This is a comprehensive summary that includes both notions and slides of the course, taught by Prof. U. Hennecke at 2nd Ma chemistry students. The reaction mechanisms are extensively covered with a specific focus on the transition states responsible for the induced stereoselectivity.
Ideally, drugs and natural products are produced enantioselectivity so that only 1 product is
obtained. Traditionally, most methods were diastereoselective, but we will place an emphasis
on the enantioselective reactions.
Chemical compounds can be chiral, hence have 4 different
substituents, called stereogenic centers. In that case, these
stereoisomers mirror images, also called enantiomers, that are
not superimposable. Most physical properties (eg. same IR,
NMR, BP) of enantiomers are identical and only become
different when placed in a chiral environment (eg. spectroscopy
with circular polarized light).
If there are multiple stereocenters in 1 compound, this doesn’t mean the molecule is chiral
because of the so-called meso-compounds → have a plane of symmetry → are not chiral.
1.1. Definitions
A racemate (or racemic mixture) is a mixture of 50% of 1 enantiomer and 50% of the other
enantiomer.
If one enantiomer is present in larger quantities than the other enantiomers, this is an
enantio-enriched mixture, and the enantiomeric ratio (er) or enantiomeric excess (% ee) can
be given:
In the past, ee was used more because the composition of an enantiomeric mixture was
determined using optical rotation, which is directly correlated to the ee. Nowadays, only a
few use optical rotation techniques, but GC or LC are now more common and deliver the er.
1
, 1.1.1. Cahn-Ingold-Prelog (CIP) nomenclature
This nomenclature is used to determine the configuration of the stereocenter:
- Orientate the substituent with the lowest priority in the back
- Then you order the substituents from high to low priority
- Depending on the order of the substituents, either anti-clock (s-configuration) or
clock-wise (R-configuration) will be identified
1.1.2. Stereogenic elements
Besides C-atoms with 4 different substituents (point chirality), also other types of chirality
exist.
An example of axial chirality is displayed in the spiro
compound → two rings (not only cyclobutene but also other
sizes) connected by a spiro C-atom. 1,3-disubstituted allenes
are also axially chiral. Also the case in BINAP and BINOL
compounds.
Planar chirality is less common than axial chirality. The
depicted example considers cyclophanes in which the
rotation is restricted → bottom plane generates the chirality.
Also the case in ferrocene’s (inorganic compounds).
1.1.2.1. How can the right configuration be assigned to axial chirality?
Example 1)
This works in a very similar way as for the CIP nomenclature. Its starts by looking at the
compound along the chiral axis, after which priority is assigned to the different substituents.
2
,The priority rules are the same as for the CIP nomenclature, with the addition that everything
that is in front of you has priority over everything that is in the back (this also means that an
H in the front has a priority over the Me in the back). Similarly to CIP, you check the order of
priority and assign either R or S with the addition of an ‘a’ index for axial chirality.
In literature, also M (minus) and P (plus) is also used, although this is less preferred. Here
priority is assigned, independently of the chirality axis, hence two same substituents have the
same priority. The arrow is drawn from the substituent with the highest priority in the front
to the substituent with the highest priority in the back. Here counter-clockwise is minus,
hence M, while for clockwise this becomes P.
Example 2)
BINOL stands Bi-naphthol, in which two naphthols are connected and have a hindered
rotation (at rt) because of sterical clashes. Here the chiral axis is in the middle and observed
from the bottom (displayed with the arrow).
Note: the S configuration is not always equal to the P configuration.
1.1.2.2. What about the planar chirality?
Example 1) cyclophane
First, the plane of chirality is assigned (see red drawing). Next, an atom out of
the plane is chosen as a reference. This atom must be connected directly to
the plane of chirality. In case different options are available, the one with the
highest priority according to the CIP rules must be chosen (see blue dot/can
also be at the other side). Afterwards, you assign the priority to the atoms and
check in which direction the rotation is.
Example 2) ferrocene
Here, the Fe-atom is the reference atom, and the Cp is the plane of
chirality. You then chose the atoms that are the most relevant for this
plane of chirality and have the highest priority. These atoms are then
projected to another plane (point chirality) and are connected →
tetraheder. By now placing an imaginary atom in the middle, the
configuration can be assigned as for point chirality.
3
, A last example of chirality is the so-called helical chirality. This is for example present in
hepta-helicene in which the chirality is due to the rings overlapping each other → can’t be
the same plane because of the Pauli repulsion.
1.1.3. Relative and absolute configurations
L-threonine has two stereocenters, hence it also has a diastereomer → L-allothreonine. Each
diastereomer appears as two enantiomers (either L or D). The L-enantiomer can be projected
under the zigzag chain, we can see that both substituents are pointing towards us → syn
relative configuration. The other enantiomer would have both substituents pointing away.
The syn-relative configuration refers to both substituents pointing in the same direction. On
the other hand, the anti-configuration has both substituents pointing in opposite directions.
The anti and syn-configurations are diastereomers of each other.
The relative configuration refers to the orientation of both substituents relative to each other
→ either syn or anti. the bonds are always drawn straight in this case absolute
configuration where the bonds are drawn as triangles. The absolute configuration considers
each stereocenter apart.
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