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org/wiki/Natural_product

Natural product
A natural product is a chemical compound or substance produced by
a living organism—that is, found in nature.[2][3] In the broadest sense,
natural products include any substance produced by life.[4][5] Natural
products can also be prepared by chemical synthesis (both
semisynthesis and total synthesis) and have played a central role in the
development of the field of organic chemistry by providing challenging
synthetic targets. The term natural product has also been extended for
commercial purposes to refer to cosmetics, dietary supplements, and
Paclitaxel (Taxol) is a natural
foods produced from natural sources without added artificial
product derived from the yew tree.[1]
ingredients.[6]

Within the field of organic chemistry, the definition of natural products


is usually restricted to mean purified organic compounds isolated from natural sources that are produced by the
pathways of primary or secondary metabolism.[7] Within the field of medicinal chemistry, the definition is often
further restricted to secondary metabolites.[8][9] Secondary metabolites are not essential for survival, but
nevertheless provide organisms that produce them an evolutionary advantage.[10] Many secondary metabolites are
cytotoxic and have been selected and optimized through evolution for use as "chemical warfare" agents against
prey, predators, and competing organisms.[11]

Natural products sometimes have therapeutic benefit as traditional medicines for treating diseases, yielding
knowledge to derive active components as lead compounds for drug discovery.[12] Although natural products have
inspired numerous U.S. Food and Drug Administration-approved drugs, drug development from natural sources
has received declining attention by pharmaceutical companies, partly due to unreliable access and supply,
intellectual property concerns, seasonal or environmental variability of composition, and loss of sources due to
rising extinction rates.[12]

Contents
Classes
Function
Primary metabolites
Secondary metabolites
Biosynthesis
Carbohydrates
Fatty acids and polyketides

Sources
Prokaryotic
Bacteria
Archaea
Eukaryotic
Fungi
Plants

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Animals

Medical uses
Traditional medicine
Modern natural product-derived drugs
Limiting and enabling factors

Isolation and purification


Synthesis
Semisynthesis
Total synthesis
Symmetry

Research and teaching


Chemistry
Biochemistry
History
Foundations of organic and natural product chemistry
Isolation
Synthesis
Structural theories
Expanding the concept
Milestones

See also
Journals

References
Further reading
External links

Classes
The broadest definition of natural product is anything that is produced by life,[4][13] and includes the likes of biotic
materials (e.g. wood, silk), bio-based materials (e.g. bioplastics, cornstarch), bodily fluids (e.g. milk, plant
exudates), and other natural materials (e.g. soil, coal). A more restrictive definition of a natural product is an
organic compound that is synthesized by a living organism.[7] The remainder of this article restricts itself to this
more narrow definition.

Natural products may be classified according to their biological function, biosynthetic pathway, or source as
described below.

Function
Following Albrecht Kossel's original proposal in 1891,[14] natural products are often divided into two major classes,
the primary and secondary metabolites.[15][16] Primary metabolites have an intrinsic function that is essential to
the survival of the organism that produces them. Secondary metabolites in contrast have an extrinsic function that
mainly affects other organisms. Secondary metabolites are not essential to survival but do increase the
competitiveness of the organism within its environment. Because of their ability to modulate biochemical and
signal transduction pathways, some secondary metabolites have useful medicinal properties.

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Natural products especially within the field of organic chemistry are often defined as primary and secondary
metabolites. A more restrictive definition limiting natural products to secondary metabolites is commonly used
within the fields of medicinal chemistry and pharmacognosy.[13]

Primary metabolites
Primary metabolites as defined
by Kossel are components of
basic metabolic pathways that
are required for life. They are
associated with essential cellular
functions such as nutrient
assimilation, energy production,
and growth/development. They
have a wide species distribution
that span many phyla and
frequently more than one
kingdom. Primary metabolites
include carbohydrates, lipids,
amino acids, and nucleic
acids[15][16] which are the basic
building blocks of life.[17] Molecular building blocks of life

Primary metabolites that are


involved with energy production include respiratory and photosynthetic enzymes. Enzymes in turn are composed
of amino acids and often non-peptidic cofactors that are essential for enzyme function.[18] The basic structure of
cells and of organisms are also composed of primary metabolites. These include cell membranes (e.g.
phospholipids), cell walls (e.g. peptidoglycan, chitin), and cytoskeletons (proteins).[19]

