Table Of Content1.1 Introduction: The Importance of Chirality in Drugs and Agrochemicals
JR Cossy,ESPCI, ParisTech, Paris, France
r2012ElsevierLtd.Allrightsreserved.
1.1.1 Drugs 1
1.1.1.1 The EnantiomersHave theSameBiological Activity (Type1) 2
1.1.1.2 The EnantiomersHave Qualitatively EqualBiological Effectsbut Their Intensitiescan beDifferent
(Type2) 2
1.1.1.3 OnlyOne Enantiomer Possesses thePharmacological Activity (Type3) 3
1.1.1.4 The TwoEnantiomers HaveDifferent Biological Properties (Type4) 3
1.1.2 Agrochemicals 5
References 6
Glossary Enantiomericallyenrichedcompounds Mixture
Achiral Notchiral. ofenantiomersinaratiodifferenttoone-to-one
Chiral Thistermisusedtodescribeamoleculethatis (1:1).
non-superimposableonitsmirrorimage. Racemic Mixtureoftwoenantiomersinaratioone-to-one
Enantiomer Acompoundwhichcorrespondstooneof (1:1).
twostereoisomersthataremirrorimagesofeachotherand
thatarenon-superimposable.
1.1.1 Drugs
Whatisachiralmolecule?Whyischiralityimportantfordrugsandagrochemicals?
AccordingtoMislow,achiralmoleculeisanobjectif,andonlyif,itisnotsuperposableonitsmirrorimage;otherwiseitis
achiral.1Thisdefinitionreferstothespatialarrangementofmoleculesbutdoesnotrefertothestereochemicalcomposition,for
exampleofadrug.Whenonesays‘chiraldrugs,’wedonotknowwhetherthisdrugisracemic,whetheritisanenantiomer,or
whetheritisamixtureofstereoisomers.Whenadrugisconstitutedbyoneenantiomeritiscalledan‘enantiomer,’byamixtureof
enantiomersitiscalled‘enantiomericallyenriched,’andbyaone-to-onemixtureoftwoenantiomersitiscalledaracemate,which
canbechiral.
Biologicalsystemslikehumanbeings,plants,insects,etc.havebeenknowntoexhibitchiralityandthecriticalmoleculesoflife
arealmostentirelyconstitutedbyoneenantiomer.Thenumberofnaturallyoccurringmoleculesisverylargeandthestructural
diversityisvast.Theycanbesmallmoleculesormacromoleculesincludingnaturalaminoacids,whicharebuildingblocksfor
peptidesandproteins.Sugars,whicharebuildingblocksofpolysaccharides;theycanbesteroidsandmanyothercompoundsthat
areconstitutedbyoneenantiomer.Itisworthnotingthatinnature,forthesameclassofcompounds,thesamesenseofchiralityis
present in the latter, for example, the same configuration. For example, with rare exceptions, alpha-amino acids have the
L-configuration and carbohydrateshave the D-configuration. Due to the chiral nature of the amino acids, drug-binding sites of
proteinsareasymmetric.Forexample,theL-andD-configurationsofaminoacidsareimportantinthesynthesisofpeptidesasthe
replacement of an amino acid of the L-configuration by an amino acid of the D-configuration can have an impact on the
conformationofthepeptidesandthusonitsbiologicalactivity(seeChapter1.5).
One of the first observations of biological enantioselectivity was made by Pasteur in 1858. Pasteur observed that when
asolutionofracemictartratewasaddedtoasourceofmicroorganism,(þ)-tartaricacidwasconsumedfasterthan((cid:2))-tartaricacid
as the latter was not transformed or was metabolized more slowly than (þ)-tartrate.2 Later, Pasteur showed that
the mold Penicillium glaucum was metabolizing (þ)-tartaric acid.3 His theory was that the enantioselective transformation of
tartaric acid by microorganisms implies selective interactions of (þ)-tartaric acid with key chiral molecules within the
microorganisms.
