Stereochemistry, Chirality and Human Health

by
Mark J Donohue

When dealing with health conditions such as multiple chemical sensitivity (MCS) one of the first
questions asked is – what’s the difference? More specifically, what’s the difference between a natural
compound and a man-made synthetic version of the same compound? Why does the smell of freshly cut
flowers placed in a room pose no problem to those with health conditions such as MCS? Verses an air
freshener (same odor as the flowers) placed in a room, which can cause a host of problems in those with
MCS… what’s the difference? The answer can be found in a field of study called stereochemistry.

Stereochemistry, a sub-discipline of chemistry, involves the study of the relative spatial arrangement of
atoms within molecules. Stereochemistry is also known as 3D chemistry because the prefix "stereo-"
means "three-dimensionality".

Chirality and Chiral Molecules

A basic concept of stereochemistry that is important to understand is that of chirality. Put simply, chiral
objects whether they are microscopic molecules or macroscopic objects are - irregularly shaped
(asymmetric) and are non-superimposable on its mirror image. Chirality exists all around us. For
example – a spiral staircase, a shoe, a tree, etc. are all chiral objects.

Human hands are perhaps the most universally recognized example of chirality: The left hand is a non-
superimposable mirror image of the right hand; no matter how the two hands are oriented, it is
impossible for all the major features of both hands to coincide. Therefore, the right hand is said to be
chiral as well as the left hand.

Objects that possess a similar handedness are said to be chiral (literally, "handed"). Those that do not
are said to be achiral. Gloves are chiral, mittens however, are often achiral (either mitten can fit on
either hand.) Feet and shoes are both chiral, but socks are achiral.
In molecules; the understanding of chirality is important because biological molecules are often chiral.
Natural compounds such as - DNA, proteins, carbohydrates, lipids, steroids, etc. are chiral molecules.
Meaning, they have very irregular shapes (asymmetric) which make each one a unique individual
molecule. Making them uniquely qualified to interact and communicate with other unique individual
chiral molecules. Chiral molecules will only recognize and interact with molecules that have a certain
stereochemistry. Hence, any substances created by man to interact with or modify nature are
interacting with a chiral environment.

Additionally, the feature that is most often the cause of chirality in molecules is the presence of an
asymmetric carbon atom, which is referred to as a chiral center (chiral
carbon) or stereo center (stereogenic). A chiral center is a carbon atom
bearing 4 different atoms or groups of atoms.

Therefore, a chiral molecule is a type of molecule that:

 Does NOT have an internal plane of symmetry

 Does NOT have an inversion center
 Has a non-superimposable mirror image.
 Has at least one chiral center or stereo center.

It is important to note that the “mirror image” being referred to may be just a theoretical molecule
generated on paper or in using a model. Or the mirror image may actually exist. A chiral molecule with
an actual corresponding mirror image, together are referred to as enantiomers or stereoisomers.

Stereochemistry can be difficult to conceptualize from just reading a description. Therefore, I have
provided links (throughout this report) to videos which will help in visualizing the various concepts
involved in stereochemistry.

 Video – Khan Academy: Introduction to Chirality (6:46) Link

 Video – Chirality: Basic Concept Explained (3:10) Link
 Video – Chiral vs. Achiral Objects: Plane of Symmetry & Inversion Centers (6:01) Link

Isomers/Isomeric Molecules

Isomers/Isomeric Molecules (iso – “same”, mers – “parts” = same parts) are molecules that have the
same number of the same kinds of atoms (and hence the same formula) but differ in chemical and
physical properties. In other words isomers are chemical compounds that have the same parts but are
nonetheless different molecules.
To make an analogy - two bracelets, each consisting of five red and five green beads, could be arranged
in many different isomeric forms, depending on the order of the colors. Each bracelet would have the
same parts—that is, the five red and five green beads—but each variation would be different.

Also, isomers are not single isolated molecules. Rather isomers refer to the relationship between one or
more other molecules. There are two main types of isomers:

1. Constitutional or Structural Isomers – are isomers in which molecules with the same molecular
formula have bonded (connected) together in different orders. They have the same parts, but the
parts are connected to each other differently.

2. Stereoisomers - are isomeric molecules that have the same molecular formula and sequence of
bonded atoms (connections), but that differ in the three-dimensional orientation of their atoms in
space. In other words stereoisomers are isomers that have the same parts and the same
connections, but that differ in the orientation of those parts in space. There are two types of
stereoisomers:

a. Diastereomers - occurs when two or more stereoisomers of a compound have different

configurations and are NOT mirror images of each other. Diastereomers have different physical
properties (i.e. melting point, boiling points, solubility, etc.).

b. Enantiomers - are two stereoisomers that are mirror images of each other that are “non-
superimposable” (like one’s hands). Enantiomers have exactly the same physical properties and
the same chemical properties. However, when they act in a chiral environment (i.e. the human
body) they exhibit a different physiological activity (i.e. odor, receptor binding, pharmacological
effect).

The obvious question at this point is – if both

chiral molecules and enantiomers are defined
as being non-superimposable on their mirror
image, then what’s the difference? The
answer – chiral is a term given to describe the
geometric form of an individual molecule. The
relationship between a chiral molecule and its
mirror image (now two chiral molecules) is
that they are enantiomers.

 Video – Stereo Isomers (4:12) Link

 Video – Stereochemistry: Isomers (9:28) Link
Nomenclature

Because enantiomers look identical there needs to be some type of nomenclature (naming) to
distinguish them apart. There are currently two naming systems to denote the difference in geometric
configurations of enantiomers. The first naming system being the - Chan-Ingold-Prelog (CIP) R/S
system, which labels enantiomers with either an ‘R’ (for rectus, Latin for right handed) or ‘S’ (for sinister,
Latin for left handed). Detailed information about the CIP nomenclature can be found in the videos
provided below.

