I WANT SOME MOORE Flashcards
Racemic Switch = Chiral Switch
a drug that is already sold as a racemate is patented and sold as a single enantiomer
examples:
- Levomoprolol/Levotensin
- Dexfenfluramine/Isomeride
- Levodropropizine/Levotuss
- Ibuprofen/Serectil
- Levofloxacin/Cravit
- Barnidipine/Hypoca
Why is drug chirality an important concept for future pharmacists and pharmaceutical scientists?
Drug metabolism
Defferent stereoisomers maybe metabolized through:
DIFFERENT MECHANISMS
DIFFERENT ENZYMES
have DIFFERENT METABOLITES
Eutomer
More Potent enantiomer
with DESIRED ACTIVITY
Distomer
LESS POTENT ENANTIOMER
with UNDESIRED activity
- an impurity (“isomeric ballast”)*
- (-)-thalidomide = a TERATOGEN*
- chemical that can cause birth defects by adversely altering development of embryo or fetus without necessarily altering organism’s genetic structure.
Eudismic Ratio
Eutomer / Distomer
High eudismic ratio when antagonist has stereogenic center in pharmacophore
Why are receptors and drugs three-dimensional?
- Bond length:
- Bond angles:
- Conformation: (torsion angle)
- Hybridization:
- Charges:
-
Size and nature of R group:
* (hydrophobic, flexible, aromatic, polar)*
Structure
Methods to determine & Related Terms
Complete Arrangement of all atoms of a molecule in space.
Determined by X-ray / Cryo-Em
Constitution
Configuration
Confirmation
Constitution
Nature & Number of atoms
types of Bonds
manner at which they are linked = Connectivity
Formula SAME
Constitution Different
Configuration
&
Isomer
Spatial arrangement of atoms that distinguishes molecules of the same CONSTITITION
Isomer = Same constitution, Different Configuration
Conformation
Spatial Arrangement of atoms in a molecule of given
CONSTITUTION & CONFIGURATION
ROTATION about single bonds
&
Pyramidal Inversions at some atoms (ie. N)
>GIVE RISE TO DIFFERENT CONFORMATIONS
Pyramidal Inversions
Change in Conformation (same consitution/configuration)
RAPID INTERCONVERSION
ex. Pyrimadal molecule like H-N-R3
*Not considered a Chiral Center
Technically CHIRAL but the rapid interconversion makes it NOT ISOLABLE
Chirality
Object that is
NOT SUPERIMPOSABLE ON ITS MIRROR IMAGE
Chirality is Removed if it acquires:
plane or center of symmetry
Can be chiral w/ symmetry of axis and none of the above
Chiral Center
=
Asymmetric Center
=
Stereogenic Center
TETRAHYDRAL (sp3) atom
Four NON-equivalent atoms or groups attached to it
- *Sulfur or Phosphate tetrahydrals count (lone pair can be a group)*
- *Nitrogen groups without the pyramidial inversions too (ex. quiniquodine)*
Optically Active UNLESS:
Has Plane or Center of Symmetry
σ Plane of Symmetry
Divides molecules so that
Points of one side of plane = Points on other side
by reflection through plane
ALWAYS ACHIRAL
A-Chiral
IS SUPERIMPOSABLE ON ITS MIRROR IMAGE
Molecule w/ σ Plane of Symmetry = Achiral
Molecule w/ Center of Symmetry = Achiral
Molecule w/ Rotational Axis of Symmetry (Cn) MAY BE CHIRAL
Center of Symmetry
“Point of Inversion”
*will be pointed out on test
Point from which ANY line drawn through the molecule
encounters identical environment in either direction from the center of symmetry
always ACHIRAL
*has chiral center but is ACHIRAL because of the center of symmetry
AXIS of Symmetry
Cn
N-fold axis
Axis which rotates molecule around by 360* / n
such that the new position is indistinguishable from OG.