Thefirstreportontherelationshipbetweenenantioselectivityandapharmacologicaleffectappearedin1886.Itwasreported
that(þ)-asparaginehadasweettasteandthat((cid:2))-asparaginehadnotaste.4Again,Pasteurinterpretedtheseresultsbysuggestingthat
the interactions of the two enantiomers of asparagine with the chiral biological receptors were different. Many studies were
performed during the mid-1880s and mid-1920s showing that the two enantiomers of an active compound can have different
pharmacologicalpropertiesand,inthe1890s,duetotheimportantworkofEmileFischer,thestereoselectiveactionofenzymeson
substrateswasdetermined.EmileFischerconcludedthattheshapeandstereochemicalconfigurationofamoleculeinfluencethe
suitabilityofamoleculetoserveasasubstrateforanenzyme.Heproposedthehypothesisthatforanenzymetobeactiveona
substrate,thetwohavetofitasalockanditskey.5Manyinvivostudiesofenantioselectivemetabolismwerecarriedoutduringthe
late1800sandearly1900s.In1926,RoberstonCushnypublishedareviewonthestudiesofenantioselectivepharmacologyand
metabolism that had been achieved during the previous 40 years. Thus, in the twentieth century, researchers were aware that a
ComprehensiveChirality,Volume1 http://dx.doi.org/10.1016/B978-0-08-095167-6.00101-4 1
2 Introduction: TheImportance ofChirality inDrugs andAgrochemicals
relationshipexistedbetweentheenantioselectivityofdrugsandthebiologicalactivityofthelatterbutitwasacademicresearchand
thiswasmainlyignoredbycompanies.Untilthe1900s,medicinalchemistsusedtheconceptthat‘similarmoleculesexertsimilar
biologicalactivies’andtheywereusingthisconcepttomodifythestructureofbiologicallyactivecompounds.6–11Severalsurprising
structure–activityrelationshipsdemonstratedthatchemicallysimilarcompoundscanhavesignificantlydifferentbiologicalactions
and activities. Due to some tragedies in the twentieth century, the thalidomide strategy (in the 1950s) probably being the most
tragic,thesituationchangedandthousandsofenantiomersofnaturalandnonnaturalproductswereidentifiedandexaminedfor
their pharmacological properties and therapeutic potential. Today, researchers and drug companies are aware of the different
biologicaleffectsofenantiomersanddiastereoisomersaswellastheirdifferentpharmacokinetics.12–29By1987,55%ofallclinically
useddrugswerebasedonchiralmoleculesand98%ofthesewereenantiomericallyenrichedandpure.Nowadays,itisrecognized
thatabiologicalreceptorreceivesasuitablemolecule,thenthereceptoremitsamessagetosometargetsintheorganism,andthis
signalcanaltertheactivityofthecell.Inadditiontodrugs,theagrochemicalindustryhasbecomeawarethattheactivityoftwo
enantiomerscanbedifferentoninsectsandplantsandthattheirrateoftheirtransformationintheecosystemcanbedifferent.Four
mainsimpletypesofrelativebiologicaleffectscanbeencounteredandafewexamples,obtainedfromthedifferentchaptersofthis
book,areusedtoillustrateeachtypeofbioactivecompounds:
– Theenantiomershavethesamebiologicalactivity(Type1);
– theenantiomershavequalitativelyequalbiologicaleffectsbuttheirintensitiescanbedifferent(Type2);
– onlyoneenantiomerisbiologicallyactive(Type3);
– twoenantiomershaveverydifferentbiologicalproperties(Type4).
1.1.1.1 TheEnantiomersHave theSame BiologicalActivity(Type 1)
AsanexampleofaType1compound,wecanconsidericlaprim,whichwasdevelopedbyRocheandArpida(seeChapter1.8).This
compoundisusedinthetreatmentofbacterialinfectionsandbothenantiomersexhibitsimilaractivityagainstthedihydrofolate
reductaseenzyme(DHFR)andasimilarantimicrobialactivityagainstabroadrangeofbacteria.Onepossibleexplanationforthe
similarinhibitoryandantibacterialactivityofbothenantiomerscouldbethecomparablebindingofthetwoenantiomerswiththe
biological target. This emerges from the observation of the crystal structure analysis in addition to the analysis of low-energy
conformation.Whensuperimposingthediaminopyrimidinerings,bothenantiomersalignpartofthecyclopropylringsclosetoa
similarspace.Thisobservationmightbeanexplanationfortheircomparablebindingproperties(Figure1).
H N N NH H N N NH
2 2 2 2
N N
O OMe O OMe
OMe OMe
(R)-Iclaprim (S)-Iclaprim
Figure1 Structureof(R)-iclaprimand(S)-iclaprim.
