Conformation and stereochemistry
Section 3.11: Prochirality
fig 64
In the isoprenoid biosynthesis pathway, two five-carbon building-block molecules combine to form a ten-carbon chain containing an E-alkene group. The enzyme does not catalyze formation of the Z diastereomer.
fig 65
In chapters 9-17 of this book, and continuing on into your study of biological and organic chemistry, you will be learning about how enzymes are able to achieve these feats of stereochemical specificity. If you take a more advanced class in organic synthesis, you will also learn how laboratory chemists are figuring out ingenious ways to exert control over the stereochemical outcomes of nonenzymatic reactions, an area of chemistry that is particularly important in the pharmaceutical industry.
fig 72
Note that if, in a 'thought experiment', we were to change either one of the prochiral hydrogens on a prochiral carbon center to a deuterium (the 2H isotope of hydrogen), the carbon would now have four different substituents and thus would be a chiral center.
Prochirality is an important concept in biological chemistry, because enzymes can distinguish between the two ‘identical’ groups bound to a prochiral carbon center due to the fact that they occupy different regions in three-dimensional space. Consider the isomerization reaction below, which is part of the biosynthesis of isoprenoid compounds.
We do not need to understand the reaction itself (it will be covered in chapter 14); all we need to recognize at this point is that the isomerase enzyme is able to distinguish between the prochiral 'red' and the 'blue' hydrogens on the isopentenyl diphosphate (IPP) substrate.
In the course of the left to right reaction, IPP specifically loses the 'red' hydrogen and keeps the 'blue' one.
fig 73
Prochiral hydrogens can be unambiguously designated using a variation on the R/S system for labeling chiral centers. For the sake of clarity, we'll look at a very simple molecule, ethanol, to explain this system. To name the 'red' and 'blue' prochiral hydrogens on ethanol, we need to engage in a thought experiment. If we, in our imagination, were to arbitrarily change red H to a deuterium, the molecule would now be chiral and the chiral carbon would have the R configuration (D has a higher priority than H).
fig 74
For this reason, we can refer to the red H as the pro-R hydrogen of ethanol, and label it HR. Conversely, if we change the blue H to D and leave red H as a hydrogen, the
configuration of the molecule would be S, so we can refer to blue H as the pro-S hydrogen of ethanol, and label it HS.
R2 R1
H H
prochiral carbon
prochiral hydrogens
R2 R1
D H
chiral carbon
change H to D
O P O O O
P O O O H
H
O P O O O
P O O O H
isopentenyl diphosphate dimethylallyl diphosphate
H3C OH H H
R
change H to D stereocenter is now R.
H3C OH H D
fig 75
Looking back at our isoprenoid biosynthesis example, we see that it is specifically the pro-R hydrogen that the isopentenyl diphosphate substrate loses in the reaction.
fig 76
Prochiral hydrogens can be designated either enantiotopic or diastereotopic. If either HR or HS on ethanol were replaced by a deuterium, the two resulting isomers would be
enantiomers (because there are no other stereocenters anywhere on the molecule)
fig 77
Thus, these two hydrogens are referred to as enantiotopic.
In (R)-glyceraldehyde-3-phosphate ((R)-GAP), however, we see something different:
fig 78
(R)-GAP already has one chiral center. If either of the prochiral hydrogens HR or HS is replaced by a deuterium, a second chiral center is created, and the two resulting molecules will be diastereomers (one is S,R, one is R,R). Thus, in this molecule, HR and HS are referred to as diastereotopic hydrogens.
Finally, hydrogens that can be designated neither enantiotopic nor diastereotopic are called homotopic. If a homotopic hydrogen is replaced by deuterium, a chiral center is
H3C OH HS HR
O P O O O
P O O O HR
HS
O P O O O
P O O O H
isopentenyl diphosphate dimethylallyl diphosphate
H3C OH HS HR
H3C OH H D
H3C OH D H
R S
enantiomers
enantiotopic hydrogens
OH O
OH HS HR
R H
O O
OH D H
R H
O O
OH H D
R H
S R
diastereomers
diastereotopic hydrogens
(R)-GAP O P
O O P
O O O
O P O O
not created. The three hydrogen atoms on the methyl (CH3) group of ethanol (and on any methyl group) are homotopic.
fig 79
An enzyme cannot distinguish among homotopic hydrogens.
