Edited by

Valentine G. Nenajdenko

Isocyanide Chemistry

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E-Book

ISBN: 978-0-470-62653-5

Edited by Valentine G. Nenajdenko

Isocyanide Chemistry

Applications in Synthesis and Material Science

The Editor

Prof. Dr. Valentine G. NenajdenkoMoscow State UniversityLeninskie Gory119992 MoscowRussia

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V

Contents

Preface XIIIListofContributors XV

1 ChiralNonracemicIsocyanides 1LucaBanfi,AndreaBasso,andRenataRiva

1.1 Introduction 11.2 SimpleUnfunctionalizedIsocyanides 11.3 IsocyanidesContainingCarboxylic,Sulfonyl,orPhosphonyl

Groups 41.3.1 α-IsocyanoEsters 41.3.2 α-IsocyanoAmides 71.3.3 OtherIsocyanoEstersorAmides 91.3.4 ChiralSulfonylmethylorPhosphonylmethylIsocyanides 101.4 IsocyanidesContainingAminoorAlcoholicFunctionalities 111.4.1 ChiralAminoorAzidoIsocyanides 111.4.2 ChiralHydroxyIsocyanides 121.5 NaturalIsocyanides 161.5.1 IsolationandNaturalSources 161.5.2 SynthesisofNaturallyOccurringIsocyanides 171.6 IsocyanidesUsedintheSynthesisofChiralPolyisocyanides 231.6.1 Properties 241.6.2 Synthesis 251.6.3 Applications 26

References 26

2 GeneralAspectsofIsocyanideReactivity 35MaximA.Mironov

2.1 Introduction 352.2 Isocyanide–CyanideRearrangement 372.3 Oxidation/ReductionoftheIsocyanoGroup 412.3.1 OxidationoftheIsocyanoGroup 412.3.2 ReactionswithSulfurandSelenium 43

VI Contents

2.3.3 ReductionoftheIsocyanoGroup 452.4 ReactionsofIsocyanideswithElectrophiles 472.4.1 ReactionwithAcids 492.4.2 ReactionswithHalogensandAcylHalides 522.4.3 ReactionswithActivatedAlkenesandAlkynes 552.4.4 ReactionswithCarbonylCompoundsandImines 582.4.5 ReactionswithActivatedHeterocumulens 602.5 ReactionsofIsocyanideswithNucleophiles 622.5.1 ReactionswithOrganometallicCompounds 622.5.2 ReactionswithHydroxide,Alcohols,andAmines 642.6 Conclusions 66

References 67

3 α-AcidicIsocyanidesinMulticomponentChemistry 75NielsElders,EelcoRuijter,ValentineG.Nenajdenko,andRomanoV.A.Orru

3.1 Introduction 753.2 Synthesisofα-AcidicIsocyanides 763.3 Reactivityofα-AcidicIsocyanides 783.4 MCRsInvolvingα-AcidicIsocyanides 803.4.1 vanLeusenImidazoleMCR 813.4.2 2,6,7-TrisubstitutedQuinoxalineMCR 823.4.3 4,5-DisubstitutedOxazoleMCR 833.4.4 NitropyrroleMCR 833.4.5 2,4,5-TrisubstitutedOxazoleMCR 843.4.5.1 2,4,5-TrisubstitutedOxazoles 843.4.5.2 Variationsonthe2,4,5-TrisubstitutedOxazoleMCR 863.4.5.3 OxazoleMCRandIn-SituDominoProcesses 883.4.6 2-ImidazolineMCR 913.4.6.1 2-ImidazolineMCRintheUnionofMCRs 933.4.7 DihydropyridoneMCR 953.5 Conclusions 97

References 98

4 SyntheticApplicationofIsocyanoaceticAcidDerivatives 109AntonV.Gulevich,AlexanderG.Zhdanko,RomanoV.A.Orru,andValentineG.Nenajdenko

4.1 Introduction 1094.2 Synthesisofα-IsocyanoacetateDerivatives 1094.3 AlkylationofIsocyanoaceticAcidDerivatives 1134.4 α-IsocyanoacetatesasMichaelDonors 1154.5 ReactionofIsocyanoaceticAcidswithAlkynes:Synthesisof

Pyrroles 1194.6 ReactionofIsocyanoaceticAcidDerivativeswithCarbonyl

CompoundsandImines 1214.6.1 Aldol-TypeReactionofIsocyanoaceticAcidswithAldehydes:

SynthesisofOxazolines 122

Contents VII

4.6.2 TransitionMetal-CatalyzedAldol-TypeReactions 1244.6.3 ReactionofIsocyanoaceticAcidswithImines:Imidazoline

Formation 1264.7 ReactionwithAcylatingAgents 1294.8 MulticomponentReactionsofIsocyanoacetic

AcidDerivatives 1334.9 ChemistryofIsocyanoacetatesBearinganAdditionalFunctional

Group 1344.10 ReactionsofIsocyanoaceticAcidswithSulfurElectrophiles 1384.11 MiscellaneousReactions 1394.12 ConcludingRemarks 1444.13 NotesAddedinProof 145

References 145

5 UgiandPasseriniReactionswithCarboxylicAcidSurrogates 159LaurentElKaïmandLaurenceGrimaud

5.1 Introduction 1595.2 CarboxylicAcidSurrogates 1605.2.1 ThiocarboxylicAcids 1605.2.2 CarbonicAcidandDerivatives 1635.2.3 SelenideandSulfide 1655.2.4 Silanol 1655.2.5 IsocyanicAcidandDerivatives 1665.2.6 HydrazoicAcid 1675.2.7 PhenolsandDerivatives 1715.2.8 Cyanamide 1795.3 UseofMineralandLewisAcids 1805.3.1 UgiandPasseriniReactionsTriggeredbyMineralAcids 1815.3.2 UgiandPasseriniReactionsTriggeredbyLewisAcids 1845.4 Conclusions 189

