A natural product is a substance made by living things and found in nature. In the widest sense, natural products include any substance created by living organisms. These products can also be made in laboratories through chemical processes, such as partial or complete chemical creation. These methods have been important in the study of organic chemistry because they offer difficult challenges for scientists to solve. The term "natural product" is sometimes used in business to describe items like cosmetics, dietary supplements, and foods made from natural sources without artificial ingredients added.

In the study of organic chemistry, natural products are usually defined as organic compounds taken from natural sources that are made through processes called primary or secondary metabolism. In the study of medicines, natural products are often limited to substances made through secondary metabolism. Secondary metabolites are not needed for an organism to live, but they help the organism survive better over time. Many of these substances are harmful to cells and have been improved by evolution to act as tools for fighting other living things, such as prey, predators, or competitors. Unlike primary metabolites, which are common in many types of living things, secondary metabolites are often found only in certain species. These substances are chemically complex, which makes them interesting to scientists.

Natural sources can help scientists study possible useful substances that might be used to create new medicines. Even though natural products have inspired many medicines, companies that make drugs have paid less attention to them in recent years. This is partly because it is hard to get a steady supply of these substances, there are issues with ownership rights, costs, profits, changes in the environment, and the loss of natural sources due to species disappearing. However, between 2017 and 2019, about 10% of new medicines approved were based on natural products or their chemical changes.

Classes

The widest meaning of natural product includes anything made by living things. This includes materials from living things, such as wood and silk; materials made from living things, such as bioplastics and cornstarch; liquids from living things, such as milk and plant liquids; and other natural materials, such as soil and coal.

Natural products can be grouped based on their purpose in living things, how they are made by living things, or where they come from. Depending on their sources, scientists have identified between 300,000 and 400,000 different natural product molecules.

Function

Natural products are often grouped into two main types: primary and secondary metabolites, as proposed by Albrecht Kossel in 1891. Primary metabolites are essential for the survival of the organism that produces them. They support basic life processes, such as taking in nutrients, making energy, and growing. These metabolites are found in many different types of organisms and include important building blocks like carbohydrates, lipids, amino acids, and nucleic acids.

Primary metabolites involved in energy production include enzymes that help with breathing and photosynthesis. These enzymes are made of amino acids and often need helper molecules to work properly. The structures of cells and organisms, such as cell membranes, cell walls, and the cytoskeleton, are also made from primary metabolites.

Some primary metabolites are vitamins that help enzymes function. For example, vitamin B1 (thiamine) helps enzymes involved in breaking down sugars. Vitamin B2 (riboflavin) is part of molecules that help with chemical reactions in cells. Vitamin B3 (niacin) is needed for energy production and other processes. Vitamin B5 (pantothenic acid) is part of a molecule that helps with making energy and building fats. Vitamin B6 (pyridoxal) helps enzymes process amino acids. Vitamin B12 (cobalamin) is involved in making fats and building proteins. Other primary metabolites include vitamin A (retinol) and vitamin C (ascorbic acid), which are important for vision and immune function, respectively.

DNA and RNA, which carry genetic information, are made from primary metabolites like nucleic acids and carbohydrates.

First messengers are molecules that help control metabolism and cell growth. These include hormones and other signaling molecules that interact with proteins in cells. This interaction activates second messengers, which are often primary metabolites like cyclic nucleotides and diacylglycerol, to send signals inside the cell.

Secondary metabolites are not essential for survival and are not found in all species. They have a variety of roles, such as helping organisms communicate with others of the same species, attracting helpful organisms, helping take in nutrients, and acting as tools to compete with other organisms. Some secondary metabolites, like alkaloids (e.g., morphine and nicotine), protect plants from being eaten. Others, like flavonoids, help attract pollinators. Terpenes, such as menthol, can repel insects. The exact purpose of some secondary metabolites is still unknown, but they may help organisms survive by giving them an advantage.

Common types of secondary metabolites include alkaloids, phenylpropanoids, polyketides, and terpenoids.

Biosynthesis

The biosynthetic pathways that create the major types of natural products are described below.

Carbohydrates are organic molecules important for storing energy, providing structure, and supporting biological functions in living things. Plants make them through photosynthesis, while animals produce them through a process called gluconeogenesis. Carbohydrates can be linked together to form larger molecules called polysaccharides:

• Photosynthesis or gluconeogenesis → simple sugars (monosaccharides) → polysaccharides (cellulose, chitin, glycogen, etc.)