Exercise 3.29: Identify in the molecules below all pairs/groups of hydrogens that are homotopic, enantiotopic, or diastereotopic. When appropriate, label prochiral hydrogens as HR or HS.
fig 79a
Groups other than hydrogens can be considered prochiral. The alcohol below has two prochiral methyl groups - the red one is pro-R, the blue is pro-S. How do we make these designations? Simple - just arbitrarily assign the red methyl a higher priority than the blue, and the compound now has the R configuration - therefore red methyl is pro-R.
fig 80
C C HR OH
HS H H H
homotopic hydrogens
enantiotopic hydrogens
N N O H
O O
O H dihydroorotate
(a nucleotide biosynthesis intermediate)
O CO2 phosphoenolpyruvate ( a glycolysis intermediate)
O2C CO2
succinate
(a citric acid cycle intermediate)
H3C C C O O
O pyruvate (endpoint of glycolysis)
a) b)
c) d)
P O O
O
OH CH3pro-R
pro-S
H3C
Citrate is another example. The central carbon is a prochiral center with two 'arms' that are identical except that one can be designated pro-R and the other pro-S.
fig 81
In an isomerization reaction of the citric acid (Krebs) cycle, a hydroxide is shifted
specifically to the pro-R arm of citrate to form isocitrate: again, the enzyme catalyzing the reaction distinguishes between the two prochiral arms of the substrate (we will study this reaction in chapter 13).
fig 82
Exercise 3.30: Assign pro-R and pro-S designations to all prochiral groups in the amino acid leucine. (Hint: there are two pairs of prochiral groups!). Are these prochiral groups diastereotopic or enantiotopic?
fig 82a
Although an alkene carbon bonded to two identical groups is not considered a prochiral center, these two groups can be diastereotopic. Ha and Hb on the alkene below, for example, are diastereotopic: if we change one, and then the other, of these hydrogens to deuterium, the resulting compounds are E and Z diastereomers.
pro-R arm
citrate O2C OH
CO2 CO2
pro-S arm
O2C OH CO2 CO2
CO2 O2C
CO2 HO
citrate
CO2 O2C
CO2
OH
isocitrate
= (draw from a different perspective) pro-R arm
pro-S arm
pro-S arm
pro-R arm hydroxide moved
specifically to the pro-R arm
H3N CO2 leucine
fig 83
3.11B: The re and si faces of carbonyl and imine groups
Trigonal planar, sp2-hybridized carbons are not, as we well know, chiral centers– but they can be prochiral centers if they are bonded to three different substitutuents. We (and the enzymes that catalyze reactions for which they are substrates) can distinguish between the two planar ‘faces’ of a prochiral sp2 - hybridized group. These faces are designated by the terms re and si. To determine which is the re and which is the si face of a planar organic group, we simply use the same priority rankings that we are familiar with from the R/S system, and trace a circle: re is clockwise and si is counterclockwise.
fig 84
Below, for example, we are looking down on the re face of the ketone group in pyruvate:
fig 85
If we flipped the molecule over, we would be looking at the si face of the ketone group.
Note that the carboxylate group does not have re and si faces, because two of the three substituents on that carbon are identical (when the two resonance forms of carboxylate are taken into account).
As we will see in chapter 10, enzymes which catalyze reactions at carbonyl carbons act specifically from one side or the other.
C C C H H
H O
OCH3
C C C H D
H O
OCH3
C C C H H
D O
OCH3
diastereomers
(Z) (E)
diastereotopic hydrogens
1
2 3
looking at the re face
1
3 2
re face si face
1
3 2
looking at the si face
H3C C C O
O
O
priority #1
priority #2 priority #3
fig 86
We need not worry about understanding the details of the reaction pictured above at this point, other than to notice the stereochemistry involved. The pro-R hydrogen (along with the two electrons in the C-H bond) is transferred to the si face of the ketone (in green), forming, in this particular example, an alcohol with the R configuration. If the transfer had taken place at the re face of the ketone, the result would have been an alcohol with the S configuration.
