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REVIEW

Organic StereochemistryPart 21)

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 thatmost important of stereogenic elements, namely the stereogenic center, as found in amajority of stereoisomers. The presentation is restricted to chiral tetrahedral structures,which contain the most important stereogenic centers in molecules of biologicalrelevance. These are either tetracoordinate or tricoordinate centers where an electronlone pair plays the role of the fourth substituent. The nature of the central element insuch structures, e.g., carbon, nitrogen, or sulfur, obviously plays an essential role in theirgeometry.

Our main focus in this review are the two rule-based conventions used to encodewith adequate descriptors the absolute three-dimensional (3D) geometry of stereogeniccenters. By absolute 3D geometry, stereochemists understand an unambiguousdescription of the sense of chirality (stereogenicity) of a center with reference to theobserver and based on the universal left-hand/right-hand discrimination.

With single stereogenic centers and the general principle of enantioselectiveprocesses explained and illustrated, the fundament will be laid to consider thestereochemistry of molecules containing two or more stereogenic centers. When there isa single stereogenic center, the compound will exist as enantiomers, namely a pair ofstructures related to each other as non-superimposable mirror images. When two ormore stereogenic centers are present, the result may be another steric relation betweenmolecules known as diastereoisomerism. The discrimination between enantiomeric anddiastereoisomeric 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 stereogenicelements, namely axes and planes of chirality, helicity, and (E,Z)-diastereoisomerism,followed in turn by a presentation of isomerisms about single bonds and in cyclicsystems in Part 4. Only then, with the principles of stereoisomerism discussed, will webe able to consider their impact on pharmacology, biochemistry, and xenobioticmetabolism. This will still leave us with just one last facet of stereochemistry toconsider, the all important concept of prostereoisomerism and its key role inendogenous and exogenous metabolism (Part 8).

Helvetica Chimica Acta – Vol. 96 (2013) 159

� 2013 Verlag Helvetica Chimica Acta AG, Z�rich

1) For the other Parts, see Helv. Chim. Acta 2013, 96, 1 – 3.

Helvetica Chimica Acta – Vol. 96 (2013)160

Fig. 2.1. This second review in the series begins by looking at compounds characterizedby a single stereogenic center and hence having a non-superimposable mirror imagewith which they form a pair of enantiomers [1 – 16]. The focus will be on chiraltetrahedral structures, namely a) with tetracoordinate centers, and b) with tricoordinatecenters where an electron lone pair plays the role of the fourth substituent. Followingan overview of the main tetrahedral structures of interest, the review goes on to explainthe two dominant convention systems, namely the d,l- and the (R,S)-conventions, thelatter being known as the CIP (Cahn�Ingold�Prelog) convention. These are systemsbased on rigorous rules and allow an absolute descriptions of molecular structures in3D space, i.e., description that yields an identical outcome for all observers. As we willsee, both conventions have their advantages, although the CIP convention is muchbroader, far more complete, and devoid of ambiguity. The review continues with thecase of compounds with two or more stereogenic centers, which result in the emergenceof diastereoisomeric relationships. As a result, we will encounter compounds whosestructures allow the simultaneous occurrence of enantiomeric and diastereoisomericrelationships.

This review will end with a qualitative discussion of the comparative configura-tional stability of C-centered chiral tetrahedral structures, which, as we will see, range

from the extremely stable to the very labile.


Fig. 2.2. Tetrahedral chemical structures contain a central atom X at the geometricalcenter of a tetrahedron, to which are attached four atoms or substituents (A, B, C, andD) each occupying one of the vertices of the tetrahedron. If the four atoms orsubstituents are different from each other as in 2.1, the generic structure is chiral. Such atetracoordinate assembly is indeed asymmetric (point group C1) and occurs in twostereoisomeric forms which form an enantiomeric pair. A comparable situation isdepicted with the generic structures 2.2. Here, there are only three atoms or substituentsattached to X, making it a tricoordinate assembly. However, if the central atom (e.g., S-atom, N-atom) possesses an electron lone pair, this will function as a virtual ligandpointing to the fourth vertex of the tetrahedron [17]. With three different atoms orsubstituents A, B, and C, and provided the chemical nature of X allows sufficientstability of such an arrangement, two enantiomers can indeed be characterized andisolated.

Should the four atoms or substituents fail to occupy the vertices of a tetrahedronand be, for example, coplanar with the central atom, a non-dissymmetric structure isobtained [18]. This is illustrated here with the well-known anticancer drug cisplatin(2.3) which shares a diastereoisomeric relationship with transplatin (2.4). Note alsothat we will not extend the current presentation to more complex structures such aspentacoordinate centers as exemplified with the trigonal-bipyramidal structure of thegeneric phosphorus(V) compound 2.5. With five different substituents, such a structure

can conceivably exist as ten diastereoisomeric pairs of enantiomers [19]!


Fig. 2.3. This Figure illustrates some chiral generic structures having as their centralatom a first- or second-row element of columns IVA and VIA in the periodic table ofchemical 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 adissymmetric mass distribution, the smallest possible one in fact, and its synthesis andabsolute-configuration assignment proved to be at the very limit of what wastheoretically and experimentally possible at the time [20] [21]. The rest of the Figureinstructs us that carbanions with a lone pair, 2.7, racemize readily, whereas carbonradicals, 2.8, and carbonium ions, 2.9, which both lack a virtual fourth ligand, areusually 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, andsulfoxides, 2.13, have rather stable trisubstituted centers [23]. The higher configura-tional stability of second-row atoms compared to first-row atoms is clear from these

generic examples.


Fig. 2.4. Moving to column VA of the periodic table, we encounter the elementsnitrogen and phosphorus which again demonstrate the difference in configurationalstability between first- and second-row atoms. Indeed, fast inversion is the rule foramines, 2.14, [24 – 26], but the molecular environment also plays a role. Fast inversion isalso 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 inresolving Trçger�s 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.