References 189

6 Amine(Imine)ComponentSurrogatesintheUgiReactionandRelatedIsocyanide-BasedMulticomponentReactions 195MikhailKrasavin

6.1 Introduction 1956.2 HydroxylamineComponentsintheUgiReaction 1966.3 HydrazineComponentsintheUgiReaction 2006.4 MiscellaneousAmineSurrogatesfortheUgiReaction 2186.5 ActivatedAzinesinReactionswithIsocyanides 2206.6 Enamines,MaskedImines,andCyclicIminesinthe

UgiReaction 2236.7 ConcludingRemarks 227

Acknowledgments 227References 227

VIII Contents

7 MultipleMulticomponentReactionswithIsocyanides 233LudgerA.Wessjohann,RicardoA.W.NevesFilho,andDanielG.Rivera

7.1 Introduction 2337.2 One-PotMultipleIMCRs 2347.2.1 SynthesisofMultivalentGlycoconjugates 2367.2.2 SynthesisofHybridPeptide–PeptoidPodands 2377.2.3 CovalentModificationandImmobilizationofProteins 2407.2.4 AssemblyofPolysaccharideNetworksasSyntheticHydrogels 2417.2.5 SynthesisofMacromoleculesbyMulticomponent

Polymerization 2437.3 Isocyanide-BasedMultipleMulticomponentMacrocyclizations 2437.3.1 SynthesisofHybridMacrocyclesbyDoubleUgi-4CR-Based

Macrocyclizations 2447.3.2 SynthesisofMacrobicyclesbyThreefoldUgi-4CR-Based

Macrocyclization 2467.4 SequentialIsocyanide-BasedMCRs 2487.4.1 SequentialApproachestoLinearandBranchedScaffolds 2487.4.2 SequentialApproachestoMacrocycles 2547.4.3 ConvergentApproachtoNaturalProductMimics 2567.5 Conclusions 257

References 258

8 ZwitterionsandZwitterion-TrappingAgentsinIsocyanideChemistry 263AhmadShaabani,AfshinSarvary,andAliMaleki

8.1 Introduction 2638.2 GenerationofZwitterionicSpeciesbytheAdditionofIsocyanidesto

Alkynes 2658.2.1 CH-AcidsasZwitterion-TrappingAgents 2668.2.2 NH-AcidsasZwitterion-TrappingAgents 2718.2.3 OH-AcidsasZwitterion-TrappingAgents 2738.2.4 CarbonylCompoundsasZwitterion-TrappingAgents 2758.2.5 ImineCompoundsasZwitterion-TrappingAgents 2788.2.6 Electron-DeficientOlefinsasZwitterion-TrappingAgents 2798.2.7 MiscellaneousCompoundsasZwitterion-TrappingAgents 2808.3 GenerationofZwitterionicSpeciesbytheAdditionofIsocyanidesto

Arynes 2838.4 GenerationofZwitterionicSpeciesbytheAdditionofIsocyanidesto

Electron-DeficientOlefins 2848.5 MiscellaneousReportsfortheGenerationofZwitterionic

Species 2868.6 IsocyanidesasZwitterion-TrappingAgents 2878.7 Conclusions 289

Acknowledgments 289References 289

Contents IX

9 RecentProgressinNonclassicalIsocyanide-BasedMCRs 299RosarioRamón,NicolaKielland,andRodolfoLavilla

9.1 Introduction 2999.2 TypeIMCRs:IsocyanideAttackonActivatedSpecies 3009.3 TypeIIMCRs:IsocyanideActivation 3089.4 TypeIIIMCRs:FormalIsocyanideInsertionProcesses 3209.5 Conclusions 327

Acknowledgments 327References 327

10 ApplicationsofIsocyanidesinIMCRsfortheRapidGenerationofMolecularDiversity 335MuhammadAyaz,FabioDeMoliner,JustinDietrich,andChristopherHulme

10.1 Introduction 33510.2 Ugi/Deprotect/Cyclize(UDC)Methodology 33710.2.1 Ugi-4CC:OneInternalNucleophile 33710.2.2 TMSN3-ModifiedUgi-4CC:OneInternalNucleophile 34310.2.3 Ugi-4CC:TwoInternalNucleophiles 34410.2.4 Ugi-4CC:ThreeInternalNucleophiles 34710.2.5 Ugi-5CC:OneInternalNucleophile 34810.3 SecondaryReactionsofUgiProducts 35010.3.1 NucleophilicAdditionsandSubstitutions 35110.3.1.1 Alkylations 35110.3.1.2 MitsunobuReactions 35210.3.1.3 LactonizationandLactamization 35410.3.2 Base-orAcid-PromotedCondensations 35510.3.3 NucleophilicAromaticSubstitutions 35510.3.4 Palladium-MediatedReactions 35610.3.5 Ring-ClosingMetatheses 35810.3.6 Staudinger–aza-WittigReactions 35810.3.7 Cycloadditions 35910.4 TheBifunctionalApproach(BIFA) 36110.4.1 ApplicationsofAminoAcids 36310.4.2 ApplicationsofCyclicImines 36510.4.3 ApplicationsofTetheredAldehydeandKetoAcids 36610.4.4 HeterocyclicAmidinesasaTetheredUgiInput 37110.4.5 CombinedBifunctionalandPost-CondensationModifications 372

Acknowledgments 375Abbreviations 375References 376

X Contents

11 SynthesisofPyrrolesandTheirDerivativesfromIsocyanides 385NoboruOnoandTetsuoOkujima

11.1 Introduction 38511.2 SynthesisofPyrrolesUsingTosMIC 38611.3 SynthesisofPyrrolesUsingIsocyanoacetates 39111.3.1 SynthesisfromNitroalkenes 39111.3.2 Synthesisfromα,β-UnsaturatedSulfones 39611.3.3 SynthesisfromAlkynes 40111.3.4 SynthesisfromAromaticNitroCompounds:Isoindole