1.1.1.2 TheEnantiomersHave QualitativelyEqual BiologicalEffects butTheirIntensities can beDifferent(Type 2)
When the effects of the enantiomers are qualitatively equal but their intensities are different, it has been assumed that both
enantiomers are associated with the same type of receptors. For example, (S)-citalopram is a potent agent against major
depression,panicdisorder,andgeneralizedanxietydisorder,whereasits(R)-enantiomerismuchlessactive(Figure2).Wehaveto
pointoutthat,afterclinicalstudies,boththeracemateaswellasthesingle(S)-enantiomerarebeingsoldsuccessfully.30
NC
O
NH
2
F
(S)-Citalopram
Figure2 Structureof(S)-citalopram.
Introduction: TheImportance ofChirality inDrugs andAgrochemicals 3
1.1.1.3 OnlyOneEnantiomer Possesses thePharmacological Activity(Type 3)
ChloramphenicolisaType3compound(seeChapter1.10).Thiscompound,discoveredin1947fromafermentationbrothof
Streptomycesvenezuelae,possessestwoasymmetriccentersandithasbeenobservedthatthenaturaldiastereomerwiththe1Rand
2R configurations displays significant antibacterial activity. The mode of action of chloramphenicol consists of blocking the
peptidyltransferaseactivitybypreventingthebindingoft-RNAtotheAsiteoftheribosome31,32(Figure3).
OH
HN O
O N
2
Cl Cl
Chloramphenicol
Configurations Relative potency
(1R,2R) 100
(1S,2S) 0.4
(1S,2R) 0.4
(1R,2S) 2
Figure3 Relativepotencyofchloramphenicolisomers.
TheimportanceoftheconfigurationofthestereogeniccentershasalsobeenobservedforsyntheticdrugssuchasforTMC207
anditsstereoisomers.TMC207wasdiscoveredandoptimizedatJohnson&JohnsonPharmaceuticalResearch&Development(see
Chapter1.6).ItisanewantimycobacterialagentwhichinhibitsmycobacterialATPsynthaseanditisalsoactiveagainstbothdrug-
susceptibleandmultidrug-resistantstrainsofMycobacteriumtuberculosis.33Amongallthestereoisomers,theTMC207,possessingR
andSconfigurationsfortheadjacentstereogeniccenters,wasshowntohavethebestinhibitoryactivityonapanelofmycobacteria.
TMC207isaverypromisingcompoundandiscurrentlyinPhaseIIbofclinicaltrialsforMDR-TB(Figure4).
Br
HO
N OMe
N(Me)
2
TMC207
Figure4 StructureofTMC207.
1.1.1.4 TheTwoEnantiomersHave Different BiologicalProperties(Type 4)
OrnidazoleisacompoundofType4(Figure5),whichisananti-infectiveusedasaracemicmixture.However,ithasbeenobserved
thatthe(S)-enantiomercouldhaveanti-infertilityactivityinmaleanimals34(seeChapter1.8).
N
N
O N
2 OH
Cl
(S)-Ornidazole
Figure5 Structureof(S)-ornidazole.
4 Introduction: TheImportance ofChirality inDrugs andAgrochemicals
Probably, the most striking example of a Type 4 enantiomer is thalidomide, which caused a major tragedy. Racemic
thalidomide was introduced on the market in the late 1950s as a sedative and hypnotic drug. The (R)-enantiomer is an
effective sedative medication and the (S)-enantiomer may be teratogenic.35 (S)-Thalidomide was shown to be responsible for
over2000cases of birth defects in children born towomenwhotook the drugduring pregnancy (Figure 6)(see Chapters 1.4
and1.8).
O
N O N O
NH NH
O O O O
(S)-Thalidomide (R)-Thalidomide
Figure6 Structureof(S)-thalidomideand(R)-thalidomide.
In view of these considerations, one has to be aware that the racemization or the stereomutation of a drug can occur in a
biologicalenvironment.Theeffectcanbedetrimentalifoneoftheisomersistoxic.Thisprocesscanoccurwhenastereogeniccenter
isepimerizedunderbasicoracidicconditions.Stereomutationscanoccurduringsyntheticoperations,biochemicalassays,andinvivo
studies,andithasbeenobservedwhenana-keto-heterocyclefunctionalityispresentontheC-terminalofapeptidicstructure.Inthe
caseofoxazepan,acentralnervoussystemdrugthatbindstobenzodiazepinereceptors,arapidinterconversionoftheenantiomers
was observed (t ¼a few min at 371C at pH 7.4). This compound has been marketed as a racemate (see Chapter 1.4)
1/2
(Figure7).36–39
H O
N
OH
Cl N
Ph
Oxazepan
Figure7 Structureofoxazepan.