Fig. 2.5 – 2.7. A need for consistency in stereochemical designation prompted EmilFischer to use C(5) of the dextrorotatory enantiomer of glucose (2.21) as a startingpoint. First, the molecule was drawn based on the following conventions: a) the longestC-chain is vertical; b) the most highly oxidized end of the chain is at the top; c) at eachcenter along the main chain, the vertical bonds point backwards and the horizontalbonds point toward the observer; and d) the central tetrahedral C-atom(s) can beomitted, an option not followed here for better clarity. (þ)-Glucose was degraded byFischer to the aldotriose (þ)-glyceraldehyde in which the only stereogenic centeroriginates from C(5) of the parent molecule. Arbitrarily, Fischer assigned the depictedconfiguration to (þ)-glyceraldehyde, which became (þ)-d-glyceraldehyde (2.22) due tothe right-hand-side position of the substituent at the stereogenic center (and not due toits optical rotation as still believed by some!). As a result, (� )-l-glyceraldehyde wasassigned the configuration shown in 2.23. All molecules that could be chemicallyrelated to d-glyceraldehyde were assigned the d-configuration, as illustrated inFigs. 2.6 and 2.7, while molecules related to (�)-l-glyceraldehyde (2.23) were assignedto the l-series. This assignment is based on chemical transformations that do not breakany bond to the highest-numbered stereogenic C-atom [5 – 15] [29]. Thus, the aldosesrelated to d-glyceraldehyde include the two aldotetroses d-erythrose (2.28) and d-

threose (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].


Whereas this convention proved useful for carbohydrates, conflicting results arose withother 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 alcoholand finally reductive debromination. To partly overcome such difficulties, theprojection convention came into use. This convention distinguishes itself from theconvention discussed above in that no reference is made to the chemical affiliation ofthe compound under examination. The latter is simply drawn in the Fischer projectionand 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. Theprojection convention is thus restricted to those molecules that can be unambiguouslydrawn in the Fischer projection, and which can also obey all relevant rules.

Further difficulties arose for distinct chemical classes such as phenylethylamineswhich are conventionally drawn �upside down�. Another problem arose with the aminoacids, the natural configuration of which is l as shown with the generic structure 2.26when R=H (R¼H is glycine, the only non-chiral natural amino acid). The majority ofnatural amino acids contain only one stereogenic center and are easily designatedaccording to the carbohydrate rules, for example, l-serine (2.26, R¼CH2OH).However, the case of threonine (2.27) is inconsistent, because its highest-numberedstereogenic C-atom center has the d-configuration, and designating it as �d-threonine�created a discrepancy with serine. The compound is thus designated as ls-threonine(2.27) where the subscript �s� indicates the serine series; the subscript �g� is then used forthe glyceraldehyde series.

The most important point to be made here is that the d,l-convention as originallyconceived and proposed by Fischer described relative configurations. In other words,there was no way to decide if all stereochemical representations reflected reality orwere objects in a mirror-universe. It was not until 1951 that publications based on the X-ray-analysis of sodium rubidium (þ)-tartrate tetrahydrate afforded an experimentalbasis for absolute configurations and showed Fischer�s gamble to have hit the correctanswer.

A further problem exists, especially in the medical literature where non-chemistauthors 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 theabove, the rapid experimental and conceptual progress in stereochemistry in the firsthalf of the 20th Century made it urgent to rely on an (ideally) universal andunambiguous description of the absolute configuration at stereogenic centers and other

stereogenic elements.


Fig. 2.6.

Fig. 2.7.


Fig. 2.8. The foundation of a new convention was laid in 1951 by Cahn and Ingold, andexpanded and clarified by Cahn, Ingold, and Prelog [5 – 15] [32 – 34]. The convention isoften referred to as the CIP System and consists in two parts, namely a) the sequencerule, which defines the ranking of the four vertices of a tetrahedron (namely thesubstituents A>B>C>D) according to a set of arbitrary but consistent subrules, andb) a rule which specifies that rotation is from A to B to C, when these point toward theviewer while D points away. The two possible arrangements are illustrated in the upperpart of the Figure, where a clockwise course is shown to translate into the (R)-configuration (2.41; Latin rectus, right), and a counterclockwise (anticlockwise) courseinto the (S)-configuration (2.42 ; Latin sinister, left). The comparison with a spinningwheel can help explain the circular path from A to B to C.

The sequence rule begins by considering the four atoms linked to the stereogeniccenter. These are ranked in an order of preference which decreases with decreasingatomic number ; isotopes are ranked according to decreasing mass number, while a loneelectron pair is considered a phantom atom with atomic number zero. The twostructures at the bottom of the Figure provide partial applications. In particular, we cannow understand how the configuration of the deuterated neopentane 2.6 in Fig. 2.3 wasdefined as (R). The case of (S)-ethyl methyl sulfoxide (2.43) involves an additional

subrule to explain why ethyl>methyl.


Fig. 2.9. The example of (R)-2-bromo-2-chloro-3-methylbutan-1-ol (2.44) is used toanswer the above question. Indeed, the case of Br and Cl is clear, but what about thetwo other adjacent atoms, both C-atoms? Here, we are instructed to consider the once-removed atoms ; on the left, we find H, C, and C, and on the right H, O, and H. Eachtriplet 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’, andstopping 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 atomsC(C,C,H) and C(C,C,H) show no difference. In such a case, exploration is continuedfurther. 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 yieldsC(Cl,H,H)>C(O,C,C), and the junior subbranches need not be compared. Insummary, the left branch has preference over the right branch, and the structure has

the (S)-configuration.