Derivatives 40211.4 SynthesisofPorphyrinsandRelatedCompounds 40711.4.1 Tetramerization 40711.4.2 Meso-TetraarylporphyrinsviatheLindseyProcedure 41211.4.3 [3+2]and[2+2]Methods 41411.4.4 Expanded,Contracted,andIsomericPorphyrins 41411.4.5 FunctionalDyesfromPyrroles 42011.5 Conclusion 423

References 424

12 Isocyanide-BasedMulticomponentReactionstowardsBenzodiazepines 431YijunHuangandAlexanderDömling

12.1 Introduction 43112.2 1,4-BenzodiazepineScaffoldsAssembledviaIMCRChemistry 43312.2.1 Two-RingSystems 43312.2.2 Fused-RingSystems 44012.3 1,5-BenzodiazepineScaffoldsAssembledviaIMCRChemistry 44312.4 Outlook 446

References 446

13 ApplicationsofIsocyanidesintheSynthesisofHeterocycles 451IriniAkritopoulou-Zanze

13.1 Introduction 45113.2 Furans 45113.3 Pyrroles 45313.4 Oxazoles 45913.5 Isoxazoles 46113.6 Thiazoles 46413.7 Imidazoles 46613.8 Pyrazoles 46613.9 OxadiazolesandTriazoles 47013.10 Tetrazoles 47113.11 BenzofuransandBenzimidazoles 47313.12 Indoles 47313.13 Quinolines 477

Contents XI

13.14 Quinoxaline 479Abbreviations 480 References 480

14 RenaissanceofIsocyanoarenesasLigandsinLow-ValentOrganometallics 493MikhailV.Barybin,JohnJ.Meyers,Jr,andBradM.Neal

14.1 HistoricalPerspective 49314.2 IsocyanidemetalatesandRelatedLow-ValentComplexes 49714.2.1 Introduction 49714.2.2 Four-CoordinateIsocyanidemetalatesandRedox-Related

Complexes 49714.2.3 Five-CoordinateIsocyanidemetalates 50214.2.4 Six-CoordinateIsocyanidemetalatesandRedox-Related

Complexes 50414.3 CoordinationandSurfaceChemistryofNonbenzenoid

Isocyanoarenes 50814.3.1 Isocyanoazulenes 50814.3.2 Organometallicη5-Isocyanocyclopentadienides 50914.3.3 HomolepticComplexesofNonbenzenoidIsocyanoarenes 51014.3.4 BridgingNonbenzenoidIsocyanoarenes 51414.3.5 Self-AssembledMonolayerFilmsofNonbenzenoidIsocyano-and

DiisocyanoarenesonGoldSurfaces 51714.4 ConclusionsandOutlook 521

Acknowledgments 522References 523

15 CarbeneComplexesDerivedfromMetal-BoundIsocyanides:RecentAdvances 531KonstantinV.LuzyaninandArmandoJ.L.Pombeiro

15.1 Introduction 53115.2 CouplingoftheIsocyanideLigandwithSimpleAminesor

Alcohols 53215.3 CouplingoftheIsocyanideLigandwithFunctionalizedAminesor

Alcohols 53715.4 CouplingoftheIsocyanideLigandwithaHydrazineor

Hydrazone 53715.5 CouplingoftheIsocyanideLigandwithanImineorAmidine 53815.6 IntramolecularCyclizationsofFunctionalizedIsocyanide

Ligands 54015.7 CouplingofIsocyanideswithDipoles 54315.8 OtherReactions 54415.9 FinalRemarks 546

Acknowledgments 546References 547

XII Contents

16 Polyisocyanides 551NielsAkeroyd,RoelandJ.M.Nolte,andAlanE.Rowan

16.1 Introduction 55116.1.1 ChiralPolymers 55116.1.2 PolyisocyanidesandTheirMonomers 55316.2 ThePolymerizationMechanism 55316.3 ConformationofthePolymericBackbone 55616.4 Polyisocyanopeptides 56116.5 PolyisocyanidesasScaffoldsfortheAnchoringofChromophoric

Molecules 56316.6 FunctionalPolyisocyanides 57016.7 ConclusionsandOutlook 575

References 576

Index 587

XIII

Preface

Isocyanide (isonitrile) chemistry began in 1859 when Lieke obtained the first com­pound of this type. In 1958, isocyanides became generally available by dehydration of formamides prepared from primary amines. This discovery and many other important inventions in the chemistry of isocyanides have been attributed to Ivar Ugi. He was probably the first person to understand the exceptional nature of isocyano functionality and its rich synthetic possibilities. Being stable carbenes, isonitriles are highly reactive compounds that can react with almost any type of reagents (electrophiles, nucleophiles and even radicals). Today isocyanide chemis­try is a broad and important part of organic chemistry; however inorganic, coordina­tion, polymeric, combinatorial and medicinal chemistry explore the rich reactivity of isonitriles as well. Multicomponent reactions with isocyanides are used for synthesis of broad varieties of peptides and peptide mimetics. The renaissance of isocyanide chemistry was at the end of the 20th century when thousands of new compounds libraries became highly desirable for diversity­oriented synthesis, high­throughput screening and drug discovery. Isocyanide­based multicomponent reactions are out of competition in terms of effectiveness and economy to synthe­size drugs like compounds or natural compounds only in a single synthetic step.

In this book, an effort has been made to provide a comprehensive modern view of all the most significant branches of isocyanide chemistry, demonstrating how important are these compounds to date and how significant is their impact on chemistry. It should be pointed out that the book Isonitrile Chemistry was published by Ivar Ugi in 1971. Since then a number of excellent reviews and monograph chapters regarding isocyanides, in particular their multicomponent reactions, have been published. However, a book devoted to the chemistry of isocyanides has not been published for more than 40 years.