can be CHIRAL if:
NO OTHER SYMMETRY PROPERTIES
WITHOUT Center or Plane of symmetry
Enantiomer
RR / SS
RS / SR
NON-Superimposable Mirror Images
type of stereoisomer
has to be CHIRAL
Enantiomers have EXACTLY the same energies
can’t be measured physically, EXCEPT by
OPTICAL ROTATION
(enantiomers rotate LIGHT in OPPOSITE directions)
Fischer Projection
to help represent TETRAHYDRAL carbon w/ its 4 substituents
as a 2-D projection
- Pretend there is a lightbulb on the left hand side
- Light is shining to make a shadow
- Pretend the shadow comes from the wedge projection
BADA BOOM A FISCHER PROJECTION
Fischer Projection of Carbohydrates
Two in VERTICLE = going INTO the plane
(Carbonyl CHO & R Group)
Two in HORIZONTAL = going OUT TOWARDS YOU
Newman Projection
for molecule with Two-Tetrahedral Centers
viewed along the C-C Axis
Enantiopure
containing ONLY ONE enantiomer
Racemate
=
Racemic Mixture
mixture that has EQUAL amounts of opposite enantiomers
50/50 mixture
*not meso (has single compound), racemate has mixture of enantiomers
levo-rotatory (-)
&
dextro-rotatory (+)
little d & little l
Optically Active Enantiomers
l = (-) = rotate plane of polarized light to the left
d = (+) = “ to the right
CAN NOT BE DETERMINED
Enantiomerismic Properties
NOT distinguished by interactions with:
ACHIRAL molecules (like solvent)
Physical properties measured by techniques
(except polarized light)
Interact differently w/ other Entantiomeric molecules
ex. Biological receptors
Hybrid Drugs
Different Therapeutic Activities
ex. Propanalol
d-(+)-enantiomer = Vasodilation
l-(-)-enantiomer = antihypertensive
CAPITAL
L / D
for Carbohydrates
Look @ stereocenter FURTHEST away from the aldehyde / ketone of the carbohydrate at the TOP.
L = -OH GROUP ON LEFT
D = -OH GROUP ON RIGHT
originated from glyceraldehyde
*carbohydrates are TYPICALLY = D
Erythrose
vs
Threose
Erythrose = Two High Priorites on the SAME SIDE
Threose = Two high priorities on Opposite Sides
CAPITAL
L / D
for Amino Acids
Look @ stereocenter FURTHEST away from the Carboxylic acid of the AA at the TOP.
L = -NH2 GROUP ON LEFT
D = -NH2 GROUP ON RIGHT
*Amino acids are TYPICALLY = L
Cahn-Ingold-Prelog (CIP) Rules
Clockwise = R
Counter Clockwise = S
Asign order by atomic MASS/NUMBER
Clockwise = R
- Counter Clockwise = S*
- If first “sphere” is the same go to the NEXT
- Double Bonds = Multiple Atoms
=O > -O x 2
Order of Atomic Masses
for presidence
C < N < O < F < Cl < (S) < Br
Lonepair < Hydrogen < D
Double Bond Geometry
Z / E
Ze same side
E = opposite
Z / E= DIASTERIOMER
Cyclic Compounds Geometry
Cis / Trans
Trans = priorities are on both on axial position
Ring flipped= Trans are both equitorial
Cis = priorites are axial / equatorial
Ring Flipped = Still on axial and equatorial
Cis / Trans = DIASTERIOMER
Diastereomers
E vs Z
Cis vs Trans
RR/RS , SS/RS , SS/SR
stereoisomers that are not enantiomers
can have:
two+ Chiral Centers, where not all chiral centers have opposite configuration ( ike RR/RS , SS/RS , SS/SR)
no chiral center(s) / non-chiral
just differ by spatial difference (not related to mirror reflection)
E / Z or Cis / Trans
Meso Compounds
Have chiral (assymetric) centers but ARE NOT CHIRAL
ACHIRAL
b/c CONTAIN A PLANE OF SYMMETRY
(can have center of symmetry but not common)
ex. mesoTartaric Acid
* *not a racemate (mixture of compounds), meso is a single compound*
Pseudo-Hybrid Drug
Multiple Isomeric Forms w/ different biologic activity
ex. Labetalol
RR = eutomer for Beta Blocker
S,R = eutomer for Alpha Blocker
S,S / R,S = Inactive (isomeric Ballast)
EPIMER
Stereoisomers thet differ by ONLY ONE STEREOCENTER
still Diastereomers if 2> stereocenters
can be enantiomers & epimers if ONLY 1 stereocenter
Number of Stereoisomers
Number of Stereoisomers = 2n
n = # of stereocenters
Z/E COUNT TOO!