Fig. 2.10. To avoid discussions on the nature of bonds, Sequence Rule III splits doubleand triple bonds into two and three single bonds, respectively. This is done byduplicating or triplicating all doubly or triply bonded atoms, respectively, but not othergroups or atoms attached to them. The duplicated or triplicated atoms are drawn inbrackets and are considered as carrying phantom atoms of atomic number zero. This isillustrated here for generic groups, namely a carbonyl (2.46), a cyano (2.47), and anethenyl group (2.48). d-Glyceraldehyde (2.22) is used as a specific example; its CHOgroup 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].


Fig. 2.11. Aromatic rings deserve a special explanation. They are treated as Kekulestructures (i.e., with alternating single and double bonds). For aryl groups such asphenyl (2.49) or naphthyl, it does not matter which resonance form is used, becausesplitting 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 ofpyridin-2-yl (2.50) where the atomic numbers (6 or 7) are written instead of the actualatoms (C or N). Each duplicate atom is then given an atomic number that is the meanof 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].


Fig. 2.12. Compounds with two or more stereogenic centers (n� 2) and an unsym-metrical constitution exist in more than two stereoisomeric forms. In Part 1, weencountered the norephedrines (1.17 in Fig. 1.11) which are natural compounds havingtwo 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 diastereoisomericrelationship with the two others. As a further example, we look at linalool (2.51), avolatile compound found in many plant tissues, a floral fragrance and a component ofperfumery substances. Its two enantiomers are oxidized in plants to a number oflinalool oxides, in particular the furanoid linalool oxide (2.52). The biochemicalreaction generates a second stereogenic center in the metabolites and yields the fourstereoisomers shown, namely a pair of trans-configured enantiomers, and a pair of cis-configured enantiomers [35].

In Fig. 2.7, we saw the eight aldohexose stereoisomers derived from d-glyceralde-hyde where n¼ 4. It was implicit that l-glyceraldehyde would lead to eight otherstereoisomers, making it a total of 16 stereoisomers (i.e., 24). Aldohexoses in their openform exist as eight pairs of enantiomers. This implies that each of the 16 stereoisomershas one enantiomer and shares a diastereoisomeric relationship with the 14 others. Animportant subgroup of diastereoisomers called epimers are those that differ in theconfiguration 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.


Fig. 2.13. A further example of constitutionally unsymmetrical molecules is providedhere: menthol (n¼ 3) and its eight stereoisomers (23) grouped in four pairs ofenantiomers (2(3–1)) . In agreement with the above examples, each stereoisomer has oneenantiomer (opposite configuration at all stereogenic centers) and six diastereoisomers(23 – 2), of which three (n) are epimers. Note that, for historical reasons, each pair ofenantiomers 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].


Fig. 2.14. Acyclic molecules having n stereogenic centers are called constitutionallysymmetrical when those centers equidistant from the geometrical center of themolecule are identically substituted. Such molecules have (2(n–1)þ 2(n–2)/2) stereo-isomers, when n is even, and 2(n–1) when n is odd. Tartaric acid (2.57) is a classicalexample for n even. Its two stereogenic C-centers are identically substituted. Thedextrorotatory 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 isthus achiral overall. This achiral (and hence optically inactive) stereoisomer is termedthe meso-form, and it shares a diastereoisomeric relationship with the other twostereoisomers. In accordance with the above rule, tartaric acid exists as 2þ 1stereoisomers. Similarly, a constitutionally symmetrical molecule with n¼ 4 exists asten stereoisomers, namely two meso-forms and four pairs of enantiomers.

For clarity, let us mention that the compound called �racemic tartaric acid� is notitself a stereoisomer but a 50 :50 mixture of the two enantiomers. This is indeed thedefinition 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 structuralproperties similar to those of acyclic molecules, as exemplified with 1,2-dihydroxycy-clohexane (2.58). A more systematic stereochemical treatment of cyclic molecules will

be presented in Part 4.


Fig. 2.15. When n is odd as in trihydroxyglutaric acid (2.59), the 2(n–1) rule predicts fourstereoisomers. The two stereoisomers (S,S) and (R,R) differ in their absoluteconfigurations at C(2) and C(4), but their central C(3)-atom carries two identicalglycolyl substituents and is thus of the type X(A,B,B,C), namely achiral and moreexactly prochiral (see Part 8). In other words, the (S,S)- and (R,R)-stereoisomers haveonly two stereogenic centers, and since, they have opposite configurations at bothcenters, they are enantiomers. A specific contradiction occurs with the two stereo-isomers having opposite configuration at C(2) and C(4). Now C(3) carries fourdifferent substituents, namely H, OH, (R)-glycolyl, and (S)-glycolyl (two enantiomor-phic substituents; see Part 1); but the molecule is also achiral, because it has a plane ofsymmetry (s) perpendicular to its main axis and cutting C(3). Due to its twoenantiomorphic substituents, C(3) may have either of two different configurations,allowing two physically distinct, but optically inactive stereoisomers both called meso-forms. Stated differently, we now face the situation of a C-atom having four differentsubstituents but lying in a plane of symmetry of the molecule. Such a C-atom is called apseudostereogenic center (also called as pseudoasymmetric center) [11 – 13] [37 – 40].A subrule of the Sequence Rule states that (R)> (S) and allows pseudostereogeniccenters to be treated like stereogenic centers. But because the molecule is achiral, thesecenters are given the lower-case symbols (r) and (s). A more general representation ofa pseudostereogenic center is given at the bottom of the Figure, where the two meso-

forms are depicted.


