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Heterocycles
Heterocycles
Synthesis,Catalysis,Sustainability,andCharacterization
EditedbyTeresaM.V.D.PinhoeMeloandMartaPineiro
Editors
Prof.TeresaM.V.D.PinhoeMelo UniversityofCoimbra CoimbraChemistryCentre(CQC) DepartmentofChemistry
RuaLarga
3004-535Coimbra
Portugal
Prof.MartaPineiro UniversityofCoimbra CoimbraChemistryCentre(CQC) DepartmentofChemistry
RuaLarga
3004-535Coimbra
Portugal
CoverImage: CourtesyofTeresaM.V.D. PinhoeMeloandMartaPineiro
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Contents
Preface xi
1HeterocyclicCompoundsinEnantioselectivePhotochemical Reactions 1
NorbertHoffmann
1.1Introduction 1
1.2AsymmetricCatalysiswithChiralTemplates 2
1.3AsymmetricPhoto-EnzymeCatalysis 7
1.4AsymmetricPhotochemicalReactionsinCrystals 9
1.5CrystallineInclusionComplexes 12
1.6InclusioninZeolites 13
1.7MemoryofChirality 14
1.8ConclusionandPerspectives 15 References 16
2HeterocyclesviaDearomatizationReactions 27
AlexeyM.StarosotnikovandMaximA.Bastrakov
2.1Introduction 27
2.2AnnulationofHeterocyclesviaDearomativeCycloadditiontoArenes andHetarenes 28
2.2.1[3+2]Cycloaddition 28
2.2.2[4+2]Cycloaddition 36
2.2.3OtherCycloadditions 41
2.3IntramolecularAdditiontoAromaticDoubleBondsLeadingto Heterocycles 42
2.4DearomativeSpirocyclizations 45
2.5ConclusionandPerspectives 51 Acknowledgments 51 References 51
3StrategiesfortheSynthesisofHeterocyclicMacrocyclesand Medium-SizedRings 59
WilliamP.UnsworthandThomasC.Stephens
3.1Introduction 59
3.2HighDilutionandPseudo-HighDilutionMethods 61
3.2.1TraditionalHighDilution/SlowAdditionMethods 61
3.2.2Solid-SupportedMethods 65
3.2.3PhaseSeparation 65
3.3MethodsDesignedtoImpartMoreFavorableCyclization Conformations 67
3.3.1TheImportanceofConformationonMacrocyclization 67
3.3.2StructuralFeaturestoBiasCyclizationConformation 69
3.3.3TemplatedMacrocyclization 71
3.4Ring-ExpansionMethods 71
3.5Medium-SizedRings:SpecialCases 75
3.6ConclusionsandPerspectives 77 References 78
4OrganocatalysisinSyntheticHeterocyclicChemistry 85 ÁngelCores,MercedesVillacampa,andJ.CarlosMenéndez
4.1Introduction 85
4.2OrganocatalyticSynthesisofFive-MemberedHeterocycles 87
4.2.1PyrrolesandPyrrolidines 87
4.2.2FuranandBenzofuranDerivatives 89
4.3OrganocatalyticSynthesisofSix-MemberedHeterocycles 90
4.3.1Pyridines,Dihydropyridines,andPiperidines 90
4.3.2FusedPyridineDerivatives 98
4.3.3Pyrimidines 101
4.3.4PyranandFusedPyrans 101
4.4OrganocatalyticSynthesisofSeven-MemberedHeterocycles 104
4.4.1DiazepinesandFusedDiazepines 104
4.4.2ThiazepinesandFusedThiazepines 106
4.5OrganocatalyticSynthesisofPolyheterocyclic,Bridged,andSpiro Compounds 107
4.6ConclusionandPerspectives 111 Acknowledgments 111 References 111
5TransitionMetalCatalysisinSyntheticHeterocyclic Chemistry 117
DinaMurtinhoandM.ElisadaSilvaSerra
5.1Introduction 117
5.2Copper-CatalyzedSynthesisofHeterocycles 118
5.2.1FusedHeterocycles 118
5.2.2Five-andSix-MemberedN-andN,N-Heterocycles 120
5.2.3Five-andSix-MemberedN,O-Heterocycles 126
5.3Pd-CatalyzedHeterocycleSynthesis 127
5.3.1NitrogenHeterocycles 128
5.3.2OxygenHeterocycles 135
5.3.3N,O-Heterocycles 140
5.4ConclusionandPerspectives 142 Acknowledgments 142 References 142
6BiocatalyticSynthesisofHeterocycles 159 AlinaNastkeandHaraldGröger
6.1Introduction 159
6.2Three-MemberedRingHeterocycles 160
6.2.1N-Heterocycles 160
6.2.2O-Heterocycles 160
6.2.2.1HalohydrinDehalogenases 161
6.2.2.2FAD-DependentMonooxygenases 162
6.2.2.3Heme-DependentMonooxygenases 164
6.2.2.4Peroxygenases 166
6.3Four-MemberedRingHeterocycles 169
6.4Five-MemberedRingHeterocycles 171
6.4.1N-Heterocycles 171
6.4.1.1AliphaticHeterocycles 171
6.4.1.2Lactams 174
6.4.1.3AromaticHeterocycles 178
6.4.2O-Heterocycles 181
6.4.2.1AliphaticHeterocycles 181
6.4.2.2Lactones 184
6.4.2.3AromaticHeterocycles 190
6.4.3S-Heterocycles 194
6.5Six-MemberedRingHeterocycles 195
6.5.1N-Heterocycles 195
6.5.2O-Heterocycles 203
6.6ConclusionandPerspectives 203 References 203
7MulticomponentSynthesisofHeterocycles 215 CarolinaS.Marques,ElisabeteP.Carreiro,andAntónioP.S.Teixeira
7.1Introduction 215
7.2Three-MemberedRingHeterocycles 216
7.3Four-MemberedRingHeterocycles 219
7.4Five-MemberedRingHeterocycles 222
7.4.1Five-MemberedRingHeterocycleswithOneHeteroatom 223
7.4.2Five-MemberedRingHeterocycleswithTwoHeteroatoms 232
7.4.3Five-MemberedRingHeterocycleswithThreeandFour Heteroatoms 236
7.5Six-MemberedRingHeterocycles 237
7.5.1Six-MemberedRingHeterocycleswithOneHeteroatom 237
7.5.2Six-MemberedRingHeterocycleswithTwoHeteroatoms 243
7.5.3Six-MemberedRingHeterocycleswithThreeHeteroatoms 247