Eventhoughtheinterconversionoftheenantiomersisnotdetrimentalforoxazepan,forsomecompounds,itcanbedangerous
as for thalidomide. For the latter compound, the in vitro racemization process can take place in contact with plasma proteins
suchashumanserumalbumin.Theracemizationiscatalyzedbyalbumin,phosphate,hydroxideoraminoacids,especiallybybasic
amino acids such as L-arginine and L-lysine (the t1/2 for the racemization of thalidomide is approximately 2.5h at pH 7.4 and
at371C).
Insomecases,oneenantiomercanbeinterconvertedintotheotherenantiomerbymetabolism37,40–42asforibuprofen(see
Chapter 1.4) (Figure 8). Of the two enantiomers, the (S)-enantiomer is the bioactive compound that inhibits cyclooxygenase
invitroandinvivo.However,itwasfoundthatinvivoeachenantiomerisinterconvertedby2-arylpropionyl-CoAepimerase.Thus,
thelessbioactive(R)-isomerproducestheactive(S)-isomerandviceversa.Duetothisracemization,ibuprufeniscommercialized
asaracemate.43,44MoreexamplesaregiveninChapter1.4.
Me
CO H
2
i-Bu
Ibuprofen
Figure8 Structureofibuprofen.
Asracemicdrugsorenantiomericallyenricheddrugsmaybepotentiallyunsafeforpatients,43–46thestudyofchiraldrugsas
single enantiomers gained momentum in the 1990s. In1992,in the United States,formalregulatory guidance for newstereo-
isomericdrugswasissuedfromtheFoodandDrugAdministration(FDA)andthenbytheEuropeanUnion(EU),Australia,Japan,
Introduction: TheImportance ofChirality inDrugs andAgrochemicals 5
etc.47,48Fortheapprovalofnewdrugs,separationandcharacterizationhastobecarriedoutforeachstereoisomerifpossible,and
alsoevaluationofthebioactivity,pharmacodynamics,pharmacokinetics,andtoxicologyofeachisomer.Arelevantrationalealso
has to be provided for the stereoisomer selected for development and marketing.49 Stereochemical identity tests and assay
methods has to be established for the active ingredient (the drug substance) and for the final formulation (drug product).
However,thedevelopmentofaracemate,aswehavepointedout,ispossibleundercertaincircumstances.
1.1.2 Agrochemicals
Asplantsandinsectsarechiralsystems,onecanassumethattheinteractionswithoneenantiomerofaspecificcompoundarealso
important.Duetothisconsideration,thesynthesisofrelativelyinexpensive,safe,andhighlyefficientpesticides,herbicidesaswell
asantifungalderivativesisimportantinmodernagriculturetosupplythedemandoffoodandenergyintheworld.Asfordrugs,
frequently, only one of the stereoisomers or enantiomers is biologically active or at least more active than the other isomer.
Probably,whenstereogeniccentersarepresentinpesticides,fungicides,orherbicides,fewerbiologicaltestshavebeencarriedout
than for drugs to determine the relative biological activity of each stereoisomer or enantiomer. However, nowadays, synthetic
effortsintheresearchanddevelopmentofagrochemicalcompanieshaveledtosomerefinementsandtotheintroductiononthe
marketofenantiomersandenantio-enrichedmixtures.
In1996,Williamsreportedthatchiralmoleculesrepresent25%ofalltheagrochemicalcompoundsand26%ofthetotalvalue
of the market, whereas single isomers or enantio-enriched compounds represent only 7% of the total value of the market.50
Among the 728 pesticides registered, 200 contain one or more chiral centers and only 38 of these (5.2%) are produced in
enantiomericallyenrichedforms.Forfungicides,onlyafewofthemareproducedinenantiomericallyenrichedformsand,among
the191fungicidesregistered,only65containoneormorechiralcenters.Inmanycases,thespecificbiologicalactivityofthese
enantiomershasnotbeeninvestigatedandonlysixcasesofenantiomericallyenrichedmixturesofsyntheticfungicideshavebeen
producedandcommercialized.
Asfordrugs,thesamebehaviorwasnoticedasoneenantiomercanbemoreactivethantheotherisomersuchas,forexample,
benthiavalicarb, which is a fungicide developed by Kumiai Chemical Industry Co., Ltd. It has been observed that of the four
isomersofbenthiavalicarb,onlythe(R,S)-isomerisbiologicallyactive.51Incontrast,iprovalicarb,asystemicfungicide,whichalso
has two asymmetric centers, is sold by Bayer as a mixture of (S,S)- and (S,R)-diastereomers, and no reports can be found on
the relative activity of the two diastereoisomers. However, an excellent fungicidal activity was found for the (R,S)-isomer on
PhytophtoraontomatoandonPlasmoparaongrape52(Figure9).