It is a great honor and pleasure for me to be the editor of this book. I would like to thank all the authors of the individual chapters for their excellent contributions. These outstanding scientists are known experts in the field of isocyanide chemis­try. This book is a result of worldwide cooperation of contributors from many countries. I would like also to thank all my collaborators at Wiley­VCH for help to realize this project.

I also wish to use this opportunity to mention my personal love for isocyanide chemistry. Almost 25 years ago as a student, I read Isonitrile Chemistry by Ivar Ugi.

XIV Preface

Such a beautiful and rich chemistry made me dream to do something important and interesting in this field. However, it was impossible at that time because I was still a student. Nevertheless, I synthesized my first isocyanide and had experience with specific odors of isonitriles. My next step to isocyanides was the conference in Yaroslavl, Russia, in 2001, where I met Ivar Ugi. We had a long and fruitful discussion, and this talk supported me significantly. Since then my laboratory has been involved in isocyanide chemistry. I would like to dedicate this book to the memory of an outstanding chemist and major pioneer of isocyanide chemistry, Ivar Ugi.

Valentine G. NenajdenkoMoscow, 2012

XV

ListofContributors

Niels AkeroydRadboud University NijmegenInstitute for Molecules and MaterialsHeyendaalseweg 1356525 AJ NijmegenThe Netherlands

Irini Akritopoulou-ZanzeAbbott LaboratoriesScaffold-Oriented SynthesisAbbott Park, IL 60064USA

Muhammad AyazThe University of ArizonaCollege of PharmacyBIO5 Oro ValleyTucson, AZ 85737USA

Luca BanfiUniversità a degli Studi di GenovaDipartimento di Chimica e Chimica IndustrialeVia Dodecaneso 3116146 GenovaItaly

Mikhail V. BarybinThe University of KansasDepartment of Chemistry1251 Wescoe Hall DriveLawrence, KS 66045USA

Andrea BassoUniversità a degli Studi di GenovaDipartimento di Chimica e Chimica IndustrialeVia Dodecaneso 3116146 GenovaItaly

Fabio De MolinerThe University of ArizonaCollege of PharmacyBIO5 Oro ValleyTucson, AZ 85737USA

Justin DietrichThe University of ArizonaCollege of PharmacyBIO5 Oro ValleyTucson, AZ 85737USA

XVI ListofContributors

Alexander DömlingUniversity of PittsburghSchool of PharmacyDepartment of Pharmaceutical SciencesPittsburgh, PA 15261USA

Laurent El KaïmEcole Nationale Supérieure des Techniques AvancéesUnité Chimie et ProcédésUMR 7652CNRS-ENSTA-Polytechnique32 Bd Victor75012 ParisFrance

Niels EldersVU University AmsterdamDepartment of Chemistry & Pharmaceutical SciencesDe Boelelaan 10831081 HV AmsterdamThe Netherlands

Laurence GrimaudEcole Nationale Supérieure des Techniques AvancéesUnité Chimie et ProcédésUMR 7652CNRS-ENSTA-Polytechnique32 Bd Victor75012 ParisFrance

Anton V. GulevichMoscow State UniversityDepartment of ChemistryLeninskie GoryMoscow 119991Russia

Yijun HuangUniversity of PittsburghSchool of PharmacyDepartment of Pharmaceutical SciencesPittsburgh, PA 15261USA

Christopher HulmeThe University of ArizonaCollege of PharmacyBIO5 Oro ValleyTucson, AZ 85737USA

Nicola KiellandBarcelona Science ParkUniversity of BarcelonaBaldiri Reixac 10-1208028 BarcelonaSpain

Mikhail KrasavinGriffith UniversityEskitis InstituteBrisbane, QLD 4111Australia

Rodolfo LavillaBarcelona Science ParkUniversity of BarcelonaBaldiri Reixac 10-1208028 BarcelonaSpain

Konstantin V. LuzyaninTechnical University of LisbonCentro de Química EstruturalInstituto Superior Técnico1049-001 LisbonPortugal

ListofContributors XVII

Ali MalekiIran University of Science and TechnologyDepartment of ChemistryNarmakTehran 16846-13114Iran

John J. Meyers, JrThe University of KansasDepartment of Chemistry1251 Wescoe Hall DriveLawrence, KS 66045USA

Maxim A. MironovUral Federal UniversityDepartment of Technology for Organic Synthesisstr. Mira, 19620002 EkaterinburgRussia

Brad M. NealThe University of KansasDepartment of Chemistry1251 Wescoe Hall DriveLawrence, KS 66045USA

Valentine G. NenajdenkoMoscow State UniversityDepartment of ChemistryLeninskie Gory119991 MoscowRussia

Ricardo A.W. Neves FilhoLeibniz Institute of Plant BiochemistryDepartment of Bioorganic ChemistryWeinberg 306120 Halle (Saale)Germany

Roeland J.M. NolteRadboud University NijmegenInstitute for Molecules and MaterialsHeyendaalseweg 1356525 AJ NijmegenThe Netherlands

Tetsuo OkujimaEhime UniversityGraduate School of Science and EngineeringDepartment of Chemistry and Biology2-5 Bunkyo-choMatsuyama 790-8577Japan

Noboru OnoKyoto UniversityInstitute for Integrated Cell-Material Sciences (iCeMS)Nishikyo-kuKyoto 615-8510Japan

Romano V.A. OrruVrije Universiteit AmsterdamDepartment of Chemistry and Pharmaceutical SciencesDe Boelelaan 10831081 HV AmsterdamThe Netherlands

Armando J.L. PombeiroTechnical University of LisbonCentro de Química EstruturalInstituto Superior Técnico1049-001 LisbonPortugal

Rosario RamónBarcelona Science ParkUniversity of BarcelonaBaldiri Reixac 10-1208028 BarcelonaSpain

XVIII ListofContributors

Renata RivaUniversità a degli Studi di GenovaDipartimento di Chimica e Chimica IndustrialeVia Dodecaneso 3116146 GenovaItaly