Primary metabolite enzymatic cofactors include members of the vitamin B family. Vitamin B1 as thiamine
diphosphate is a coenzyme for pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, and transketolase which
are all involved in carbohydrate metabolism. Vitamin B2 (riboflavin) is a constituent of FMN and FAD which are
necessary for many redox reactions. Vitamin B3 (nicotinic acid or niacin), synthesized from tryptophan is a
component of the coenzymes NAD+ and NADP+ which in turn are required for electron transport in the Krebs
cycle, oxidative phosphorylation, as well as many other redox reactions. Vitamin B5 (pantothenic acid) is a
constituent of coenzyme A, a basic component of carbohydrate and amino acid metabolism as well as the
biosynthesis of fatty acids and polyketides. Vitamin B6 (pyridoxol, pyridoxal, and pyridoxamine) as pyridoxal
5′-phosphate is a cofactor for many enzymes especially transaminases involve in amino acid metabolism. Vitamin
B12 (cobalamins) contain a corrin ring similar in structure to porphyrin and is an essential coenzyme for the
catabolism of fatty acids as well for the biosynthesis of methionine.[20]:Chapter 2

DNA and RNA which store and transmit genetic information are composed of nucleic acid primary metabolites.[18]

First messengers are signaling molecules that control metabolism or cellular differentiation. These signaling
molecules include hormones and growth factors in turn are composed of peptides, biogenic amines, steroid
hormones, auxins, gibberellins etc. These first messengers interact with cellular receptors which are composed of
proteins. Cellular receptors in turn activate second messengers are used to relay the extracellular message to
intracellular targets. These signaling molecules include the primary metabolites cyclic nucleotides, diacyl glycerol
etc.[21]

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Secondary metabolites
Secondary in contrast to primary
metabolites are dispensable and not
absolutely required for survival.
Furthermore, secondary metabolites
typically have a narrow species
distribution.

Secondary metabolites have a broad


range of functions. These include
pheromones that act as social signaling
molecules with other individuals of the Representative examples of each of the major classes of
same species, communication molecules secondary metabolites
that attract and activate symbiotic
organisms, agents that solubilize and
transport nutrients (siderophores etc.), and competitive weapons (repellants, venoms, toxins etc.) that are used
against competitors, prey, and predators.[22] For many other secondary metabolites, the function is unknown. One
hypothesis is that they confer a competitive advantage to the organism that produces them.[23] An alternative view
is that, in analogy to the immune system, these secondary metabolites have no specific function, but having the
machinery in place to produce these diverse chemical structures is important and a few secondary metabolites are
therefore produced and selected for.[24]

General structural classes of secondary metabolites include alkaloids, phenylpropanoids, polyketides, and
terpenoids,[7] which are described in more detail in the biosynthesis section below.

Biosynthesis
The biosynthetic pathways leading to the major classes of natural products are described below.[13][20]:Chapter 2

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


Acetate pathway → fatty acids and polyketides
Shikimate pathway → aromatic amino acids and phenylpropanoids
Mevalonate pathway and methyletrythritol phosphate pathway → terpenoids and steroids
Amino acids → alkaloids

Carbohydrates
Carbohydrates are an essential energy source for most life forms. In addition, polysaccharides formed from simpler
carbohydrates are important structural components of many organisms such the cell walls of bacteria and plants.

Carbohydrate are the products of plant photosynthesis and animal gluconeogenesis. Photosynthesis produces
initially 3-phosphoglyceraldehyde, a three carbon atom containing sugar (a triose).[20]:Chapter 8 This triose in turn
may be converted into glucose (a six carbon atom containing sugar) or a variety of pentoses (five carbon atom
containing sugars) through the Calvin cycle. In animals, the three carbon precursors lactate or glycerol can be
converted into pyruvate which in turn can be converted into carbohydrates in the liver.

Fatty acids and polyketides


Through the process of glycolysis sugars are broken down into acetyl-CoA. In an ATP dependent enzymatically

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catalyzed reaction,
acetyl-CoA is
carboxylated to form
malonyl-CoA.
Acetyl-CoA and
malonyl-CoA
undergo a Claisen
condensation with
lose of carbon
dioxide to form
acetoacetyl-CoA.
Additional
condensation
reactions produce
successively higher
molecular weight
poly-β-keto chains
which are then
converted into other
polyketides.
[20]:Chapter 3 The
polyketide class of
natural products
have diverse
structures and
functions and
include
prostaglandins and
macrolide
antibiotics.

Biosynthesis of primary and secondary metabolites.[20]:Chapter 2

One molecule of acetyl-CoA (the "starter unit") and several molecules malonyl-CoA (the "extender units") are
condensed by fatty acid synthase to produce fatty acids.[20]:Chapter 3 Fatty acid are essential components of lipid
bilayers that form cell membranes as well as fat energy stores in animals.