The second naming system being the - D/L prefix system, which is an older system and is still commonly
applied to carbohydrates and amino acids (i.e. L-Taurine, L-Cystine, etc.). Capitol ‘D’ (for dexter, Latin for
on the right) - is assigned to reference right-handed compounds and Capital ‘L’ (for laevus, Latin for on
the left) – is assigned to reference left-handed compounds. However, the D/L designation in its general
application is considered ambiguous because they do not fully designate absolute stereochemistry and
there is no fixed relation to the R/S system.

 Video – Khan Academy: Cahn-Ingold-Prelog System (11:02) Link

 Video – Introduction to the R,S Stereochemical Nomenclature (8:16) Link

Optically Active

There is an additional naming system for enantiomers referred to as the - optically active (+), (-) or (d),
(l) system. This system came about with the discovery that enantiomers can rotate plane-polarized light
and are considered to be optically active. Enantiomers are sometimes referred to as optical isomers.

If you could analyze the light that travels toward you from a lamp, you would find the electric and
magnetic components of this radiation oscillating in all of the planes parallel to the path of the light.
However, if you analyzed light that has passed through a polarizer, such as a Nicol prism or the lens of
polarized sunglasses, you would find that these oscillations were now confined to a single plane.
Compounds or substances that can rotate plane-polarized light are said to be optically active.
Enantiomers that rotate the plane-polarized light clockwise (to the right) are said to be dextrorotatory
(from the Latin dexter, "right") and are indicated with a little ‘d’ or a positive sign (+). Those that rotate
the plane counterclockwise (to the left) are called levorotatory (from the Latin laevus, "left") and are
indicated with a little ‘l’ or a negative sign (-).

When there are equal amounts of both left handed (-) and right handed (+) enantiomers, this is referred
to as a racemic mixture or racemate (a 1:1 mixture of enantiomers). A racemic mixture is optically
inactive meaning that there is no net rotation of plane-polarized light. Although the two enantiomers
rotate plane-polarized light in opposite directions, the rotations cancel because they are present in
equal amounts.

It is important to note that the optically active

(+)/(-) or d/l notations used for identifying
rotation of polarized light, are not related to the
CIP-R/S or D/L nomenclature which identify the
geometric configurations of enantiomers.
However, the optically active notations are used
in conjunction with the CIP-R/S and D/L systems.
It is also recognized that using the d/l notations
to identify the direction of optical activity in an
enantiomer can easily be confused with the
unrelated D/L notations. Therefore, use of the d/l
notations are strongly discouraged while use of
the (+) and (-) notations are strongly encouraged.

This phenomenon of optical activity in enantiomers may seem pretty straight forward however there is
some confusion with the use of this term amongst scientist:

“Now comes the confusion. Optically active was generally used as a synonym for chiral in
the earlier literature, and unfortunately this usage continues at times even today. We
discourage this use. The problem is that there are many examples of chemical samples
that contain chiral molecules, but the samples themselves are not optically active. A
racemic mixture, a 50:50 mixture of enantiomers, is not optically active, but every
molecule in the sample is chiral. It is important to distinguish between a sample that is
optically inactive because it contains a racemic mixture and a sample that is optically
inactive because it contains achiral molecules, and the earlier terminology made this
difficult…. … ‘‘Optically active’’ is an ambiguous description.”(Anslyn 2006)

 Video – Khan Academy: Optical Activity (13:23) Link

 Video – Ted-Ed: What is chirality and how did it get in my molecules? (5:04) Link
 Why is Stereochemistry and Chirality Important?

We’ve now learned the basics of stereochemistry - chirality, isomers, enantiomers, and optical activity.
Which leaves the question – why is this so important? And how does it relate to human health?

The simple answer was alluded to earlier in this report, which is - humans are chiral beings. From the
top or our heads to the tip of our toes practically every molecule in the human body is chiral. Thereby
creating a chiral environment in which all the body’s biochemical interactions take place. This is
important because the biochemical response to a particular molecule often depends on how that
molecule fits a particular site on a receptor molecule. As only the left-handed glove will fit the left hand,
so too will a left-handed receptor require a particular enantiomer (left-handed) for a correct fit.

Over the last several decades scientist have become more aware of the principle that much of
nature/biology is chiral. And more importantly that nature is having to interact more and more with a
manufactured synthetic world of chemicals. Chemicals which may or may not have the proper chiral
configuration and thus the desired biochemical response. This is especially obvious in the
pharmaceutical industry and in the development of new drugs.

In the manufacturing of pharmaceuticals, often only one enantiomer of a racemic drug is the effective
agent and has a therapeutically useful action. While the second enantiomer does not have the desired
therapeutic affect and may actually have an adverse toxic effect (serious side effects). As a result
legislation now requires both enantiomers of a racemic drug to be pharmacologically investigated.

For example, one enantiomer of penicillamine is a potent anti-arthritic agent whereas the other
enantiomer is highly toxic. Another example and perhaps one of the most startling examples of the
difference in activity between enantiomers is Thalidomide. This drug was seen as a panacea for the
treatment of morning sickness in pregnant women, and indeed one enantiomer reliably had this effect.
The other enantiomer, unfortunately, has been associated with well-characterized birth defects.

Smell (olfaction) and taste are two other common areas where the biological chiral world interacts with
the synthetic world of chemicals. For example - limonene contains a chiral carbon atom. One
enantiomer produces the smell of oranges whereas the other gives rise to the smell of lemons. Most
chemists are familiar with the role of chirality on odorants such as (4S)-(+)-carvone, which has a distinct
caraway odor, as compared to (4R)-(-)-carvone which has a characteristically sweet spearmint odor.