7.6Seven-MemberedRingHeterocycles 249
7.7ConclusionsandPerspectives 253 Acknowledgments 253 References 254
8HeterocyclicCompoundsfromRenewableResources 277 GiuseppeMele,SelmaE.Mazzetto,andDiegoLomonaco
8.1Introduction 277
8.2Three-,Five-,Six-,andSeven-MemberedRingHeterocyclesBasedon CNSL 278
8.2.1Oxiranes(Epoxides) 278
8.2.2Benzoxazines 281
8.2.3Cardanol-BasedLactones 284
8.2.4Cardanol-BasedAmphiphilicHeterocycles 284
8.2.5Fulleropyrolidines 285
8.2.6TriazolesandPyrimidineHybrids 286
8.3PorphyrinsandPhthalocyaninesDerivedfromCardanol-Based Precursors 286
8.3.1SynthesesofPorphyrins(Pps)andPhthalocyanines(Pcs)from Cardanol-BasedPrecursors 286
8.3.2ApplicationsofCardanol-DerivedPorphyrins(Pps)andPhthalocyanines (Pcs) 288
8.3.2.1Langmuir–BlodgettFilms 288
8.3.2.2SuperparamagneticFluorescentNanosystems 289
8.3.2.3CorrosionProtection 289
8.3.2.4OrganicLight-EmittingDiodes(OLEDs) 289
8.3.2.5PhotodynamicTherapy 290
8.3.2.6CompositesSemiconductor@SensitizerforEnhancingPhotocatalytic Processes 290
8.3.2.7Photo-ignitionofCarbonNanotubes/Ferrocene/PorphyrinUnderLED Irradiation 291
8.3.2.8IntercalationofPpsintoVesicularNanosystems 292
8.3.2.9NanomaterialsBasedonFe3 O4 andPhthalocyaninesDerivedfrom CNSL 292
8.4ConclusionsandPerspectives 293 Acknowledgments 293 References 293
9SynthesisofHeterocyclesinNonconventionalBio-based ReactionMedia 301
AntonV.Dolzhenko
9.1Introduction 301
9.2HeterocyclizationsinGlycerol 302
9.2.1SynthesisofFive-MemberedHeterocyclesinGlycerol 303
9.2.2SynthesisofSix-MemberedHeterocyclesinGlycerol 308
9.2.3SynthesisofSeven-MemberedHeterocyclesinGlycerol 312
9.3HeterocyclizationsinLacticAcid 313
9.3.1SynthesisofFive-MemberedHeterocyclesinLacticAcid 313
9.3.2SynthesisofSix-MemberedHeterocyclesinLacticAcid 315
9.4Heterocyclizationsin γ-Valerolactone 317
9.4.1SynthesisofFive-MemberedHeterocyclesin γ-Valerolactone 318
9.4.2SynthesisofSix-MemberedHeterocyclesin γ-Valerolactone 320
9.5Heterocyclizationsin2-Methyltetrahydrofuran 322
9.5.1SynthesisofFive-MemberedHeterocyclesin 2-Methyltetrahydrofuran 323
9.5.2SynthesisofSix-MemberedHeterocyclesin 2-Methyltetrahydrofuran 325
9.6HeterocyclizationsinMiscellaneousUnconventionalBio-based Media 327
9.7ConclusionandPerspectives 330 Acknowledgments 330 References 330
10MechanochemistryinHeterocyclicSynthesis 339 VjekoslavŠtrukilandDavorMargeti´c
10.1Introduction 339
10.2MechanosynthesisofN-Heterocycles 341
10.2.1Five-MemberedRingHeterocycles 341
10.2.2Six-MemberedRingHeterocycles 351
10.2.3Porphyrins 354
10.3MechanosynthesisofO-,S-,andOtherHeterocycles 355
10.3.1Three-MemberedRingHeterocycles 355
10.3.2Five-MemberedRingHeterocycles 356
10.3.3Six-MemberedRingHeterocycles 359
10.3.4Eight-MemberedRingHeterocycles 363
10.4ConclusionsandPerspectives 363 References 364
11FlowChemistry:SequentialFlowProcessesfortheSynthesis ofHeterocycles 371 PedroBrandão,MartaPineiro,andTeresaM.V.D.PinhoeMelo
11.1Introduction 371
11.2FlowSynthesisofHeterocycles 372
x Contents
11.2.1Three-MemberedRingHeterocycles 372
11.2.2Four-MemberedRingHeterocycles 374
11.2.3Five-MemberedRingHeterocycles 374
11.2.4Six-MemberedRingHeterocycles 384
11.2.5Seven-MemberedRingHeterocycles 390
11.3ConclusionsandPerspectives 391
Acknowledgments 391 References 391
12MatrixIsolationinHeterocyclicChemistry 401
JoséP.L.Roque,CláudioM.Nunes,andRuiFausto 12.1Introduction 401
12.2StructuralCharacterization 403
12.3UV-InducedPhotochemicalReactivity 412
12.4ThermalReactivity 424
12.5IR-InducedProcesses 429
12.6TunnelinginHeterocyclicChemistry 435
12.7ConclusionandPerspectives 444 Acknowledgments 445 References 445
13NMRStructuralCharacterizationofOxygenHeterocyclic Compounds 453
RicardoA.L.S.Santos,DianaC.G.A.Pinto,andArturM.S.Silva 13.1Introduction 453
13.2Three-MemberedHeterocyclicCompounds 454
13.3Four-MemberedHeterocyclicCompounds 459
13.4Five-MemberedHeterocyclicCompounds 466
13.5Six-MemberedHeterocyclicCompounds 477
13.6ChromeneandXanthene-RelatedCompounds 494
13.7ConclusionsandPerspectives 505 Acknowledgments 506 References 506
Index 525
Preface
Heterocyclicchemistryplaysacentralroleinorganicchemistry,beingthefieldwith thegreatestimpactintermsofapplications.Heterocyclesarewidelypresentinmany naturallyoccurringcompoundsandareparticularlyrelevantinthepharmaceutical andagrochemicalindustriesbesidesbeingimportantmaterialsinotherindustrial applications.Therefore,itdoesnotcomeasasurprisethatanimpressivenumber ofcontributionsonheterocyclicchemistryappeareachyearaimingatthedevelopmentofnovelandmoresustainablesyntheticmethodologiesandtoachievehigher structuraldiversitytomeetthedemandsofthevariousheterocycles’applications.
