Dynamic Stereochemistry of Chiral Compounds: Principles and Applications PDF
Preview Dynamic Stereochemistry of Chiral Compounds: Principles and Applications
Dynamic Stereochemistry of Chiral Compounds Principles and Applications Dynamic Stereochemistry of Chiral Compounds Principles and Applications Christian Wolf Department of Chemistry, Georgetown University, Washington, DC, USA ISBN:978-0-85404-246-3 AcataloguerecordforthisbookisavailablefromtheBritishLibrary rTheRoyalSocietyofChemistry2008 Allrightsreserved Apartfromfairdealingforthepurposesofresearchfornon-commercialpurposesorforprivatestudy,criticismor review,aspermittedundertheCopyright,DesignsandPatentsAct1988andtheCopyrightandRelatedRights Regulations2003,thispublicationmaynotbereproduced,storedortransmitted,inanyformorbyanymeans, withoutthepriorpermissioninwritingofTheRoyalSocietyofChemistryorthecopyrightowner,orinthecaseof reproductioninaccordancewiththetermsoflicencesissuedbytheCopyrightLicensingAgencyintheUK,orin accordancewiththetermsofthelicencesissuedbytheappropriateReproductionRightsOrganizationoutsidethe UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistryattheaddressprintedonthispage. PublishedbyTheRoyalSocietyofChemistry, ThomasGrahamHouse,SciencePark,MiltonRoad, CambridgeCB40WF,UK RegisteredCharityNumber207890 Forfurtherinformationseeourwebsiteatwww.rsc.org Preface SincethepioneeringworkofPasteur,LeBelandvan’tHoffstereochemistryhasevolvedtoamulti- faceted and interdisciplinary field that continues to grow at an exponential rate. Today, dynamic stereochemistry plays a fundamental role across the chemical sciences, ranging from asymmetric synthesis to drug discovery and nanomaterials. The immense interest and activity in these areas haveledtothedevelopmentofnewmethodologiesandresearchdirectionsinrecentyears.Chirality plays a pivotalrole in efforts tocontrol molecular motionand haspavedthe way for microscopic propellers, gears, switches, motors and other technomimetic devices. The concepts of Euclidian chirality have been extended to topological chirality of fascinating mechanically interlocked assembliesincludingrotaxanes,catenanes,andevenmolecularknotsorpretzelanes.Theimpressive advance of asymmetric synthesis has been accompanied by significant progress in stereochemical analysis. Mechanistic insights into isomerization reactions and information about the conforma- tionalandconfigurationalstabilityofchiralcompoundsareindispensablefortoday’schemist,and new techniques such as dynamic chromatography and stopped-flow procedures that complement chiropticalandNMRspectroscopicmethodshavebeenestablished.Aprofoundunderstandingof the stability of chiral target compounds, intermediates and starting materials to racemization and diastereomerization is indispensable for planning an efficient synthetic route. In many cases, interconversion of stereoisomers compromises the efficacy of asymmetric synthesis and ultimately results in the loss of stereochemical purity, but it can also be advantageous. While the usefulness andscopeofasymmetrictransformationsofthefirstandsecondkindhavebeenknownforalong time, dynamic kinetic resolution, dynamic kinetic asymmetric transformation and dynamic ther- modynamic resolution have become powerful synthetic alternatives. Many strategies that afford excellentcontrolofstereolabilesubstratesandreactionintermediateshavebeendevelopedandare nowadays routinely employed in the synthesis of a wide range of chiral compounds including natural products. Asymmetric synthesis of complex target compounds generally entails incorpo- ration of several chiral elements in addition to strategic carbon-carbon bond formation. Once molecular chirality has been established it is often necessary to further manipulate it. Numerous methods for selective translocation of a chiral element along an existing carbon framework or interconversionofelementsofchiralitywithoutlossofstereochemicalpurityhavebeenintroduced