Fig. 2.16. With molecules having several stereogenic centers, the chemist may face theproblem of identifying one pure enantiomer of known relative configuration butunknown absolute configuration. The Sequence Rule prescribes to use the stereo-descriptors (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 mayknow that the two stereogenic centers have opposite absolute configurations but ignorewhich is (R) and which is (S). The subrule states that the stereogenic center with thelowest 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). Amore 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 manystereogenic centers exist, as, e.g., in steroids. In this case and as shown, it is acceptableto use the simplified notation of rel-(1R,3R,5R).

The (R*,S*)-convention has been sometimes used to indicate the relativeconfiguration of racemates. This is an infelicitous and rejected practice, since theIUPAC rules [13] recommend to use (RS) for racemates containing a single stereogeniccenter. When there is more than one center, that with the lowest locant is arbitrarilylabeled (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 totartaric acid (2.57) represented here differently from Fig. 2.14, we see that for itsracemate, the prefixes (2RS,3RS) or more simply as (�) are used. The prefix rac has

also been proposed [42].


Fig. 2.17. While asymmetrically substituted C-atoms are considered as configuration-ally stable, this may not always be the case, depending on the functional groups on andclose to the C-atom. Similar arguments apply to asymmetric arrangements aroundother atoms (see, e.g., Figs. 2.3 and 2.4) [43 – 48].

First, we reflect on the configurational instability of compounds containing a singlestereogenic center, i.e., enantiomers. The term of racemization describes the macro-scopic and statistical process by which one optically active compound (be itenantiomerically pure or impure) is irreversibly transformed to the racemic mixture,which by definition, contains equal amounts of the two enantiomers. When startingwith a pure optically active compound, this equilibrium state is reached when one halfof the molecules have changed configuration. The rate constant of the macroscopicreaction 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 ofindividual molecules and is defined as the reversible conversion of one enantiomer intothe 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. Thecorresponding rate constant, kenant , is again the same in both directions. Interestingly,the rate constants and kinetic activation parameters (e.g., activation energy, free energybarrier) are experimentally accessible, most notably by dynamic chromatographictechniques [49 – 51]. Since the conversion of one molecule reduces the enantiomerexcess by two molecules, it is clear that the rate of enantiomerization is by definition

half that of racemization.


Fig. 2.18. Racemization involving stereogenic C-centers is illustrated here with theexamples of the anorectic drug amfepramone (2.62 ; R¼Et) and its N,N-didemeth-ylated metabolite 2.63 (R¼H) whose (S)-enantiomer is an amphetamine-likestimulant found in khat (Catha edulis) and known as cathinone [52] [53]. Their rateof racemization in aqueous solutions were found to be highly pH-dependent and toincrease ca. 1000-fold between pH 2.3 and 7.5, pointing to a base-catalyzed reactionwith 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 atphysiological pH and 378 are presented here as half-lifes (t1/2) of racemization; thesewere in the order of one to a few hours, demonstrating that the reactions were ratherfast and could have pharmacological implications. Taken globally, the results indicated

a general base-catalyzed SE1 mechanism as shown in the Figure [54].


Fig. 2.19. Here, we present two extreme examples of racemization, one quite slow butnot slow enough to avoid a stability and activity problem, and the other so fast that theseparation and pharmacological testing of the separate enantiomers would be pointlessand 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 isfound in plants is not atropine but an unequal mixture of (S)- and (R)-hyoscyaminewhose proportions range from 100 :0 (in young plants) to 51 :49 [55]. Yet what is usedin medicine is the configurationally stable atropine, since (S)-hyoscyamine solutionsundergo a slow racemization with progressive halving in therapeutic activity [45].Atropine solutions are used extensively in ophthalmology, for example, but much of itis stored as autoinjectors for troop protection against poisoning by organophosphatenerve gases.

Our example of a very fast racemization is provided by the tranquillizer andhypnotic oxazepam (2.66) [56 – 59]. The drug contains an stereogenic center at C(3)which undergoes rapid inversion via ring�chain tautomerism, namely the reversiblecleavage of the N�C(OH) bond. The kinetics of racemization of oxazepam isinteresting and relevant from a pharmacological viewpoint, since it racemizes atambient temperature and in the neutral pH range with a pseudo-first-order rateconstant of 0.1� 0.05 min�1, suggesting a half-life (t1/2) of racemization of 1 – 4 min at378. This rate of racemization is extremely fast compared to the duration of action ofthe drug, indicating that oxazepam is correctly viewed as a single compound existing in

two very rapidly interconverting configurations.


Fig. 2.20. Its sad history made thalidomide (2.67) one of the most infamous chiraldrugs, to become synonymous with tragedy following the discovery of its catastrophicteratogenic effects in the early 1960s [48] [60] [61]. Although the mechanisms of actionof thalidomide are poorly understood, some of its activities may be related to itscapacity to inhibit the production of Tumor Necrosis Factor a (TNF-a). Consideringthe fact that enantiomers can have very different pharmacological activities (see Part5), the question arises whether the teratogenic activity of thalidomide (a racemate) wasassociated with either one or both of its enantiomers. Unfortunately, findings in theliterature are confusing. The problem is complicated by the fact that the enantiomers ofthalidomide 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 withamfepramone and cathinone (Fig. 2.18), the reaction was linearly dependent onphosphate concentration, indicating a general base catalysis. Simultaneously with itsracemization, thalidomide was hydrolyzed to ring-opened products [66]. At pH 7.4 in0.1m phosphate buffer at 378, the half-lives of racemization and hydrolysis were ca. 3and 2 h, respectively. Human serum albumin, presumably acting as a base, alsocatalyzed racemization. Because the reaction was markedly medium-dependent, care isrequired 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-phthalimidoglu-taramic acid (2.68), 4-phthalimidoglutaramic acid (2.69), and 2-phthalimidoglutaric


