Download Organic Stereochemistry. Part 2

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REVIEW
Organic Stereochemistry
Part 2 1)
Stereoisomerism Resulting from One or Several Stereogenic Centers
by Bernard Testa
Department of Pharmacy, Lausanne University Hospital (CHUV), Rue du Bugnon, CH-1011 Lausanne
(e-mail: [email protected])
With this second review, our Work on organic stereochemistry continues with that
most important of stereogenic elements, namely the stereogenic center, as found in a
majority of stereoisomers. The presentation is restricted to chiral tetrahedral structures,
which contain the most important stereogenic centers in molecules of biological
relevance. These are either tetracoordinate or tricoordinate centers where an electron
lone pair plays the role of the fourth substituent. The nature of the central element in
such structures, e.g., carbon, nitrogen, or sulfur, obviously plays an essential role in their
geometry.
Our main focus in this review are the two rule-based conventions used to encode
with adequate descriptors the absolute three-dimensional (3D) geometry of stereogenic
centers. By absolute 3D geometry, stereochemists understand an unambiguous
description of the sense of chirality (stereogenicity) of a center with reference to the
observer and based on the universal left-hand/right-hand discrimination.
With single stereogenic centers and the general principle of enantioselective
processes explained and illustrated, the fundament will be laid to consider the
stereochemistry of molecules containing two or more stereogenic centers. When there is
a single stereogenic center, the compound will exist as enantiomers, namely a pair of
structures related to each other as non-superimposable mirror images. When two or
more stereogenic centers are present, the result may be another steric relation between
molecules known as diastereoisomerism. The discrimination between enantiomeric and
diastereoisomeric relationships is a critical one in the chemical and related sciences,
and care will be taken to illustrate this difference.
This Part 2 will be followed by a presentation, in Part 3, of other stereogenic
elements, namely axes and planes of chirality, helicity, and (E,Z)-diastereoisomerism,
followed in turn by a presentation of isomerisms about single bonds and in cyclic
systems in Part 4. Only then, with the principles of stereoisomerism discussed, will we
be able to consider their impact on pharmacology, biochemistry, and xenobiotic
metabolism. This will still leave us with just one last facet of stereochemistry to
consider, the all important concept of prostereoisomerism and its key role in
endogenous and exogenous metabolism (Part 8).
1)
For the other Parts, see Helv. Chim. Acta 2013, 96, 1 – 3.
2013 Verlag Helvetica Chimica Acta AG, Zrich
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Fig. 2.1. This second review in the series begins by looking at compounds characterized
by a single stereogenic center and hence having a non-superimposable mirror image
with which they form a pair of enantiomers [1 – 16]. The focus will be on chiral
tetrahedral structures, namely a) with tetracoordinate centers, and b) with tricoordinate
centers where an electron lone pair plays the role of the fourth substituent. Following
an overview of the main tetrahedral structures of interest, the review goes on to explain
the two dominant convention systems, namely the d,l- and the (R,S)-conventions, the
latter being known as the CIP (CahnIngoldPrelog) convention. These are systems
based on rigorous rules and allow an absolute descriptions of molecular structures in
3D space, i.e., description that yields an identical outcome for all observers. As we will
see, both conventions have their advantages, although the CIP convention is much
broader, far more complete, and devoid of ambiguity. The review continues with the
case of compounds with two or more stereogenic centers, which result in the emergence
of diastereoisomeric relationships. As a result, we will encounter compounds whose
structures allow the simultaneous occurrence of enantiomeric and diastereoisomeric
relationships.
This review will end with a qualitative discussion of the comparative configurational stability of C-centered chiral tetrahedral structures, which, as we will see, range
from the extremely stable to the very labile.
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Fig. 2.2. Tetrahedral chemical structures contain a central atom X at the geometrical
center of a tetrahedron, to which are attached four atoms or substituents (A, B, C, and
D) each occupying one of the vertices of the tetrahedron. If the four atoms or
substituents are different from each other as in 2.1, the generic structure is chiral. Such a
tetracoordinate assembly is indeed asymmetric (point group C1) and occurs in two
stereoisomeric forms which form an enantiomeric pair. A comparable situation is
depicted with the generic structures 2.2. Here, there are only three atoms or substituents
attached to X, making it a tricoordinate assembly. However, if the central atom (e.g., Satom, N-atom) possesses an electron lone pair, this will function as a virtual ligand
pointing to the fourth vertex of the tetrahedron [17]. With three different atoms or
substituents A, B, and C, and provided the chemical nature of X allows sufficient
stability of such an arrangement, two enantiomers can indeed be characterized and
isolated.