and provide invaluable synthetic prospects. Both, the progress and the diversity of stereodynamic chemistry,inparticularasymmetricsynthesis,areunrivaledandconstantlyfueledbyanenormous amount of new scientific contributions. Over the last twenty years, several excellent books about asymmetric synthesis have appeared. Traditionally, asymmetric synthesis is discussed based on (1) reaction types, for example aldol v vi Preface reactions,hydroboration,epoxidation,dihydroxylation,hydrogenation,andsoon,or(2)emerging concepts such as organocatalysis, biomimetic methods and phase-transfer catalysis. In addition, many reviews on broadly applicable asymmetric catalysts and methods can be found in the literature. While there is no need to duplicate these books and articles, I have felt that a conceptually different textbook that embraces asymmetric synthesis, interconversion of chiral compounds, analytical methods suitable for the study of racemization and diastereomerization reactions, as well as a discussion of topologically chiral assemblies and molecular propellers, switches and motors in the context of dynamic stereochemistry would be very helpful for both teaching and research. Stereoselective synthesis, analysis and stereodynamic properties and appli- cationsofchiralcompoundsarenowcombinedinonetext.Thebookisaimedatgraduatestudents and is intended to serve as a guide for researchers with an interest in synthetic, analytical and mechanistic aspects of dynamic stereochemistry of chiral compounds. This book is organized into three parts that contain nine chapters and a glossary of important stereochemicaltermsanddefinitions.Thefirstchapterprovidesanintroductiontothesignificance and interdisciplinary character of dynamic stereochemistry. Chapter 2 covers principles, termino- logyandnomenclatureofstereochemistrywithanemphasisonEuclidianandtopologicalchirality. The reader is familiarized with stereodynamic properties of chiral compounds and the relative contributions of interconverting configurational and conformational isomers to selectivity, reac- tivity and chiral recognition. Racemization, enantiomerization and diastereomerization including mutarotationandepimerizationarediscussedinChapter3.Mathematicaltreatmentsofreversible and irreversible isomerization kinetics are presented and the wealth of racemization and dia- stereomerization mechanisms is reviewed separately for each class of compounds to provide a systematic overview. Numerous examples of compounds with individual energy barriers to enan- tioconversion are given to highlight steric and electronic effects. The principles and scope of analyticaltechniquesthatarecommonlyusedtodeterminetheconformationalandconfigurational stability of chiral compounds are discussed in Chapter 4. Special emphasis is given to chiroptical methods, variable-temperature NMR spectroscopy, dynamic chromatography, and stopped-flow analysis. Thesecondpartofthisbookfocusesonasymmetricsynthesis.Chapter5introducesthereaderto the principles of asymmetric synthesis and outlines basic concepts of stereodifferentiation and reactioncontrol.Chapter6coversasymmetricsynthesiswithchiralorganolithiumcompoundsand atroposelectivesynthesisofbiarylsandnonbiaryls.Thisdiscussionleadstootherstrategiesthatare aimed at manipulation of chirality without concomitant racemization or diastereomerization, for examplechiralitytransferandinterconversionofchiralelementsduringpericyclicrearrangements, S 20 and S 20 displacements, and self-regeneration of stereogenicity with temporary or transient N E chiral intermediates. Synthetic methods that utilize relays and stereodynamic catalysts for ampli- fication of chirality and asymmetric induction link the above topics to the following chapter. Strategies that incorporate stereolabile chiral compounds and intermediates into asymmetric synthesisunderthermodynamic(asymmetrictransformationsofthefirstandsecondkind,dynamic thermodynamic