O O O
O O O
HN HN HN
N HN (S) HN (S) HN (S)
O O O
F S (R) (S) and (R) (R)
Benthiavalicarb Iprovalicarb (R,S)-Iprovalicarb
Figure9 Fungicides.
In the case of insecticides and according to the Insecticide Resistance Action Committee (IRAC) classification, 245 active
compoundsareregisteredasinsecticidesandacaricidesand72ofthesehaveachiralcenter.53,54Evenifthereisadifferencein
biological activity between the enantiomers, most of these compounds are commercialized as racemates. Only 12 synthetic
insecticidesandninenaturalproductsaresoldassingleenantiomersorenantiomericallyenrichedmixtures.
Indoxacarb is a broad-spectrum lepidopteran insecticide active on contact and ingestion, and this compound was com-
mercialized by Dupont in 2000.55,56 Initially, its development was planned as a mixture of racemates but bioassays on the
enantiomersshowedthatthe(S)-enantiomerwastwiceasactiveastheracemicmixtureandthatthe(R)-enantiomerwasinactive
(Figure 10). Thus, enantioselective synthesis of indoxacarb was carried out; even though indoxacarb is only enantiomerically
enriched(S/R¼75:25),itcorrespondstoanapproximately30%decreaseinapplicationratescomparedwiththeracemate,which
representsasubstantialbenefitfortheenvironment.Anotherexampleislambda-cyhalothrin(Syngenta),whichisapyrethroid
insecticide whose biological activity is limited to the isomer possessing the (1R) configuration; the (1S)-isomer is at least 100
timeslesspotentthanthe(1R)-isomer.
Forherbicides,theHerbicideResistanceActionCommittee(HRAC)hasclassified292activecompoundsand62oftheseare
chiral. Currently, for herbicides,7% is supplied in anenantio-enriched formbut enantio-enriched compounds are being com-
mercializedastheyaremuchmoreenvironmentallysafe.AfterWorldWarII,mecopropanddichloroprop,whichbelongtothe
6 Introduction: TheImportance ofChirality inDrugs andAgrochemicals
O CH3
N
O CN
N N
F C
3 OPh
O
O Cl
OCF
3
Cl CO Me
2
(S)-Indoxacarb Lambda cyhalothrin
Figure10 Insecticides.
auxin family of herbicides, were introduced on the market as racemates; even though its herbicidal activity is related to the
(R)-enantiomer,itwasonlyin1988thatthe(R)-isomerwasintroducedonthemarketbyBASF.Mecopropanddichloropropwere
thefirstherbicideswhoseenvironmentaleffectswerestudiedusingenantio-discriminatingmethods.Asonlythe(R)-isomerwas
herbicidally active the following question can be raised: what is the behavior of the (S)-enantiomer in the environment? The
biodegradationofthe(R)-and(S)-isomerswasstudiedandapreferentialdegradationofthe(S)-isomerwasobservedinbroadleaf
weedsandinsoilbutnotingrass.57ItwasalsoobservedthatseweragesludgeinSwitzerlandcoulddegradethe(S)-enantiomer
of dichloroprop from the racemic mixture before the (R)-enantiomer but this was not the case for mecoprop.58 Furthermore,
the Brazilian pasture soil degraded the (S)-dichloroprop faster than the (R)-isomer whereas the forest soil degraded the active
(R)-isomer at least as fast as the (S)-isomer or even faster.59 This example shows that the biodegradability of agrochemicals is
complexandreinforcesthefactthattheuseofenantiomersorenantio-enrichedcompoundscandecreasetheecotoxicityifwell
studied(Figure11).
O Cl O
O O
OH OH
Cl Cl
(R)-Mecoprop (R)-Dichlorprop
Figure11 Herbicides.
