Pharmaceutical Chemistry · Short notes

Stereochemistry of Drugs: Short Notes & Cheat Sheet

Chirality, enantiomers and diastereomers, R/S and D/L naming, geometric isomers and why single enantiomers matter clinically.

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Short notes

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Kinds of stereoisomer

Start by asking: are the two structures mirror images? If yes they are enantiomers; if not, diastereomers.

Types of isomer

Enantiomers are non-superimposable mirror images. They have identical physical properties except the direction in which they rotate plane-polarised light, but can differ greatly in biological activity.
Diastereomers are stereoisomers that are not mirror images. They differ in physical properties (e.g. quinine and quinidine).
A racemic mixture (50:50 of two enantiomers) is optically inactive. A meso compound has chiral centres but an internal plane of symmetry, so it is also optically inactive (meso-tartaric acid).
A molecule with n chiral centres has up to 2ⁿ stereoisomers.
Geometric (cis/trans or E/Z) isomers need restricted rotation, around a double bond or in a ring.

Naming

R/S (Cahn–Ingold–Prelog): rank groups by atomic number, point the lowest away, and read 1 → 2 → 3. Clockwise is R, anticlockwise is S.
D/L relates configuration to glyceraldehyde (Fischer projection). Natural amino acids are L; natural sugars are D.
(+)/(−) or d/l describe the direction of optical rotation measured with a polarimeter. They have no fixed relationship to R/S or D/L.
Specific rotation is usually measured at 20 °C with the sodium D line (589 nm).

Why it matters in drugs

Receptors are chiral, so enantiomers often differ (three-point attachment, Easson–Stedman). The more active one is the eutomer; the less active is the distomer; their activity ratio is the eudismic ratio.
Thalidomide: one enantiomer is sedative and the other teratogenic, but they interconvert in the body, so giving a single enantiomer would not have prevented harm.
Only L-dopa is used (D-dopa is inactive and toxic). D-penicillamine is used because L-penicillamine is toxic.
Cisplatin's cis isomer is active; the trans isomer is not.
Ibuprofen's S-form is active, and the body converts much of the R-form into S.
Single-enantiomer drugs (chiral switches): esomeprazole, escitalopram, levocetirizine, levofloxacin, levosalbutamol, esketamine.

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Enantiomer examples

Drug	Key point
Thalidomide	R sedative, S teratogenic; interconvert in vivo
Levodopa	L-form only; D-form toxic
Penicillamine	D-form used; L-form toxic
Dextromethorphan	Antitussive; its levo-isomer is an opioid (levorphanol)
Ibuprofen	S active; R converted to S
Warfarin	S-warfarin 2–5× more potent
Quinine / quinidine	Diastereomers: antimalarial / antiarrhythmic
Cisplatin	Only the cis isomer is active

Naming systems

System	Based on
R / S	CIP priority rules (absolute configuration)
D / L	Comparison with glyceraldehyde
(+) / (−)	Measured direction of optical rotation
E / Z	CIP priorities across a double bond
cis / trans	Same or opposite side

Memory aids

R = Right turn (clockwise): With the lowest-priority group pointing away, clockwise 1 → 2 → 3 is R.

Exam traps

An R compound is not necessarily dextrorotatory; R/S and (+)/(−) are unrelated.
Enantiomers have the same melting point and solubility; diastereomers do not.
Meso compounds contain chiral centres but are optically inactive.
Giving pure R-thalidomide would not have prevented birth defects, because it converts to S in the body.

Revised? Now test yourself.

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