Theplanningofthebookhad Synthesis,Catalysis,SustainabilityandCharacterization asthemainguidelines.The SyntheticMethods includechaptersonselected “hottopics”coveringthestate-of-the-artonsyntheticapproachestoheterocycles. Thechoiceofthemeswasbasedontherelevanceofthetransformationswithregard tothehighpotentialalreadydemonstratedandprospectsfornewdevelopments. Theycomprisethefollowingtopics:chiralheterocyclesviaenantioselectivephotochemicalreactions,heterocyclesviadearomatizationreactions,andanoverview ofsyntheticstrategiestowardheterocyclicmacrocyclesandmedium-sizedrings. Specialfocuswasalsogivento CatalyticMethods withchaptersonorganocatalysis, transition-metalcatalysis,andbiocatalysis.
Atpresent,therelevanceofgreenchemistryisjustifiedbytheinclusionofselected topicson Sustainability inthecontextofthesynthesisofheterocycliccompounds. Multicomponentsynthesis,synthesisfromrenewableresources,synthesisinnonconventionalreactionmedia,mechanochemistry,andflowchemistryarecovered.
Thebookincludesachapterontheuseofmatrixisolationspectroscopyasatool forstructural Characterization andforunprecedentedmechanisticinsightson reactionsinvolvingheterocycliccompounds.Thefinalchapterisacomprehensive overviewonoxygenheterocycles Characterization byNMRspectroscopy,withgreat practicalutilityforthoseworkingwiththesescaffolds.
Thebookisaimedatadvanced-levelreadersandspecialistsintheareaofheterocyclicchemistry.Thisincludesresearchersfromacademiaandstudentsofadvanced coursesonOrganicChemistry,MedicinalChemistry,andGreenChemistry,aswell asresearchersinthefieldofFineChemicalIndustry.
xii Preface
Thisfeatureofhavingtopicscoveringcutting-edgeresearchonheterocyclicchemistrywasonlypossibleduetocontributionsfromanoutstandinginternationalteam of30authors,whicharegratefullyacknowledged,making Heterocycles–Synthesis, Catalysis,Sustainability,andCharacterization auniquebookthatwehopewill becomeareferenceintheareaofHeterocyclicChemistry.
UniversityofCoimbra,Coimbra 22March2022
TeresaM.V.D.PinhoeMelo MartaPineiro
HeterocyclicCompoundsinEnantioselectivePhotochemical Reactions
NorbertHoffmann
UniversitédeReimsChampagne-Ardenne,CNRS,ICMR,EquipedePhotochimie,UFRSciences,B.P.1039, Reims51687,France
1.1Introduction
Thepresentchapterdealswithdifferentkeytopics.Heterocycliccompoundsplaya centralroleinmanydomainsofchemistrysuchasthesearchofnewbiologically activecompoundsinpharmaceuticalandagriculturalchemistry[1].Also,many newmaterialssuchassemiconductingcompoundscontainheterocyclicmoieties[2].Inthesedomains,alargestructuraldiversityandmolecularcomplexity ishighlyneeded.Here,traditionalmethodsoforganicsynthesisfindtheirlimits. Photochemicalreactionsextendsuchlimits.Aselectronicexcitationcompletely changesthechemicalreactivityofcompoundsorwholefamilyofcompounds[3], products,whichcannotbesynthesizedbymoreconventionalmethodsbecome accessibleandareofhighinterestforapplicationinthefieldofbioactivecompounds[4,5].Furthermore,theoutcomeofknownreactions,especiallycatalytic reactions,canbeimprovedwhentheyarecarriedoutunderphotochemical conditions.Basedontheenormousquantityofrecentandpastresultsinthefield ofphotochemicalreactions,itmakessensetosubdividechemicalreactionsinto twoclasses:reactionsthatoccurintheelectronicgroundstateandreactionsin whichelectronicexcitationisinvolved.Fromtheeconomicandecologicalpointof view,photochemicalreactionsareparticularlyinteresting,sincemanyofthemcan becarriedoutwithoutanadditionalchemicalreagent.Thephotonisconsidered asatracelessreagent[6,7].Forthesereasons,thesereactionsarenowhighly appreciatedinchemicalandpharmaceuticalindustry[8–10].