When it comes to chirality and taste… there’s nothing like having

sweet tooth. Though the typical American gets more sugar than
they need, sugar is still needed in our diets, especially for the
brain. However, our brains need and can only metabolize the
right-handed (D) form of sugar (D-glucose). Sugar’s enantiomer
(L-glucose), though sweet tasting, cannot be metabolized by the
body. Manufacturers of artificial sweeteners have taken
advantage of this principle by producing left-handed (L)
enantiomers of sugar that will taste sweet, but cannot be
metabolized and absorbed. Meaning – same great flavor with
zero calories.

It should also be pointed out that all the principles described to this point also apply to environmental
pollutants and toxins. Classic examples are herbicides and pesticides containing chiral stereogenic
centers which greatly affect human health, especially in those with MCS, asthma, neurological
hypersensitivity, etc.

And finally, chirality is very important in the cosmetic and personal care products industry. So much so
that the industry is investing a lot of money to produce more products that are “chirally correct”. No
surprise they are also spending a lot of money to use the principle of chiral correctness as a marketing
tool.

To understand more about the connection between chiral molecules and their relation to taste, smell,
pharmaceutical drugs, environmental toxins, cosmetics and the ever growing world of synthetic
chemicals, read the next section below. Also, the video below gives a nice short synopsis of what this
report is about.

 Video – Resolve Project: Understanding Chirality (3:57) Link

 Natural vs. Synthetic Compounds: The Chiral Connection

The resources and information provide in this section, though not directly related to human health,
should be of considerable interest to anyone wishing to learn more about the differences between
natural and synthetic compounds (fragrances, flavors, drugs, cosmetics, toxins etc.). Therefore, below is
a list (in reverse chronological order) of resources pertaining to the phenomenon of stereochemistry,
chirality and their connection to both natural and synthetic compounds.

Note: Many of the resources below are linked to Google Books. To find quoted remarks… click the link,
then type in the title of the book and the author’s name. Then scroll to page or input page number in
the search window. Update - this report was originally written several years ago and it appears (after
re-testing) several of the Google Books links are no longer available.

Chiral Natural Products

 Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, By Stephen Caron.
Wiley, (2011)
Chapter 14: Access to Chirality (pg. 649) http://books.google.com/

“Synthesis or optically active compounds, whether natural or synthetic molecules, is a

significant challenge to the synthetic organic chemist…

… An obvious starting point for the synthesis of chiral molecules is to use a natural
product that is readily available as a single enantiomer. Many sugars, terpenes, amino
acids, have been used as the starting materials for the synthesis of a wide variety of
chiral molecules. Obviously this method works best when there is a large degree of
structural similarity between the chiral pool starting material and the final product. The
greater the structural differences, the more complex the synthesis will become.”

 Mori K., Bioactive Natural Products and Chirality, Chirality, 23(6):449-462, (2011) Link

“Results indicate that bioactive natural products are not always enantiomerically pure,
and the stereochemistry–bioactivity relationships are not simple but complicated.”
 Natural Product Chemistry for Drug Discovery, by Antony Buss, RSC Publishing, (2010)
Chapter 2: 5.4 Chiral Centers (pg.37) http://books.google.com/

“The percentage distribution of the number of chiral centers in three classes of

compounds (drugs, natural products, and combinatorial) was markedly different. The
mean numbers of chiral centers were 6.2 for natural products, 2.3 for drugs and 0.4 for
combinatorial molecules. Since natural products are synthesized by enzymes the
introduction of a chiral center appears to be effortless, whereas it requires special
attention to synthesize chiral compounds in the laboratory…

… The presence of chiral centers in the natural products provides for higher affinity and
target specificity and clearly differentiates them from non-natural compounds…

… The presence of large numbers of chiral centers in natural products compared with de
novo man-made synthetic compounds is the biggest and most important difference
between the two groups of compounds. Since the biological targets for these drugs are
chiral, ligands with correctly constructed chiral centers should provide increased target
engagement. Attempts have been made during the synthesis of DOS libraries to
synthesize compounds with more chiral centers, thus making them more like natural
products. Despite these efforts, natural products still provide most structural and chiral
complexity…

… It is clear from these analyses that natural products cover much wider and larger
chemical space not covered by combinatorial and synthetic compounds. Natural
products contain large numbers of chiral centers, ring fusions and a higher density of
functional groups allowing for higher ligand affinity and better specificity to biological
targets that is generally not achieved by architecturally flat synthetic drugs…

… Natural products tend to have properties such as unexpected cell penetration,

absorption or solubility that are generally not well understood. This may be due to their
co-evolution with the proteins in the cells, which are densely populated with biological
materials.”

 Bioactive Natural Products, By Steven Colgate, CRC Press (2008),

Chapter 7: 7.1.1 Enantiomers (page 209) http://books.google.com/

“In biological systems, chirality is the rule rather than the exception, controlling the
utilization of nutrients, influencing the functioning of genes and enzymes, and regulating
interactions at receptor sites. For example the human body can only utilize (-)-amino
acids but not the unnatural (+)-enantiomers….
 … Thus, humans can metabolize (+)-glucose and not (-)-glucose, and (+)-leucine taste
sweet while (-)- leucine is bitter. Aroma characteristics are highly dependent on chirality;
for example, 4S-(+)-carvone, which occurs in caraway, dill, and certain fruits, smell of
caraway whereas 4R-(-)-carvone, the main constituent of spearmint, has a minty odor. “

 Strategies of Life Detection, By Oliver Botta, Springer (2008)

Molecular Biosignatures: 2.1 Enantiomeric Excess (page 136) http://books.google.com/

“The high fidelity with which enantiomers are produced by biological systems is due to
the fact that the molecules are put together by reactions catalyzed by enzymes, proteins
which are themselves made of exclusively L-amino acids in a lock-and-key manner.”