Sources
Natural products may be extracted from the cells, tissues, and secretions of microorganisms, plants and
animals.[25] A crude (unfractionated) extract from any one of these sources will contain a range of structurally
diverse and often novel chemical compounds. Chemical diversity in nature is based on biological diversity, so

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researchers travel around the world obtaining samples to analyze and evaluate in drug discovery screens or
bioassays. This effort to search for natural products is known as bioprospecting.

Pharmacognosy provides the tools to identify, select and process natural products destined for medicinal use.
Usually, the natural product compound has some form of biological activity and that compound is known as the
active principle - such a structure can evolve to become a discovery "lead". In this and related ways, some current
medicines are obtained directly from natural sources.

On the other hand, some medicines are developed from the natural product lead originally obtained from the
natural source. This means the lead may be:

produced by total synthesis, or


a starting point (precursor) for a semisynthetic compound, or
a framework that serves as the basis for a structurally different compound arrived at by total/semisynthesis.
This is because many biologically active natural products are secondary metabolites often with complex chemical
structures. This has an advantage in that they are novel compounds but this complexity also makes difficult the
synthesis of such compounds; instead the compound may need to be extracted from its natural source – a slow,
expensive and inefficient process. As a result, there is usually an advantage in designing simpler analogues.

Prokaryotic

Bacteria
The serendipitous discovery and subsequent clinical success of
penicillin prompted a large-scale search for other environmental
microorganisms that might produce anti-infective natural products.
Soil and water samples were collected from all over the world, leading
to the discovery of streptomycin (derived from Streptomyces griseus),
and the realization that bacteria, not just fungi, represent an important
source of pharmacologically active natural products.[26] This, in turn,
led to the development of an impressive arsenal of antibacterial and
antifungal agents including amphotericin B, chloramphenicol,
daptomycin and tetracycline (from Streptomyces spp.),[27] the
polymyxins (from Paenibacillus polymyxa),[28] and the rifamycins Botulinum toxin types A and B
(from Amycolatopsis rifamycinica).[29] (Botox, Dysport, Xeomin, MyoBloc),
used both medicinally and
Although most of the drugs derived from bacteria are employed as anti- cosmetically, are natural products
infectives, some have found use in other fields of medicine. Botulinum from the bacterium Clostridium
toxin (from Clostridium botulinum) and bleomycin (from Streptomyces botulinum
verticillus) are two examples. Botulinum, the neurotoxin responsible
for botulism, can be injected into specific muscles (such as those
controlling the eyelid) to prevent muscle spasm.[30] Also, the glycopeptide bleomycin is used for the treatment of
several cancers including Hodgkin's lymphoma, head and neck cancer, and testicular cancer.[31] Newer trends in
the field include the metabolic profiling and isolation of natural products from novel bacterial species present in
underexplored environments. Examples include symbionts or endophytes from tropical environments,[32]
subterranean bacteria found deep underground via mining/drilling,[33][34] and marine bacteria.[35]

Archaea

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Because many Archaea have adapted to life in extreme environments such as polar regions, hot springs, acidic
springs, alkaline springs, salt lakes, and the high pressure of deep ocean water, they possess enzymes that are
functional under quite unusual conditions. These enzymes are of potential use in the food, chemical, and
pharmaceutical industries, where biotechnological processes frequently involve high temperatures, extremes of
pH, high salt concentrations, and / or high pressure. Examples of enzymes identified to date include amylases,
pullulanases, cyclodextrin glycosyltransferases, cellulases, xylanases, chitinases, proteases, alcohol dehydrogenase,
and esterases.[36] Archaea represent a source of novel chemical compounds also, for example isoprenyl glycerol
ethers 1 and 2 from Thermococcus S557 and Methanocaldococcus jannaschii, respectively.[37]

Eukaryotic

Fungi
Several anti-infective medications have been derived from fungi
including penicillin and the cephalosporins (antibacterial drugs from
Penicillium chrysogenum and Cephalosporium acremonium,
respectively)[26] and griseofulvin (an antifungal drug from Penicillium
griseofulvum).[38] Other medicinally useful fungal metabolites include
lovastatin (from Pleurotus ostreatus), which became a lead for a series
of drugs that lower cholesterol levels, cyclosporin (from Tolypocladium
inflatum), which is used to suppress the immune response after organ
transplant operations, and ergometrine (from Claviceps spp.), which
acts as a vasoconstrictor, and is used to prevent bleeding after
childbirth.[20]:Chapter 6 Asperlicin (from Aspergillus alliaceus) is
The antibiotic penicillin is a natural
another example. Asperlicin is a novel antagonist of cholecystokinin, a product derived from the fungus
neurotransmitter thought to be involved in panic attacks, and could Penicillium chrysogenum
potentially be used to treat anxiety.

