9.5 Natural Products

Overview of Natural Products

Natural products are organic compounds that are produced by living organisms. They include a huge variety of molecules found in plants, animals, fungi, and microorganisms. Many everyday substances—such as sugars, fats, proteins, caffeine, essential oils, and many medicines—are natural products or derived from them.

In this chapter, the focus is on:

• What natural products are and how they are categorized.
• How they differ structurally and functionally from simple hydrocarbons.
• Why organisms produce them (biological roles).
• How chemists obtain, modify, and use them.

Details on specific important groups of natural products (carbohydrates, fats, amino acids, peptides, and proteins) are covered in their own subchapters and are only sketched here when needed for context.

What Are Natural Products?

Natural products are:

• Organic compounds
• Formed by biosynthesis in living organisms
• Often built from a limited set of basic building blocks (e.g. sugars, amino acids, acetate units, isoprene units)

They can be:

• Primary metabolites – essential for basic life processes (e.g. glucose, fatty acids, amino acids, nucleotides).
• Secondary metabolites – not strictly required for survival of the individual cell in laboratory conditions, but important in ecological interactions (e.g. plant alkaloids, antibiotics, pigments, toxins, pheromones).

Natural products often serve as:

• Structural materials (e.g. cellulose in plants, chitin in insects and fungi)
• Energy storage (e.g. starch, fats)
• Signaling molecules (e.g. hormones, pheromones)
• Defense chemicals (e.g. plant toxins, antibiotics)
• Pigments and light-harvesting molecules (e.g. chlorophylls, carotenoids)

Structural Features Typical of Natural Products

Compared with the relatively simple molecules often used as examples in basic organic chemistry (e.g. small alkanes or simple alcohols), natural products show characteristic patterns:

Abundance of Heteroatoms

Many natural products contain:

• Oxygen: in functional groups such as alcohols, ethers, aldehydes, ketones, carboxylic acids, esters, and anhydrides.
• Nitrogen: in amines, amides, imines, heteroaromatic rings (e.g. pyridine), and more complex motifs.
• Sulfur and phosphorus: in fewer but important natural products (e.g. cysteine, methionine, thiols, phosphates).

These heteroatoms make molecules:

• More polar
• More reactive
• Able to form hydrogen bonds
• Suitable for specific recognition in biological systems (e.g. enzyme–substrate binding)

Multiple Functional Groups and Functional Group Combinations

Natural products usually contain several functional groups in one molecule. Common combinations include:

• Alcohol + ether + acetal (e.g. in many sugars)
• Ester + double bonds (e.g. in many fats and waxes)
• Amine + amide + carboxylic acid (e.g. in amino acid derivatives and peptides)
• Aromatic ring + hydroxyl or methoxy groups (e.g. in many plant phenolic compounds)

The arrangement of functional groups determines:

• Solubility in water or lipids
• Acidity/basicity
• Hydrogen bonding ability
• Reaction pathways in metabolism

Stereochemistry and Chirality

Natural products are often highly stereoselective:

• Many contain several chiral centers (e.g. sugars, amino acids, steroids, terpenes).
• Biological systems usually produce only one specific stereoisomer (or a defined set of stereoisomers).

Consequences:

• Different stereoisomers can have different tastes, smells, and biological activities.
• Enzymes are stereospecific: they recognize and transform only particular 3D arrangements.

For example, the “D” and “L” forms of sugars and amino acids differ in configuration at a chiral carbon and are handled differently in metabolism.

Ring Systems, Especially 5- and 6-Membered Rings

A large number of natural products contain:

• Five-membered rings (e.g. furanose sugars, some heterocycles in nucleotides).
• Six-membered rings (e.g. pyranose sugars, benzene rings, cyclohexane rings in steroids).
• Fused ring systems (e.g. steroids, many alkaloids, polycyclic aromatic compounds).

Ring structures influence:

• Rigidity and shape
• Ability to stack or interact with membranes
• Binding to biological targets (e.g. receptors, enzymes, DNA)

Conjugation and Aromaticity

Many natural pigments and signaling molecules have:

• Conjugated $\pi$-systems (alternating single and double bonds).
• Aromatic rings or polycyclic aromatic frameworks.