Stereoselectivityalsoplaysacentralroleinorganicsynthesis.Biologicalactivity andmaterialpropertiesstronglydependonthestereochemistryofchemical compounds.Soonerorlater,almostallsynthesismethodswillfacethisproblem. Inthepast,photochemicalreactionshavebeenconsideredasbeinginherently stereo-unselective.Itwasthoughtthatthehighenergyuptakebylightabsorption inducesuncontrolledrelaxationprocessesthatleadtounselectivereactionswith largeamountsofdegradationeitherofthesubstratesorthephotoproducts[11].
Heterocycles:Synthesis,Catalysis,Sustainability,andCharacterization,FirstEdition. EditedbyTeresaM.V.D.PinhoeMeloandMartaPineiro. ©2022WILEY-VCHGmbH.Published2022byWILEY-VCHGmbH.
1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions
Inthisregard,itmusthoweverbepointedoutthatstereoselectiveandstereospecific photochemicalreactionshavebeenknownfromtheverybeginningofthisresearch area[12,13].Thecontrolleddissipationofthehighelectronicexcitationenergy inphotochemicalreactionsisthereasonforthehighstereoselectivityinsuch reactions[11].Inparticular,photochemicalreactionscanbeconductedenantioselectivelyinchiralsupramolecularstructures[14,15].Enantiopurecompoundsare obtainedindifferentways:theycanbeprepareddirectlyfromotherchiralprecursorssuchasnaturalproducts(“chiralpool”)orbyopticalresolutionusingdifferent typesofchromatographyorcrystallizationtechniques.Asymmetricsyntheses usingchiralauxiliaries,whichareremovedafterthestereoselectivereaction,also provideenantiopurecompounds.Asymmetriccatalysisandenzymaticcatalysis directlyyieldenantioenrichedcompounds.Achiralenantiopureenvironment inasupramolecularstructureorinacrystalmaybetheinductorofchiralityin asymmetricreactions.Inthepresentchapter,methodswillbediscussedleading directlytoenantiopureheterocycliccompoundsviaphotochemicalreactions.
1.2AsymmetricCatalysiswithChiralTemplates
Photochemicalsubstratesmaybecomplexedwithchiralstructuresthatinduce chirality[16].AtypicalexampleisdescribedinScheme1.1[17].Thequinolone derivative 1 carryingapyrrolidinemoietyundergoesanintramolecularcyclization leadingtothespirocyclicindolizidinecompound 6.Thesubstrateiscomplexedwith theenantiopureKempacidderivative(2)viahydrogenbondsbetweentwolactam
Scheme1.1 Enantioselectivesynthesisofaspirocyclicindolizidinecompoundinducedby aphotochemicalelectrontransfer.
1.2AsymmetricCatalysiswithChiralTemplates 3 moieties.Inthisarrangement,thepyrrolidineapproachesthereactioncenter mainlybyonediastereotopichalf-space.Inthiscomplex,theshieldinggroupacts alsoasanaromaticketonesensitizer(sens).Afterphotochemicalexcitationofthe latter,electrontransferfromthetertiaryaminemoietytotheketoneleadsfirsttoa radicalionpair 3 andafterprotontransfertointermediate 4 [18].Thenucleophilic α-aminoalkylradicalattackswith70%ofstereoselectivitytheelectrophilicdouble bondofthequinolonemoiety.Thus,anelectrophilicoxoallylradicalisgenerated affordingthediradicalintermediate 5.Thefinalproduct 6 resultsfromahydrogen transferfromtheketylradicaltotheoxoallylradical.Itmustbepointedoutthatin thepresentcasethisstepisfavoredbecauseitisanintramolecularprocess.Inthese radicalsteps,polareffectsplayanimportantrole[19–21].Inthecorresponding intermolecularstereoselectivereactions,theseeffectscontributeessentiallytothe efficiencyoftheseprocesses[18].Theintermolecularadditionoftertiaryamines toindolonederivativeswithanexocyclicelectron-deficientolefinicdoublebond hasbeencarriedoutwithsimilarKempacidderivatives[22].Inthiscase,however, rutheniumoriridiumcomplexeshavebeenusedasexternalphotoredoxcatalysts thatwereexcitedbyvisiblelightabsorption.
Usingasimilarchiralsensitizer,anintramolecular[2+2]photocycloadditionhas beencarriedoutwithhighenantioselectivity(Scheme1.2)[23].Thequinolone derivative 7 istransformed,undervisiblelightirradiation,intoacomplexpolycyclic compound 8 containingapyrrolidinemoiety.Itmustbepointedoutthatthe same[2+2]photocycloadditionisalsoinducedbyUVirradiationviadirectlight absorptionbutnochiralinductiontakesplace.Itisthereforenecessarytochoose asensitizerthatabsorbsinthevisibledomainofthelightspectrumtoensure enantioselectivity.Thethioxanthonederivative 9 absorbsinthevisiblelightregion andtransferitstripletenergytothecomplexedsubstrate(10).Again,thiscomplexationoccursviahydrogenbondsbetweenthetwolactamsofthesubstrateandthe Kempacidmoietyofthesensitizer.Inthisstructuretheolefinicdoublebondin thesidechainapproachesthereactivecenterofthequinolonealmostonlybyone
Scheme1.2 Constructionofapyrrolidinemoietyusinganenantioselective[2+2] photocycloaddition.Source:AlonsoandBach[23]/JohnWiley&Sons.
