleontologists have discovered the first known fossilized bee nests built inside ancient bones, uncovered in a cave that came close to being used as a latrine.

A cave on Hispaniola preserves rare evidence that ancient bees nested inside fossil cavities. The find suggests an unusual local environment and a much deeper story about what brought so many remains into the cave.

A giant barn owl, a rodent known as a hutia, and a burrowing bee went into a cave. Only two later left. Which one remained behind? Hint: It’s the one that can’t fly.

This likely happened thousands of years ago on Hispaniola in the Caribbean. The owl carried the hutia back to its cave, apparently as food for its family. For the hutia, the visit ended quickly, because the owl delivered it to waiting chicks. The bee showed up far later, after the feeding was long finished and the hutia’s remains had been scattered and buried within the cave.

Searching for a safe place to raise its young, the bee began excavating a tunnel through fine, clay-rich silt that had built up in the cave’s darker interior. Before the tunnel reached the depth the bee preferred, it hit an unexpected obstacle: remnants of the owl’s ancient meal.

That discovery may have helped the bee. The hutia’s teeth were about the right size for the kind of nesting chamber the insect aimed to make. The teeth themselves were missing, likely displaced elsewhere in the cave, but the tooth sockets in the jaw (called alveoli) were still preserved and, importantly, already empty.

The rest is history. A swarm of such bees made their nests in the cave’s fossils for an unknown length of time. Later, that history was carefully excavated by paleontologists many thousands of years after the owl, hutia and potentially the bee had gone extinct.

A Curious Observation

The story might have ended there, had it not been for a keen eye and a friendly competition between colleagues.

“Usually, when collecting fossils, you get all the sediment out of the alveoli while cleaning the specimen,” said Lazaro Viñola Lopez, who excavated the fossils while working as a doctoral student at the Florida Museum of Natural History.

But Viñola Lopez was particularly interested in this species of hutia, for which fossils were incredibly rare across the island, consisting of a few isolated teeth and partial mandibles. In this single cave, called the Cueva de Mono, in the southern Dominican Republic, he found thousands of hutia fossils, most belonging to the same, previously rare, species.

Apparently, the giant barn owls that lived in the cave had repeated the same dinner scene throughout multiple generations, slowly turning the cave into a charnel house. In other instances, the birds likely consumed their prey while hunting, in which cases the bones would have been condensed into a pellet that the owls later regurgitated in the cave.

Instead of mindlessly placing the fossil in a bag bound for the lab and a thorough cleaning, Viñola Lopez took his time to inspect it before putting it away. He noticed that one alveolus had a smooth inner lining, unlike the rest, which had the rough texture of bone.

From Wasps to Bees

“I’d seen something similar in Montana when I was collecting dinosaur fossils in 2014,” he said. At the time, he and his colleagues kept finding isolated wasp cocoons interspersed with the bones in the rocky matrix. He assumed what he found in the cave was more of the same. He recalls thinking, “It would be nice to write a short paper reporting the occurrence of these wasp nests in the mandibles.”

Viñola Lopez proposed the idea to his colleague Mitchell Riegler, also a doctoral student at the museum and present for the excavation. Riegler, who studied extinct lizards and had a dissertation to finish, was skeptical. “I was like, Lazaro, that’s a niche project, and I have a lot of other things to do.”

So, for a time, the idea was shelved along with the specimens. Until, that is, Riegler received a challenge from his former undergraduate advisor at the University of Texas at Austin.

“He and I played this game back and forth in which we tried to write a paper in a week.”

Riegler had lost the first round and was itching for a rematch. The wasp nests, he thought, might just be the thing he needed to win.

“I told Lazaro we could do it only because I thought it’d be fast,” he said. “We’d scan them, describe their shape and say that they were there. Boy, was I wrong.”

A Surprising Discovery

Things initially went well. Selby Olsen, another doctoral student at the museum, also signed on to the project. “We locked ourselves in Lazaro’s apartment for five straight days and didn’t stop writing,” Riegler said. “Each of us sat in a corner and wrote a section, then swapped.”

They emerged feeling confident they’d win. Later, Viñola Lopez and Riegler independently came across the same study on ichnofossils, a term used to describe indirect fossil evidence of an organism, such as a footprint, preserved poop and in this case nests. The study contained a description of wasp nests, which they realized differed from theirs in one key regard.

The Wrong Insect

Wasp nests are made from a mix of saliva and chewed plant fibers or dirt, which gives the interior and exterior walls a rough texture. But bees are more fastidious. After constructing the nest out of compacted soil, many will secrete a waxy substance from a specialized gland, which they use to generously coat the inside of the nest, making it waterproof. This also makes the inside of their nests look smooth, precisely like the ones they’d found in the hutia mandibles.

They’d written about the wrong insects.