Conjugation leads to:

• Absorption of visible or UV light (color)
• Stabilization of charge-separated intermediates
• Participation in electron transfer (e.g. in photosynthesis, respiration)

Examples include carotenoids, chlorophyll, flavonoids, and many aromatic alkaloids.

Biosynthetic Building Blocks and Pathways (Overview)

Despite their diversity, many natural products are assembled from a relatively small number of basic building blocks via characteristic biosynthetic pathways controlled by enzymes.

Three especially important classes of building blocks are:

• Carbohydrate units – forming polysaccharides and also providing carbon skeletons for many other compounds.
• Acetate (C$_2$ units) – leading to fatty acids, polyketides, and related structures.
• Isoprene units (C$_5$) – underlying terpenes and terpenoids.

Peptides and proteins are built from amino acids; nucleic acids from nucleotides. These are covered in more detail in the subchapters dedicated to carbohydrates, fats, and amino acids/peptides/proteins.

Here, the emphasis is on how these building blocks give rise to broader families of natural products.

Carbohydrate-Derived Natural Products (Brief)

Carbohydrates serve not only as energy storage and structural components, but also as starting points for:

• Sugar alcohols (via reduction)
• Deoxy sugars (via substitution and elimination)
• Sugar acids (via oxidation)
• Glycosides: compounds where a sugar is linked via an acetal-type bond (glycosidic bond) to another molecule (aglycone), which may be:
• Another sugar (forming oligo- or polysaccharides)
• A non-sugar (e.g. steroid, aromatic compound, many plant secondary metabolites)

Glycosylation (attachment of sugars) strongly affects:

• Solubility in water
• Stability
• Transport and storage in organisms
• Biological recognition (e.g. in cell-cell communication)

Acetate and Polyketide Pathway (Brief)

Many natural fatty acids and polyketides are built stepwise from:

• Repeated $-CH_3CO-$ (acetyl or malonyl) units.

General features:

• C–C bond formation via Claisen-type condensations (in biochemistry, catalyzed by enzymes rather than base).
• Occurrence of $\beta$-keto groups which can undergo reduction, dehydration, and further reduction.
• Formation of long chains, rings, and sometimes conjugated polyenes.

Polyketides include:

• Many antibiotics
• Some pigments and toxins
• Complex macrolide structures with large rings

The specific reaction types (condensation, reduction, dehydration) are covered in general organic reaction chapters; here the key point is that many complex natural products share this modular origin.

Isoprenoid (Terpene) Pathway (Brief)

Isoprenoids (terpenes and terpenoids) are composed of repeating units of isoprene-like C$_5$ units. Conceptually, they can be thought of as assembled from:

• “Isoprene units” ($C_5H_8$ equivalents)

Typical classes:

• Monoterpenes (C$_{10}$) – 2 isoprene units
• Sesquiterpenes (C$_{15}$) – 3 units
• Diterpenes (C$_{20}$) – 4 units
• Triterpenes (C$_{30}$) – 6 units
• Tetraterpenes (C$_{40}$) – 8 units

Many compounds such as essential oils, plant scents, steroids (via triterpene precursors), and carotenoids belong to this family.

Isoprenoids often show:

• Multiple double bonds (often conjugated)
• Complex cyclization patterns
• Numerous chiral centers

Primary and Secondary Metabolites

A useful way to classify natural products is by their role in metabolism.

Primary Metabolites

Primary metabolites are directly involved in growth, development, and reproduction. Examples include:

• Carbohydrates (e.g. glucose, fructose, starch, glycogen, cellulose)
• Lipids/fats (e.g. triglycerides, phospholipids, fatty acids)
• Amino acids and peptides
• Nucleotides and nucleic acids

Common features:

• Occur in almost all living organisms
• Highly conserved structures between species
• Concentrations can be relatively high
• Biosynthetic pathways are tightly regulated and essential

Their structures and reactions are treated in detail in the subchapters on carbohydrates, fats, and amino acids/peptides/proteins, and in the chapter on chemistry in biological systems.

Secondary Metabolites

Secondary metabolites are often characteristic of specific groups of organisms (e.g. certain plants, fungi, bacteria). They are usually not directly essential for basic survival but provide ecological advantages.