1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions diastereotopichalf-space.Similarasymmetricreactionshavebeenperformedwith 3-alkylquinolonescarryinga4-O alkenesidechain.Inthiscase,tetrahydrofuran moietiesareformed[24].
Thesubstratecanalsobecomplexedtoametalorastrongcoordinatingatom. Insuchacase,chiralityisinducedbyachiralligandsphere[25].Inthiscontext, chiralLewisacid 11 wasusedtocatalyzetheasymmetricintramolecular[2+2]photocycloadditionofthedihydropyridinonederivative 12 (Scheme1.3)[26].Inthis reaction,a δ-valerolactammoiety(13)isformed.BycomplexationwithaLewisacid, theabsorptionmaximumofcompound 12 isshiftedfrom290to350nm.Usingfluorescentlampswithanemission ��max = 366nm,complex 14 wasexcitedalmost exclusivelysincethenoncomplexedsubstrate 12 doesnotabsorblightinthisspectral range.Thus,theformationofracemicproductasbackgroundreactionissuppressed. Inthecomplex 14,theapproachoftheolefintothereactioncenteragainoccursby onediastereotopichalf-space.
Scheme1.3 EnantioselectiveLewisacidcatalysisofanintramolecular[2+2] photocycloadditionreaction.Source:BrimioulleandBach[26]/AmericanAssociationfor theAdvancementofScience.
α,α,α′ ,α′ -Tetraaryl-2,2-disubstituted1,3-dioxolane-4,5-dimethanols(TADDOLs, e.g. 23)arecapableofcomplexingnumeroussubstratesviahydrogenbonds[27]. Whenaphotochemicalsubstrateiscomplexedwithsuchcompounds,chiralitycan beinduced.Undertheseconditions,whentheflavonederivative 15 wasirradiated withthediphenylbutadiene 16,a[2+3]cycloadditiontookplace,leadingto compounds 17 and 18 (Scheme1.4)[28].AfterreductionwithNaBH4 ,compounds 19 and 20 wereisolatedingoodyields.Furthermore,themajordiastereoisomer 19 wasobtainedinhighenantioselectivity,andrecrystallizationledtoalmost enantiopuresamples.Thehighenantioselectivityofthephotochemicalreaction wasexplainedbythestructureofcomplex 21,whichstronglyfavorstheattackofthe olefinbyonlyonediastereotopichalf-space.Interestingly,whenthestericallymuch lessencumberedchiralalcohol 22 wasaddedinsteadoftheTADDOLcompound
Scheme1.4 Asymmetricsynthesisof( )-foveoglinAusingESIPT-promoted[2+3] cycloadditionwithaflavonederivative.Source:Wangetal.[28]/JohnWiley&Sons.
23,anefficientchiralinductionwasstillobserved.Thehighenantioselectivity observedwithhydrogenbondcomplexescanalsobeexplainedbythefactthat excitedstateintramolecularprotontransfer(ESIPT)playsakeyroleinthereaction mechanism[29].Infact,itwasshownthatthecycloadditionoccurredatthetriplet stateof 15 andthatmostprobablysingleelectrontransferisinvolved.Compound 19 wastransformedinto(+)-foveoglinA,whichistheenantiomerofanatural product.Thiscompoundfamilyplaysanimportantroleinmedicinalchemistryas theypossessanticancerandantiviralactivities.
Thecyclizationreactionoftwoalkynesandonenitrilefunctionisaconvenient methodforthepreparationofpyridinecompounds[30].Itcanbecarriedoutunder particularmildconditionswhensimpleandinexpensivecobaltcatalystssuchas 24 areused(Scheme1.5)[31].Underirradiationwithvisiblelight,theformation ofthecobaltacyclopentadieneintermediate 25 isaccelerated,andtheadditionof thenitrileleadingtotheintermediate 26 or 27 becomestherate-determiningstep. Theconsumptionofthenitrilesubstratebecomesthefirst-orderreactionstep. Undertheseparticularlymildconditions,avarietyofpyridinederivativeshave beensynthesizedpossessingfragilesubstituents(Figure1.1)[32].Asymmetric catalysiswasalsosuccessfullyperformed.Thecyclopentadienylligandinthe
Scheme1.5 Visiblelight-supportedcobalt-catalyzed[2+2+2]cycloadditionappliedtothe synthesisofpyridines.
Figure1.1 Pyridinesthathavebeensynthesizedundermildconditionsusing photochemicallypromotedcobalt-catalyzed[2+2+2]cycloaddition.
cobaltcatalystwasreplacedbychiralanalogs,bestresultsbeingobtainedwith catalyst 28 (Scheme1.6)[33].Withthisreactionaxialchiralitycanbeefficiently inducedasshownbythetransformationofcompound 29 intonaphthylpyridine 30.Similarreactionshavebeencarriedoutstartingfrom2-alkoxy-1-naphthonitriles 31 usingdifferentchiralcobaltcomplexesascatalysts.Eitherdiineswereused, leadingtotetracycliccompounds 32,or2equivofamonoalkynewereemployed, yieldingthecorrespondingtricyclicproducts 33.Inthispartofthestudy,the chiralcatalysts ent-28, 34, 35, 36,and 37 havealsobeentested.Thestudyof thistypeofchirality,atropisomerism,hasrecentlygainedparticularattentionin photochemistry[34].
Scheme1.6 Visiblelight-supportedasymmetric[2+2+2]cycloadditionusingchiralcobalt catalysts.
1.3AsymmetricPhoto-EnzymeCatalysis
Enzymecatalysisisageneralmethodtoproduceenantiomericallyenrichedorpure compounds.Manysuchtransformationsneedmulti-enzymesystemsthatcomplicatetheapplicationtoorganicsynthesis.Insomecases,however,thereplacement ofoneormoreenzymeactivitiesbyachemicaltransformationfacilitatesthetransformations.Astheytoleratealargevarietyofreactionconditions,photochemical reactionswereefficientlyappliedinthiscontext[35].