acid (2.70). These metabolites also showed teratogenic activity [67]. An investigation ofthe teratogenic potency of the enantiomers of 2-phthalimidoglutaric acid (2.70) inpregnant 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, and2.70, called for an investigation of their configurational stability. This question wasaddressed by an indirect method which revealed a complete configurational stabilityover a period of 1 week at neutral pH and 378 [62]. This finding is in agreement with thefact that a carboxylic group is known to stabilize stereogenically substituted C-atoms ofthe type R’’R’RC�H, as outlined in Fig. 2.22. From a toxicological viewpoint, itindicates that the teratogenicity testing of the separated enantiomers of 2-phthalimi-doglutaric acid (2.70) in pregnant mice produced reliable results. Further, theconfigurational stability of the three teratogenic metabolites of thalidomide invitesreflection on a possible enantioselectivity in the teratogenicity of thalidomide. Given theconfigurational stability of the three teratogenic metabolites, inversion of theconfiguration at the stereogenic center must stop with the hydrolysis of thalidomide.Thus, after administration of (S)-thalidomide the concentration of teratogenicmetabolites with (S)-configuration is postulated to be higher than after applicationof (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.


Fig. 2.21. The examples above dealt with the configurational stability of compoundshaving one stereogenic center and undergoing racemization. Compounds having twoor more stereogenic centers can also undergo interconversion in a process calledepimerization if and when one of these centers is configurationally labile [47] [48]. Asshown in the Figure, the term epimerization defines the reversible interconversion ofone stereoisomer into another, as does the term enantiomerization. This type ofreaction is documented for a number of drugs and is thus of relevance inpharmaceutical research. Since two epimers, being diastereoisomers, obligatorilydiffer in their internal energy (see Part 1), it follows that, when the interconversion oftwo 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 bedifferent from that of the reverse reaction, the magnitude of the difference dependingon the thermodynamic profile of the two reactions. The two rate constants ofepimerization are designated here as kepim[(R,R)!(R,S)] and kepim[(R,S)!(R,R)] , and they areperforce different. Note that some diastereoisomers other than epimers are also knownto undergo interconversion, in which cases the process is called diastereoisomerization.

Here, we take the alkaloid drug pilocarpine (2.71), used in ophthalmology to dilatethe 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 theconfiguration at C(2). Both compounds are dextrorotatory, and only pilocarpine ispharmacologically active. In addition, pilocarpine undergoes reversible hydrolytic


lactone ring opening to pilocarpic acid (2.73), whereas isopilocarpic acid (2.74) isproduced reversibly from isopilocarpine. Detailed mechanistic and kinetic studies haverevealed HO�-ion-catalyzed epimerization and hydrolytic ring opening [69] [70]. Fromthe data, one can estimate a pseudo-first-order rate constant of pilocarpinedisappearance (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 mechanisticimportance 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 configurationalstabilizer. The percent of pilocarpine at or near equilibrium having undergoneepimerization 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 ofpilocarpine epimerization and hydrolysis, respectively, indicating a higher energybarrier for epimerization than for hydrolysis. The trend for an increasing proportion ofisopilocarpine (2.72) being formed relative to pilocarpic acid (2.73) as temperatureincreases is verified among others by the respective half-lives of epimerization andhydrolysis of pilocarpine at pH 5.7, which were 630 and 80 days (ratio 7.9) at 408compared to 8 and 2.4 days (ratio 3.3) at 808 [70]. This trend was also confirmed by thefinding that, during sterilization, epimerization predominated over hydrolysis, whereasstorage at room temperature favored hydrolysis [71]. From a practical and pharma-ceutical viewpoint, the above data imply that both reactions can contribute to adecreased activity of pilocarpine solutions following sterilization and inadequatestorage. As for the back-epimerization of isopilocarpine (2.72), it was detectable buttoo slow to be measurable with good precision, ca. 1% of pilocarpine being formedfrom isopilocarpine at pH 5.9 and 608 [70]. This was due to trans-configuredisopilocarpine being intrinsically of lower internal energy than cis-configurated

pilocarpine (see Part 4).


Fig. 2.22. The above examples and others in the literature allow a preliminarygeneralization of the structural factors causing configurational instability at a stereo-genically substituted C-atom of the type R’’’R’’R’C�H. Configurational inversion atsuch centers is catalyzed by the HO� anion (specific base catalysis) and in several casesalso 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 distinguishbetween acid-strengthening, neutral, and acid-weakening substituents [45] [72 – 74].Substituents in the former group usually act by stabilizing the carbanion, butstereoelectronic effects on the substrate or transition state should not be neglected.Two types of acid-strengthening groups are frequently involved in labilizing astereogenically substituted C-atom by favoring its deprotonation, namely a carbonylfunction 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 alsobe found, as seen in Figs. 2.18 – 2.20. To be of relevance (see next Fig.), configurationalinstability appears to require the presence of at least one strong carbanion-stabilizingsubstituent at the stereogenic center, and the absence of any acid-weakening group. Apreliminary list of such groups based on available evidence is presented here in tabularform [45] [48]; question marks indicate the absence of enough examples. Muchadditional quantitative work would be needed to confirm some of the above results, tocomplete the table and arrive at a ranking of the listed groups, to offer rules forquantitative prediction, and, from a mechanistic viewpoint, to assess the relative

importance of mesomeric and inductive contributions.

The author is indebted to his former colleague Dr. Antoine Daina, University of Geneva, for helpwith the bibliography.


Fig. 2.23. An important aspect to be taken into account when considering theconfigurational lability of stereoisomers is its significance in drug research anddevelopment. First, one should always bear in mind that configurational stability andlability are relative phenomena. Under the appropriate conditions of temperature, pHetc., no stereoisomer is configurationally stable. However, only two time scales (andtheir 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 ofresidence of a drug in the body and under physiological conditions (378, pH 7.4). Ahalf-life of isomerization of several months is no longer of importance in pharmacologyand therapy, while very fast rates of isomerization (in the order of minutes, e.g.,oxazepam) are of interest only for drug�receptor or drug�enzyme interactions. Half-lives of isomerization in the order of weeks, months, or a few years are important in apharmaceutical and formulation perspective, i.e., compared to the duration of themanufacturing 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.

