Stereochemistry of Medicinal

Compounds
PHRM 412
 Enantiotopic Hydrogens
• If a carbon is bonded to two hydrogens and to
two different groups, the two hydrogens are
called enantiotopic hydrogens.
 Enantiotopic Hydrogens
• For example, the two hydrogens ( Ha and Hb)
in the group of ethanol are enantiotopic
hydrogens because the other two groups
bonded to the carbon ( CH3 and OH) are not
identical.
• Replacing an enantiotopic hydrogen by a
deuterium (or any other atom or group other
than CH3 or OH) forms a chiral molecule.
 Prochiral Carbon
• The carbon to which the enantiotopic
hydrogens are attached is called a prochiral
carbon because it will become a chirality
center (an asymmetric carbon) if one of the
hydrogens is replaced by a deuterium (or any
group other than CH3 or OH).
 pro-R-hydrogen
• If the Ha hydrogen is replaced by a deuterium,
the asymmetric carbon will have the R
configuration. Thus, the Ha hydrogen is called
the pro-R-hydrogen.
 pro-S-hydrogen
• The hydrogen Hb is called the pro-S-hydrogen
because if it is replaced by a deuterium, the
asymmetric carbon will have the S
configuration.
 pro-R- and pro-S-hydrogens
• The pro-R- and pro-S-hydrogens are
chemically equivalent, so they have the same
chemical reactivity and cannot be
distinguished by achiral reagents.
• Enantiotopic hydrogens, however, are not
chemically equivalent toward chiral reagents.
 Diastereotopic Hydrogens
• If a carbon is bonded to two hydrogens and
replacing each of them in turn with deuterium
(or another group) creates a pair of
diastereomers, the hydrogens are called
diastereotopic hydrogens.
 Regioselective Reactions
• A regioselective reaction is one in which two
constitutional isomers can be obtained as
products but more of one is obtained than of
the other.
• In other words, a regioselective reaction
selects for a particular constitutional isomer.
 Regioselective Reactions

• There are degrees of regioselectivity: A

reaction can be moderately regioselective,
highly regioselective, or completely
regioselective: depending on the relative
amounts of the constitutional isomers formed
in the reaction
 Regioselective Reactions
• Hydrogen halide + 2-methylpropene is more
highly regioselective (3o and 1o) than the
addition of a hydrogen halide to 2-methyl-2-
butene because the two carbocations formed
from 2-methyl-2-butene are closer in stability
(3o and 2o).
• The addition of HBr to 2-pentene is not
regioselective (1o and 2o). Approximately
equal amounts of the two alkyl halides will be
formed.
 Stereoselective Reaction
• Stereoselective is a similar term like
regioselective, but it refers to the preferential
formation of a stereoisomer rather than a
constitutional isomer.
 Stereoselective Reaction
• If a reaction that generates a carbon–carbon
double bond or an asymmetric carbon in a
product forms one stereoisomer preferentially
over another, it is a stereoselective reaction.
• In other words, it selects for a particular
stereoisomer.
• Depending on the degree of preference for a
particular stereoisomer, a reaction can be
described as being moderately
stereoselective, highly stereoselective, or
completely stereoselective.
 Stereospecific Reaction
• A reaction is stereospecific if the reactant can
exist as stereoisomers and each
stereoisomeric reactant leads to a different
stereoisomeric product or a different set of
stereoisomeric products: under the same
reaction conditions.
 Stereospecific Reaction
• In the preceding reaction, stereoisomer A
forms stereoisomer B but does not form D, so
the reaction is stereoselective in addition to
being stereospecific.
• All stereospecific reactions, therefore, are also
stereoselective. All stereoselective reactions
are not stereospecific, however, because
there are stereoselective reactions in which
the reactant does not have a carbon–carbon
double bond or an asymmetric carbon, so it
cannot exist as stereoisomers.
Two methyl groups
remain cis
(<1% trans product
formed)

Two methyl groups

remain trans
(<1% cis product
formed)
 Separating Enantiomers
• Separation of enantiomers is called the
resolution of a racemic mixture.
• Enantiomers cannot be separated by the usual
separation techniques such as fractional
distillation or crystallization because their
identical boiling points and solubilities cause
them to distill or crystallize simultaneously.
 Separating Enantiomers
• Louis Pasteur was the first to separate a pair
of enantiomers successfully.
• He found that crystals of sodium ammonium
tartrate: were not identical.