Daniel G. RiveraLeibniz Institute of Plant BiochemistryDepartment of Bioorganic ChemistryWeinberg 306120 Halle (Saale)GermanyandFaculty of ChemistryUniversity of HavanaCenter for Natural Products StudyZapata y G10400 La HabanaCuba

Alan E. RowanRadboud University NijmegenInstitute for Molecules and MaterialsHeyendaalseweg 1356525 AJ NijmegenThe Netherlands

Eelco RuijterVU University AmsterdamDepartment of Chemistry & Pharmaceutical SciencesDe Boelelaan 10831081 HV AmsterdamThe Netherlands

Afshin SarvaryShahid Beheshti UniversityDepartment of ChemistryG. C. P. O. Box 19396-4716TehranIran

Ahmad ShaabaniShahid Beheshti UniversityDepartment of ChemistryG. C. P. O. Box 19396-4716TehranIran

Ludger A. WessjohannLeibniz Institute of Plant BiochemistryDepartment of Bioorganic ChemistryWeinberg 306120 Halle (Saale)Germany

Alexander G. ZhdankoMoscow State UniversityDepartment of ChemistryLeninskie GoryMoscow 119991Russia

1

1ChiralNonracemicIsocyanidesLucaBanfi,AndreaBasso,andRenataRiva

Isocyanide Chemistry: Applications in Synthesis and Material Science, First Edition. Edited by Valentine G. Nenajdenko.© 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

1.1Introduction

Although isocyanides have proven to be very useful synthetic intermediates – especially in the field of multicomponent reactions – most research investigations performed to date on isocyanides have involved commercially available, unfunc-tionalized and achiral (or chiral racemic) compounds. Two reasons can be envi-sioned for the infrequent use of enantiomerically pure isocyanides: (i) the general lack of asymmetric induction produced by them; and (ii) the high tendency to lose stereochemical integrity in some particular classes of isonitriles. However, it is believed that when these drawbacks are overcome, the use of chiral non-racemic isocyanides in multicomponent reactions can be very precious, allowing a more thorough exploration of diversity (in particular stereochemical diversity) in the final products. Recently, several reports have been made describing the preparation and use of new classes of functionalized chiral isocyanides. In fact, several chiral isocyanides may be found in nature, and these will be briefly described in Section 1.5, with attention focused on their total syntheses. Another growing application of chiral isocyanides is in the synthesis of chiral helical polyisocyanides.

It is hoped that this review will encourage chemists first to synthesize a larger number of chiral isocyanides, and subsequently to exploit them in multicompo-nent reactions, in total synthesis, and in the material sciences.

1.2SimpleUnfunctionalizedIsocyanides

The standard method used to prepare chiral isocyanides (whether functionalized, or not) begins from the corresponding amines, and employs a two-step se-quence of formylation and dehydration (Scheme 1.1). Many enantiomerically pure amines are easily available from natural sources, classical resolution [1], or asymmetric synthesis. Formylation is commonly achieved via four general

2 1 ChiralNonracemicIsocyanides

methods: (i) refluxing the amine in ethyl formate [2]; (ii) reacting the amine with the mixed formic–acetic anhydride [2]; (iii) reacting the amine with formic acid and DCC (dicyclohexylcarbodiimide) [3] or other carbodiimides [4]; and (iv) react-ing the amine with an activated formic ester, such as cyanomethyl formate [5], p-nitrophenyl formate [6], or 2,4,5-trichlorophenyl formate [7]. For the dehydration step, several reagents are available, with the commonest and mildest methods involving POCl3, diphosgene, or triphosgene at low temperatures in the presence of a tertiary amine [2]. Although less commonly used, Burgess reagent (methyl N-(triethylammoniumsulfonyl)carbamate) [8] and the CCl4/PPh3/Et3N system [7] have also been employed.

Alternatively, formamides can be obtained from chiral carboxylic acids, through a stereospecific Curtius rearrangement followed by reduction of the resulting isocyanate [9, 10].

Isocyanides may also be prepared from alcohols, by conversion of the alcohol into a sulfonate or halide, followed by SN2 substitution with AgCN [11]; however, this method works well only with primary alcohols. In contrast, a series of chiral isocyanides have been synthesized from chiral secondary alcohols via a two-step protocol that involves conversion first into diphenylphosphinite, followed by a stereospecific substitution that proceeds with a complete inversion of configura-tion [12]. The substitution step is indeed an oxidation–substitution, that employs dimethyl-1,4-benzoquinone (DMBQ) as a stoichiometric oxidant and ZnO as an additive. Alternatively, primary or secondary alcohols can be converted into forma-mides through the corresponding alkyl azides and amines.

Some examples of simple chiral isocyanides are shown in Scheme 1.1. These materials have all been prepared in a traditional manner, starting from chiral amines; the exception here is 5, which was synthesized from the secondary alcohol.

Scheme1.1

NH2

R1

R2*

NHCHOR1

R2*

CO2HR1

R2*

NCR1

R2*

NC

1

NC

2a: R = H2b: R = p-Cl2c: R = p-OMe2d: R = iBu

RNC

4

NC

MeO3

6

RCHO, AcOH

O

R

OAc

d.r. = 92-93%

OHR1

R2*

Ph2PCl, Et3NOPPh2

R1

R2*

(EtO)2POCN, DMBQ,ZnO

NC

5

AcOH H

NC

7*THF

CN HN

1.2 SimpleUnfunctionalizedIsocyanides 3

The compounds comprise fully aliphatic examples such as 1 [13], α-substituted benzyl isocyanides such as 2 [1, 2, 13, 14] and 3 [14, 15], and α-substituted phene-thyl or phenylpropyl isocyanides such as 4 [2] and 5 [12].