Plants
Plants are a major source of complex and highly structurally diverse
chemical compounds (phytochemicals), this structural diversity
attributed in part to the natural selection of organisms producing
potent compounds to deter herbivory (feeding deterrents).[39] Major
classes of phytochemical include phenols, polyphenols, tannins,
terpenes, and alkaloids.[40] Though the number of plants that have
been extensively studied is relatively small, many pharmacologically
active natural products have already been identified. Clinically useful
examples include the anticancer agents paclitaxel and omacetaxine The opioid analgesic drug morphine
mepesuccinate (from Taxus brevifolia and Cephalotaxus harringtonii, is a natural product derived from the
respectively),[41] the antimalarial agent artemisinin (from Artemisia plant Papaver somniferum
annua),[42] and the acetylcholinesterase inhibitor galantamine (from
Galanthus spp.), used to treat Alzheimer's disease.[43] Other plant-
derived drugs, used medicinally and/or recreationally include morphine, cocaine, quinine, tubocurarine,
muscarine, and nicotine.[20]:Chapter 6

Animals

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Animals also represent a source of bioactive natural products. In


particular, venomous animals such as snakes, spiders, scorpions,
caterpillars, bees, wasps, centipedes, ants, toads, and frogs have
attracted much attention. This is because venom constituents (peptides,
enzymes, nucleotides, lipids, biogenic amines etc.) often have very
specific interactions with a macromolecular target in the body (e.g.
α-bungarotoxin from cobras).[44][45] As with plant feeding deterrents,
this biological activity is attributed to natural selection, organisms
capable of killing or paralyzing their prey and/or defending themselves
against predators being more likely to survive and reproduce.[45]

Because of these specific chemical-target interactions, venom The analgesic drug ω-conotoxin
(ziconotide) is a natural product
constituents have proved important tools for studying receptors, ion
derived from the sea snail Conus
channels, and enzymes. In some cases, they have also served as leads in
magus
the development of novel drugs. For example, teprotide, a peptide
isolated from the venom of the Brazilian pit viper Bothrops jararaca,
was a lead in the development of the antihypertensive agents cilazapril and captopril. Also, echistatin, a disintegrin
from the venom of the saw-scaled viper Echis carinatus was a lead in the development of the antiplatelet drug
tirofiban.[45]

In addition to the terrestrial animals and amphibians described above, many marine animals have been examined
for pharmacologically active natural products, with corals, sponges, tunicates, sea snails, and bryozoans yielding
chemicals with interesting analgesic, antiviral, and anticancer activities.[46] Two examples developed for clinical
use include ω-conotoxin (from the marine snail Conus magus)[47][48] and ecteinascidin 743 (from the tunicate
Ecteinascidia turbinata).[49] The former, ω-conotoxin, is used to relieve severe and chronic pain,[48][47] while the
latter, ecteinascidin 743 is used to treat metastatic soft tissue sarcoma.[50] Other natural products derived from
marine animals and under investigation as possible therapies include the antitumour agents discodermolide (from
the sponge Discodermia dissoluta),[51] eleutherobin (from the coral Erythropodium caribaeorum), and the
bryostatins (from the bryozoan Bugula neritina).[51]

Medical uses
Natural products sometimes have pharmacological activity that can be of therapeutic benefit in treating diseases.
As such, natural products are the active components of many traditional medicines.[12][11][52][53][54] Moreover,
synthetic analogs of natural products with improved potency and safety can be prepared and therefore natural
products are often used as starting points for drug discovery. Natural product constituents have inspired numerous
drug discovery efforts that eventually gained approval as new drugs by the U.S. Food and Drug
Administration[55][56]

Traditional medicine
Indigenous peoples and ancient civilizations experimented with various plant and animal parts to determine what
effect they might have. Through trial and error in isolated cases, traditional healers or shamans found some
sources to provide therapeutic effect, representing knowledge of a crude drug that was passed down through
generations in such practices as traditional Chinese medicine and Ayurveda.[57] Extracts of some natural products
led to modern discovery of their active ingredients and eventually to the development of new drugs.[58]

Modern natural product-derived drugs

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A large number of currently prescribed


drugs have been either directly derived
from or inspired by natural products.
[1][59] A few representative examples are
listed below.