TheBaeyer–Villigermonooxygenase(BVMO)asymmetricallycatalyzesthe transformationofketonesintoestersorlactonesinthecaseofcyclicketones (Scheme1.7)[36].Thisenzymecontainsaflavinadeninedinucleotide(E-FADred ) unit,whichreducesmolecularoxygenintohydrogenperoxidecapableofoxidizingtheketonesubstrate.Theoxidizedflavinspecies(E-FADox )isreduced bynicotinamideadeninedinucleotidephosphate(H)(NADPH).Theresulting nicotinamideadeninedinucleotidephosphate(NADP+ )isreducedviaaglucose dehydrogenase-catalyzedreaction.Thissecondenzymeactivitycanbereplacedby addingflavin(FAD)tothereactionmixture.Thereducedformofthenonbound FADred iscapableofreducingtheenzyme-boundE-FADox .Attheexcitedstate, FADox (generatedbyirradiationwithvisiblelight)iseasilyreducedviaelectron transferfromasacrificialelectrondonorsuchasethylenediaminetetraaceticacid (EDTA).
β-D-glucose D-glucono1,5-lactone
Glucose dehydrogenase
BVMO:Baeyer–Villiger monooxygenase NADP+ NADPH
R:Adeninedinucleotide
E-FAD:EnzymeboundFAD
Coproduct
FADox FADred
R:Adeninedinucleotide
E-FAD:EnzymeboundFAD
BVMO:Baeyer–Villiger monooxygenase
Scheme1.7 Replacementoftheglucosedehydrogenasebyasimplephotoredoxcatalytic systembasedonnonboundFAD.
UndertheseconditionstheasymmetricBaeyer–Villigerreactionwascarriedoutwiththeracemic2-phenylcyclohexanone 38 (Scheme1.8)[37].Only the R-enantiomerwasoxidized,andthephenylcaprolactone 39 wasobtained inhighenantioselectivity.Theracemiccyclobutanonederivative 40 hasbeen transformedunderthesameconditions.Interestinglybothenantiomerswere oxidizedbutdifferentoutcomeswereobserved.The α-S-enantiomeryieldsthe bicyclicbutyrolactone 41,whereasthe α-R-enantiomeristransformedintoregioisomer 42.Bothcompoundsareformedinhighenantioselectivity.Compound 41 istheexpectedregioisomerofaBaeyer–Villigerreaction.Dependingonthe stereochemistryofthestartingketone,theenzymeactivityisthereforecapable ofdirectingtheregioselectivityofthereaction[38].Itshouldbepointedoutthat undersuchreactionconditions,hydrogenperoxideisgeneratedinlowstationary concentrationthatreducestheenzymedegradation[39].
Combinedphoto-andenzymecatalysiswasalsocarriedoutwithalcohol dehydrogenases(ADH)[40].TheseenzymesuseNAD(P)H/NAD(P)+ ascofactor[41].Inordertooptimizetheenzymeactivity,thiscofactorsystemmustbe regenerated[42].Oneofthehydroxylfunctionalitiesoftheachiraldiol 43 isdehydrogenatedtoanaldehydebyhorseliveralcoholdehydrogenase(HLADH)with molecularoxygen(Scheme1.9)[43].Cyclizationleadstothelactol 44,areversible step.InaseconddehydrogenationalsocatalyzedbyHLADH,thelactolisoxidized
Scheme1.8 Enzyme-catalyzedenantioselectiveBaeyer–Villigerreactionappliedtothe synthesisoflactones.Source:Hollmannetal.[37]/JohnWiley&Sons.
Scheme1.9 Enantiospecificoxidationoftheachiraldiol 43 to4-methyl-δ-valerolactone 45 usingaphotobiocatalyticprocess.Source:Rauchetal.[43]/RoyalSocietyofChemistry.
tothe4-methyl-δ-valerolactone 45,obtainedwithcompleteenantioselectivity. Inthesesteps,hydrogenistransferredtoNAD+ andNADHisformed.NAD+ is regeneratedbyhydrogentransfertooxygenleadingtohydrogenperoxide.Thisstep isphotocatalyzedbyflavinmononucleotide(FMN).Theirradiationwascarried outwithblueLED(��max = 465nm).Undersimilarreactionconditionsandusinga flavin-dependent“ene”-reductase,avarietyoflactamshavebeenobtainedinhigh enantioselectivity[44].
Thecombinationofenzymaticreactionswithphotochemical,inparticular photoredoxprocesses,offersnumerousperspectivesfororganicsynthesis[45]. Thiscombinationisaparticularlyefficientapproachinconnectionwithsustainable orgreenchemistry.Astheseprocessesarethebasisofphotosynthesisingreen plants,theyhavebeensuggestedofpotentialrelevanceforasustainablechemical industrybyG.Ciamicianmorethan100yearsago[46].Itwasthebeginningof greenchemistry[47]althoughithasbeenalmostforgottenoverthedecades.
1.4AsymmetricPhotochemicalReactionsinCrystals
Asymmetricsynthesisisoftenbasedonselectionofconformations.Anefficient methodtodothisistocarryoutreactionsatthecrystallinestate.Molecular
1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions symmetryandcrystallographyarestronglylinked[48].Particularlyimpressive photochemicalreactionshavebeenreportedwithachiralsubstratesthatcrystallize inSohnckespacegroups[49,50].Whenachiralcompoundscrystallizeinthese spacegroups,mostfrequently,oneenantiopureconformerispresentinsuch homochiralcrystals[51,52].