Whatever the biologically active compounds, drugs, fungicides insecticides, or herbicides, all the examples reported in this
chapterstresstheneedforenantio-enrichedmoleculesasfarasthebiologicalsystemisconcerned.Thisisastrongincentiveto
registerenantiopureor,atleast,enantio-enrichedactiveingredients.Itisalsoastrongincentivetodevelopefficient,nonexpensive
methods to synthesize enantiomers and one of them is probably asymmetric hydrogenation, commonly used in companies
(see Chapter 1.9), or reduction, which can be easily scalable. The development of new, clean, efficient, chemoselective, and
nonracemizatingreagentssuchasforexample,peptidiccouplingreagentstoproducepeptidesorproteinswithoutpurifications
(seeChapter1.6)orreagentsthatallowtheintroductionoffluorineatomsinanenantioselectivemannerinordertoincreasethe
activityofthecompounds(seeChapter1.5)isimportant.Thediscoveryofnewactiveandselectivebiologicallyactivecompounds
couldbearesultofserendipityorobservations,andagoodstartingpointmaybenaturalproducts,which,inmostcases,arein
enantiomerically pure forms as Nature has already done a selection. Starting from natural products, one can access several
compoundsandoneofthemmaybefoundtobemoreselectiveandpotentthanthenaturalproductitself(seeChapter1.10).
Furthermore, and not the least important, it is crucial to develop sensitive enantioselective analytical methods to verify the
enantiomericpurityofthesynthesizedcompounds(seeChapter1.3).
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1.2 Importance of Chirality in the Field of Anti-infective Agents
DLesuisse, Sanofi,Chilly-Mazarin, France
MTabart, Sanofi,Vitry-Alfortville, France
r2012ElsevierLtd.Allrightsreserved.
1.2.1 Introduction 8
1.2.2 Antiinfectives fromNatural Origin 9
1.2.2.1 Antiinfectives That are UnmodifiedNaturalProducts 9
1.2.2.2 Antiinfectives from Hemisynthetic Origin 9
1.2.2.2.1 Theresulting chirality isidentical tothe chirality ofthe original natural product: b-lactamines derived from
6-aminopenicillanic acid and7-aminocephalosporanic acid 9
1.2.2.2.2 Theresulting chirality isdifferent from the chirality of the original natural product: deepermodifications ofthe
b-lactam scaffold ofb-lactamines 11
1.2.2.2.3 Thescaffold is different from the original natural product: non-b-lactam compounds 14
1.2.2.2.4 Introduction of afluorine ata chiral center ofantiinfectives 15
1.2.2.2.4.1 Replacement ofa hydrogen bya fluorine atom: the case ofketolides 15
1.2.2.2.4.2 Replacement ofa carbonyl functionby afluorine: the case ofpristinamycins 17
1.2.2.3 Antiinfectives Obtained by Total Synthesis 17
1.2.3 Antiinfectives fromNonnaturalOrigin 18
1.2.3.1 The TwoEnantiomers HavetheSameBiological Activity 18
1.2.3.2 The TwoEnantiomers HaveQuite Different Biological or Pharmacological Activity 20
1.2.3.3 One Enantiomer Bears thePharmacological Activity 21
1.2.4 Conclusion 27
Acknowledgments 27
References 27
Glossary thepenicillinsandthecephalosporins.Thesebugsare
Gram-negativebacteria Prokaryoticorganismssuchas responsibleforlife-threateningnosocomialinfectionssuch
EscherichiacoliorPseudomonasaeruginosathatarenotableto assepticemia.
retainthecrystalvioletstainofGramcolorationbecauseof QRSA/QSSA Quinolone-resistant(/sensitive)
theirthinpeptidoglycanlayer.Outsidethislayerisfound Staphylococcusaureus.
theoutermembranecontaininglipopolysaccharide. Resistance Phenomenonofadaptationofbacteriatoa
Aminoglycosidessuchaskanamycin,gentamicin,and certainclassofantiinfectiveagentsastheresultofa
tobramycinhaveamainlyGram-negativespectrumof selectionpressurestemmingfromtheuseofthisagentto
activity. treatinfectionscausedbythesebacteria.Thisadaptationof
Gram-positivebacteria Prokaryoticorganismssuchas bacteriatodrugspreventsthetreatmentofthe
StaphylococcusaureusorStreptococcuspneumoniaethatare correspondinginfectionbythedrugwhichhasbecome
abletoretainthecrystalvioletstainofGramcoloration inactiveduetogeneticmutationsthatcanbetransmittedto
becauseofthehighamountofpeptidoglycanintheircell otherbacteria,evenfromotherspecies.
wall.Theycommonlylacktheoutermembranefoundin VREF Vancomycin-resistantEnterococcusfaecalisandE.