Carbohydrates are a main energy source for most living organisms. Polysaccharides made from simple sugars are also important for structure, forming the cell walls of bacteria and plants.

During photosynthesis, plants first create a molecule called 3-phosphoglyceraldehyde, which is a three-carbon sugar. This can be turned into glucose (a six-carbon sugar) or other five-carbon sugars through the Calvin cycle. In animals, three-carbon molecules like lactate or glycerol are converted into pyruvate, which is then used to make carbohydrates in the liver.

Fatty acids and polyketides are made through the acetate pathway, which starts with basic building blocks from sugars:

• Sugars → acetate pathway → fatty acids and polyketides

During glycolysis, sugars are broken down into acetyl-CoA. In a reaction that uses energy (ATP), acetyl-CoA is converted into malonyl-CoA. Acetyl-CoA and malonyl-CoA then undergo a chemical reaction called Claisen condensation, releasing carbon dioxide to form acetoacetyl-CoA. This is used by the mevalonate pathway to create steroids. In fatty acid synthesis, one acetyl-CoA molecule (the "starter unit") and several malonyl-CoA molecules (the "extender units") are combined by fatty acid synthase. After each step, the keto group is reduced, the intermediate is dehydrated, and the resulting enoyl-CoAs are reduced to acyl-CoAs. Fatty acids are essential parts of cell membranes and serve as energy storage in the form of fat in animals.

The plant-made fatty acid linoleic acid is changed in animals through steps called elongation and desaturation to form arachidonic acid. This is then used to make eicosanoids, such as leukotrienes, prostaglandins, and thromboxanes. These molecules help send signals in the body and are important for inflammation and immune responses.

In some cases, intermediates from chemical reactions are not reduced, forming poly-β-keto chains. These chains are later turned into polyketides. Polyketides have many different structures and functions, and include important compounds like macrolide antibiotics.

The shikimate pathway is a key process that creates aromatic amino acids and their related molecules in plants, fungi, bacteria, and some protozoans:

• Shikimate pathway → aromatic amino acids and phenylpropanoids

This pathway makes aromatic amino acids (AAAs)—phenylalanine, tyrosine, and tryptophan. It is important because it connects basic life processes to specialized functions, using about 20-50% of all fixed carbon in its reactions. The pathway starts with the joining of phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P), leading through several steps to form chorismate, which is the starting point for all three AAAs.

From chorismate, the pathway splits to make each AAA. In plants, phenylalanine and tyrosine are usually made through an intermediate called arogenate. Phenylalanine is the starting point for the phenylpropanoid pathway, which creates many different secondary metabolites.

Besides making proteins, AAAs and their related molecules are important in plants for making pigments, hormones, cell walls, and defending against stress. Since animals cannot make these amino acids, the shikimate pathway is a target for herbicides, like glyphosate, which stops a key enzyme in this process.

The creation of terpenoids and steroids uses two main pathways, which make the basic parts of these compounds:

• Mevalonate pathway and methylerythritol phosphate pathway → terpenoids and steroids

The mevalonate (MVA) and methylerythritol phosphate (MEP) pathways create five-carbon units called isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are used to build all terpenoids.

The MVA pathway, discovered in the 1950s, works in eukaryotes, some bacteria, and plants. It turns acetyl-CoA into IPP through HMG-CoA and mevalonate, and is needed for making steroids. Statins, which lower cholesterol, work by blocking HMG-CoA reductase in this pathway. The MEP pathway, found in bacteria, some parasites, and plant chloroplasts, starts with pyruvate and glyceraldehyde 3-phosphate to make IPP and DMAPP. This pathway is important for making terpenoids in chloroplasts, like carotenoids and chlorophyll. Both pathways meet at IPP and DMAPP, which combine to form longer molecules like geranyl (C10), farnesyl (C15), and geranylgeranyl (C20). These molecules are used to make many terpenoids, including monoterpenes, sesquiterpenes, and triterpenes.

The variety of terpenoids comes from changes like cyclization, oxidation, and glycosylation, allowing them to help plants defend against threats, attract pollinators, and send signals. Steroids, mainly made through the MVA pathway, are created from farnesyl diphosphate using molecules like squalene and lanosterol, which are used to make cholesterol and other steroids.

