stereochemistry of medicinal compounds

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

Ketone

Separating Enantiomers

Enzymatic technique

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 • R-isomer: Methotrexate• D-isomer: Cephalexin

• Related to few no of drugs

Preferentially absorbed

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

Drug Phase I

Oxidation,reduction and/orhydrolysis

Phase IIConjugation products

Following Phase I, the drug may be activated, unchanged,

inactivated.

Conjugated drug is usually inactive.

Some drugs directly Enter Phase II

metabolism

Directly

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)

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.

Sulfinyl group Sulfoxide

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?