Should the four atoms or substituents fail to occupy the vertices of a tetrahedron
and be, for example, coplanar with the central atom, a non-dissymmetric structure is
obtained [18]. This is illustrated here with the well-known anticancer drug cisplatin
(2.3) which shares a diastereoisomeric relationship with transplatin (2.4). Note also
that we will not extend the current presentation to more complex structures such as
pentacoordinate centers as exemplified with the trigonal-bipyramidal structure of the
generic phosphorus(V) compound 2.5. With five different substituents, such a structure
can conceivably exist as ten diastereoisomeric pairs of enantiomers [19]!
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Fig. 2.3. This Figure illustrates some chiral generic structures having as their central
atom a first- or second-row element of columns IVA and VIA in the periodic table of
chemical elements. But first, we present an extraordinary chiral molecule, namely (R)[2H1 ,2H2 ,2H3 ]neopentane (2.6). This chemically inert compound is chiral as a result of a
dissymmetric mass distribution, the smallest possible one in fact, and its synthesis and
absolute-configuration assignment proved to be at the very limit of what was
theoretically and experimentally possible at the time [20] [21]. The rest of the Figure
instructs us that carbanions with a lone pair, 2.7, racemize readily, whereas carbon
radicals, 2.8, and carbonium ions, 2.9, which both lack a virtual fourth ligand, are
usually close to planarity and tend to be achiral independently of their substituents
[22]. In column IVA, silanes, 2.10, are configurationally stable. As for column VIA,
oxonium salts, 2.11, show very rapid inversion. In contrast, sulfonium salts, 2.12, and
sulfoxides, 2.13, have rather stable trisubstituted centers [23]. The higher configurational stability of second-row atoms compared to first-row atoms is clear from these
generic examples.
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Fig. 2.4. Moving to column VA of the periodic table, we encounter the elements
nitrogen and phosphorus which again demonstrate the difference in configurational
stability between first- and second-row atoms. Indeed, fast inversion is the rule for
amines, 2.14, [24 – 26], but the molecular environment also plays a role. Fast inversion is
also the case when the N-atom is included in a monocyclic system as in 2.15. In contrast,
a N-atom incorporated as bridgehead in a bicyclic system will be configurationally
frozen. This was established for the first time when Prelog and Wieland succeeded in
resolving Trçgers base whose dextrorotatory (S,S)-enantiomer 2.16 is shown here
[27] [28]. In contrast to tertiary amines such as 2.14, N-oxides (tertiary amine oxides),
2.17, and quaternary ammonium species, 2.18, are configurationally stable. The same is
true for phosphines, 2.19, and for phosphonium salts, 2.20.
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Fig. 2.5 – 2.7. A need for consistency in stereochemical designation prompted Emil
Fischer to use C(5) of the dextrorotatory enantiomer of glucose (2.21) as a starting
point. First, the molecule was drawn based on the following conventions: a) the longest
C-chain is vertical; b) the most highly oxidized end of the chain is at the top; c) at each
center along the main chain, the vertical bonds point backwards and the horizontal
bonds point toward the observer; and d) the central tetrahedral C-atom(s) can be
omitted, an option not followed here for better clarity. (þ)-Glucose was degraded by
Fischer to the aldotriose (þ)-glyceraldehyde in which the only stereogenic center
originates from C(5) of the parent molecule. Arbitrarily, Fischer assigned the depicted
configuration to (þ)-glyceraldehyde, which became (þ)-d-glyceraldehyde (2.22) due to
the right-hand-side position of the substituent at the stereogenic center (and not due to
its optical rotation as still believed by some!). As a result, ( )-l-glyceraldehyde was
assigned the configuration shown in 2.23. All molecules that could be chemically
related to d-glyceraldehyde were assigned the d-configuration, as illustrated in
Figs. 2.6 and 2.7, while molecules related to ()-l-glyceraldehyde (2.23) were assigned
to the l-series. This assignment is based on chemical transformations that do not break
any bond to the highest-numbered stereogenic C-atom [5 – 15] [29]. Thus, the aldoses
related to d-glyceraldehyde include the two aldotetroses d-erythrose (2.28) and dthreose (2.29), the four aldopentoses d-ribose (2.30), d-arabinose (2.31), d-xylose
(2.32), and d-lyxose (2.33), and the eight aldohexoses d-allose (2.34), d-altrose (2.35),
d-glucose (2.21), d-mannose (2.36), d-gulose (2.37), d-idose (2.38), d-galactose (2.39),
and d-talose (2.40) [30] [31].