Gram-negativebacteria.Fusidicacidisatypicaldrugwitha faeciumwhichareGram-positivebacteriaresistantto
Gram-positivespectrumofactivity. vancomycinandresponsibleforextremelysevere
MRSA Methicillin-resistantStaphylococcusaureusthathas nosocomialinfectionssuchasendocarditis.
developedresistancetob-lactamantibiotics,whichinclude
1.2.1 Introduction
Duetothefactthatantibiotics,asotherdrugs,interactwithchiraltargetsinbacteriasuchasenzymes,receptors,ribosomes,etc.,
thechiralityoftheantiinfectiveagenthasadramaticinfluenceontheinvivopropertiesofthedrug.Inotherwords,theinversion
ofoneorseveralchiralcentersofthedrugcanresultinthelossofantiinfectiveproperties.Manysuchexamplescanbefound
amongtheantiinfectivecompounds.Forinstance,intheanthracyclineantibioticsfamily,whichincludesimportantclinicaldrugs
usedinthetreatmentofhumancancer,epimerizationoftheC9-positionleadstoadramaticlossoftheDNA-bindingproperties.1
Linezolid,anoxazolidinone,thelatestclassofantiinfectiveagents,isactiveonlywhentheacetamidomethylgrouppossessesthe
(S)absoluteconfiguration2(Figure1).
8 ComprehensiveChirality,Volume1 http://dx.doi.org/10.1016/B978-0-08-095167-6.00112-9
Importance ofChirality inthe FieldofAnti-infective Agents 9
O OH R1 O
N
R2 O
F N
O
OMe O OH O
O
O
N
H
NH
OH 2
R1 = H, R2 = OH 9-Deacetyl daunorubicin, active Linezolid
R1 = OH, R2 = H 9-epi Deacetyl daunorubicin, inactive
Figure1 Structuresof9-Deacetyldaunorubicin,9-epiDeacetyldaunorubicinandLinezolid.
Theobjectiveofthischapterisnottobecomprehensivebuttopresentafewinterestingcasestudiestoillustratethescopeand
synthesisofsomerelevantexamplesthatareemblematicoftheinfluenceofchiralityonthebiologicalpropertiesofthedrug.
Naturalproducts areofparamountimportancein thefieldof antiinfectiveagentsas60–80%ofthem are,orderivedfrom,
natural origin.3 In addition, more than 80% of natural products incorporate at least one chiral center, with 15% of them
incorporating11stereocentersormore.4Boththesefactsstresstheimportanceofchiralityintheantiinfectivefield.Inthischapter,
wewillsequentiallyaddresstheantiinfectivesoriginatingfromnaturalproductsandthosethataretheresultofdrugdesignand
syntheticchemistryefforts.
1.2.2 Antiinfectives from Natural Origin
InthisSection,wewilldistinguishbetweentheantibioticsthatareusedasproducedbythelivingorganismswithnostructural
modification and those that are produced by hemisynthetic pathways from highly functionalized intermediates from fermen-
tation,andfinallytheonesthatareproducedbytotalsynthesis.
1.2.2.1 Antiinfectives ThatareUnmodified Natural Products
Severalcommonlyusedantiinfectiveagentsareunmodifiednaturalproducts.Amongthese,wecanciteerythromycin,rifampicin,
vancomycin,mupirocin,aminoglycosideslikestreptomycin,andsteroidalantiinfectiveslikefusidicacid(Figure2).
Thehighcomplexityoftheirchemicalscaffoldsbearingmanychiralcenters,alongwithagoodbiologicalactivitybecauseof
theunmodifiedprinciples,accountforthefactthattheyarestillusedessentiallyasproducedbyfermentation.
1.2.2.2 Antiinfectives fromHemisynthetic Origin
Antibiotics currently on the market largely arise from hemisynthesis: b-lactamines (penams, cephems, penems, and mono-
bactams),macrolides,pristinamycinstocitesomeofthemostprominentclasses.Wewilldividethissectionasafunctionofthe
resultingchiralitythatcanbeidenticaltoordifferentfromthechiralityoftheoriginalnaturalproduct.
1.2.2.2.1 The resulting chirality is identical to the chirality of the original natural product: b-lactamines derived from
6-aminopenicillanic acid and 7-aminocephalosporanic acid
Since the discovery, in 1929, by Fleming that a strain of the mold Penicillium was producing an antibacterial agent, which he
namedpenicillin,anditsisolationadecadelater,theantibacterialfieldhasbeendevelopedtremendously.Theproductionofthe
6-aminopenicillanicacid(6-APA)and7-aminocephalosporanicacid(7-ACA)byfermentationandenzymatichydrolysismadeit
possibletosynthesizemanyanalogsvaryingbythe6-and7-positionofthesidechain.Todate,severaloftheseantibacterialsare
onthemarketandheavilyused.Forexample,amoxicillindirectlyproducedfrom6-APA(Scheme1),andatleast20analogsof
cephalosporinderivedfrom7-ACA,likecefuroxime,ceftazidime,ceftriaxone,orcepfpirome,thecloseststructurallyrelatedto7-
ACAbeingcefotaxime.