Some of the oldest natural product based


drugs are analgesics. The bark of the
willow tree has been known from
antiquity to have pain relieving
properties. This is due to presence of the
natural product salicin which in turn
may be hydrolyzed into salicylic acid. A
synthetic derivative acetylsalicylic acid
better known as aspirin is a widely used
pain reliever. Its mechanism of action is
inhibition of the cyclooxygenase (COX)
enzyme.[60] Another notable example is
opium is extracted from the latex from
Papaver somniferous (a flowering poppy
plant). The most potent narcotic
component of opium is the alkaloid
morphine which acts as an opioid
receptor agonist.[61] A more recent
example is the N-type calcium channel
blocker ziconotide analgesic which is
based on a cyclic peptide cone snail toxin
(ω-conotoxin MVIIA) from the species
Conus magus.[62]

A significant number of anti-infectives


are based on natural products. The first
antibiotic to be discovered, penicillin,
was isolated from the mold Penicillium.
Penicillin and related beta lactams work Representative examples of drugs based on natural products
by inhibiting DD-transpeptidase enzyme
that is required by bacteria to cross link
peptidoglycan to form the cell wall.[63]

Several natural product drugs target tubulin, which is a component of the cytoskeleton. These include the tubulin
polymerization inhibitor colchicine isolated from the Colchicum autumnale (autumn crocus flowering plant),
which is used to treat gout.[64] Colchicine is biosynthesized from the amino acids phenylalanine and tryptophan.
Paclitaxel, in contrast, is a tubulin polymerization stabilizer and is used as a chemotherapeutic drug. Paclitaxel is
based on the terpenoid natural product taxol, which is isolated from Taxus brevifolia (the pacific yew tree).[65]

A class of drugs widely used to lower cholesterol are the HMG-CoA reductase inhibitors, for example atorvastatin.
These were developed from mevastatin, a polyketide produced by the fungus Penicillium citrinum.[66] Finally, a
number natural product drugs are used to treat hypertension and congestive heart failure. These include the
angiotensin-converting enzyme inhibitor captopril. Captopril is based on the peptidic bradykinin potentiating

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factor isolated from venom of the Brazilian arrowhead viper (Bothrops jararaca).[67]

Limiting and enabling factors


Numerous challenges limit the use of natural products for drug discovery, resulting in 21st century preference by
pharmaceutical companies to dedicate discovery efforts toward high-throughput screening of pure synthetic
compounds with shorter timelines to refinement.[12] Natural product sources are often unreliable to access and
supply, have a high probability of duplication, inherently create intellectual property concerns about patent
protection, vary in composition due to sourcing season or environment, and are susceptible to rising extinction
rates.[12]

The biological resource for drug discovery from natural products remains abundant, with small percentages of
microorganisms, plant species, and insects assessed for bioactivity.[12] In enormous numbers, bacteria and marine
microorganisms remain unexamined.[68][69] As of 2008, the field of metagenomics was proposed to examine genes
and their function in soil microbes,[69][70] but most pharmaceutical firms have not exploited this resource fully,
choosing instead to develop “diversity-oriented synthesis” from libraries of known drugs or natural sources for lead
compounds with higher potential for bioactivity.[12]

Isolation and purification


All natural products begin as mixtures with other compounds from
the natural source, often very complex mixtures, from which the
product of interest must be isolated and purified. The isolation of
a natural product refers, depending on context, either to the
isolation of sufficient quantities of pure chemical matter for
chemical structure elucidation, derivitzation/degradation
chemistry, biological testing, and other research needs (generally
Penicillin G, the first of its class fungal
milligrams to grams, but historically, often more), or to the
antibiotic, first studied by Scottish
isolation of "analytical quantities" of the substance of interest, microbiologist Alexander Fleming in the
where the focus is on identification and quantitation of the late 1920s, and made practical as a
substance (e.g. in biological tissue or fluid), and where the therapeutic via natural product isolation
quantity isolated depends on the analytical method applied (but is in the late 1930s by Ernst Boris Chain,
generally always sub-microgram in scale).[72] The ease with which Howard Florey, and others, these three
named scientists sharing the 1945 Nobel
the active agent can be isolated and purified depends on the
Prize in Medicine for the work. Fleming
structure, stability, and quantity of the natural product. The
recognized the antibacterial activity and
methods of isolation applied toward achieving these two distinct clinical potential of "pen G", but was
scales of product are likewise distinct, but generally involve unable to purify or stabilize it.[71]
extraction, precipitation, adsorptions, chromatography, and Developments in chromatographic
sometimes crystallizations. In both cases, the isolated substance is separations and freeze drying helped
purified to chemical homogeneity, i.e. specific combined move progress forward in the production
of commercial quantities of penicillin and
separation and analytical methods such as LC-MS methods are
other natural products.
chosen to be "orthogonal"—achieving their separations based on
distinct modes of interaction between substance and isolating
matrix—with the goal being repeated detection of only a single species present in the putative pure sample. Early
isolation is almost inevitably followed by structure determination, especially if an important pharmacologic
activity is associated with the purified natural product.