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Whereas this convention proved useful for carbohydrates, conflicting results arose with
other chemical classes. Thus, (þ)-d-glyceraldehyde (2.22) can be chemically related to
()-lactic acid (2.24) via carbonyl reduction, followed by alcohol oxidation, and to (þ)lactic acid (2.25) via oxidation of the carbonyl, followed by bromination of the alcohol
and finally reductive debromination. To partly overcome such difficulties, the
projection convention came into use. This convention distinguishes itself from the
convention discussed above in that no reference is made to the chemical affiliation of
the compound under examination. The latter is simply drawn in the Fischer projection
and is designated as d or l depending on the right-hand or left-hand position,
respectively, of the substituent at the highest-numbered stereogenic C-atom. The
projection convention is thus restricted to those molecules that can be unambiguously
drawn in the Fischer projection, and which can also obey all relevant rules.
Further difficulties arose for distinct chemical classes such as phenylethylamines
which are conventionally drawn upside down. Another problem arose with the amino
acids, the natural configuration of which is l as shown with the generic structure 2.26
when R=H (R ¼ H is glycine, the only non-chiral natural amino acid). The majority of
natural amino acids contain only one stereogenic center and are easily designated
according to the carbohydrate rules, for example, l-serine (2.26, R ¼ CH2OH).
However, the case of threonine (2.27) is inconsistent, because its highest-numbered
stereogenic C-atom center has the d-configuration, and designating it as d-threonine
created a discrepancy with serine. The compound is thus designated as l s-threonine
(2.27) where the subscript s indicates the serine series; the subscript g is then used for
the glyceraldehyde series.
The most important point to be made here is that the d,l-convention as originally
conceived and proposed by Fischer described relative configurations. In other words,
there was no way to decide if all stereochemical representations reflected reality or
were objects in a mirror-universe. It was not until 1951 that publications based on the Xray-analysis of sodium rubidium (þ)-tartrate tetrahydrate afforded an experimental
basis for absolute configurations and showed Fischers gamble to have hit the correct
answer.
A further problem exists, especially in the medical literature where non-chemist
authors use the low-case letters d and l to indicate the sense of optical rotation
(dextro- and levorotatory, resp.), thereby creating a confusion with the d,l-convention.
No serious publication should tolerate such uninformed practice. As is clear from the
above, the rapid experimental and conceptual progress in stereochemistry in the first
half of the 20th Century made it urgent to rely on an (ideally) universal and
unambiguous description of the absolute configuration at stereogenic centers and other
stereogenic elements.
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Fig. 2.6.
Fig. 2.7.
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Fig. 2.8. The foundation of a new convention was laid in 1951 by Cahn and Ingold, and
expanded and clarified by Cahn, Ingold, and Prelog [5 – 15] [32 – 34]. The convention is
often referred to as the CIP System and consists in two parts, namely a) the sequence
rule, which defines the ranking of the four vertices of a tetrahedron (namely the
substituents A > B > C > D) according to a set of arbitrary but consistent subrules, and
b) a rule which specifies that rotation is from A to B to C, when these point toward the
viewer while D points away. The two possible arrangements are illustrated in the upper
part of the Figure, where a clockwise course is shown to translate into the (R)configuration (2.41; Latin rectus, right), and a counterclockwise (anticlockwise) course
into the (S)-configuration (2.42; Latin sinister, left). The comparison with a spinning
wheel can help explain the circular path from A to B to C.
The sequence rule begins by considering the four atoms linked to the stereogenic
center. These are ranked in an order of preference which decreases with decreasing
atomic number; isotopes are ranked according to decreasing mass number, while a lone
electron pair is considered a phantom atom with atomic number zero. The two
structures at the bottom of the Figure provide partial applications. In particular, we can
now understand how the configuration of the deuterated neopentane 2.6 in Fig. 2.3 was
defined as (R). The case of (S)-ethyl methyl sulfoxide (2.43) involves an additional
subrule to explain why ethyl > methyl.
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Fig. 2.9. The example of (R)-2-bromo-2-chloro-3-methylbutan-1-ol (2.44) is used to
answer the above question. Indeed, the case of Br and Cl is clear, but what about the
two other adjacent atoms, both C-atoms? Here, we are instructed to consider the onceremoved atoms; on the left, we find H, C, and C, and on the right H, O, and H. Each
triplet is arranged according to atomic number (A > B > C), yielding (C C > H) and
(O > H H), respectively. Comparing A with A’, B with B’, and C with C’, and
stopping at the first difference yields (O,H,H) > (C,C,H), as shown.
The case of compound 2.45 is more complex, since the once-removed atoms
C(C,C,H) and C(C,C,H) show no difference. In such a case, exploration is continued
further. The two subbranches of the left branch are arranged in the order C(Cl,H,H)
and C(H,H,H), while, for the right branch, we find C(O,C,C) and C(O,H,H).