REFERENCES

[1] J. P. Riehl, �Mirror-Image Asymmetry. An Introduction to the Origin and Consequences ofChirality�, John Wiley & Sons, Hoboken, 2010, 210 p.

[2] G. H. Wagniere, �On Chirality and the Universal Asymmetry�, Verlag Helvetica Chimica Acta,Z�rich, and Wiley-VCH, Weinheim, 2007, 247 p.

[3] C. McManus, �Right Hand, Left Hand�, Phoenix, London, 2003, 460 p.[4] D. G. Morris, �Stereochemistry�, The Royal Society of Chemistry, London, 2001, 170 p.[5] E. L. Eliel, S. H. Wilen, M. P. Doyle, �Basic Organic Stereochemistry�, John Wiley & Sons, 2001,

704 p.[6] E. L. Eliel, S. H. Wilen, �Stereochemistry of Organic Compounds�, John Wiley & Sons, 1994, 1267 p.[7] B. Testa, �The Geometry of Molecules: Basic Principles and Nomenclatures�, in �Stereochemistry�,

Ed. C. Tamm, Elsevier, Amsterdam, 1982, pp. 1 – 47.[8] B. Testa, �Principles of Organic Stereochemistry�, Dekker, New York, 1979, 248 p.[9] F. D. Gunstone, �Guidebook to Stereochemistry�, Longman, London, 1975, 110 p.

[10] K. Mislow, �Introduction to Stereochemistry�, Benjamin, New York, 1966, 193 p.[11] International Union of Pure and Applied Chemistry (IUPAC), Organic Chemistry Division, �Basic

Terminology of Stereochemistry�, http://www.chem.qmul.ac.uk/iupac/stereo/, last accessed January2013.

[12] International Union of Pure and Applied Chemistry (IUPAC), �Recommendations 1996 – BasicTerminology of Stereochemistry�, Pure Appl. Chem. 1996, 68, 2193 – 2222.

[13] International Union of Pure and Applied Chemistry (IUPAC), Organic Chemistry Division, �Rulesfor the Nomenclature of Organic Chemistry – Section E: Stereochemistry�, Pure Appl. Chem. 1976, 45,13 – 30.

[14] International Union of Pure and Applied Chemistry (IUPAC), �Commission on Nomenclature ofOrganic Chemistry. A Guide to IUPAC Nomenclature of Organic Compounds (Recommendations1993)�, Blackwell Scientific Publications, Oxford, 1993.

[15] International Union of Pure and Applied Chemistry (IUPAC), �Nomenclature of OrganicChemistry, Sections A, B, C, D, E, F, and H�, Pergamon Press, Oxford, 1979.

[16] A. D. McNaught, A. Wilkinson, �Compendium of Chemical Terminology�, 2nd edn. (the IUPAC�Gold Book�), Blackwell Scientific Publications, Oxford, 1997; XML on-line corrected version,http://goldbook.iupac.org (last accessed December 2012) created by M. Nic, J. Jirat, B. Kosata;updates compiled by A. Jenkins, doi: 10.1351/goldbook.

[17] H. D. B. Jenkins, T. C. Waddington, �Lone Electron Pairs and Stereochemistry�, Nature 1975, 255,623.

[18] S. Fujita, �Chirality and Stereogenicity of Square-Planar Complexes�, Helv. Chim. Acta 2002, 85,2440 – 2457.

[19] M. J. Gallagher, I. D. Jenkins, �Stereochemical Aspects of Phosphorus Chemistry�, Topics Stereochem.1968, 3, 1 – 96.

[20] J. Haesler, I. Schindelholz, E. Riguet, C. G. Bochet, W. Hug, �Absolute Configuration of ChirallyDeuterated Neopentane�, Nature 2007, 446, 526 – 529.

[21] D. Arigoni, E. L. Eliel, �Chirality Due to the Presence of Hydrogen Isotopes at Noncyclic Positions�,Topics Stereochem. 1969, 4, 127 – 243.

[22] J. W. Henderson, �Chirality in Carbonium Ions, Carbanions, and Radicals�, Chem. Soc. Rev. 1973, 2,397 – 413.

[23] R. J. P. Corriu, C. Guerin, J. J. E. Moreau, �Stereochemistry at Silicon�, Topics Stereochem. 1984, 15,43 – 198; M. Mikołajczyk, J. Drabowicz, �Chiral Organosulfur Compounds�, Topics Stereochem. 1982,13, 333 – 468; H. Marom, P. U. Biedermann, I. Agranat, �Pyramidal Inversion Mechanism of SimpleChiral and Achiral Sulfoxides: A Theoretical Study�, Chirality 2007, 19, 559 – 569.

[24] A. R. Katritzky, R. C. Patel, F. G. Ridell, �N-Methyl Inversion Barriers in Six-membered Rings�,Angew. Chem., Int. Ed. 1981, 20, 521 – 529.

[25] C. H. Bushweller, C. Y. Wang, J. Reny, M. Z. Lourandos, �The Rotation-Inversion Dichotomy inTrialkylamines. Direct 1H DNMR Observations of Distinct Different Rates of Nitrogen Inversion and


Carbon-Nitrogen Bond Rotation in Isopropylmethylethylamine�, J. Am. Chem. Soc. 1977, 99, 3938 –3941.