Because of the great synthetic importance of isocyanide-based multicomponent reactions, these chiral isocyanides have been often used as inputs in these reac-tions. The use of enantiomerically pure isocyanides can, in principle, bring about two advantages: (i) the possibility to obtain a stereochemically diverse adduct, controlling the absolute configuration of the starting isonitrile; and (ii) the possibil-ity to induce diastereoselection in the multicomponent reaction. With regards to the second of these benefits, the results have been often disappointing, most likely because of the relative unbulkiness of this functional group. For example, Seebach has screened a series of chiral isocyanides, including 2a and 4 in the TiCl4-mediated addition to aldehydes, but with no diastereoselection at all [2]. This behavior seems quite general also for the functionalized isocyanides described later, the only exception known to date being represented by the camphor-derived isocyanide 6 [16], which afforded good levels of diastereoselection in Passerini reactions. The same isonitrile gave no asymmetric induction in the corresponding Ugi reaction, however. Steroidal isocyanides have also been reported (i.e., 7) [17, 18].

Apart from multicomponent reactions, and the synthesis of polyisocyanides (see Section 1.6), chiral unfunctionalized isocyanides have been used as intermediates in the synthesis of chiral nitriles, exploiting the stereospecific (retention) rear-rangement of isocyanides into nitriles under flash vacuum pyrolysis conditions (FVP) [14, 19]. This methodology was used for the enantioselective synthesis of the anti-inflammatory drugs ibuprofen and naproxen, from 2d and 3, respectively. As isocyanides are usually prepared from amines, the overall sequence represents the homologation of an amine to a carboxylic derivative, and is therefore opposite to the Curtius rearrangement.

Another interesting application of 2a, as a chiral auxiliary, was reported by Alcock et al. (Scheme 1.2). Here, the chiral isocyanide reacts with racemic vinylket-ene tricarbonyliron(0) complex 8 to produce two diastereomeric (vinylketeneimine)tricarbonyliron complexes 9 that can be separated. Subsequent reaction with an organolithium reagent, followed by an oxidative work-up, was found to be highly diastereoselective, forming only adduct 10. This represents a useful method for

Scheme1.2

Fe(CO)3

NC

2a

+ PhO

PhN

Fe(CO)3

PhPh

N Ph(CO)3Fe

+

8 9a 9b1) EtLi

2) oxidative work-up(air)Ph

NHEt

O

Ph10

4 1 ChiralNonracemicIsocyanides

accessing quaternary stereogenic centers, with the induction being clearly due to the tricarbonyliron group, while the isocyanide chirality serves only as a means of separating the two axial stereoisomers 9a and 9b [15].

1.3IsocyanidesContainingCarboxylic,Sulfonyl,orPhosphonylGroups

As the reactivity of α-isocyano esters and amides is reviewed in Chapters 3 and 4 of this book, attention at this point will be focused only on stereochemical issues; reactions exploiting reactivity at the α position will not be described.

1.3.1 α-IsocyanoEsters

Enantiomerically pure α-isocyano esters 12 can be prepared by the dehydration of formamides 11, which in turn are synthesized in two steps from the corresponding α-amino acids [20, 21] (Scheme 1.3). The most critical step is dehydration, which has been demonstrated in some instances to be partly racemizing. The combina-tion of diphosgene with N-methylmorpholine (NMM) at a low (<−25 °C) tempera-ture has been reported in various studies to be able to avoid racemization and to be superior to the use of POCl3 with more basic amines [2, 22–25]. In a recent extensive study, the use of triphosgene/NMM at −30 °C was suggested as the method of choice [26], although a direct comparison of triphosgene with diphos-gene was not carried out.

These isocyanides would be very useful in multicomponent reactions, such as the Passerini and Ugi condensations, for the straightforward preparation of dep-sipetides or peptides, although racemization may be a relevant issue. Under Pas-serini conditions, these compounds appear to be configurationally stable during reaction with various aldehydes [22, 27–29], and this approach has been used, for

Scheme1.3

R1

NH3

O

OR1

NHCHO

O

OR2

R1

NC

O

OR2

11 12

NC

O

OR2

13R2 = Me or Bn

NH(Fmoc)

O

H

+

14

NH(Boc)

O

OH

NH(Cbz) 15

(Boc)HN

O

O

NH(Cbz)O N

H

CO2R2Passerini

16

base

(Boc)HN

O

HN

NH(Cbz)

OH HN

O

CO2R2

NH(Fmoc)

1.3 IsocyanidesContainingCarboxylic,Sulfonyl,orPhosphonylGroups 5

example, in the total synthesis of eurystatin A [22] (Scheme 1.3). The quite complex tripeptide 16 has been assembled in just two steps by using a PADAM (Passerini–Amine Deprotection–Acyl Migration) strategy [30], starting from three enantio-merically pure substrates 13, 14, and 15. Once again, none of the three chiral inputs was able to induce any diastereoselection, but at least three of the four stereogenic centers could be fully controlled by the appropriate substrate con-figurations. α-Isocyano esters are also configurationally stable during the TiCl4-mediated condensation of isocyanides with aldehydes [2].

With ketones, the Passerini reaction is slower such that some degree of racemi-zation may occur, depending on the carboxylic acid employed [31]. Chiral α-isocyano esters have been used also in the synthesis of optically active hydantoins such as 20 (Scheme 1.4) [5]; however, the enantiomeric purity was not precisely assessed, and it could not be ascertained if these conditions were racemizing, or not.