Comparing the senior subbranches and stopping at the first difference yields
C(Cl,H,H) > C(O,C,C), and the junior subbranches need not be compared. In
summary, the left branch has preference over the right branch, and the structure has
the (S)-configuration.
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Fig. 2.10. To avoid discussions on the nature of bonds, Sequence Rule III splits double
and triple bonds into two and three single bonds, respectively. This is done by
duplicating or triplicating all doubly or triply bonded atoms, respectively, but not other
groups or atoms attached to them. The duplicated or triplicated atoms are drawn in
brackets and are considered as carrying phantom atoms of atomic number zero. This is
illustrated here for generic groups, namely a carbonyl (2.46), a cyano (2.47), and an
ethenyl group (2.48). d-Glyceraldehyde (2.22) is used as a specific example; its CHO
group is treated as C(O,(O),H) and is thus preferred to the CH2OH group treated as
C(O,H,H); hence, the absolute configuration of d-glyceraldehyde is (R) [13].
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Fig. 2.11. Aromatic rings deserve a special explanation. They are treated as Kekulé
structures (i.e., with alternating single and double bonds). For aryl groups such as
phenyl (2.49) or naphthyl, it does not matter which resonance form is used, because
splitting the double bonds gives the same results in all cases. For aromatic heterocycles,
however, each resonance form is used in turn, as shown here for the two forms of
pyridin-2-yl (2.50) where the atomic numbers (6 or 7) are written instead of the actual
atoms (C or N). Each duplicate atom is then given an atomic number that is the mean
of what it would have if the double bond were located at each of the possible positions.
Thus, we see that in two duplications the mean is 6.5 [13].
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Fig. 2.12. Compounds with two or more stereogenic centers (n 2) and an unsymmetrical constitution exist in more than two stereoisomeric forms. In Part 1, we
encountered the norephedrines (1.17 in Fig. 1.11) which are natural compounds having
two stereogenic centers (n ¼ 2), allowing for the existence of four stereoisomers (i.e.,
2n ). Each of these, as explained, has one enantiomer and shares a diastereoisomeric
relationship with the two others. As a further example, we look at linalool (2.51), a
volatile compound found in many plant tissues, a floral fragrance and a component of
perfumery substances. Its two enantiomers are oxidized in plants to a number of
linalool oxides, in particular the furanoid linalool oxide (2.52). The biochemical
reaction generates a second stereogenic center in the metabolites and yields the four
stereoisomers shown, namely a pair of trans-configured enantiomers, and a pair of cisconfigured enantiomers [35].
In Fig. 2.7, we saw the eight aldohexose stereoisomers derived from d-glyceraldehyde where n ¼ 4. It was implicit that l-glyceraldehyde would lead to eight other
stereoisomers, making it a total of 16 stereoisomers (i.e., 24 ). Aldohexoses in their open
form exist as eight pairs of enantiomers. This implies that each of the 16 stereoisomers
has one enantiomer and shares a diastereoisomeric relationship with the 14 others. An
important subgroup of diastereoisomers called epimers are those that differ in the
configuration of only one stereogenic center. Thus, d-allose (2.34 in Fig. 2.7) has four
epimers, namely d-altrose (2.35), d-glucose (2.21), d-gulose (2.37), and l-talose.
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Fig. 2.13. A further example of constitutionally unsymmetrical molecules is provided
here: menthol (n ¼ 3) and its eight stereoisomers (23 ) grouped in four pairs of
enantiomers (2(3–1)). In agreement with the above examples, each stereoisomer has one
enantiomer (opposite configuration at all stereogenic centers) and six diastereoisomers
(23 – 2), of which three (n) are epimers. Note that, for historical reasons, each pair of
enantiomers bears a distinct yet related chemical name. Thus, we have (þ)- and ( )menthol (2.53), (þ)- and ()-isomenthol (2.54), (þ)- and ( )-neomenthol (2.55), and
(þ)- and ( )-neoisomenthol (2.56), with their absolute configurations shown and
described according to the (R,S)-convention [31] [36].