Alkaloids are nitrogen-containing molecules made by plants through complex processes that start with amino acids. Making alkaloids from amino acids is important for creating many active compounds in plants. These compounds range from simple nitrogen-based molecules to complex ring structures.

Alkaloid production usually follows four steps: (i) making an amine precursor, (ii) making an aldehyde precursor, (iii) forming an iminium cation, and (iv) a reaction similar to the Mannich reaction. These steps create the basic structure of many alkaloids. A

Medical uses

Natural products sometimes have medical benefits that help treat diseases. Scientists can also create man-made versions of natural products that work better and are safer. Because of this, natural products are often used as starting points for finding new medicines. Many medicines that doctors prescribe today were either made directly from natural products or were inspired by them. About 35% of all medicines sold worldwide each year come from natural products or are related to them. This includes 25% from plants, 13% from tiny living things like bacteria, and 3% from animals.

Between 1981 and 2019, the FDA approved 1,881 new drug compounds. Of these, 65 (3.5%) were natural products used without changes, 99 (5.3%) were mixtures of plant materials, 178 (9.5%) were natural products modified slightly, and 164 (8.7%) were man-made drugs that include parts of natural products. Together, these make up 506 (26.9%) of all new medicines approved. Natural products and their modified versions often succeed more often in later stages of testing and may cause fewer harmful effects compared to man-made drugs.

Some of the oldest medicines come from natural products. For example, the bark of the willow tree has been used for centuries to relieve pain because it contains salicin, which can be broken down into salicylic acid. A man-made version of this, called aspirin, is now a common pain reliever. Aspirin works by stopping a specific enzyme involved in pain and inflammation. Another example is opium, which comes from a type of poppy plant. Opium contains morphine, a powerful painkiller that activates certain brain receptors. A drug called ziconotide, used to treat pain, is based on a toxin from a type of sea snail.

Many medicines that fight infections are also based on natural products. The first antibiotic, penicillin, was discovered from a type of mold. Penicillin and similar drugs stop bacteria from building their cell walls by blocking a key enzyme.

Some medicines target a structure inside cells called tubulin. Colchicine, a drug used to treat gout, comes from a type of plant and stops tubulin from forming. It is made from amino acids. Another drug, paclitaxel, helps treat cancer by stabilizing tubulin. Paclitaxel is based on a chemical called taxol, which is found in a type of yew tree.

Drugs that lower cholesterol, such as atorvastatin, were developed from a substance called mevastatin, which is made by a type of fungus. Another drug used for heart conditions, captopril, is based on a substance found in the venom of a type of snake.

Using natural products for medicine has challenges. Natural sources can be hard to find or supply, may repeat the same chemicals, and can lead to problems with protecting intellectual property. Also, the amount of natural material available may change depending on where and when it is collected. Many natural resources, like certain bacteria and ocean microbes, remain untested. Scientists proposed a method called metagenomics to study genes in soil microbes, but many companies have not used this fully. Instead, they focus on creating new drugs from existing libraries of chemicals or natural sources.

Isolation and purification

Natural products are often found in mixtures with other substances from their natural source, which can be very complex. To study these products, scientists must separate and purify the specific substance they are interested in. Isolating a natural product means obtaining enough of the pure substance to analyze its chemical structure, test its properties, or study how it interacts with other chemicals.

Structure determination is the process used to identify the exact chemical structure of a purified natural product. For example, in 1945, Dorothy Crowfoot Hodgkin determined the chemical structure of penicillin. Her work earned her a Nobel Prize in Chemistry in 1964.

Today, scientists use several advanced tools to determine the structure of natural products. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography are two main methods used to study molecular structures. High-resolution tandem mass spectrometry (MS/MS) helps scientists find the molecular formula and understand how molecules break apart. For very complex structures, computers are used to help predict and compare chemical data. These tools include computer-assisted structure elucidation (CASE) platforms and programs that predict how molecules might fragment.

To determine the exact 3D shape of a molecule, scientists often combine NMR data, such as coupling constants and nuclear Overhauser effect (NOE) measurements, with chemical methods like Mosher's ester analysis. Techniques such as vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD) also provide useful information. When traditional methods are not enough, especially for completely new types of molecules, scientists use advanced computer models to predict and compare chemical data, helping them fully understand the structure, including its 3D shape.