Major classes of secondary metabolites include:

• Alkaloids (typically nitrogen-containing heterocycles; many are pharmacologically active)
• Terpenes and terpenoids (often volatile, components of essential oils and resins)
• Phenolic compounds (including flavonoids, tannins, lignin precursors)
• Polyketides (many antibiotics and pigments)
• Non-proteinogenic peptides and peptide-derived compounds
• Glycosides of various aglycones (e.g. cardiac glycosides in plants)

Typical functions:

• Defense against herbivores, microbes, and competitors (toxins, deterrents, antibiotics)
• Attraction of pollinators or seed dispersers (colors, scents)
• UV protection (e.g. flavonoids)
• Signaling within or between organisms (e.g. pheromones, quorum sensing molecules)

Secondary metabolites often display striking structural features:

• Several ring systems, including fused and bridged rings
• Multiple functional groups in a defined 3D arrangement
• Complex chirality patterns

Typical Structural Motifs in Natural Products

While the detailed study of each natural product family is outside the scope of this overview, some recurring motifs deserve mention because they appear again and again in the subchapters.

Glycosides

A glycoside consists of:

• A sugar part (glycone)
• A non-sugar part (aglycone) linked via a glycosidic bond (usually through an oxygen, but sometimes through nitrogen, sulfur, or carbon)

Glycosides are widespread in plants, where they:

• Serve as storage forms of active compounds (the aglycone may be toxic or reactive)
• Are more water-soluble than the free aglycone
• Can be activated by enzymatic hydrolysis (breaking the glycosidic bond)

Chemically, glycosides involve typical carbohydrate chemistry (hemiacetal/acetal formation and hydrolysis) combined with other functional groups from the aglycone.

Lactones and Lactams

Intramolecular esters and amides are common in natural products:

• Lactones – cyclic esters formed by intramolecular reaction between a hydroxyl and carboxylic acid group.
• Lactams – cyclic amides formed by intramolecular reaction between an amine and carboxylic acid (or derivative).

They appear in:

• Many polyketides
• Some peptide-based natural products (e.g. β-lactam antibiotics)
• Flavor and fragrance compounds

Their formation and reactivity follow the general rules of ester and amide chemistry, with additional constraints from ring size.

Aromatic and Polycyclic Frameworks

Many bioactive natural products use an aromatic or polycyclic framework as a rigid “scaffold” to position functional groups precisely. Examples include:

• Benzene, phenyl, and substituted aromatic rings (e.g. phenols, anilines, aromatic ethers)
• Heteroaromatics (e.g. indole, pyridine, imidazole, pyrimidine)
• Steroid nucleus (four fused rings)
• Polycyclic aromatic hydrocarbons (various ring-fused systems)

These frameworks:

• Are relatively stable
• Allow for substitution patterns that fine-tune solubility and reactivity
• Enable specific binding to biological targets due to their shape and rigidity

Reactions of Natural Products (Conceptual Overview)

Natural products undergo the same types of reactions as other organic compounds. However, within cells and organisms, these reactions are:

• Catalyzed by enzymes
• Often highly selective (regioselective, chemoselective, stereoselective)
• Integrated into metabolic pathways

Only a conceptual overview is given here; detailed reaction types (substitution, addition, elimination, oxidation–reduction, etc.) and mechanisms are discussed in the general organic chemistry chapters.

Common Transformations in Biosynthesis and Metabolism

Examples of reaction types frequently encountered in natural product chemistry:

• Oxidation and reduction
• Alcohols $\leftrightarrow$ aldehydes/ketones $\leftrightarrow$ carboxylic acids
• Saturated $\leftrightarrow$ unsaturated bonds
• Hydrolysis and condensation
• Formation and breakdown of esters, amides, glycosides
• Peptide bond formation and hydrolysis
• Addition and elimination
• Formation of double bonds by dehydration
• Hydration or addition of small molecules such as $H_2O$, $H_2$, $HX$
• Substitution
• Functional group exchange on carbon frameworks (e.g. halogen for hydroxyl, amine for halide)
• Cyclization and ring-opening
• Formation of rings in terpene biosynthesis
• Ring-opening of sugars (pyranose/furanose $\leftrightarrow$ open-chain forms)

In living systems these reactions are usually “mild” in terms of temperature and pH because they are controlled by enzymes and coupled to energy-providing processes (e.g. ATP hydrolysis).