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Fig. 2.14. Acyclic molecules having n stereogenic centers are called constitutionally
symmetrical when those centers equidistant from the geometrical center of the
molecule are identically substituted. Such molecules have (2(n–1) þ 2(n–2)/2 ) stereoisomers, when n is even, and 2(n–1) when n is odd. Tartaric acid (2.57) is a classical
example for n even. Its two stereogenic C-centers are identically substituted. The
dextrorotatory form has the (2R,3R)-configuration, and the levorotatory form is
(2S,3S)-configured [31]. The expected pair of (2R,3S)- and (2S,3R)-enantiomers,
however, does not exist since the molecule is bisected by a plane of symmetry (s) and is
thus achiral overall. This achiral (and hence optically inactive) stereoisomer is termed
the meso-form, and it shares a diastereoisomeric relationship with the other two
stereoisomers. In accordance with the above rule, tartaric acid exists as 2 þ 1
stereoisomers. Similarly, a constitutionally symmetrical molecule with n ¼ 4 exists as
ten stereoisomers, namely two meso-forms and four pairs of enantiomers.
For clarity, let us mention that the compound called racemic tartaric acid is not
itself a stereoisomer but a 50 : 50 mixture of the two enantiomers. This is indeed the
definition of a racemate. The issue is considered further in Fig. 2.16.
As shown in the lower part of the Figure, some cyclic molecules have structural
properties similar to those of acyclic molecules, as exemplified with 1,2-dihydroxycyclohexane (2.58). A more systematic stereochemical treatment of cyclic molecules will
be presented in Part 4.
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Fig. 2.15. When n is odd as in trihydroxyglutaric acid (2.59), the 2(n–1) rule predicts four
stereoisomers. The two stereoisomers (S,S) and (R,R) differ in their absolute
configurations at C(2) and C(4), but their central C(3)-atom carries two identical
glycolyl substituents and is thus of the type X(A,B,B,C), namely achiral and more
exactly prochiral (see Part 8). In other words, the (S,S)- and (R,R)-stereoisomers have
only two stereogenic centers, and since, they have opposite configurations at both
centers, they are enantiomers. A specific contradiction occurs with the two stereoisomers having opposite configuration at C(2) and C(4). Now C(3) carries four
different substituents, namely H, OH, (R)-glycolyl, and (S)-glycolyl (two enantiomorphic substituents; see Part 1); but the molecule is also achiral, because it has a plane of
symmetry (s) perpendicular to its main axis and cutting C(3). Due to its two
enantiomorphic substituents, C(3) may have either of two different configurations,
allowing two physically distinct, but optically inactive stereoisomers both called mesoforms. Stated differently, we now face the situation of a C-atom having four different
substituents but lying in a plane of symmetry of the molecule. Such a C-atom is called a
pseudostereogenic center (also called as pseudoasymmetric center) [11 – 13] [37 – 40].
A subrule of the Sequence Rule states that (R) > (S) and allows pseudostereogenic
centers to be treated like stereogenic centers. But because the molecule is achiral, these
centers are given the lower-case symbols (r) and (s). A more general representation of
a pseudostereogenic center is given at the bottom of the Figure, where the two mesoforms are depicted.
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Fig. 2.16. With molecules having several stereogenic centers, the chemist may face the
problem of identifying one pure enantiomer of known relative configuration but
unknown absolute configuration. The Sequence Rule prescribes to use the stereodescriptors (R*) and (S*) (R-star and S-star) to describe relative configurations
[13] [41]. In the example of 1-bromo-3-chlorocyclohexane (2.60), the chemist may
know that the two stereogenic centers have opposite absolute configurations but ignore
which is (R) and which is (S). The subrule states that the stereogenic center with the
lowest locant, i.e., C(1) here, is arbitrarily assigned (R*), while the other center(s)
become(s) (R*) or (S*) depending on its/their configuration relative to that at C(1). A
more complex example is provided [13] by 1-bromo-3-chloro-5-nitrocyclohexane (2.61)
whose relative configuration is (1R*,3R*,5R*), a cumbersome formulation when many
stereogenic centers exist, as, e.g., in steroids. In this case and as shown, it is acceptable
to use the simplified notation of rel-(1R,3R,5R).
The (R*,S*)-convention has been sometimes used to indicate the relative
configuration of racemates. This is an infelicitous and rejected practice, since the
IUPAC rules [13] recommend to use (RS) for racemates containing a single stereogenic
center. When there is more than one center, that with the lowest locant is arbitrarily
labeled (RS), and the others (RS) or (SR), depending whether they are (R)- or (S)configured, when the first is considered to have the (R)-configuration. Coming back to
tartaric acid (2.57) represented here differently from Fig. 2.14, we see that for its
racemate, the prefixes (2RS,3RS) or more simply as () are used. The prefix rac has
also been proposed [42].
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Fig. 2.17. While asymmetrically substituted C-atoms are considered as configurationally stable, this may not always be the case, depending on the functional groups on and
close to the C-atom. Similar arguments apply to asymmetric arrangements around
other atoms (see, e.g., Figs. 2.3 and 2.4) [43 – 48].