Thesynthesisofcefotaxime5isquitestraightforwardwiththeaminothiazolesidechainobtainedbycondensationofthiourea
withtheoximederivativefrom2,3-dioxo-butyricacid(Scheme2).
Cefotaxime,alongwithmanyothercephalosporinsonthemarket,incorporatesanoximeofsynconfigurationrelativetothe
cephemcore.TheimportanceofthisfeatureforthebiologicalactivitywasdiscoveredatRousselUclafandpavedthewayforall
modifiedoximesinthispositionwithinvariablythesynconfiguration.5
Amongthevariouscephalosporinsindevelopment,thecaseofcatechosporinsisinteresting.Cephalosporins,widelyusedas
antibacterial drugs for the treatment of infections, have long been studied and modified chemically because of the continuing
needtoproduceincreasinglytargetedandeffectivetherapies.6Thisismostlyduetotheevolutionofresistanceofawiderangeof
10 Importance of Chiralityin theFieldofAnti-infective Agents
O
MeO
HOOC
HO OH
OH O OH OH H
HO NMe2 OH OH HO
O O NH O
O O
O
O O OMe O O O
HO
OH N
H
Erythromycin OH O N
O Rifampicin N Fusidic acid
OH NHMe
HO H
O Cl N NH
O O HN NH2
NH2 H O HN O HO OH
HO O NH
H O
HO O NH H2N NH OH
O O NH2 O
O
Cl
HO
HN O
O H H O O
OH OH
O
H
NH O MeNH OH
HO OH
H OH OH
OH
O N Streptomycin
H
Vancomycin
OH
O O OH
O O
OH Mupirocin
O
OH OH
Figure2 Structuresoferythromycin,rifampicin,fusidicacid,vancomycin,streptomycinandmupirocin.
bacteriaconferredbynewb-lactamases7ordifferentmechanisms.Equallyimportanthasbeenthenecessitytofindagentseffective
againstspecificorganismssuchasPseudomonasaeruginosa,whichhaveprovedelusivetotreatmentbyantibacterialdrugsinthe
past.8 Consequently, manyarticles havebeen published concerning invitrostructure–activity relationship studies in thisfield.9
The first report by Mochida et al.10 that the cephalosporin M14659, incorporating a catechol on the amide chain, showed
an excellent antibacterial activity in vitro against other Gram-negative bacteria and opened a new avenue of improving
thesecompounds.ItwashypothesizedthatM14659maybeactivelytakenupwithFe3þ intobacterialcells,probablythroughthe
iron-transport systems and, thus, kills the bacteria. It was later shown that these outstandingly low minimum inhibitory con-
centrations(MICs)areduetotheutilizationofthetonB-dependentiron-transportprocess.11Subsequently,severalauthorshave
confirmed these interesting properties of catechol b-lactams,in particular penicillins,12 monobactams,13and cephalosporins.14
These compounds display an exceptional in vitro activity and b-lactamase stability notably against Enterobacteriaceae and P.
aeruginosa.15
However,Beebyetal.in1977,showedthattheinsertionofatransdoublebondresultsinvinylogouscephalosporinssuchas
compoundBdisplayinghigherpotencythanthenonvinylanalogA16(generalreview17)(Figure3).
Thisobservationpromptedscientistsfromseveralpharmacompaniestoincorporatebothmodificationsintoonecompound.
ThisgaverisetoseveralveryactivecompoundslikeRU5986318orLB10552219displayingaverybroadspectrumofGram-positive
andGram-negativeantibacterialactivity,includingtheresistantPseudomonasstrains.Itisworthnotingthatherealsotheabsolute
configurationofthedihydroxymandelicacidhastobe(S)foroptimalantibacterialactivity(Figure4).ThesynthesisofRU59863
isdepictedinSchemes3and4.20Thechiralityofthesidechainwasobtainedbyachiralseparationoftheenantiomers.Theside
chainwasthencondensedto6-ACAafterintroductionofthequinolylmoiety(Scheme4).