 Flavors & Fragrances: Chemistry, Bioprocessing and Sustainability, By Ralf Berger, Springer (2007)
4.2 Impact of Chirality: Enantiomers (pg. 71) http://books.google.com/

“Chirality is an important aspect of aroma chemicals since enantiomers of the same

compound may possess different organoleptic characters…

… Many natural compounds originating from essential oils which are used in perfumes,
flavors and fragrances are optically active. Each enantiomer may display entirely
different organoleptic properties. Each enantiomer may be characteristic for a particular
essential oil source.”

 Modern Physical Organic Chemistry, By Eric Anslyn, University Science Books (2006)
6.8.3 The Origin of Chirality in Nature (pg. 339) http://books.google.com/

“The molecules of life are for the most part chiral, and in living systems they are almost
always enantiomerically pure…

… the chirality of the amino acids leads to chiral enzymes, which in turn produce chiral
natural products. All the chiral compounds found in nature that are readily accessible to
synthetic chemists for the construction of more complex molecules are referred to as the
chiral pool.”
 Chirality in Drug Research by Eric Francotte, Wiley (2006)
3.2.1. Chirality Analysis of Natural Products versus Drugs and Synthetics (pg. 71)
http://books.google.com/

“Natural products differ from synthetic compounds in various properties. They are
structurally very diverse, often exhibit specific biological activities and reveal an
astonishing sterical complexity. This is an obvious consequence of the fact that the
biosynthesis enzymes are inherently three dimensional and chiral…

… Compared with drugs and synthetic compounds, natural products contain fewer
nitrogen, sulfur or halogen atoms on average, but considerably more oxygen-rich and
contain more hydrogen-bond donors. This divergence probably reflects the fundamental
differences between biosynthesis and synthetic chemistry…

… Compared to synthetic compounds natural compounds contain significantly more …

chiral centers.”

 Ruiz del Castillo M.L., Natural Variability of the Enantiomeric Composition of Bioactive Chiral
Terpenes in Mentha piperita, Journal of Chromatography A, 1054(1-2):87-93 (2004) Link

“Aromatic plants are at present widely studied for their large therapeutical interest and
benefits…

…Specifically, menthol exhibits numerous pharmacological activities including anti-

inflammatory, analgesic, anti-fungal and central nervous system excitation effects. This
monoterpene is also responsible for the typical minty smell and flavour shown by some
commercial products. Menthol is mainly obtained from Mentha piperita and Mentha
arvensis,..

… Specifically for menthol, some researchers have reported that only (−)-menthol, of the
eight stereoisomers of menthol (i.e., (+/−)-menthol, (+/−)-neoisomenthol, (+/−)-
neomenthol and (+/−)-isomenthol), exhibits the greatest cooling activity as well as the
typical peppermint odour. It is also interesting to point out that many of the chiral
components that occur in nature are enantiomeric mixtures formed by specific
proportions because of the enzymatic pathways involved in their biogenesis.”
 The Third Dimension, By Lesley Smart, Royal Society of Chemistry (2002),
Chapter 7: page 162 http://books.google.com/

“Many naturally occurring molecules possess a considerable number of chiral centers,

each one with a specific configuration. This means that the natural product is only one
out of many possible stereoisomers…

… The configuration of each chiral center has first to be determined, and then a synthesis
has to be devised to put each chiral center in place with its correct stereochemistry.
When we look at a comparatively simple natural product – for example, oestrone
(female hormone) – we can see there are four different chiral centers in the molecule.
This means that in theory there are 24 or 16 different stereoisomers, comprising eight
pairs of enantiomers. However, only one of theses has hormonal activity.”

 Bryn Mawr College, Organic Chemistry Study Aids, Prof. Maryellen Nerz-Storms Ph.D.
Chirality, Enantiomers and Optical Rotation Link

“You might wonder why resolution is significant and why optical purities and rotations
are measured. One application is particularly effective at illustrating the importance of
chirality and optical purity. Most drugs that are in use today are chiral molecules, many
of which are natural products or derivatives of natural products. A drug that is a natural
product is a compound isolated from a plant or an animal that exhibits some sort of
biological activity. In other words, we get a lot of our inspiration for drug design from
mother nature. Conventional synthesis of chiral molecules results in the formation of
racemic mixtures or racemates, whereas the natural products usually exist in optically
pure form. If a racemate was administered to a human subject to treat some disease,
the two forms might not behave the same way in the chiral world of the human body.
Those enantiomers would encounter many different chiral molecules and would not
necessarily interact with them in the same or even a beneficial way. For this reason, it is
essential for most drug synthesis to result in optically pure material.”

Chiral Fragrances and Flavors

 Biocatalysis for Green Chemistry & Chemical Process Development, By Junhua Tao, Wiley, (2011),
Chapter9: 9.1 Introduction (page 224) http://books.google.com/

“Moreover, since both flavors and fragrances are often a complex mixture of isomers,
the identification and the sensory evaluation of each component are necessary. In this
context, chiral chemistry plays a primary role…
 … It is known that the enantioeric composition of an odorous compound greatly affects
its olfactory properties in terms of either the quality of its perceived odor or its odor
threshold.”

 The Chemistry and Biology of Volatiles, By Andreas Herrmann, Wiley (2011)

7.4 Remaining Challenges in the Large-Scale Synthesis of Natural & Non-Natural Volatiles
(pg. not listed) http://books.google.com/

“In the initial phase of designing future novel non-natural volatile molecules as
perfumery ingredients, chemists face the question of whether greater understanding of
the olfactory system is an advantage. The interaction of volatile molecules with the
olfactory system is extremely complex. Both the immune system and the olfactory
system rely on a huge number of possible combinations of receptors to recognize and
interact with both self and nonself molecules, and both play an essential role in the
detection of molecules present in the environment surrounding the organism…

… The environment immediately surrounding the binding domain in odor receptors or

odor binding proteins is made up of L-amino acids linked via peptide bonds; thus, the
binding sites are chiral environments and are capable of interacting differently with
enantiomers and diastereoisomers that may be present in odorants.”