First, we reflect on the configurational instability of compounds containing a single
stereogenic center, i.e., enantiomers. The term of racemization describes the macroscopic and statistical process by which one optically active compound (be it
enantiomerically pure or impure) is irreversibly transformed to the racemic mixture,
which by definition, contains equal amounts of the two enantiomers. When starting
with a pure optically active compound, this equilibrium state is reached when one half
of the molecules have changed configuration. The rate constant of the macroscopic
reaction is known as krac , and it is identical for (R) ! rac and for (S) ! rac.
The process of enantiomerization describes the process occurring at the level of
individual molecules and is defined as the reversible conversion of one enantiomer into
the other. This configurational inversion, be it from (R) to (S), or from (S) to (R),
occurs by passing through a transition state or an intermediate product. The
corresponding rate constant, kenant , is again the same in both directions. Interestingly,
the rate constants and kinetic activation parameters (e.g., activation energy, free energy
barrier) are experimentally accessible, most notably by dynamic chromatographic
techniques [49 – 51]. Since the conversion of one molecule reduces the enantiomer
excess by two molecules, it is clear that the rate of enantiomerization is by definition
half that of racemization.
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Fig. 2.18. Racemization involving stereogenic C-centers is illustrated here with the
examples of the anorectic drug amfepramone (2.62; R ¼ Et) and its N,N-didemethylated metabolite 2.63 (R ¼ H) whose (S)-enantiomer is an amphetamine-like
stimulant found in khat (Catha edulis) and known as cathinone [52] [53]. Their rate
of racemization in aqueous solutions were found to be highly pH-dependent and to
increase ca. 1000-fold between pH 2.3 and 7.5, pointing to a base-catalyzed reaction
with Hþ abstraction. What is more, the rate increased at constant pH and ionic strength,
when the concentration of the phosphate buffer was increased. A few results at
physiological pH and 378 are presented here as half-lifes (t1/2 ) of racemization; these
were in the order of one to a few hours, demonstrating that the reactions were rather
fast and could have pharmacological implications. Taken globally, the results indicated
a general base-catalyzed SE1 mechanism as shown in the Figure [54].
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Fig. 2.19. Here, we present two extreme examples of racemization, one quite slow but
not slow enough to avoid a stability and activity problem, and the other so fast that the
separation and pharmacological testing of the separate enantiomers would be pointless
and impossible, respectively.
Atropine (2.65) is a racemic mixture of the active alkaloid ( )-(S)-hyoscyamine
((S)-2.64) and its weakly active enantiomer (R)-hyoscyamine ((R)-2.64). What is
found in plants is not atropine but an unequal mixture of (S)- and (R)-hyoscyamine
whose proportions range from 100 : 0 (in young plants) to 51 : 49 [55]. Yet what is used
in medicine is the configurationally stable atropine, since (S)-hyoscyamine solutions
undergo a slow racemization with progressive halving in therapeutic activity [45].
Atropine solutions are used extensively in ophthalmology, for example, but much of it
is stored as autoinjectors for troop protection against poisoning by organophosphate
nerve gases.
Our example of a very fast racemization is provided by the tranquillizer and
hypnotic oxazepam (2.66) [56 – 59]. The drug contains an stereogenic center at C(3)
which undergoes rapid inversion via ringchain tautomerism, namely the reversible
cleavage of the NC(OH) bond. The kinetics of racemization of oxazepam is
interesting and relevant from a pharmacological viewpoint, since it racemizes at
ambient temperature and in the neutral pH range with a pseudo-first-order rate
constant of 0.1 0.05 min1, suggesting a half-life (t1/2 ) of racemization of 1 – 4 min at
378. This rate of racemization is extremely fast compared to the duration of action of
the drug, indicating that oxazepam is correctly viewed as a single compound existing in
two very rapidly interconverting configurations.
Helvetica Chimica Acta – Vol. 96 (2013)
179
Fig. 2.20. Its sad history made thalidomide (2.67) one of the most infamous chiral
drugs, to become synonymous with tragedy following the discovery of its catastrophic
teratogenic effects in the early 1960s [48] [60] [61]. Although the mechanisms of action
of thalidomide are poorly understood, some of its activities may be related to its
capacity to inhibit the production of Tumor Necrosis Factor a (TNF-a). Considering
the fact that enantiomers can have very different pharmacological activities (see Part
5), the question arises whether the teratogenic activity of thalidomide (a racemate) was
associated with either one or both of its enantiomers. Unfortunately, findings in the
literature are confusing. The problem is complicated by the fact that the enantiomers of
thalidomide are subject to rapid racemization, as discussed below [47] [62 – 65].