Synthesis

Natural products often have complex structures. The complexity depends on factors such as the size of molecules, how their parts are arranged (like rings or special chemical groups), how many of these groups are present, their stability, how they are shaped in space, their physical characteristics, how new the structure is, and how much effort has been made to create it in the lab.

Some natural products with simpler structures can be made in the lab using total synthesis, which means creating them from basic chemical ingredients. However, not all natural products can be made this way. The most complex ones are often too expensive or difficult to produce in large amounts. In these cases, scientists may instead collect the product directly from its natural source. For example, drugs like penicillin, morphine, and paclitaxel have been made in large quantities by extracting them from plants or other natural sources, without using complex chemical methods.

Extracting natural products from their sources can be time-consuming and expensive. It may also harm the environment or reduce the availability of the natural resource. For instance, making enough paclitaxel for one dose of medicine might require cutting down an entire yew tree. Additionally, the number of similar structures available for testing how changes affect a product’s function is limited by the biology of the organism that produces it, and scientists cannot control this.

When a desired product is hard to get or change to create similar versions, scientists may use a middle step in the natural process to make the final product. This method, called semisynthesis or partial synthesis, involves taking a natural chemical that is partway through the production process and using chemical reactions to complete it.

This approach has two benefits. First, the middle chemical may be easier to collect and produce in larger amounts than the final product. For example, paclitaxel can be made by taking a chemical called 10-deacetylbaccatin III from yew tree needles and then completing it with four chemical steps. Second, semisynthesis allows scientists to create similar versions of the final product, as seen in the development of newer types of penicillin.

In general, total synthesis of natural products is not used for commercial purposes but is instead used for research. It helps scientists understand how to build complex natural product structures and develop new chemical methods. Even though it is not used to make products for sale, it has been important for the field of chemistry. Before modern chemical analysis tools were developed, scientists confirmed the structures of natural products by making them in the lab. Early research focused on complex substances like cobalamin (vitamin B12), which is important for cell function.

Biomimetic synthesis is a type of chemistry that uses natural processes as a guide to make natural products in the lab. This method copies how living organisms create complex molecules, often in very specific ways. These methods have helped scientists make complex structures more easily, especially those with unusual parts like spiro-ring systems or specific carbon atoms. Techniques like Diels-Alder reactions, photocycloadditions, and other chemical steps are used to build these structures efficiently.

Studies of natural products that have two or three parts often show a type of symmetry called bilateral symmetry. This means the molecule or system has a balanced structure, often with a C2, Cs, or C2v identity. C2 symmetry is more common than other types. This discovery helps scientists understand how these compounds are made and why they are more stable. Calculations using methods like density functional theory and the Hartree-Fock method also suggest that dimerization (making two parts) is more favorable than making three or four parts. This may be because the way molecules connect in a head-to-head shape causes less crowding than other shapes.

Research and teaching

Research and teaching about natural products are part of many different areas of study, such as organic chemistry, medicinal chemistry, pharmacognosy, ethnobotany, traditional medicine, and ethnopharmacology. Other areas include chemical biology, chemical ecology, chemogenomics, systems biology, molecular modeling, chemometrics, and chemoinformatics.

Natural products chemistry is a unique area of chemical research that has played an important role in the history of chemistry. Scientists have isolated and identified natural products to find substances for early drug research, to understand traditional medicine and ethnopharmacology, and to explore useful chemical structures. To do this, many technological advances have been developed, such as improvements in separating chemicals and modern methods for determining chemical structures, like Nuclear Magnetic Resonance (NMR). Early studies of how natural products are made used radiolabeling, and later, stable isotope labeling combined with NMR experiments. Additionally, natural products are often created through organic synthesis to confirm their structure or to produce larger amounts of them. In this process, the structure of some natural products has been corrected, and the challenge of making them has led to new methods in chemistry. Natural products are also important in training new chemists and have inspired the development of new chemical reactions, such as the Evans aldol reaction, as well as the discovery of completely new reactions, like the Woodward cis-hydroxylation, Sharpless epoxidation, and Suzuki–Miyaura cross-coupling reactions.

History

The idea of natural products began in the early 1800s, when scientists started learning about organic chemistry. Organic chemistry studied substances found in plants and animals, which was more complex than inorganic chemistry. Inorganic chemistry had been studied since 1789 by Antoine Lavoisier, a French scientist, in his book Traité Élémentaire de Chimie.