[26] J. B. Lambert, �Pyramidal Atomic Inversion�, Topics Stereochem. 1971, 6, 19 – 105.[27] V. Prelog, P. Wieland, ��ber die Spaltung der Trçger�schen Base in optische Antipoden, ein Beitrag

zur Stereochemie des dreiwertigen Stickstoffs�, Helv. Chim. Acta 1944, 27, 1127 – 1134.[28] S. Borman, �Centennial of First Determination of Glucose Configuration Honored�, Chem. Eng. News

1992, 70(23), 25 – 26; S. Sergeyev, �Recent Development in Synthetic Chemistry, Chiral Separations,and Applications of Trçger�s Base Analogues�, Helv. Chim. Acta 2009, 92, 415 – 444.

[29] http://en.wikipedia.org/wiki/Fischer_projection, last accessed March 2012; D. W. Slocum, D. Sugar-man, S. P. Tucker, �The Two Faces of d and l Nomenclature�, J. Chem. Educ. 1971, 48, 597 – 600; M.Freemantle, �Chemistry at Its Most Beautiful�, Chem. Eng. News 2003, 81(34), 27 – 30.

[30] �Geigy Scientific Tables, Vol. 4’, Ed. C. Lentner, Ciba-Geigy, Basel, 1986, pp. 9 – 24.[31] W. Klyne, J. Buckingham, �Atlas of Stereochemistry – Absolute Configurations of Organic

Molecules�, Chapman and Hall, London, 1974.[32] R. S. Cahn, �An Introduction to the Sequence Rule – A System for the Specification of Absolute

Configuration�, J. Chem. Educ. 1964, 41, 116 – 125; S. Borman, �Chemical Pioneer Sir ChristopherIngold Remembered in Centenary of His Birth�, Chem. Eng. News 1993, 71(39), 29 – 32.

[33] R. S. Cahn, C. Ingold, V. Prelog, �Specification of Molecular Chirality�, Angew. Chem., Int. Ed. 1966,5, 385 – 415, 511.

[34] V. Prelog, G. Helmchen, �Basic Principles of the CIP-System and Proposals for a Revision�, Angew.Chem., Int. Ed. 1982, 21, 567 – 583.

[35] A. J. Matich, B. J. Bunn, M. B. Hunt, �The Enantiomeric Composition of Linalool and LinaloolOxide in the Flowers of Kiwifruit (Actinidia) Species�, Chirality 2010, 22, 110 – 119.

[36] N. A. Corvalan, J. A. Zygadlo, D. A. Garc�a, �Stereo-selective Activity of Menthol on GABAA

Receptor�, Chirality 2009, 21, 525 – 530.[37] V. Prelog, G. Helmchen, �Pseudoasymmetrie in der organischen Chemie�, Helv. Chim. Acta 1972, 55,

2581 – 2598.[38] J. G. Nourse, �Pseudochirality�, J. Am. Chem. Soc. 1975, 97, 4594 – 4601.[39] K. Mislow, �Stereochemical Terminology and Its Discontents�, Chirality 2002, 14, 126 – 134.[40] S. Chandrasekhar, �Pseudoasymmetry: A Final Twist�, Chirality 2008, 20, 771 – 774.[41] J. H. Brewster, �On the Distinction of Diastereoisomers in the Cahn�Ingold�Prelog (RS) Notation�,

J. Org. Chem. 1986, 51, 4751 – 4753.[42] M. Simonyi, J. Gal, B. Testa, �Signs of the Times: The Need for a Stereochemically Informative

Generic Name System�, Trends Pharmacol. Sci. 1989, 10, 349 – 354.[43] M. Quack, �Structure and Dynamics of Chiral Molecules�, Angew. Chem., Int. Ed. 1989, 28, 571 –

586.[44] M. Raban, D. Kost, �Stereolabile Configurational Units. Torsional and Inversional Stereochemistry in

Sulfenamides and Hydroxylamines�, Tetrahedron 1984, 40, 3345 – 3381.[45] B. Testa, P. A. Carrupt, J. Gal, �The So-Called �Interconversion� of Stereoisomeric Drugs: An Attempt

at Clarification�, Chirality 1993, 5, 105 – 111.[46] M. Reist, B. Testa, P. A. Carrupt, �The Racemization of Enantiopure Drugs: Helping Medicinal

Chemists to Approach the Problem�, Enantiomer 1997, 2, 147 – 155.[47] M. Reist, B. Testa, P. A. Carrupt, M. Jung, V. Schurig, �Racemization, Enantiomerization,

Diastereomerization, and epimerization: Their Meaning and Pharmacological Significance�, Chirality1995, 7, 396 – 400.

[48] M. Reist, B. Testa, P. A. Carrupt, �Drug Racemization and Its Significance in PharmaceuticalResearch�, in � Handbook of Experimental Pharmacology, Vol. 153, Stereochemical Aspects of DrugAction and Disposition�, Eds. M. Eichelbaum, B. Testa, A. Somogyi, Springer Verlag, Berlin, 2003,pp. 91 – 112.

[49] O. Trapp, G. Schoetz, V. Schurig, �Determination of Enantiomerization Barriers by Dynamic andStopped-Flow Chromatographic Methods�, Chirality 2001, 13, 403 – 414.

[50] O. Trapp, �Fast and Precise Access to Enantiomerization Rate Constants in Dynamic Chromatog-raphy�, Chirality 2006, 18, 489 – 497.


[51] J. Oxelbark, S. Claeson, S. Allenmark, �Enantiomerization at Sulfur, Selenium and TelluriumStereogenic Centres: Studies by Dynamic Chiral Liquid Chromatography and Chiroptical Methods�,Enantiomer 2000, 5, 413 – 419.

[52] M. Reist, L. H. Christiansen, P. Christoffersen, P. A. Carrupt, B. Testa, �Low ConfigurationalStability of Amfepramone and Cathinone: Mechanism and Kinetics of Chiral Inversion�, Chirality1995, 7, 469 – 473.