 Citrus Essential Oils: Flavor and Fragrance, By Masayoshi Sawamura, Wiley, (2010)
Chapter 4: 4.1 Enantiomeric Analysis (pg. 166) http://books.google.com/

“Flavor and fragrance research frequently deals with the phenomenon of chirality
because many flavor and fragrance components are chiral. Chiral flavor and fragrance
components of natural origin generally have a characteristic distribution of enantiomers
that is attributable to stereoselectively controlled biogenetic formation mechanisms.
Thus an excess of one or the other enantiomer occurs in a variety of essential oils and
natural flavor extracts.”

 Chemistry and Technology of Flavors and Fragrances, By David Rowe, Wiley, (2009)
Chapter 8: 8.3 Chirality (pg. 171) http://books.google.com/

“Many natural aroma chemicals occur in nature as a specific chiral isomer, and the
aroma of that specific enantiomer can be very distinctive and characteristic. Chemical
synthesis tends to result in racemic mixtures and this can be extremely detrimental to
the sensory characteristics of the aroma chemical…
 … It may be impossible to develop a stereo-specific synthetic route, the separation of the
resultant mixture may not be possible or the subsequent separation process may be very
expensive.”

 Hoferl M., Chirality Influences the Effects of Linalool on Physiological Parameters of Stress,
Pharmacology, 72(13):1188-1192 (2006) Link

“In conclusion, the results revealed that (1) chirality crucially influences the physiological
effects of odorants and that (2) odorants may act differently on certain physiological
parameters.”

 The World of Chemistry, By Melvin Joesten, Cengage Learning (2006)

Chapter 15: The Chemistry of Life (page 357) http://books.google.com/

“Aspartame (Nutra Sweet), widely used as an artificial sweetener, has two enantiomers.
However, one enantiomer has a sweet taste, while the other enantiomer is bitter. This
indicates that the receptor sites on our taste buds must be chiral, since they respond
differently to the “handedness” of aspartame enantiomers. This becomes clearer when
looking at the properties of the simple sugars. D-Glucose is sweet and nutritious,
whereas L-glucose is tasteless and cannot be metabolized by the body.”

 Perspectives in Flavor and Fragrance Research, By Philip Kraft, Helvetica (2005)

(page 55) http://books.google.com/

“Mankind has been trying for more than a century to reproduce by synthesis the complex
world of odors and perfumes provided by nature. Fragrance chemists try to diversify
odor response by synthesizing new, but structurally often very similar, derivatives of
known odorous compounds…

… When a molecular-recognition process is involved, as it does happen in olfaction,

diversity originates from both constitutional and configurational isomers… When chiral,
exogenous compounds are introduced into the body, they can be discriminated by their
different interactions with enantiomerically pure targets, such as receptors and enzymes.
Fragrances are also such exogenous compound.”
 Right Hand, Left Hand: The Origins of Asymmetry in Brains, Bodies, Atoms & Cultures, By Chris
McManus, Harvard University Press, (2004)
Chapter 6: (page 125) http://books.google.com/

“Many biological molecules are stereo-isomers, the L- and D- forms having very different
properties. A well-known example is the molecule carvone, for which the D-stereo-
isomer smells of spearmint, and the L-stereo-isomer smells of caraway. Likewise, one
stereo-isomer of phellandrene smells of eucalyptus and the other of fennel. Many books
also cite the molecule limonene, which is said in one chiral form to smell of oranges and
in the other chiral form to smell of lemons. Oranges and lemons both actually produce D-
limonene, which when pure has a sort of generically citrus smell. L-limonene is found in
peppermint oil, and pure L-limonene smells of pine. Generally, D- and L-isomers have
different odors because our sense of smell detects the three-dimensional shape of
molecules, which engage like a key in a lock with receptors in the olfactory membrane in
the nose. If two molecules have different three-dimensional shapes and engage different
receptors, then they smell different.”

 Organic Chemistry, By Marye Anne Fox, Jones & Bartlett Learning, (2004)
Chapter 5: Chemical Perspectives (page 244) http://books.google.com/

“Because stereochemistry significantly affects the shape of a molecule, a molecule’s

absolute configuration also strongly affects its odor…

.. For many components of perfume, shape seems to be more important than chemical
composition: hexachloroesthane, (+)-camphor, and cyclooctane have nearly the same
odor, even though their molecular formulas are quite different. However, all of these
molecules are roughly bowl shaped, which allows a reasonable fit with the receptor
site.”

 Brenna E., Enantioselective Perception of Chiral Odorants, Tetrahedron Asymmetry, 14(1): 1-42
(2003) Link

“One of the basic laws of chemistry is that only chiral means are able to distinguish chiral
objects. Human beings are themselves chiral, so it is not surprising that they can
recognize enantiomers. The extent of this recognition varies according to the
effectiveness of the interaction between the odorous molecule and our chiral receptors.
There are examples of enantiomers which cannot be discriminated by human nose, as
well as there are reactions involving chiral reagents or auxiliaries that unluckily proceed
without enantioselectivity.”
 Laska M, Olfactory Discrimination Ability of Human Subjects for Ten Pairs of Enantiomers,
Chemical Senses, 24(2):161-170 (1999) Link

“The results of this study demonstrate that the ability of human subjects to discriminate
between enantiomeric odor pairs is substance-specific and thus not a generalizable
phenomenon. Whereas almost all subjects had few difficulties in distinguishing the (+)-
and the (−)-forms of α-pinene, carvone and limonene, most panelists failed to
discriminate between the antipodes of β-citronellol, menthol, fenchone, rose oxide,
camphor,α -terpineol and 2-butanol when presented at equal concentrations.”