Lavoisier showed in the late 1700s that organic substances were made of a few elements, mainly carbon and hydrogen, with some oxygen and nitrogen. He focused on isolating these substances because they often had useful effects on health. Plants were the main source of these compounds, especially alkaloids and glycosides. For example, opium, a sticky mixture of alkaloids like codeine, morphine, and others, was known to cause sleepiness and change mental states. By 1805, a German chemist named Friedrich Sertürner isolated morphine from opium. In the 1870s, scientists found that heating morphine with acetic anhydride created heroin, a substance that strongly reduced pain. In 1815, Eugène Chevreul isolated cholesterol, a crystalline substance from animal tissue, and in 1819, he isolated strychnine, an alkaloid.

A major step was creating organic compounds in the lab. While making inorganic substances was known, making organic ones was difficult. In 1827, Swedish chemist Jöns Jacob Berzelius believed a "vital force" was needed to create organic compounds. This idea, called vitalism, was widely accepted even after scientists began using atomic theory. Vitalism also matched traditional medicine, which often saw disease as caused by imbalances in life forces.

In 1828, German chemist Friedrich Wöhler challenged vitalism by making urea, a substance found in urine, from an inorganic compound called ammonium cyanate. This showed a life force was not needed to create organic substances. At first, people doubted this, but by the 1840s, Adolph Kolbe proved this by making acetic acid from carbon disulfide. Since then, organic chemistry has become a separate field focused on carbon-based compounds found in nature.

Another key step was understanding the structure of organic compounds. Scientists could determine the elements in pure organic substances, but their structures were unclear. This became clear when Friedrich Wöhler and Justus von Liebig studied silver salts with the same elements but different properties. Wöhler studied silver cyanate, a harmless compound, while von Liebig studied silver fulminate, an explosive substance. Both had the same elements but different behaviors, showing that structure affects properties.

Berzelius explained this with his theory of isomers, which said the arrangement of atoms changes a compound’s properties. This led to theories like the radical theory by Jean-Baptiste Dumas and the substitution theory by Auguste Laurent. In 1858, August Kekulé proposed that carbon has four bonding sites and can form chains, a key idea in understanding natural products.

The idea of natural products, originally from plants, expanded to include animal materials in the mid-1800s, thanks to Justus von Liebig. In 1884, Hermann Emil Fischer studied carbohydrates and purines, work that earned him a Nobel Prize in 1902. He also made glucose and mannose in the lab. After Alexander Fleming discovered penicillin in 1928, fungi and other microbes became sources of natural products.

By the 1930s, scientists had identified major classes of natural products. Key milestones include:

• Terpenes: Studied by Otto Wallach (Nobel Prize 1910) and Leopold Ružička (Nobel Prize 1939).
• Porphyrin-based dyes: Research by Richard Willstätter (Nobel Prize 1915) and Hans Fischer (Nobel Prize 1930). These compounds, like chlorophyll and heme, are important for processes like photosynthesis and respiration.
• Steroids: Work by Heinrich Wieland (Nobel Prize 1927) and Adolf Windaus (Nobel Prize 1928) helped explain sterol structures.
• Carotenoids: Studied by Paul Karrer (Nobel Prize 1937). These pigments protect cells and are used in photosynthesis and vision.
• Vitamins: Research by scientists like Paul Karrer, Adolf Windaus, and Albert Szent-Györgyi (Nobel Prize 1937) showed how vitamins affect health.
• Steroid hormones: Work by Adolf Butenandt (Nobel Prize 1939) and Edward Kendall (Nobel Prize 1950) advanced endocrinology.
• Alkaloids and anthocyanins: Studied by Robert Robinson (Nobel Prize 1947) and others. These compounds are used in medicines.
• Polypeptide hormones: Vincent du Vigneaud (Nobel Prize 1955) made the first lab synthesis of oxytocin and vasopressin.
• Total synthesis: Robert Burns Woodward (Nobel Prize 1965) and Elias Corey (Nobel Prize 1990) created complex natural products like quinine, cholesterol, and vitamin B12.

These discoveries helped scientists understand natural product chemistry and biochemistry, leading to many Nobel Prizes in Chemistry and Medicine. Today, research continues to explore how these compounds evolved and function in nature.