- unless there are MESO compounds*
- <2n *
Torsion Angle
(or Dihedral)
The single parameter differentiated such conformers is the TORSION ANGLE
Angle between two planes
You look down the two atoms that are IN COMMON
*NEWMAN PROJECTION
synperi-planar
(eclipsed)
-30° to +30°
sp
HIGH ENERGY
synclinal
(gauche)
+30° to +90°
(+sc shown)
- 90° to -30°
- sc as well
anticlinal
(also eclipsed)
+90° to +150°
+ac (as shown)
- 150° to -90°
- ac
antiperi-planar
(trans/anti)
+150° to -150°
ap
lowest energy
Conformer
One set of stereoisomers
each characterized by a Conformation corresponding to a potential energy
Interconversion of conformations = infinite number
Staggered Conformations
180°/ 60° / -60°
Torsion angle = groups are AS FAR AWAY AS POSSIBLE
- *typically have LOWEST potential energies*
- local/global minimums*
Eclipsed Conformations
-120°/ 120° / 0°
Torsion angle between the 3 bonds = ZERO
- *typically have the HIGHER potential energy*
- maximums*
Amide Bond
E / Z
Conformation
C-N bond acts like the Double Bond
C-N bond is much shorter than a single bond
(trans) Z is PREFFERED, due to sterics
*=O is the higher presidence group
Ester Bonds
Cis (E) / Trans (Z)
Conformation
C-O bond acts like the Double Bond
C-O bond is much shorter than a single bond
(trans) Z is PREFFERED, due to sterics
*=O is the higher presidence group
Hydrogen Bonding
on Conforormers
H-bonding can have a LOCKING EFFECT
on conformation about C-C Bonds.
Can overide unfavorable interactions
*synclinal interactions
Why are all cyclic compounds NONPLANAR?
(except for 3-mem & aromatics)
Baeyer Strain
Balance between valence bond angle strain
Wants to be 109* but to be flat it needs to be 120*
Torsional Strain
If eclipsed (~flat) = torsional strain
If staggered (chair form) = tortional strain is relieved
6-Membered Ring Conformations
Chair -> Half Chair (least favorable) ->Twist -> Boat -> Chair Flip
What does the rate & equilibrium of chair-chair transitions depend on?
(6-membered rings)
–Presence of heteroatoms(O,N,S,P) instead of carbon atoms
–Steric size of substituents
–Existence of interactions which stabilize one particular conformer
–Presence of local dipoles
–Stereoelectronic effects (e.g. gauche effect, anomeric effect)
Larger Substituants want to be placed in the ______ position
Why?
EQUITORIAL
Because of SYNAXIAL REPULSION
& sterics
A-value (conformational energy) = energy difference between the axial & equitorial positions
5-Membered Systems
Envelope
Half Chair (MOST PREFFERED) -substituant is in EQUITORIAL
Envelope (ring flip)
Ring Pseudorotation / Conformational flux
much less ring strain, ring is constantly changing unlike 6mem
-30° to +30°
HIGH ENERGY
synperi-planar
(eclipsed)
+30° to +90°
(shown)
-90° to -30°
synclinal
(gauche)
+90° to +150°
(as shown)
-150° to -90°
anticlinal
(also eclipsed)
+150° to -150°
lowest energy
“Global Minimum”
antiperi-planar
(trans/anti)