This wasn’t necessarily a fatal blow to their now tenuous victory. It wouldn’t take much work to swap out the information they’d included on wasps with that of bees, and they still had a little time left. But now things were getting interesting.

There is only one other documented case of a burrowing bee nesting inside a cave, and there are no documented cases at all of bees making their nests in a pre-existing fossil structure. A study published in 2001 gives a macabre report of human bones from an ancient Roman necropolis that bees that drilled into, but bees nesting inside fossils without altering them was something new.

From Sprint to Marathon

They conceded the race and adopted a more measured approach. They consulted with scientists who study modern bees and consigned themselves to a year-long dive into literature on entomology. Viñola Lopez travelled back to the cave to study its stratigraphy. At some point along the way, someone decided they wanted to build a house nearby and turn the cave into a septic tank. Given that the person who wanted to build on the land didn’t actually own it, their plans were ultimately thwarted, but the paleontologists didn’t take any chances while the cave’s fate was in limbo.

“We had to go on a rescue mission and get as many fossils out as possible, and we got a lot of them,” Viñola Lopez said.

Now, with the final publication of the expanded paper, their hard work has arguably paid off. It features a rich account of the cave’s natural history and stratigraphy and descriptions of two other fossil types in which the bees made their nests.

Fossils Within Fossils

In one unique instance, a nest was found inside the pulp cavity of a sloth tooth. Tree sloths were once common in parts of the Caribbean, but they went extinct following the arrival of humans. Another nest was found in the cavity of a hutia vertebra, though which its spinal cord would have passed when it was alive.

CT scans of the specimens showed that n some cases they’d actually gotten multiple nests for the price of one. Rather than having to make a new tunnel every time they need to lay eggs, some burrowing bees will craw down into existing burrows to see if their tenants have hatched or not. If empty, the bee may decide to place a new nest in the same spot.

The unlucky hutia that dropped by for dinner had a total of six nests in one alveolus, cupped inside each other like Russian dolls.

Why Bees Went Underground

The study also contains a plausible explanation for why the bees bucked tradition and made nests inside a cave rather than somewhere out in the open, which Riegler learned about firsthand. “The area we were collecting in is karst, so it’s made of sharp, edgy limestone, and it’s lost all of its natural soils,” he said. “I actually fell on it at one point, so I can tell you all about it.” The soils that do manage to build up over time are periodically washed into the thousands of caves that dot the island, where they accumulate and provide some of the only suitable habitat for burrowing bees in that region.

The authors are currently working on several other fossils retrieved from the cave that will be described in future studies published at a leisurely pace.

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Coffee beans pooped out by civets really are tastier. Here’s why

The world’s most prized coffee comes from partially digested beans pooped out by the Asian palm civet. Now, researchers are delving into why this “civet coffee” is so tasty.

New chemical analyses of beans collected from civet poop, alongside beans picked directly from the coffee plants, suggest that fermentation in the civet’s innards does add a little something extra to the coffee’s flavor, including amping up the fat content and the concentrations of certain aromatic compounds. These alterations help create civet coffee’s unique taste profile, researchers report in Scientific Reports.

Asian palm civets (Paradoxurus hermaphroditus) are catlike mammals found from India to Indonesia that love fruit including ripened coffee beans. As the beans pass through their digestive system, the civets absorb the pulp and deposit the worked-over beans in their dung.

The resulting coffee is so prized that the beans may cost $600 to $1,300 a pound a price tag that has led to concerns about civet captivity and animal welfare in some civet coffee farms.

Meanwhile, questions linger about whether civet coffee is truly chemically distinct. Previous studies suggested that the fermenting genius behind the flavor may be Gluconobacter, a bacteria genus found in civets’ feces, but not that of other animals. But what happens during that fermentation is still uncertain.

Zoologist Ramit Mitra, then at the Central University of Kerala in India, and colleagues turned to Kodagu in southern India, a coffee-producing district of Robusta beans also home to wild palm civets. The team collected 68 fecal matter samples from wild civets on estates in India growing Robusta, as well as uneaten coffee beans from the same estates.

The civet-consumed beans had higher fat content and also higher levels of two fatty acid methyl esters: caprylic acid methyl ester and capric acid methyl ester. Fat, the team notes, can have a big impact on coffee’s aroma and overall taste profile, and the fatty acids could also add a dairylike flavor. The civet beans also had lower levels of protein and caffeine relative to uneaten beans, which could explain the coffee’s low bitterness compared with other beans.

The findings confirm that civet coffee has a unique chemistry but take these specific flavor notes with a grain of salt, the team cautions. These analyses were performed on unroasted beans; roasting can tweak to a coffee’s flavor by altering acidity and the concentrations of other chemical parameters. Furthermore, the vast majority of civet coffee grounds are produced with a different bean, Arabica.