Exercise 3.31: For each of the carbonyl groups in uracil, state whether we are looking at the re or the si face in the structural drawing below.
fig 86a
CO2 HO
H2C O
OH N
R
NH2 HS HR O
+
CO2 HO
H2C HO
OH N
R
NH2 O H +
H
R
we are looking at the si face of the ketone
N N O
H O H
uracil
Summary of Key Concepts
Before you move on to the next chapter, you should be confortable with the following concepts:
Conformations of open-chain compounds:
Be able to distinguish between eclipsed, staggered, gauche, and anti conformations, and the rational for trends in stability.
Be able to draw and interpret Newman projections.
Conformations of cyclic compounds:
Understand the concept of angle strain in 3- and 4-membered rings.
Be able to draw the envelope conformation of five-membered rings Be able to draw the chair and boat conformations of six-membered rings.
In the chair conformation, be able to draw equatorial and axial substituents. Understand that large groups in the axial position experience considerable 1,3-diaxial repulsion, and thus are more stable in the equatorial position.
Stereochemistry:
Hierarchy of isomeric relationships:
You should understand the relevant terms and concepts:
A chiral object or molecule is cannot be superimposed on its mirror image.
A chiral center is an sp3-hybridized (tetrahedral) carbon bonded to four different groups.
A chiral center can be labeled R or S.
A stereogenic alkene is an alkene is one in which both sides of the alkene are asymmetric, and which can therefore be labeled E or Z.
isomers
stereoisomers constitutional isomers
diastereomers enantiomers
epimers not epimers
conformational isomers
Stereoisomers have the same molecular formula and same connectivity, but a different orientation of atoms in space.
Enantiomers are stereoisomers which are mirror images.
In practice, the enantiomer of a compound is the one in which all chiral centers are in the opposite configuration.
Every chiral molecule has one and only one enantiomer.
Achiral molecules are superimposable on their mirror image, and thus cannot have an enantiomer.
Enantiomers have equal but opposite specific rotations, but identical physical properties otherwise.
Diastereomers are stereoisomers which are not mirror images. They have different physical properties.
In practice, a diastereomer of a chiral molecule with have at least one, but not all chiral centers in the opposite configuration.
Alternatively, two diastereomers may contain a stereogenic alkene with the opposite E/Z configuration.
A molecule has 2n-2 diastereomers, where n is the number of chiral centers plus stereogenic alkene groups. Meso compounds are an exception to this rule.
Epimers are diastereomers which differ at only one chiral center.
A racemic mixture is a 50:50 mixture of two enantiomers.
A meso compound has multiple chiral centers but, because it has a plane of symmetry, is achiral.
You should know how to assign R/S and E/Z configuration to chiral centers and stereogenic alkenes, respectively.
You should understand the concept of optical rotation and the definition of specific rotation.
You should recognize that in general, a protein can distinguish between its natural ligand and a stereoisomer of that ligand.
You should also recognize that enzymes are highly specific with respect to
stereochemistry, catalyzing the formation of only one stereoisomer of their products.
You should be able to recognize and label pro-R and pro-S groups on prochiral tetrahetral carbons.
You should be able to recognize re and si faces of carbonyl and imine groups
Problems
P3.1: Draw an energy vs dihedral angle graph for rotations about the C2-C3 bond of 2-methylbutane. Start with the highest-energy conformation as the 0o point. For each energy peak and valley, draw a corresponding Newman projection.
P3.2:
a) Which has the highest energy diaxial chair conformation:
trans-1,2-dimethylcyclohexane, cis-1,3-trans-1,2-dimethylcyclohexane, or trans-1,4-dimethylcyclohexane?
Explain.
b) Which of the following are trans disubstituted cyclohexanes?
c) Draw A-F above in two dimensions (rings in the plane of the page, substituents drawn as solid or dashed wedges).
d) Structure D does not have any chiral centers. Explain.
e) Draw a diastereomer of structure D (in two dimensions, as in part c).
f) Are structure D and its diastereomer chiral?
g) Assign R/S designations to the two chiral centers in structure B (hint: making a model will be very helpful!)
P 3.3: The following are structures, drawn in two dimensions, of drugs listed on the products web page of Merck Pharmaceutical. One of the compounds is achiral.
a) Circle all chiral centers. (Hint: Don't panic! Remember - you are looking for sp3 -hybridized carbons with four different substituents.)
OH OH
OH
OH
OH OH
OH
OH
OH
OH OH
A B C
D OH E F