Assymetric crystals
 Separating Enantiomers
• Separated crystal enantiomers by hand
• Sodium ammonium tartrate forms asymmetric
crystals only under certain conditions—
precisely the conditions that Pasteur had
employed.
• Not a universally useful method to resolve a
racemic mixture because few compounds
form asymmetric crystals
 Separating Enantiomers
By converting enantiomers into diastereomers:
• A racemic mixture of a carboxylic acid reacts
with a naturally occurring optically pure (a
single enantiomer) base to form two
diastereomeric salts.
 Separating Enantiomers
By converting enantiomers into diastereomers:
• Morphine, strychnine, and brucine are
examples of naturally occurring chiral bases
commonly used for this purpose. The chiral
base exists as a single enantiomer because
when a chiral compound is synthesized in a
living system, generally only one enantiomer
is formed.
Separate

HCl
 Separating Enantiomers
Chromatographic technique
 Separating Enantiomers

Enzymatic technique

Ketone
Stereochemistry: Drug Absorption
Passive diffusion:
• The drug moves from a region of high
concentration to lower concentration
• The vast majority of the drugs gain access to
the body by this mechanism
Stereochemistry: Drug Absorption
Passive diffusion:
• Lipid-soluble drugs: biological membrane
• Water-soluble drugs: aqueous channels

Two factors:
• Lipophilicity of drug and
• Degree of ionization
Figure: Passive and active transport
Stereochemistry: Drug Absorption
• There will be no difference in either of these
parameters between a pair of enantiomers

• No difference in the extent or rate of

absorption

• Passive diffusion can be considered to be

achiral
Stereochemistry: Drug Absorption
Active transport:
• Involves specific carrier proteins that span the
membrane and energy
• A few drugs that closely resemble the
structure of naturally occurring metabolites
are actively transported across the cell
membrane
• Capable of moving drugs against a
concentration gradient
Stereochemistry: Drug Absorption
Active transport:
• Requires recognition of the enantiomers by its
carrier protein

• L-isomer: Dopamine
Preferentially
• R-isomer: Methotrexate
absorbed
• D-isomer: Cephalexin

• Related to few no of drugs

Stereochemistry: Drug Distribution
Factor influences the drug distribution:
1. Binding of drugs to plasma protein
• At therapeutic concentrations in plasma,
many drugs exist mainly in bound form.
– Albumin for acidic drug
– β-globulin and an acid glycoprotein for basic drug

• Unbound drug (can be as low as 1%) is

pharmacologically active.
Stereochemistry: Drug Distribution
Warfarin:
• R (+)-warfarin had a free fraction of 1.2% in
human plasma, compared to 0.9% for the S
(-)-enantiomer.
Stereochemistry: Drug Distribution
Factor influences the drug distribution:
2. Partition into body fat and other tissues
• Drug molecule pass through the bloodstream
then goes to tissue or body fat.
• Mainly drug with high lipophilicity
sequestrates to the CNS and adipose tissue
and exert their action.
Stereochemistry: Drug Distribution
Thiopental:
• It was studied that unbound plasma
concentrations of S-thiopental were
approximately 10%–20% higher than those of
R-thiopental, corresponding to its higher
clearance.
• CNS tissue concentrations of S-thiopental
were approximately 20% higher than those of
R-thiopental.
Stereochemistry: Drug Distribution
Factor influences the drug distribution:
3. Volume of distribution
• It is defined as the volume in which the
amount of drug would need to be uniformly
distributed to produce the observed blood
concentration.
Stereochemistry: Drug Distribution
Methadone:
• There is strong evidence that the volume of
distribution of (R)-methadone is double that
of (S)-methadone due to lower plasma binding
and increased tissue binding.