Using a stereoselective HPLC assay, the racemization of both (R)- and (S)thalidomide was found to be pH-dependent, being practically nil at acidic pH. As with
amfepramone and cathinone (Fig. 2.18), the reaction was linearly dependent on
phosphate concentration, indicating a general base catalysis. Simultaneously with its
racemization, thalidomide was hydrolyzed to ring-opened products [66]. At pH 7.4 in
0.1m phosphate buffer at 378, the half-lives of racemization and hydrolysis were ca. 3
and 2 h, respectively. Human serum albumin, presumably acting as a base, also
catalyzed racemization. Because the reaction was markedly medium-dependent, care is
required when drawing conclusions on in vivo racemization from in vitro studies.
Twelve products of (non-enzymatic) hydrolysis have been reported in human urine,
only three of them retaining the intact phthalimido moiety, namely 2-phthalimidoglutaramic acid (2.68), 4-phthalimidoglutaramic acid (2.69), and 2-phthalimidoglutaric
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acid (2.70). These metabolites also showed teratogenic activity [67]. An investigation of
the teratogenic potency of the enantiomers of 2-phthalimidoglutaric acid (2.70) in
pregnant mice showed that the (S)-enantiomer caused dose-dependent teratogenicity,
whereas the (R)-enantiomer was devoid of this effect, even at four-times higher doses
[68].
The teratogenic activity of the ring-opened products of hydrolysis, 2.68, 2.69, and
2.70, called for an investigation of their configurational stability. This question was
addressed by an indirect method which revealed a complete configurational stability
over a period of 1 week at neutral pH and 378 [62]. This finding is in agreement with the
fact that a carboxylic group is known to stabilize stereogenically substituted C-atoms of
the type R’’R’RCH, as outlined in Fig. 2.22. From a toxicological viewpoint, it
indicates that the teratogenicity testing of the separated enantiomers of 2-phthalimidoglutaric acid (2.70) in pregnant mice produced reliable results. Further, the
configurational stability of the three teratogenic metabolites of thalidomide invites
reflection on a possible enantioselectivity in the teratogenicity of thalidomide. Given the
configurational stability of the three teratogenic metabolites, inversion of the
configuration at the stereogenic center must stop with the hydrolysis of thalidomide.
Thus, after administration of (S)-thalidomide the concentration of teratogenic
metabolites with (S)-configuration is postulated to be higher than after application
of (R)-thalidomide. Assuming that the teratogenic potency of the metabolites with (S)configuration is markedly greater than that of the metabolites with (R)-configuration,
as shown with 2-phthalimidoglutaric acid (2.70), it is conceivable that (R)-thalidomide
might be somewhat less teratogenic than its enantiomer.
Helvetica Chimica Acta – Vol. 96 (2013)
181
Fig. 2.21. The examples above dealt with the configurational stability of compounds
having one stereogenic center and undergoing racemization. Compounds having two
or more stereogenic centers can also undergo interconversion in a process called
epimerization if and when one of these centers is configurationally labile [47] [48]. As
shown in the Figure, the term epimerization defines the reversible interconversion of
one stereoisomer into another, as does the term enantiomerization. This type of
reaction is documented for a number of drugs and is thus of relevance in
pharmaceutical research. Since two epimers, being diastereoisomers, obligatorily
differ in their internal energy (see Part 1), it follows that, when the interconversion of
two epimers is left to proceed to equilibrium, an exact 50 : 50 ratio cannot be reached.
As a result, the rate constant of the conversion of epimer A to epimer B must be
different from that of the reverse reaction, the magnitude of the difference depending
on the thermodynamic profile of the two reactions. The two rate constants of
epimerization are designated here as kepim[(R,R)!(R,S)] and kepim[(R,S)!(R,R)] , and they are
perforce different. Note that some diastereoisomers other than epimers are also known
to undergo interconversion, in which cases the process is called diastereoisomerization.
Here, we take the alkaloid drug pilocarpine (2.71), used in ophthalmology to dilate
the pupil, as a pharmaceutically relevant example. Its absolute configuration is (2S,3R)cis and it epimerizes to (2R,3R)-trans-isopilocarpine (2.72) by inversion of the
configuration at C(2). Both compounds are dextrorotatory, and only pilocarpine is
pharmacologically active. In addition, pilocarpine undergoes reversible hydrolytic
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lactone ring opening to pilocarpic acid (2.73), whereas isopilocarpic acid (2.74) is
produced reversibly from isopilocarpine. Detailed mechanistic and kinetic studies have
revealed HO-ion-catalyzed epimerization and hydrolytic ring opening [69] [70]. From
the data, one can estimate a pseudo-first-order rate constant of pilocarpine
disappearance (epimerization to isopilocarpine plus hydrolysis to pilocarpic acid)
corresponding to a half-life (t1/2 ) of ca. 36 days at pH 7.4 and 358. Of mechanistic
importance is the fact that neither pilocarpic acid nor isopilocarpic acid can epimerize,
due to the presence of the free COO group which acts as a strong configurational
stabilizer. The percent of pilocarpine at or near equilibrium having undergone
epimerization to isopilocarpine was found to be ca. 20% at room temperature.