 Chirality in Industry II: Developments in the Commercial Manufacture and Applications of

Optically Active Compounds, By A.N. Collins, Wiley (1998),
Chapter 16: Enantioselective Protonation in Fragrance Synthesis (page 335)
http://books.google.com/

“The fragrance industry is not subjected to the same regulatory constraints as the
pharmaceutical industries with respect to the enantiomeric purity of chiral compounds.
However, very often one enantiomer shows superior odor properties compared with the
other, justifying its synthetic development. As an example the odor of (S)-damascene is
reminiscent of rose petals, whereas the (R)-enantiomer has a more pronounced apple
note and is also responsible for an undesired cork odor. “

 Chirality and Odor Perception By John Leffingwell Ph.D. Link

This website contains several long lists (broken down into subcategories) of enantiomers and their
correlating odor description, along with 3D molecular formulas.

Chiral Cosmetics

 M.I.L.F. Cosmetics, What does Chiral Mean?

“The greatest benefit of these products is that your body will not be asked to process the
"wrong-handed", and potentially damaging, molecules. When you use a run-of-the-mill,
over-the-counter (non-Chiral, "Racemic") skin care product, every molecule in that
product contains both the "L" and "D" sides, or the whole molecule. The result is that you
end up with a lot of unwanted, unusable molecules left over in your system, and not a
very effective product…
 … These "extra" molecule sides are the ones that can cause irritation, stress, and
inflammation. Over a long period of time, they can even become toxic. This is one reason
why so many people are allergic, or become allergic over time, to certain cosmetics and
skin care products.”

 iSO-CARE, What is Chiral and what does it mean to me? Link

“Simply stated, if an active ingredient is chirally correct - meaning it has the right optical
activity so as to be recognized and "fit" the chemistry of the human body, it will do the
job it is intended to do. If the compound is not chirally correct, it won't work or worse yet
it will do actual harm.”

 Bizymoms Sircuit Skin, What role do Chiral Technologies play in skincare? Link

“Chiral technology has been an important milestone for skin care companies. It has also
provided a reason for skincare product customers, like you, to raise the bench mark and
expectations regarding what you should get from a skin care company.”

 Kyra Beauty Products, Nobel Prize Winning Science – Chiral Technology Link

“…chiral incorrectness" and the use of petroleum byproducts are the two principal
reasons that mainstream skin care really can't offer us any hope of delivering meaningful
results. On the other hand, if an active ingredient is chirally correct - meaning it has the
right optical activity so as to be recognized and "fit" the chemistry of the human body, it
will do the job nature designed it to do. Welcome to the future of true anti-aging skin
care, and all the future breakthroughs that chiral science can and will make possible!”

Chiral Drugs/Pharmaceuticals

 Chiral Analysis, By Kenneth Busch, Elsevier (2011)

Chapter 12: Introduction (page 364) http://books.google.com/

“When drug molecules interact with biological systems (which are themselves optically
active), one enantiomer may be metabolized at a different rate or by a different
pathway from the other…
 … For example, differences in binding to plasma proteins and differences in binding at
the active sites of pharmacological action may be different for the two enantiomers. This
may be particularly true of drugs whose metabolic pathway involves high-affinity, low
capacity enzymes such as the human cytochromes P450, 2C18, and 2D6.”

 Pharmaceutical Analysis, By David C Lee, Wiley (2009)

(page 79) http://books.google.com/

“In the early days of the pharmaceutical industry most drugs came from natural sources
and hence single enantiomer drugs predominated. As the proportion of synthetic drugs
increased, the proportion of achiral and racemic drugs increased. Now, the proportion of
single enantiomer drugs will continue to increase…

… Therefore the main emphasis with respect to analysis is that stereoselective separative
methods are needed primarily to resolve any unwanted trace enantiomeric impurity
from the main enantiomer present in a drug substance.”

 Bielory L., Stereoconfiguration of Antiallergic and Immunologic Drugs, Annals of Allergy, Asthma
and Immunology, 100(1):1-9 (2008) Link

“Chirality plays an important role in pharmacokinetics and pharmacodynamics of various

pharmaceutical agents. The importance of stereoisomeric purity in the pharmacologic
industry has increased during the past decade as demonstrated by the increased number
of studies that examined the in vivo and in vitro effects produced by changes in
stereoconfiguration of pharmaceutical agents.”

 Shivannand Kanavi, Molecular Jekyll and Hyde, (2007) Link

“Many of the pure enantiomers sold today are derived from plants or micro-organisms.
Only about 10 per cent of the synthetic drugs are sold as chiral molecules while the rest
are marketed as mixtures of both enantiomers called 'racemates.”

 Drug Monitoring and Clinical Chemistry, By Georg Hempel, Elsevier, (2004)

2.7 Introduction (page 49) http://books.google.com/

“Molecular chirality is a fundamental phenomenon that plays an important role in

biological processes. Wide ranges of biological and physical functions are generated
through precise molecular recognition because enzymes, receptors and other natural
 binding sites within the biological systems interact with different enantiomers in
decisively different ways. As a result of such chiral recognition, drug enantiomers may
differ in their pharmacological and/or toxicological profiles…

… For drugs with a single stereogenic center, both enantiomers may be

pharmacologically active. However, if the main pharmacological effect is due to only one
enantiomer, several possibilities exist for the other enantiomer: inactivity, a qualitatively
different effect, an antagonistic effect or severe toxicity. “

 Chirality in Drug Design and Development, By Indra Reddy, CRC Press (2004)
Chapter 1: Introduction (page 1) http://books.google.com/

“It is well established that the opposite enantiomer of a chiral drug often differs
significantly in its pharmacological, toxicological, pharmacodynamics and
pharmacokinetic properties. Therefore from the points of view of safety and efficacy, the
pure enantiomer is preferred over the racemate in many marketed dosage forms.
However, the chiral drug is often synthesized in the racemic form, and it is frequently
costly to resolve the racemic mixture into the pure enantiomers.”

