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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