Activation energies of ca. 120 and 105 kJ/mol were calculated for the reactions of
pilocarpine epimerization and hydrolysis, respectively, indicating a higher energy
barrier for epimerization than for hydrolysis. The trend for an increasing proportion of
isopilocarpine (2.72) being formed relative to pilocarpic acid (2.73) as temperature
increases is verified among others by the respective half-lives of epimerization and
hydrolysis of pilocarpine at pH 5.7, which were 630 and 80 days (ratio 7.9) at 408
compared to 8 and 2.4 days (ratio 3.3) at 808 [70]. This trend was also confirmed by the
finding that, during sterilization, epimerization predominated over hydrolysis, whereas
storage at room temperature favored hydrolysis [71]. From a practical and pharmaceutical viewpoint, the above data imply that both reactions can contribute to a
decreased activity of pilocarpine solutions following sterilization and inadequate
storage. As for the back-epimerization of isopilocarpine (2.72), it was detectable but
too slow to be measurable with good precision, ca. 1% of pilocarpine being formed
from isopilocarpine at pH 5.9 and 608 [70]. This was due to trans-configured
isopilocarpine being intrinsically of lower internal energy than cis-configurated
pilocarpine (see Part 4).
Helvetica Chimica Acta – Vol. 96 (2013)
183
Fig. 2.22. The above examples and others in the literature allow a preliminary
generalization of the structural factors causing configurational instability at a stereogenically substituted C-atom of the type R’’’R’’R’CH. Configurational inversion at
such centers is catalyzed by the HO anion (specific base catalysis) and in several cases
also by other bases (general base catalysis), and it involves the deprotonated form (i.e.,
the carbanion R’’’R’’R’C ) as intermediate. It thus appears convenient to distinguish
between acid-strengthening, neutral, and acid-weakening substituents [45] [72 – 74].
Substituents in the former group usually act by stabilizing the carbanion, but
stereoelectronic effects on the substrate or transition state should not be neglected.
Two types of acid-strengthening groups are frequently involved in labilizing a
stereogenically substituted C-atom by favoring its deprotonation, namely a carbonyl
function and an aryl group, often potentiating each other as seen with amfepramone,
cathinone, and hyoscyamine (Figs. 2.18 and 2.19). An amino or amido group may also
be found, as seen in Figs. 2.18 – 2.20. To be of relevance (see next Fig.), configurational
instability appears to require the presence of at least one strong carbanion-stabilizing
substituent at the stereogenic center, and the absence of any acid-weakening group. A
preliminary list of such groups based on available evidence is presented here in tabular
form [45] [48]; question marks indicate the absence of enough examples. Much
additional quantitative work would be needed to confirm some of the above results, to
complete the table and arrive at a ranking of the listed groups, to offer rules for
quantitative prediction, and, from a mechanistic viewpoint, to assess the relative
importance of mesomeric and inductive contributions.
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Fig. 2.23. An important aspect to be taken into account when considering the
configurational lability of stereoisomers is its significance in drug research and
development. First, one should always bear in mind that configurational stability and
lability are relative phenomena. Under the appropriate conditions of temperature, pH
etc., no stereoisomer is configurationally stable. However, only two time scales (and
their related sets of conditions) are of relevance as far as drugs are concerned [47] [48].
As schematized in the Figure, the pharmacological time scale applies to the time of
residence of a drug in the body and under physiological conditions (378, pH 7.4). A
half-life of isomerization of several months is no longer of importance in pharmacology
and therapy, while very fast rates of isomerization (in the order of minutes, e.g.,
oxazepam) are of interest only for drugreceptor or drugenzyme interactions. Halflives of isomerization in the order of weeks, months, or a few years are important in a
pharmaceutical and formulation perspective, i.e., compared to the duration of the
manufacturing process and the shelf-life of drugs. This is the pharmaceutical time scale,
which applies to the manufacturing process and to the shelf-life of medicines, as
illustrated above with hyoscyamine and pilocarpine.
The author is indebted to his former colleague Dr. Antoine Daina, University of Geneva, for help
with the bibliography.
Helvetica Chimica Acta – Vol. 96 (2013)
185
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Received August 14, 2012