(-)- isomer enhanced activity

(+)- isomer much reduced activity
 Stereochemistry: Drug Metabolism
Directly Some drugs directly
Enter Phase II
metabolism
Oxidation,
reduction Conjugation
Drug Phase I Phase II products
and/or
hydrolysis

Conjugated drug is
Following Phase I, the drug may usually inactive.
be activated, unchanged,
inactivated.
Stereochemistry: Drug Metabolism
Verapamil:
• Clinically available formulations of verapamil
are racemic mixtures of S- and R-enantiomers.
Stereochemistry: Drug Metabolism
Verapamil:
• S-verapamil is preferentially eliminated during
first-pass metabolism, and as a consequence,
the plasma concentration ratio of R- to S-
verapamil is around 5:1 after oral
administration and is approximately 2:1 after
intravenous administration.
Stereochemistry: Drug Metabolism
Warfarin:
• An examination of the metabolic fate of the R
and the S isomers of warfarin revealed that
the two isomers were metabolized by
different routes.
S warfarin: Metabolites
R warfarin: Metabolites

These observations suggested that interactions

between warfarin and other drugs are
stereospecific. e.g.Phenylbutazone
In presence of phenylbutazone plasma clearance of

The rate of clearance of racemic warfarin remain

unaffected by phenylbutazone.
 Stereochemistry: Drug Excretion
• Omeprazole was the first commercially
available PPI.
• Esomeprazole, the S-isomer of omeprazole (a
racemic mixture of S- & R- optical isomers), is
the first PPI to be developed as a single optical
isomer.
 Stereochemistry: Drug Excretion
• Both S- and R-omeprazole are pro-drugs,
which are converted within the parietal cell to
the active proton pump inhibitor, which lacks
a chiral centre.
 Stereochemistry: Drug Excretion
• Because S-omeprazole is less susceptible to
small intestinal and hepatic metabolism than
the R-form, at equal doses, esomeprazole
achieves 70 to 90% higher steady-state serum
concentrations than racemic omeprazole.

• Eliminated 3 times slowly than R isoform, thus

has prolong half life (due to slow metabolism)
 Sulfinyl group Sulfoxide

A lone pair of electrons resides on the sulfur atom

giving it tetrahedral molecular geometry as for sp³
carbon. When the two organic residues are
dissimilar, the sulfur is a chiral center, for
example, methylphenylsulfoxide.
 Stereochemistry: Drug Excretion
• Stereoselective renal clearance may be
observed as a result of active transport or
renal metabolism.
• (+) - terbutaline can completely inhibit the
reuptake of (-)- enetiomers in renal tubular,
resulting the increase in the latter renal
excretion.
 Stereochemistry: Drug Excretion
• Renal excretion of S-sotalol was significantly
reduced after administration of racemate due
to the renal perfusion changes caused by the
beta blocking effects of R-sotalol.
 Streochemistry: Drug Toxicity
• When the toxicity produced by a drug isomer
is associated with the Stereochemistry or
Chirality, the toxicity is termed as Chiral
Toxicity.
 Streochemistry: Drug Toxicity
Thalidomide
• Prescribed for treating morning sickness in
pregnant women
• The drug however was discovered to cause
deformation in babies
• only one particular optical isomer of
thalidomide (S isomer) caused the
teratogenicity, other enantiomer was
considered as safe
 Streochemistry: Drug Toxicity
Thalidomide
• Humans interconvert (S) - and (R) -
thalidomide enantiomers rapidly with both
oral and intravenous dosing
• That is, if a human is given pure (R)-
thalidomide or (S)-thalidomide, both isomers
will later be found in the serum – therefore,
administering only one enantiomer will not
prevent the teratogenic effect.
 Enantiomeric excess
• The enantiomeric excess of a substance is a
measure of how pure it is.
• A sample with 70% of R isomer and 30% of S
will have an enantiomeric excess of 40%.
• This can also be thought of as a mixture of
40% pure R with 60% of a racemic mixture
(which contributes 30% R and 30% S to the
overall composition).
 Enantiomeric excess
• In practice, it is most often expressed as a
percent enantiomeric excess.
 Enantiomeric excess
• Ideally, the contribution of each component of
the mixture to the total optical rotation is
directly proportional to its mole fraction, and
as a result the numerical value of the optical
purity is identical to the enantiomeric excess.
 Enantiomeric excess
• Pure (S)-(+)-2-bromobutane has a specific
rotation of +23.1o. A sample of 2-
bromobutane has an observed optical
rotation = +9.2o? What is the percent of R and
S in the mixture?