Structure determination refers to methods applied to determine the chemical structure of an isolated, pure natural
product, a process that involves an array of chemical and physical methods that have changed markedly over the

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history of natural products research; in earliest days, these focused on chemical transformation of unknown
substances into known substances, and measurement of physical properties such as melting point and boiling
point, and related methods for determining molecular weight. In the modern era, methods focus on mass
spectrometry and nuclear magnetic resonance methods, often multidimensional, and, when feasible, small
molecule crystallography. For instance, the chemical structure of penicillin was determined by Dorothy Crowfoot
Hodgkin in 1945, work for which she later received a Nobel Prize in Chemistry (1964).[73]

Synthesis
Many natural products have very complex structures. The perceived complexity of a natural product is a qualitative
matter, consisting of consideration of its molecular mass, the particular arrangements of substructures (functional
groups, rings etc.) with respect to one another, the number and density of those functional groups, the stability of
those groups and of the molecule as a whole, the number and type of stereochemical elements, the physical
properties of the molecule and its intermediates (which bear on the ease of its handling and purification), all of
these viewed in the context of the novelty of the structure and whether preceding related synthetic efforts have
been successful (see below for details). Some natural products, especially those less complex, are easily and cost-
effectively prepared via complete chemical synthesis from readily available, simpler chemical ingredients, a process
referred to as total synthesis (especially when the process involves no steps mediated by biological agents). Not all
natural products are amenable to total synthesis, cost-effective or otherwise. In particular, those most complex
often are not. Many are accessible, but the required routes are simply too expensive to allow synthesis on any
practical or industrial scale. However, in order to be available for further study, all natural products must yield to
isolation and purification. This may suffice if isolation provides appropriate quantities of the natural product for
the intended purpose (e.g. as a drug to alleviate disease). Drugs such as penicillin, morphine, and paclitaxel proved
to be affordably acquired at needed commercial scales solely via isolation procedures (without any significant
synthetic chemistry contributing). However, in other cases, needed agents are not available without synthetic
chemistry manipulations.

Semisynthesis
The process of isolating a natural product from its source can be costly in terms of committed time and material
expense, and it may challenge the availability of the relied upon natural resource (or have ecological consequences
for the resource). For instance, it has been estimated that the bark of an entire yew tree (Taxus brevifolia) would
have to be harvested to extract enough paclitaxel for just a single dose of therapy.[74] Furthermore, the number of
structural analogues obtainable for structure-activity analysis (SAR) simply via harvest (if more than one structural
analogue is even present) is limited by the biology at work in the organism, and so outside of the experimentalist's
control.

In such cases where the ultimate target is harder to come by, or limits SAR, it is sometimes possible to source a
middle-to-late stage biosynthetic precursor or analogue from which the ultimate target can be prepared. This is
termed semisynthesis or partial synthesis. With this approach, the related biosynthetic intermediate is harvested
and then converted to the final product by conventional procedures of chemical synthesis.

This strategy can have two advantages. Firstly, the intermediate may be more easily extracted, and in higher yield,
than the ultimate desired product. An example of this is paclitaxel, which can be manufactured by extracting 10-
deacetylbaccatin III from T. brevifolia needles, then carrying out a four-step synthesis. Secondly, the route
designed between semisynthetic starting material and ultimate product may permit analogues of the final product
to be synthesized. The newer generation semisynthetic penicillins are an illustration of the benefit of this approach.

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Total synthesis
In general, the total synthesis of natural products is a non-commercial
research activity, aimed at deeper understanding of the synthesis of
particular natural product frameworks, and the development of
fundamental new synthetic methods. Even so, it is of tremendous
commercial and societal importance. By providing challenging
synthetic targets, for example, it has played a central role in the
development of the field of organic chemistry.[78][79] Prior to the
development of analytical chemistry methods in the twentieth century,
the structures of natural products were affirmed by total synthesis (so-
called "structure proof by synthesis").[80] Early efforts in natural
products synthesis targeted complex substances such as cobalamin
(vitamin B12), an essential cofactor in cellular metabolism.[76][77]

Symmetry
Examination of dimerized and trimerized natural products has shown
that an element of bilateral symmetry is often present. Bilateral Structural representation of
symmetry refers to a molecule or system that contains a C2, Cs, or C2v cobalamin, an early natural product
point group identity. C2 symmetry tends to be much more abundant isolated and structurally
characterized.[75] The variable R
than other types of bilateral symmetry. This finding sheds light on how
group can be a methyl or 5'-
these compounds might be mechanistically created, as well as providing
adenosyl group, or a cyanide or
insight into the thermodynamic properties that make these compounds hydroxide anion. The "proof" by
more favorable. Density functional theoretical (DFT), Hartree Fock, synthesis of vitamin B12 was
and semiempirical calculations also show some favorability for accomplished in 1972 by the groups
dimerization in natural products due to evolution of more energy per of R.B. Woodward[76] and A.
bond than the equivalent trimer or tetramer. This is proposed to be due Eschenmoser.[77]
to steric hindrance at the core of the molecule, as most natural products
dimerize and trimerize in a head-to-head fashion rather than head-to-
tail.[81]