When α-ketoamides 46 areirradicatedatthesolidstate,thehydroxy-β-lactams 47 areobtainedinhighenantioselectivity(Scheme1.10)[53].Afterlightabsorption,a hydrogenatomistransferredfromanisopropylgrouptothe α-ketofunctionleading tothediradical 48.Radicalcyclizationyieldsthefinalproduct 47.Allthesereaction stepsoccurunderconformationalcontrolexertedbythecrystalenvironment. Inmostcases,enantiomericexcesses(ee)werehigherthan90%.Inthecaseof Ar = Ph,thesubstratecrystallizedinthechiralspacegroup P21 21 21 [54].Irradiation ofthehomochiralcrystalsyieldsproduct 47 (Ar = Ph)in93%ee,whichcrystallized inthesamespacegroup P21 21 21 .Bothenantiomershavebeenselectivelyprepared choosingthecorrespondinghomochiralcrystalsofthesubstrate.Undersimilar conditionstheachiral α,β-unsaturatedthioamide 49 wastransformedintothe thio-β-lactam 50 [55].Afterphotochemicalexcitation,ahydrogenwastransferred fromoneofthebenzylpositionsintothe β-positionofthecyclohexenemoiety(51). Radicalcombinationyieldsthefinalproduct 50.Thestartingproductcrystallizedin the P21 spacegroup,andwhenhomochiralcrystalswereirradiated,oneenantiomer of 50 wasobtainedinhighenantiomericexcess.Itisnoteworthythat,when compound 49 wasirradiatedinsolution,thesameproduct 50 wasisolatedbutas aracemicmixturealongwithsideproducts[56].Variousotherexamplesofthis approachtochiralcompoundshavebeenreported[57].
Scheme1.10 Synthesisof β-lactamsusingabsoluteasymmetricsynthesiswith homochiralcrystalsoftheachiralsubstrates.Eachenantiomerhasbeenselectively producedfromthecorrespondinghomochiralcrystalofthesubstrate.
Thismethodfortheproductionofonlyoneenantiomerwithoutexternalchiral inductionispartofabsoluteasymmetricsynthesis.Usingparticularcrystallization methods,e.g.seedingcrystallizationwiththedesiredhomochiralcrystal,the achiralstartingcompoundcanbeselectivelytransformedintoonlyoneofthe homochiralcrystals[58].Itshouldfurtherbepointedoutthatsuchsolid-statephotochemicalreactionscanalsobecarriedoutonlargerscalewhensuspensionsare irradiated[59].
1.4AsymmetricPhotochemicalReactionsinCrystals 11
Acertaincontrolofthecrystalsymmetrycanbeobtainedbyattachinga homochiralelementtothesubstrate.Inthiscase,thenumberofpossiblespace groupsisreducedto65(Sohnckegroups).Adefinedchiralenvironmentisthus createdaroundthephotochemicalsubstrate[48–51].Inordertoobtainenantiomericallypureorenrichedphotochemicalproducts,thechiralelementshouldnotbe covalentlybondedtothephotochemicalsubstrate[60].Inthiscontext,ammonium saltsofchiralaminesand α-ketoamide 52 carryingacarboxylatefunctionhave beenprepared,andthecrystallinephasewasirradiated(Scheme1.11)[61].In mostcases,theresultinghydroxyl β-lactams 53 havebeenobtainedinhighyield andenantioselectivity.Theoxooxazolidinederivatives 54 wereformedinminor amounts.Bothenantiomersofcarboxylates 53 or 54 havebeenobtainedasmajor stereoisomersdependingontheconfigurationofthechiralammoniumcation.The absoluteconfigurationofthecarboxylateshasnotbeendeterminedinthisstudy.
Scheme1.11 Synthesisof β-lactamsbyirradiationofcrystallinechiralammoniumsalts.
Source:Natarajanetal.[61]/AmericanChemicalSociety.
Asimilarnorbornene 55 derivativehasbeentransformedunderthesameconditions(Scheme1.12)[62].Uponirradiation,thecarbonylisaddedtothealkene functionleadingtothetriplet1,4-diradicalintermediate 56,whichisatypicalintermediateofthePaternò–Büchireaction[63].SuchintermediatesmayundergoC—C bondformationleadingtooxetanes.BondcleavageofthenewlyformedC—Obond (b)canalsotakeplaceregeneratingthestartingcompound.Thisreactionstepplays akeyroleinthestereoselectivePaternò–Büchireactioninsolution[11,64].However,inthepresentcase,aC—Cbond(a)ofthenorbornenemoietyiscleaved, yieldingthefinalproduct 57,abicyclicdihydrofuranderivative.Inmostcases,high stereoselectivitywasobserved.Thereactionisaphoto-Claisenrearrangement[65] withintersystemcrossingtakingplace.
Scheme1.12 Asymmetricphoto-Claisenrearrangementbyirradiationofcrystallinechiral ammoniumsalts.Source:Xiaetal.[62]/AmericanChemicalSociety.