In contrast, the conditions of the Ugi reaction are often incompatible with the stereochemical integrity of chiral α-isocyano esters [20, 25, 32]. A careful study of reaction conditions has shown that – at least for the reaction with ketones – racemi-zation can be almost completely suppressed by carrying out the reaction in CH2Cl2 with BF3·Et2O as catalyst [25]. In this case, racemization is believed to be provoked by the free amine; in fact, α-isocyano esters will readily racemize when treated with amines at room temperature (r.t.) [2]. On this basis, the use of preformed imines would be expected to be capable of preventing racemization, although such success was stated only in few cases, that always involved preformed cyclic imines (Scheme 1.5). For example, Joullié has reported the formation of only two dias-tereomers 23 in the condensation of chiral imine 21 with chiral isocyano ester 22 [33]. Similarly, Sello has obtained only two diastereomers in the condensation of achiral imine 24 with chiral isocyanide 25 and Boc-proline. Interestingly, the two diastereomers have been obtained in 70 : 30 ratio [34]; this was unusual since, in most cases, chiral isocyanides and chiral carboxylic acids provide no stereochemi-cal control in Ugi reactions. The absence of racemization in Ugi–Joullié reactions is not general. Rather, the present authors experienced the formation of four diastereomers in the reaction of chiral pyrroline 27 with leucine-derived isocyano ester 28 [24].

An ingenious approach to avoid these racemization issues was recently devised by Nenajdenko and coworkers [35], who employed orthoesters 30 as surrogates of

Scheme1.4

NC

O

OtBu

17

F3C CF3

N OtBu

O+

18

NHN

CO2tBu

OF3C

CF3

ON

OF3C

F3C NCO2tBu

OtBu

2019

6 1 ChiralNonracemicIsocyanides

α-isocyano esters. After the Ugi reaction, which proceeds with no racemization, the free carboxylic acids 32 could be obtained in quantitative yield via a two-step/one-pot methodology.

A non-multicomponent application of chiral α-isocyano esters was recently developed by Danishefsky, who created a general method for the synthesis of N-methylated peptides, a moiety which is present in many important natural substances, such as cyclosporine [36] (Scheme 1.6). The coupling of an iso-cyano ester with a thioacid produces a thioformyl amide that can be conveniently reduced by tributyltin hydride, with the overall sequence taking place without racemization.

Scheme1.5

N

OAr

CN

CO2Me

MeOH48%

NH

CO2MeO

N

ArO

OPh

NH

CO2MeO

N

ArO

OPh

+

57 : 4321 22 23a 23b

N CN

CO2MeN

Boc

CO2H76% N

O

NH

CO2MeON

Boc

major (d.r .= 70:30)24 25 26

N

TBDMSO

CO2H

NH(Fmoc)

CN

CO2Me

+ +

+ N

TBDMSOHN

O CO2Me

O

NH(Fmoc)

27 28

29

O

O

OR1

NC

O

O

OR1

HN

Ugi reaction

O

CO2HR1

HN

O30 31

1) CF3CO2H

32

MeOH

70%

MeOH

2) NaOH, quant.NR4

O

R3

R2

N

R4

O

R3

R2

PhCO2H

Scheme1.6

O

SH

BocNH

O

N

BocNH O

OBnCN

O

OBn+

O

N

BocNH O

OBn

S

CHCl3

33

34

nBu3SnH, AIBN100°C

cyclosporine52% (2 steps)

1.3 IsocyanidesContainingCarboxylic,Sulfonyl,orPhosphonylGroups 7

α-Isocyano esters can provide a variety of reactions involving enolization at the α positions (these are reviewed in Chapters 3 and 4). Whilst deprotonation clearly brings about the loss of the stereogenic center, if chirality is present elsewhere (e.g., in the alcoholic counterpart of the ester), then asymmetric induction is, in principle, viable. To date, very few α-isocyanoacetates of chiral alcohols have been prepared [37, 38], and their efficient application in asymmetric synthesis has never been reported [21].

1.3.2 α-IsocyanoAmides

Although, in principle, chiral α-isocyano amides can be prepared by the reaction of α-isocyano esters with amines, the easy racemization of the latter compounds under basic conditions makes this approach unfeasible. By using chiral enantio-merically pure amines, it is even possible to realize a dynamic kinetic resolution of racemic α-isocyano esters, obtaining α-isocyanoamides in good diastereomeric ratios, as in the case of compound 35 [2] (Scheme 1.7). Due to the lower α-acidity, the stereoconservative preparation of chiral α-isocyano amides from the corre-sponding formamides is less problematic than that of the corresponding esters, and combinations of POCl3 with Et3N may also be used. The only exception here is represented by penicillin- or cephalosporin-derived isocyanides [6]. Cephalosporin-derived isocyanide 39 can be obtained without epimerization, but only when weaker NMM is used as the base (with Et3N, extensive epimerization takes place). On the other hand, with penicillin-derived formamide 36 a near to 1 : 1 epimeric mixture is obtained, even with NMM.α-Isocyano amides are also less prone to racemize during multicomponent reac-

tions, although in this case the yields may be impaired by concurrent oxazole formation [24, 39] (see Chapter 3).

Scheme1.7

NH2 PhCO2Me

NC+

50 °C, 2 daysPh

NCracemic

O

NH

35 d.r. = 89:11

N

S

O

HN

OHC

CO2Bn

N

S

O

CN

CO2Bn

phosgene, NMM− 40 °C

36 37

NO

HN

OHC S

CO2Me

NO

CN S

CO2Me

phosgene, NMM− 40 °C

38 39

8 1 ChiralNonracemicIsocyanides

Nonetheless, α-isocyanoamides have been employed successfully in both the Passerini [27, 40] and Ugi reactions [41], some representative examples of which are shown in Scheme 1.8. Aitken and Fauré have accomplished a highly conver-gent synthesis of cyclotheonamide C by exploiting the above-cited PADAM strategy [30], and using three polyfunctionalized substrates, namely α-isocyano amide 40, protected α-amino aldehyde 41, and protected amino acid 42 [40]. Despite none of these three chiral substrates being capable of affording any stereoselection, this is unimportant because the new stereogenic center is later lost by oxidation. Ugi et al. have demonstrated the applicability of their reaction in the straightforward synthesis of tetrapeptide 46 [41] although, in this case, two problems had first to be resolved: (i) the poor asymmetric induction provided by both the chiral isocya-nide and the carboxylic acid; and (ii) the need for secondary amides (the use of ammonia is often inadequate in Ugi reactions). Ultimately, both issues were resolved by using the chiral ferrocenyl auxiliary 45, which afforded a good stereoin-duction and could easily be removed under acidic conditions.