Research and teaching


Research and teaching activities related to natural products fall into a number of different academic areas,
including organic chemistry, medicinal chemistry, pharmacognosy, ethnobotany, traditional medicine and
ethnopharmacology. Other biological areas include chemical biology, chemical ecology, chemogenomics, and
systems biology.

Chemistry
Natural products chemistry is a distinct area of chemical research which was important in the history of chemistry,
the sourcing of substances in early preclinical drug discovery research, the understanding of traditional medicine
and ethnopharmacology, the evolution of technology associated with chemical separations, the development of
modern methods in chemical structure determination by NMR and other techniques, and in identification of
pharmacologically useful areas of chemical diversity space. In addition, natural products are prepared by organic
synthesis, and have played a central role to the development of the field of organic chemistry by providing
tremendously challenging targets and problems for synthetic strategy and tactics.[78][79] In this regard, natural

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products play a central role in the training of new synthetic organic chemists, and are a principal motivation in the
development of new variants of old chemical reactions (e.g., the Evans aldol reaction), as well as the discovery of
completely new chemical reactions (e.g., the Woodward cis-hydroxylation, Sharpless epoxidation, and Suzuki–
Miyaura cross-coupling reactions).

Biochemistry
Research is being carried out to understand and manipulate the biochemical pathways involved in natural product
synthesis in plants. It is hoped this knowledge will enable medicinally useful phytochemicals such as alkaloids to be
produced more efficiently and economically.[82]

History

Foundations of organic and natural product


chemistry
The concept of natural products dates back to the early 19th century, when
the foundations of organic chemistry were laid. Organic chemistry was
regarded at that time as the chemistry of substances that plants and
animals are composed of. It was a relatively complex form of chemistry and
stood in stark contrast to inorganic chemistry, the principles of which had
been established in 1789 by the Frenchman Antoine Lavoisier in his work
Traité Élémentaire de Chimie.[83]

Isolation Antoine Lavoisier (1743-1794)


Lavoisier showed at the end of the 18th century that organic substances
consisted of a limited number of elements: primarily carbon and hydrogen
and supplemented by oxygen and nitrogen. He quickly focused on the
isolation of these substances, often because they had an interesting
pharmacological activity. Plants were the main source of such compounds,
especially alkaloids and glycosides. It was long been known that opium, a
sticky mixture of alkaloids (including codeine, morphine, noscapine,
thebaine, and papaverine) from the opium poppy (Papaver somniferum),
possessed a narcotic and at the same time mind-altering properties. By
1805, morphine had already been isolated by the German chemist
Friedrich Sertürner and in the 1870s it was discovered that boiling
morphine with acetic anhydride produced a substance with a strong pain
suppressive effect: heroin.[84] In 1815, Eugène Chevreul isolated
cholesterol, a crystalline substance, from animal tissue that belongs to the
class of steroids, and in 1820 strychnine, an alkaloid was isolated.
Friedrich Wöhler (1800-1882)

Synthesis
A second important step was the synthesis of organic compounds. Whereas the synthesis of inorganic substances
had been known for a long time, the synthesis of organic substances was a difficult hurdle. In 1827 the Swedish
chemist Jöns Jacob Berzelius held that an indispensable force of nature for the synthesis of organic compounds,

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called vital force or life force, was needed. This philosophical idea, vitalism,
well into the 19th century had many supporters, even after the introduction
of the atomic theory. The idea of vitalism especially fitted in with beliefs in
medicine; the most traditional healing practices believed that disease was
the result of some imbalance in the vital energies that distinguishes life
from nonlife. A first attempt to break the vitalism idea in science was made
in 1828, when the German chemist Friedrich Wöhler succeeded in
synthesizing urea, a natural product found in urine, by heating ammonium
cyanate, an inorganic substance:[85]

This reaction showed that there was no need for a life force in order to
prepare organic substances. This idea, however, was initially met with a
high degree of skepticism, and only 20 years later, with the synthesis of Hermann Emil Fischer
acetic acid from carbon by Adolph Wilhelm Hermann Kolbe, was the idea (1852-1919)
accepted. Organic chemistry has since developed into an independent area
of research dedicated to the study of carbon-containing compounds, since
that element in common was detected in a variety of nature-derived
substances. An important factor in the characterization of organic
materials was on the basis of their physical properties (such as melting
point, boiling point, solubility, crystallinity, or color).