1.5CrystallineInclusionComplexes
Aspointedoutearlier,TADDOLsareauxiliariesthatefficientlyinducechiralitywithoutbeingcovalentlybondedtothereactingmolecule[27].Using co-crystallizationofthesecompoundswithsubstratesofphotochemicalreactions isaninterestingstrategyforasymmetricsynthesis[66,67].CrystalsofTADDOLs arehoststructureswithcavitiesthatcanbefilledbyguestmolecules.When co-crystallizedwithaTADDOLderivativeina1:1ratio,thefuroicacidamide 58 undergoesenantioselectivelyphotocycloadditionyieldingthequinolinonecompound 59 (Scheme1.13)[68].Duetoitspolarmesomericstructure 60,theamide constitutesa6π systemwithbenzeneandfuranmoieties.Therefore,itundergoes conrotatoryphotocyclizationleadingto 61.Thefinalproduct 59 isformedviaa tautomerizationstep.Thesamereactionwascarriedoutwiththeacrylanilide derivative 62 (Scheme1.13).Co-crystalsofa1:1ratiowiththesameTADDOL havebeenirradiated.Again,thequinolinonecompound(63)wasobtainedinhigh enantiomericexcess.Guestmoleculescaninteractprincipallyintwodifferentways withtheTADDOLhostmatrix.Theycanapproachthehostmoleculeswiththeir polarface,whichmayleadtotheformationofhydrogenbonds.Thiswasobserved forthefuroicacidamide 58 (Figure1.2a).Guestmoleculesmayalsointeractwith thearylsubstituentsoftheTADDOLs.Insuchcases,vanderWaals, π–π-stacking,or
Scheme1.13 PhotocyclizationinTADDOLco-crystalsyieldingquinolonesinhigh enantioselectivity.Source:Todaetal.[68]/AmericanChemicalSociety.
Figure1.2 X-raystructuresofcompound 58 (a)and 62 (b)in1:1co-crystalswitha TADDOL(compareScheme1.13).
edge-to-faceinteractions[69]canbeobserved.Thismaybethecaseinthereaction ofcompound 62 (Figure1.2b).
Numerousphotochemicalreactionshavebeenperformedusingcyclodextrins inclusioncomplexes[15,70].Inwatersolution,cyclodextrinsformsuchcomplexes withavarietyoforganicmolecules.However,inmanycaseswhen β-cyclodextrin isused,theinclusioncomplexesarelesssoluble,andthecorrespondingsuspensions,powders,orfilmsareirradiated.Inthiscontext,asuspensionofthe1:1 complexof β-cyclodextrinandtheazepinone 64 hasbeenirradiatedwithUVlight (Scheme1.14)[71].Thephotochemicalproduct 65 washydrogenated,andthe correspondingbicyclic γ-butyrolactam 66 wasisolatedingoodyieldsandmoderate enantioselectivity.Similarresultshavebeenobtainedwhenfilmsoftheinclusion complexwereirradiated.Whenthephotochemicalreactionof 64 inthepresence of β-cyclodextrinwascarriedoutinsolution,followedbyhydrogenation, 66 was isolatedasaracemicmixture.Obviously,undertheseconditions,noinclusionof 66 takesplace.
-Cyclodextrin
Scheme1.14 Photocyclizationofthedihydroazepinone 64 aspartofaninclusion complexwith β-cyclodextrin.Source:Mansouretal.[71]/AmericanChemicalSociety.
1.6InclusioninZeolites
Zeolitesareinorganiccrystallineporousmaterialsthatabsorbsmall-or medium-sizedmoleculesdependingonthecavitysize[72].Theyarefrequently usedascatalysts.Concerningphotochemicalreactions,theyhavebeenusedasa
1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions
hoststructurefororganicmolecules[73,74].Thephotocyclizationofpyridones 67 tothebicyclic β-lactams 68 hasbeenperformedinsupercagesofMYzeolites,where Maredifferentalkalimetalions(Scheme1.15)[75].Inordertocreateachiral environment,inclusionintothesupercagesofMYzeoliteof( )-norephedrineor ( )-ephedrinetogetherwiththesubstrate 67 wascarriedout.Inordertoassure maximuminteractionwiththechiralinductor,theaminoalcoholswereusedin a10-foldexcess.IncasesoflargersubstituentsR,thebicyclic β-lactams 68 have beenobtainedwithenantiomericexcessesupto53%.Theconfinementofthe non-covalentlybondedchiralinductorwiththepyridonesubstratesreducesthe numberofconformers.Theproximityofthechiralinductordirectsthisselection inanenantioselectiveway.Itmustbepointedoutthatwhenthesamereactions werecarriedoutinsolution,almostnochiralinductionwasobserved.Thereaction wasalsoperformedwithpyridonesubstratesinwhichchiralaminederivatives werecovalentlybonded.Insuchcases,significantdiastereoselectivitywasobserved whencompoundswereabsorbedbyYzeolites.
Scheme1.15 Photochemicaltransformationofpyridones 67 tobicyclic β-lactams 68 co-absorbedwithchiralaminoalcoholsinYzeolites.Source:Sivasubramanianetal.[75]/ RoyalSocietyofChemistry.
1.7MemoryofChirality
Inmanystereoselectivereactions,thechiralinformationistransferredfromachiral center,forexample,achiralcarbonatom,tothereactioncenter[76].Theresulting productsareformedwithdiastereoselectivity.Insomecases,however,suchachiral centerisdestroyed,andthechiralinformationisconserved(memoryofchirality) inmoreorlessstableconformersorothernon-covalentinteractions.Inthisway, suchreactionsbecomestereo-orenantioselective.Suchphenomenaarepartof chiralmemoryeffects[77,78].Inthiscontext,theprolinederivative 69 hasbeen irradiatedinanacetone/watermixture(Scheme1.16)[79].Undertheseconditions, sensitizationoccursviatripletenergytransferfromphotochemicalexcitedacetone to 69.Intramolecularelectrontransferoccursfromthecarboxylatefunctionality tothephthalimidemoiety(70).Immediatedecarboxylationtakesplaceandan α-aminoalkylradical(71)isgenerated.Inthisreactionstep,thechiralinformation attheformerprolinemoietyislost.Radicalcyclizationleadstothefinalproduct