 Burke D, Chirality: A Blueprint for the Future, British Journal of Anaesthesia, 88(4):563-76, (2002)
Link

“Until recently, the majority of single‐isomer drugs available were those derived from
natural sources (e.g. morphine, epinephrine, hyoscine), and racemates predominated.
There is now clear evidence of a trend in the pharmaceutical industry towards the
development of chiral drugs. Several factors have influenced this trend, which has
occurred independently and in parallel with a quest in the industry as a whole to develop
more potent, selective and specific drugs….

… Coinciding with this has been the awakening of the drug regulatory authorities to the
different pharmacological and toxicological profiles of enantiomers. The FDA policy
statement for the development of stereoisomeric drugs, issued in 1992, made it more
difficult to obtain approval for racemates. This statement made it clear that approval
could not be granted for a drug containing more than one isomer unless the
pharmacokinetic and pharmacodynamic properties of each could be described and, more
importantly, justified. In addition, the FDA offers a shortened approval process for the
enantiomeric versions of approved drugs, with the promise of patent protection.”
 Handbook of Analytical Therapeutic Drug Monitoring and Toxicology, By Steven How-Yan Wong,
CRC Press (1997)
(page 23) http://books.google.com/

“Living organisms contain asymmetric environments such as proteins, enzymes and

receptors. These components are chiral compounds made from enantiomeric subunits
such as L-amino acids, D-sugars, etc. Therefore, when a chiral compound interacts with
the body, it is possible that the enantiomers will vary in their interaction with the various
chiral environments producing differing responses…

… Enantiomers usually differ in their pharmacokinetics, pharmacodynamics and toxicity,

and these differences are often dramatic.”

Chiral Pollutants, Xenobiotics and Toxicology

 Xavier University, Thomas Wiese Ph.D., Associate Professor of Biochemistry Link

“The main focus of my endocrine disruption work has been pesticides, industrial
chemicals and compounds from plants that are components of dietary supplements or
activated soy (phytochemicals). A particular interest is the different receptor mediated
effects of the individual enantiomers of chiral xenobiotics. Many industrial contaminants
and pesticides are chiral with racemic mixtures ending up in the environment and/or in
human exposure scenarios. Since the metabolic process of individual environmental
compartments and/or metabolism in humans often results in degradation or
accumulation of only one enantiomer or the other, then understanding the toxic effects
of each enantiomer is important. We have found that in some cases, one enantiomer of
a pesticide is estrogenic and the other is not. In addition, we have found some cases
where both enantiomers bind hormone receptors equally well, but each induces different
receptor mediated responses.”

 Medicinal Chemistry, By William Foye, Williams & Wilkins (2012)

Chapter 4: Drug Metabolism (page 167) http://books.google.com/

“In addition to the physiochemical factors that affect xenobiotic metabolism,

stereochemical factors that affect xenobiotic metabolism, stereochemical factors play an
important role in the biotransformation of drugs. This involvement is not unexpected,
because the xenobiotic metabolizing enzymes also are the same enzymes that
metabolize certain endogenous substrates, which for the most part are chiral molecules.
Most of these enzymes show stereoselectivity.”
 Kasprzyk-Hordern B., Pharmacologically Active Compounds in the Environment and their Chirality,
Chemical Society Review, 39(11):4466-4503 (2010) Link

“The one very important phenomenon that has been overlooked by environmental
researchers studying the fate of pharmacologically active compounds in the environment
is their chirality. Chiral drugs can exist in the form of enantiomers, which have similar
physicochemical properties but differ in their biological properties such as distribution,
metabolism and excretion, as these processes (due to stereospecific interactions of
enantiomers with biological systems) usually favor one enantiomer over the other.
Additionally, due to different pharmacological activity, enantiomers of chiral drugs can
differ in toxicity. Furthermore, degradation of chiral drugs during wastewater treatment
and in the environment can be stereoselective and can lead to chiral products of varied
toxicity.”

 Smith S.W., Chiral Toxicology, Toxicological Sciences, 110(1):4-30, (2009) Link

“Many environmental contaminants are chiral, including organophosphorus compounds,

organochlorines, pyrethroids, PCBs, pharmaceutical contaminants, etc.. Degradation of
these compounds, as well as compound bioaccumulation, persistence, and toxicity often
show chiral dependence…

… Chiral considerations are relevant to diverse aspects of toxicology and pharmacology.

The additional complexity permits a more complete and precise understanding of
toxicological pathophysiology. Evaluation of chiral compounds must take into account
three-dimensional structure-activity relationships, which may take on varied importance
at different receptor types.