Structural theories
A third step was the structure elucidation of organic substances: although
the elemental composition of pure organic substances (irrespective of
whether they were of natural or synthetic origin) could be determined
fairly accurately, the molecular structure was still a problem. The urge to
do structural elucidation resulted from a dispute between Friedrich Wöhler
and Justus von Liebig, who both studied a silver salt of the same
composition but had different properties. Wöhler studied silver cyanate, a
harmless substance, while von Liebig investigated silver fulminate, a salt Richard Willstätter (1872-1942)

with explosive properties.[86] The elemental analysis shows that both salts
contain equal quantities of silver, carbon, oxygen and nitrogen. According to the then prevailing ideas, both
substances should possess the same properties, but this was not the case. This apparent contradiction was later
solved by Berzelius's theory of isomers, whereby not only the number and type of elements are of importance to the
properties and chemical reactivity, but also the position of atoms in within a compound. This was a direct cause for
the development of structure theories, such as the radical theory of Jean-Baptiste Dumas and the substitution
theory of Auguste Laurent.[87] However, it took until 1858 before by August Kekulé formulated a definite structure
theory. He posited that carbon tetravalent ad can bind itself to carbon chains as they occur in natural products.[88]

Expanding the concept


The concept of natural product, which initially based on organic compounds that could be isolated from plants, was
extended to include animal material in the middle of the 19th century by the German Justus von Liebig. Hermann
Emil Fischer in 1884, turned his attention to the study of carbohydrates and purines, work for which he was
awarded the Nobel Prize in 1902. He also succeeded to make synthetically in the laboratory in a variety of

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carbohydrates, including glucose and mannose. After the discovery of


penicillin by Alexander Fleming in 1928, fungi and other micro-organisms
were added to the arsenal of sources of natural products.[84]

Milestones
By the 1930s, several large classes of natural products were known.
Important milestones included:

Terpenes, first systematically studied by Otto Wallach (Nobel Prize


1910) and later by Leopold Ružička (Nobel Prize 1939)
Dyes based on porphins (including chlorophyll and heme), studied by
Richard Willstätter (Nobel Prize 1915) and Hans Fischer (Nobel Prize
1930)
Steroids, studied by Heinrich Otto Wieland (Nobel Prize 1927) and
Adolf Windaus (Nobel Prize 1928)
Robert Robinson (1886-1975)
Carotenoids, studied by Paul Karrer (Nobel Prize 1937)
Vitamins, studied among others by Paul Karrer, Adolf Windaus, Robert
R. Williams, Norman Haworth (Nobel Prize 1937), Richard Kuhn (Nobel Prize 1938) and Albert Szent-Györgyi
Hormones studied by Adolf Butenandt (Nobel Prize 1939) and Edward Calvin Kendall (Nobel Prize 1950)
Alkaloids and anthocyanins, studied by, among others, Robert Robinson (Nobel Prize 1947)

See also
Appeal to nature
Ethnobotany
Pharmacognosy
Phytotherapy
Secondary metabolite

Journals
Chemistry of Natural Compounds
Journal of Natural Products
Natural Product Reports
Natural Product Research

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Further reading
Bhat SV, Nagasampagi BA, Sivakumar M (2005). Chemistry of Natural Products (2 ed.). Berlin: Springer.
ISBN 3-540-40669-7.
Hanson JR (2003). Natural Products: The Secondary Metabolites. Royal Society of Chemistry.
ISBN 0-85404-490-6.
Kaufman PB (1999). Natural Products from Plants. CRC Press. ISBN 0-8493-3134-X.
Liang XT, Fang WS, eds. (2006). Medicinal Chemistry of Bioactive Natural Products. Wiley-Interscience.
ISBN 0-471-73933-2.

External links
Reusch W (2010). "Natural Products page" (https://web.archive.org/web/20070203050704/http:
//www.cem.msu.edu/~reusch/VirtualText/biomol.htm). Virtual Textbook of Organic Chemistry. Ann Arbor, Mich.:
Michigan State University, Department of Chemistry. Archived from the original (http://www.cem.msu.edu
/~reusch/VirtualText/biomol.htm) on 3 February 2007.
"NAPROC-13 Base de datos de Carbono 13 de Productos Naturales y Relacionados (Carbon-13 Database of
Natural Products and Related Substances)" (http://c13.usal.es). Spanish language tools to facilitate structural
identification of natural products.
Porter N, ed. (1913). "Natural product". Webster's Dictionary. Springfield, Massachusetts: C. & G. Merriam Co.

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