Selectivity and Stereochemistry in Biosynthetic Reactions

Biological reactions are typically:

• Regioselective – reacting at a specific position even when several similar sites are available.
• Chemoselective – transforming one functional group in the presence of others.
• Stereoselective and stereospecific – producing predominantly one stereoisomer.

This leads to natural products with well-defined 3D structures. In laboratory synthesis, reproducing such selectivity without enzymes is often challenging and is a central topic in advanced organic synthesis and medicinal chemistry.

Isolation and Analysis of Natural Products

To study or use natural products, chemists first have to obtain them from their natural sources and then determine their structures. The specific analytical techniques are covered in the analytical methods chapters; here we outline only the typical workflow.

Isolation from Natural Sources

Natural products are often present in complex mixtures and at low concentrations. Typical steps include:

• Extraction – transferring the compound from the biological matrix into a solvent (water or organic solvents, sometimes supercritical CO$_2$).
• Purification – removing unwanted substances using:
• Crystallization
• Distillation (for volatile compounds, e.g. essential oils)
• Chromatography (e.g. column, thin-layer, high-performance liquid chromatography)
• Concentration and stabilization – removal of solvent, protection from light or oxygen if needed.

The choice of method depends on:

• Polarity and solubility of the compound
• Thermal stability
• Volatility
• Sensitivity to oxidation, light, or pH

Structural Elucidation (Overview)

To determine the structure of a natural product, chemists combine:

• Elemental analysis and mass spectrometry (molecular formula, fragments)
• Infrared (IR) spectroscopy (functional groups)
• Nuclear magnetic resonance (NMR) spectroscopy (carbon skeleton, hydrogen positions, coupling, stereochemistry)
• UV–Vis spectroscopy (conjugated systems, chromophores)
• X-ray crystallography (exact 3D structure when crystals can be obtained)

The interplay between these techniques enables reconstruction of complex structures, including stereochemistry. This is especially important for secondary metabolites with pharmacological activity.

Natural Products as a Basis for Pharmaceuticals and Materials

Natural products play an important role as:

• Direct drugs (e.g. antibiotics, cardiac glycosides, some anticancer agents)
• Lead compounds – starting points that are chemically modified to improve activity or reduce side effects.
• Templates for synthetic analogs – inspiring entirely new synthetic structures.

Features that make them valuable:

• Evolutionarily “tested” interaction with biological targets
• Structural complexity that is difficult to invent from scratch
• Diverse functional groups allowing fine-tuning by chemical modification

Typical modifications include:

• Changing functional groups (e.g. ester to amide)
• Introducing or removing methyl or hydroxyl groups
• Simplifying or rigidifying ring systems
• Attaching sugar residues or changing existing ones (glycoengineering)

Some natural products are also significant as materials or precursors for materials:

• Cellulose, lignin, and natural rubber
• Bioplastics derived from natural monomers
• Surfactants and detergents based on fatty acids and plant-derived alcohols

Natural vs. Synthetic: Boundaries and Combinations

Modern chemistry often combines natural and synthetic approaches:

• Semi-synthesis: starting from a natural product and modifying it chemically to obtain a derivative with desired properties.
• Total synthesis: constructing a natural product entirely from simple starting materials in the laboratory.
• Biotechnology: using genetically engineered microorganisms or cell cultures to produce natural products or analogs on an industrial scale.

The distinction between “natural” and “synthetic” is therefore sometimes blurred:

• The same compound can be obtained from plants, microbes, or purely synthetic methods.
• The body does not “see” a difference if the structure is identical at the molecular level.

In practice, questions of sustainability, cost, and purity often determine whether a substance is isolated from natural sources, produced biotechnologically, or synthesized chemically.

Summary

Natural products are a vast and structurally diverse group of organic compounds produced by living organisms. Their structures are characterized by:

• Multiple functional groups and heteroatoms
• Complex stereochemistry and ring systems
• Often modular construction from simple building blocks (sugars, acetate units, isoprene units, amino acids)

They are divided conceptually into primary and secondary metabolites, reflecting their roles in basic metabolism and ecological interactions. Natural products underline the close relationship between structure and function in chemistry and biology and form the basis for many foods, medicines, materials, and industrial chemicals.

The following subchapters on carbohydrates, fats, and amino acids/peptides/proteins examine three especially important families of natural products in more detail.