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Scientists unlocked a superconductor mystery under crushing pressure

Superconductors are materials that allow electrical current to flow with no resistance. This unique ability makes them extremely valuable for technologies such as efficient power transmission, energy storage, magnetic levitation systems, and quantum computers.

The challenge is that superconductivity usually occurs only at very low temperatures, far below everyday conditions. This limitation has prevented widespread practical use. That picture began to change with the discovery of superconductivity in hydrogen-rich materials. Hydrogen sulfide (H3S) becomes superconducting at 203 Kelvin (-70°Celsius), while lanthanum decahydrid (LaH10) reaches superconductivity at 250 Kelvin (-23°Celsius). These temperatures are far higher than those of earlier superconductors and are above the boiling point of liquid nitrogen, which is why scientists classify them as high temperature superconductors. Their discovery marked a major step toward the long-standing goal of room-temperature superconductivity.

The Superconducting Gap and Why It Is Crucial

At the heart of superconductivity is a feature known as the superconducting gap. This property reveals how electrons join together to form the superconducting state and serves as a clear signature that distinguishes a superconductor from an ordinary metal.

Understanding the superconducting gap is essential because it directly reflects how electrons interact inside the material. Without measuring this gap, scientists cannot fully explain why a material becomes superconducting or what mechanism makes resistance disappear.

Why Measuring Hydrogen Superconductors Is So Difficult

Despite their importance, hydrogen-rich superconductors such as H3S have been extremely challenging to study. These materials can only be created under enormous pressures that exceed atmospheric pressure by more than a million times. Because of these extreme conditions, widely used techniques like scanning tunneling spectroscopy and angle-resolved photoemission spectroscopy cannot be applied.

As a result, the superconducting gap in these materials had remained unmeasured, leaving a major gap in scientists' understanding of how high-temperature superconductivity works in hydrogen-rich compounds.

A New Tunneling Technique Breaks the Barrier

To solve this problem, researchers at the Max Planck Institute in Mainz developed a planar electron tunneling spectroscopy method that can operate under these extreme pressures. This new approach made it possible to directly probe the superconducting gap in H3S for the first time.

With this technique, the team obtained a clear picture of the superconducting state in hydrogen-rich materials, overcoming a barrier that had limited progress in the field for years.

What the Measurements Revealed

The researchers found that H3S has a fully open superconducting gap of approximately 60 millielectronvolt (meV). They also studied its deuterium counterpart, D3S, which showed a smaller gap of about 44 meV. Deuterium is a hydrogen isotope and has one more neutron.

This difference is significant because it confirms that superconductivity in H3S is driven by interactions between electrons and phonons. Phonons are quantized vibrations of a material's atomic lattice. The results support long-standing theoretical predictions about the mechanism behind superconductivity in hydrogen-rich compounds.

Why This Breakthrough Matters

For the researchers in Mainz, the achievement goes beyond technical success. It provides a foundation for uncovering the fundamental origins of high-temperature superconductivity in hydrogen-based materials. "We hope that by extending this tunneling technique to other hydride superconductors, the key factors that enable superconductivity at even higher temperatures can be pinpointed. This should ultimately enable the development of new materials that can operate under more practical conditions," states Dr. Feng Du, first author of the now published study.

Dr. Mikhail Eremets, a leading figure in high-pressure superconductivity research who deceased in November 2024, described the study as "the most important work in the field of hydride superconductivity since the discovery of superconductivity in H3S in 2015." Vasily Minkov, project leader of High-Pressure Chemistry and Physics at the Max Planck Institute for Chemistry, added: "Mikhail´s vision of superconductors operating at room temperature and moderate pressures comes a step closer to reality through this work."

A Brief History of Superconductivity

Superconductivity refers to the ability of certain materials to conduct electrical current without resistance. It was first discovered in pure mercury in 1911 by Heike Kamerlingh Onnes. For many decades, scientists believed this phenomenon could only occur at temperatures near absolute zero (-273 °C).

That assumption changed in the late 1980s when Georg Bednorz and Karl Alexander Müller discovered copper-oxide superconductors, also known as cuprates, that exhibited high-temperature superconductivity under normal atmospheric pressure. This discovery sparked worldwide research efforts.

Over time, scientists reached critical temperatures (Tc) of about 133 K at ambient pressure and 164 K under high pressure. Progress then stalled until hydrogen-rich compounds entered the picture.

Hydrogen-Rich Materials Push the Limits

The discovery of superconductivity in H3S at megabar pressures, with a Tc = 203 K by the research group led by Dr. Mikhail Eremets, represented a turning point. Soon after, even higher critical temperatures were observed in hydrogen-rich metal hydrides such as YH9 (Tc ≈ 244 K) and LaH10 (Tc ≈ 250 K).

Current theoretical models now suggest that superconductivity above room temperature may be possible in several hydrogen-dominated systems when subjected to extreme pressure.

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