The α-isocyano amides may also provide a wide variety of stereoselective reac-tions that involve enolization at the α positions, provided that chirality is present in the amine counterpart. Consequently, various chiral α-isocyano amides have

Scheme1.8

ButO2C NH

Ar

N

ZHN NH

Z

OHC NHFmoc40 41

NHO2C

O

HN

O

H

42

ONC

1) Passerini2) Et2NH - Et3N

39%

ButO2C NH

ONH

O

OH

NH

N

ZHN NH

Z

O

NO

3 stepscyclotheonamide C

43

NH2

FeCN

HN

OMeO

O

+ OHCHNO

OHO H+ +

OHCHN

O

HN

NH

HN CO2Me

O

O

1) Ugi, d.r. = 91:92) H+

44 45

46

BocHN

NHCHO

NHBoc

Ar

1.3 IsocyanidesContainingCarboxylic,Sulfonyl,orPhosphonylGroups 9

been prepared [6, 42–46], some of which have provided good levels of diastereose-lectivity [6, 42, 45, 46] (these reactions are reviewed in Chapters 3 and 4).

1.3.3 OtherIsocyanoEstersorAmides

The β-isocyano esters are not expected to suffer from the racemization issues of their α counterparts, and may be very valuable inputs for the multicomponent assembly of peptidomimetics. Somewhat surprisingly, however, very few reports have been made on this class of compound, most likely because of the limited availability of enantiomerically pure β-amino acids (Scheme 1.9). Previously, Palomo et al. [47] have successfully prepared β-isocyano esters such as 49 through an opening of the β-lactam 47, which in turn was stereoselectively accessed by the Staudinger condensation of a lactaldehyde imine. Although this approach may represent a fairly general entry to these isocyanides, its potential has not been further exploited, and the isocyanide 49 has been used simply as an intermediate for deamination procedures.

Within the present authors’ group, a general organocatalytic entry to β-isocyano esters of general formula 52 in both enantiomeric forms has recently been identi-fied. While N-formyl imines have been demonstrated to be unstable, they can be generated in situ from sulfonyl derivatives 50 under phase-transfer conditions. Subsequently, the use of quinine- or quinidine-derived catalysts allowed, after careful optimization, malonates 51 to be obtained in both enantiomeric forms, with enantiomeric excess (e.e.) values ranging between 64% and 90%. Moreover, the yields were almost quantitative and the e.e.-values could be brought to 98% by crystallization. Subsequently, malonates 51 have been converted in high yields into isocyanides 52 by decarboxylation and dehydration (F. Morana, et al., unpublished results).

Scheme1.9

NO PMP

BnO H H

MeO2C

OBn

NH2

OBn

MeO2C

OBn

NC

OBn1) (NH4)2Ce(NO3)62) Me3SiCl, MeOH

1) AcOCHO2) diphosgene, Et3N

47 48 49

Ar NHCHO

SO2Tol

ArCO2R

NHCHO

*

CO

2

R

chiral phase-transfercatalysts

ArCO2Et

NC

*

50 51e.e. up to 90%

52

CHO

NHCHO

53

NC

+

AcOHCH2Cl2

NH

OAc

NH

O NC

OAc

NH

Otriphosgene,NMM, - 30 °C

5456% 87%

OBn

OHC

10 1 ChiralNonracemicIsocyanides

During the total synthesis of the antiviral agent telaprevir, Orru and Ruijter have recently reported an interesting approach (that in principle may be general) for the synthesis of protected α-hydroxy-β-isocyano esters such as 54, based on the Passerini reaction of a chiral α-formylamino aldehyde 53 [48]. The only drawback of this methodology is the low stereoselection of the Passerini reaction, though this is not influential if the targeted products are peptidomimetic and contain the α-keto-β-amino amide transition state mimic.

1.3.4 ChiralSulfonylmethylorPhosphonylmethylIsocyanides

Sulfonylmethyl isocyanides are synthetic equivalents of formaldehyde mono- or di-anions, and have found several useful applications. Chiral derivatives can, in principle, be used for achieving asymmetric induction, with Van Leusen and col-leagues having prepared a series of chiral analogues with either stereocenters in the group attached to sulfur (i.e., 55) or with a stereogenic sulfur atom (56) (Scheme 1.10). These chiral p-toluenesulfonylmethyl isocyanide (TosMIC) ana-logues were tested in the synthesis of cyclobutanones [49] or oxazolines [50]. In the latter case, two trans diastereomers (57a and 57b) were usually obtained, and the best results in terms of stereoselectivity were obtained with sulfonimide 56 (diastereomeric excess (d.e.) = 80%). The preparation of enantiomerically pure sulfonimide 56 is not trivial, however. Oxazolines 57 can be hydrolyzed to α-hydroxyaldehydes 58.

Van Leusen has also prepared the chiral phosphonylmethyl isocyanide 61 (as well as its trans epimer), starting from enantiomerically pure dioxaphosphorinane 59 [51]. Here, the key step is an Arbuzov reaction of 59 with a N-methylformamide equipped with a good leaving group. It is worth noting that this represents an unconventional formamide synthesis, that does not proceed through a primary amine.

Scheme1.10

55

Ph CF3

O+

base

SO N

NC

56

Ar *

or

Tos

O

N

F3C

Ph

SRO X

57a

O

N

F3C

Ph

SRO X

+H3O+ CHO

OHF3C

Ph

57b 58

O

PO

O

Ph

O

PO

OR

Ph

O

PO

O

PhN N

H

CHO

59 60 61

NHCHO NC

S NCO O