[53] B. Mey, H. Paulus, E. Lamparter, G. Blaschke, �Kinetics of Racemization of (þ)- and (� )-Diethylpropion: Studies in Aqueous Solution, with and without the Addition of Cyclodextrins, inOrganic Solvents and in Human Plasma�, Chirality 1998, 10, 307 – 315.

[54] M. Reist, P. A. Carrupt, B. Testa, S. Lehmann, J. J. Hansen, �Kinetics and Mechanisms ofRacemization: 5-Substituted Hydantoins (¼ Imidazoline-2,4-diones) as Models of Chiral Drugs�,Helv. Chim. Acta 1996, 79, 767 – 778.

[55] E. Eich, �Solanaceae and Convolvulaceae: Secondary Metabolites – Biosynthesis, Chemotaxonomy,Biological and Economic Significance (A Handbook)�, Springer, Berlin, 2008.

[56] Y. Aso, S. Yoshioka, T. Shibazaki, M. Uchiyama, �The Kinetics of the Racemization of Oxazepam inAqueous Solution�, Chem. Pharm. Bull. 1988, 36, 1834 – 1840.

[57] S. K. Yang, K. L. Liu, �Resolution and Stability of Oxazepam Enantiomers�, Chirality 1992, 4, 443 –446.

[58] S. K. Yang, X. L. Lu, �Racemization Kinetics of Enantiomeric Oxazepams and StereoselectiveHydrolysis of Enantiomeric Oxazepam 3-Acetates in Rat Liver Microsomes and Brain�, J. Pharm. Sci.1989, 78, 790 – 795.

[59] G. Schoetz, O. Trapp, V. Schurig, �Determination of the Enantiomerization Barrier of Oxazepam byDynamic Micellar Electrokinetic Chromatography – Comparison of Experiment and Simulation withChromWin 99�, Enantiomer 2000, 5, 391 – 396.

[60] G. W. Mellin, M. Katzenstein, �The Saga of Thalidomide: Neuropathy to Embryopathy, with CaseReports and Congenital Anomalies�, N. Engl. J. Med. 1962, 267, 1184 – 1244.

[61] E. J. Shannon, E. J. Morales, F. Sandoval, �Immunomodulatory Assays to Study Structure-ActivityRelationships of Thalidomide�, Immunopharmacology 1997, 35, 203 – 212.

[62] M. Reist, P. A. Carrupt, E. Francotte, B. Testa, �Chiral Inversion and Hydrolysis of Thalidomide:Mechanisms and Catalysis by Bases and Serum Albumin, and Chiral Stability of TeratogenicMetabolites�, Chem. Res. Toxicol. 1998, 11, 1521 – 1528.

[63] T. Eriksson, S. Bjçrkman, B. Roth, �. Fyge, P. Hçglund, �Enantiomers of Thalidomide: BloodDistribution and the Influence of Serum Albumin on Chiral Inversion and Hydrolysis�, Chirality 1998,10, 223 – 228.

[64] T. Eriksson, S. Bjçrkman, B. Roth, �. Fyge, P. Hçglund, �Stereospecific Determination, ChiralInversion In Vitro and Pharmacokinetics in Humans of the Enantiomers of Thalidomide�, Chirality1995, 7, 44 – 52.

[65] B. Knoche, G. Blaschke, �Investigations on the in vitro Racemization of Thalidomide by High-Performance Liquid Chromatography�, J. Chromatogr. 1994, 666, 235 – 240.

[66] T. L. Chen, G. B. Vogelsang, B. G. Petty, R. B. Brundrett, D. A. Noe, G. W. Santos, O. M. Colvin,�Plasma Pharmacokinetics and Urinary Excretion of Thalidomide after Oral Dosing in Healthy MaleVolunteers�, Drug Metab. Dispos. 1989, 17, 402 – 405.

[67] H. Koch, �The Arene Oxide Hypothesis of Thalidomide Activity. Considerations on the Mechanism ofAction of This �Classical� Teratogen�, Sci. Pharm. 1981, 49, 67 – 99.

[68] H. Ockenfels, F. Kçhler, W. Meise, �Teratogenic Effect and Stereospecificity of a ThalidomideMetabolite�, Pharmazie 1976, 31, 492 – 493.

[69] M. A. Nunes, E. Brochmann-Hanssen, �Hydrolysis and Epimerization Kinetics of Pilocarpine inAqueous Solution�, J. Pharm. Sci. 1974, 63, 716 – 721.

[70] H. Porst, L. Kny, �On the Stability of Pilocarpine Hydrochloride in Eye Drops�, Pharmazie 1985, 40,23 – 29.

[71] P. F. M. Kuks, L. E. A. Weekers, P. B. Goldhoorn, �Decomposition of Pilocarpine Eye DropsAssessed by a Highly Efficient High Pressure Liquid Chromatographic Method�, Pharm. Weekbl. Sci.1990, 12, 196 – 199.


[72] L. Gu, R. G. Strickley, �Diketopiperazine Formation, Hydrolysis, and Epimerization of the NewDipeptide Angiotensin-Converting Enzyme Inhibitor RS-10085�, Pharm. Res. 1987, 4, 392 – 397.

[73] C. Pepper, H. J. Smith, K. J. Barrell, P. J. Nicholls, M. J. E. Hewlins, �Racemization of DrugEnantiomers by Benzylic Proton Abstraction at Physiological pH�, Chirality 1994, 6, 400 – 404.

[74] R. Cirilli, R. Costi, R. Di Santo, F. Gasparrini, F. La Torre, M. Pierini, G. Siani, �A RationalApproach to Predict and Modulate Stereolability of Chiral a-Substituted Ketones�, Chirality 2009, 21,24 – 34.

Received August 14, 2012


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