 Dynamic Sterechemistry of Chiral Compounds, Christian Wolf, Royal Society of Chemistry (2008)
3.3.4 Atropisomeric Xenobiotics (page 107) http://books.google.com/

“The pharmacological and toxicological activities of some pesticides and herbicides are
closely related to their chirality. Analysis of human tissue as well as aquatic samples
(salmon, penguin, seal) revealed stereoselective metabolism of chlordane, a widely used
pesticide mixture. Apparently the enantiomeric composition of these environmental
pollutants changes during biological transformation because uptake, metabolism and
excretion proceed enantioselectively.”
 Wong C., Environmental Fate Processes and Biochemical Transformations of Chiral Emerging
Organic Pollutants, Springer, 386(3):544-558 (2006) Link

“Pollutant enantiomers are a growing area of research in the field of environmental

chemistry for several reasons. First, many chemicals of environmental interest and
concern are chiral. About 25 % of all agrochemicals are chiral, as are many other legacy
and current-use chemicals. Surprisingly, contaminant stereoisomerism has received little
attention, despite the significantly different toxicology that enantiomers can have
compared to each other and to the parent mixture…

… A compound’s enantiomers have identical physical and chemical properties. Thus,

abiotic environmental processes (e.g., air–water exchange, sorption, abiotic
transformation) are generally identical for both stereoisomers. However, biochemical
processes (e.g., biotransformation) and toxicological effects can be enantioselective
because individual stereoisomers can interact differentially with other chiral molecules,
such as enzymes and biological receptors. Thus, stereoisomers can have different
biological and toxicological effects…

… Most studies on chiral chemicals do not explicitly account for individual stereoisomers,
even though they have different biological fates and endpoints. As a result, current
knowledge of chiral pollutants is often inaccurate, as it implicitly and incorrectly assumes
that enantiomers have identical environmental behavior. “

 Ali I., Chirality: A Challenge for the Environmental Scientists, Current Science, 84(2):152-156 (2003)
Link

“ Most of the pollutants are present in the environment as a mixture of their chiral
isomers. Studies have revealed that these isomers have an enantioselective distribution,
metabolism and toxicity of these pollutants…

… Unfortunately, unlike in drugs and pharmaceuticals the enantioselective toxicities of

the chiral pollutant have not been searched in detail. Therefore, there is an urgent need
to explore the enantioselectiveness of the chiral pollutants. Existing data in the
literature on the hazardous effects of the chiral pollutants should be modified in terms
of the enantioselective toxicities. The chiral isomers of the pollutants are metabolized
differentially in the biological systems and accordingly the stereoselective metabolism
of the chiral pollutants is a demanding field. The knowledge of the stereoselective
metabolism and enantioselective toxicities of the chiral pollutants will be useful for the
treatment of the diseases caused by the chiral pollutants.”
 Leffingwell Reports, Chirality & Bioactivity I: Pharmacology, (2003) Link

“For example, the (R)-(+)-enantiomer of the herbicide dichlorprop (as well as the (R)-(+)-
enantiomers of all the phenoxypropionic acid herbicides) is the active enantiomer in
killing the weeds, while the (S)-(-)-enantiomer is inactive as an herbicide. In order to
reduce the amount of herbicides used and avoid the possibility of the unnecessary
enantiomer causing possible adverse impact, several European countries have recently
decreed that only the (R)-enantiomers will be used for phenoxypropionic acid
herbicides.”

 Toxicological Chemistry and Biochemistry, by Stanley E. Manahan, CRC Press, (2003)

1.9 Optical Isomerism (pg. 34) http://books.google.com/

“Except for the property of rotating plane-polarized light in opposite directions, the
physical properties of enantiomers of the same compound are identical. In addition, their
chemical properties are identical, except when they are acted upon by another chiral
molecule. One such kind of molecule consists of enzymes, large molecules of proteins
that catalyze biochemical reactions. Therefore, many biochemical reactions involve
chiral molecules.”

 Chiral Environmental Pollutants, By Ronald Kallenborn, Springer (2001)

(page 53) http://books.google.com/

“In the case of chiral pollutants, environmental studies have historically neglected to
determine the adverse effects associated with particular enantiomers, and which
enantiomers may persist in the environment. Consequently, much of the environmental
data that has been collected for chiral pollutants, including many of the chemicals
raising the greatest public concern, may have represented only the presence of relatively
innocuous enantiomers.”

Chiral Chemicals

 D-L Chiral Chemicals Link

“D-L Chiral Chemicals, LLC is a niche player in fine chemical market with a focus on chiral
nonracemic compounds. We position ourselves to be a bulk supplier for both enantiomers of a
wide variety of chiral chemicals. Our high quality bulk and customer chemicals have served
many pharmaceutical, biotech, agrochemical and specialty chemical companies worldwide.”
 Leffingwell and Associates Link

“We are dedicated to serving the Perfume, flavor, food and beverage community with
information, products and services. This Web site offers information on interesting subjects
related to Perfume and Flavor Chemistry...and many links for those interested in flavors,
fragrance, olfaction, herbs and spices, botanical medicine, as well as organoleptic properties and
molecular visualization of selected flavor & fragrance materials.”

 ChiroSolv Inc. Link

“Chirosolve, Inc. offers 'peace of mind' with solutions that, within a matter of days, define a
step-by-step optimized chiral separation method that can be scaled up to multi-kilo quantities.
Since we use the industry standard technique - diastereomeric crystallization, you can be sure
that the method developed will be robust, consistent, and cost-effective. The chirally pure
products can be drug molecules, intermediates, agrochemicals, flavors/fragrances, or
petrochemicals.”

 Chiral Technologies Worldwide Link

From pre-clinical studies to commercial production, Chiral Technologies Worldwide together

with our parent Daicel Chemical Industries LTD., is the ideal partner for separation of chiral
compounds. Our technical expertise, combined with Daicel technologies, provides you with the
most rapid and cost-effective way to obtain pure enantiomers to accelerate drug development.

References

 DSM Pharma Chemicals

 Encyclopedia Britannica
 The Rowland Institute at Harvard
 UCLA Chemistry Lectures
 USCI Books – Modern Physical Organic Chemistry, by Eric V. Anslyn & Dennis A. Dougherty, 2006
 Yale University Organic Chemistry Lectures
 Wikipedia

o Videos with links contained within report

o Publications with links contained within report
o Websites with links contained within report