resolution) or kinetic reaction control (dynamic kinetic resolution and dynamic kineticasymmetrictransformation)arepresentedinChapter7.Becauseoftheconsiderableoverlap and relevance to some of the above methodologies, kinetic resolutions are also covered in detail. ThescopeandapplicationspectrumofasymmetricreactionsandconceptspresentedinChapters5 to 7 are highlighted with many examples and the stereochemical outcome is explained with a mechanistic rationale including transition state structures whenever possible. Thethirdpartofthisbookcomprisesstereodynamicdevices,manipulationofmolecularmotion, and the chemistry of topologically chiral assemblies. Chapter 8 examines the central role that chirality plays in the design of molecular propellers, bevel gears, brakes, switches, sensors, and motors. The synthesis, chirality and stereodynamics of catenanes, rotaxanes and other mechani- cally interlocked compounds are presented in Chapter 9. Preface vii Asinglemonographcannotcomprehensivelycovertheenormousscopeandthemanyfacetsof dynamicstereochemistry.Topicssuchasswitchingandamplificationofchiralityinpolymers,gels and liquid crystals had to be excluded due to limitations of space and time. In writing this book during the last two and a half years, I have tried to adhere to well-defined and established stereochemicalterminologyandemphasizedimportantlimitationsandconflictingdefinitionsinthe text.Toassistthereader,adetailedglossaryofstereochemicaldefinitionsandtermsisincludedat the end of the book, and a list of abbreviations and acronyms is provided at the beginning. All topics are extensively referenced and the principal researcher is frequently named in the text to encourage further reading and to facilitate additional literature search. I would like to thank my colleagues, in particular Professors William H. Pirkle and the late Wilfried A. Ko¨nig, and my students for continuing inspiration and helpful discussions. I wish to thank Thomas J. Nguyen for the technical drawings illustrating the conceptual linkage between macroscopicmechanicaldevicesandtheirmolecularanalogs.AndIamparticularlygratefultomy wifeJuliaforherpatience,encouragementandunderstandingduringtheendlesshoursinvolvedin writing this book. Christian Wolf Washington, DC This book is dedicated to my wife Julia Contents Chapter 1 Introduction 1 References 4 Chapter 2 Principles of Chirality and Dynamic Stereochemistry 6 2.1 Stereochemistry of Chiral Compounds 6 2.2 Dynamic Stereochemistry of Cyclic and Acyclic Chiral Compounds 15 References 27 Chapter 3 Racemization, Enantiomerization and Diastereomerization 29 3.1 Classification of Isomerization Reactions of Chiral Compounds 30 3.1.1 Racemization 31 3.1.2 Enantiomerization 34 3.1.3 Diastereomerization 36 3.1.4 Epimerization and Mutarotation 40 3.2 StereomutationsofChiralCompounds:MechanismsandEnergyBarriers 44 3.2.1 Alkanes 44 3.2.2 Alkenes and Annulenes 46 3.2.3 Allenes and Cumulenes 52 3.2.4 Helicenes and Phenanthrenes 53 3.2.5 Alkyl Halides, Nitriles and Nitro Compounds 54 3.2.6 Amines 56 3.2.7 Aldehydes, Ketones and Imines 58 3.2.8 Alcohols, Ethers, Acetals, and Ketals 60 3.2.9 Carboxylic Acids and Derivatives 65 3.2.10 Amino Acids 68 3.2.11 Silicon, Phosphorus and Sulfur Compounds 71 3.2.12 Organometallic Compounds 74 3.2.13 Supramolecular Structures 80 ix x Contents 3.3 Atropisomerization 84 3.3.1 Biaryls, Triaryls and Diarylacetylenes 85 3.3.2 Nonbiaryl Atropisomers 94 3.3.3 Cyclophanes 104 3.3.4 Atropisomeric Xenobiotics 107 3.4 Pharmacological and Pharmacokinetic Significance of Racemization 109 References 112 Chapter 4 Analytical Methods 136 4.1 Chiroptical Methods 140 4.2 NMR Spectroscopy 143 4.3 Dynamic Chromatography 153 4.3.1 Dynamic High Performance Liquid Chromatography 159 4.3.2 Dynamic Gas Chromatography 164 4.3.3 Dynamic Supercritical Fluid Chromatography and Electrokinetic Chromatography 167 4.4 Chromatographic and Electrophoretic Stopped-flow Analysis 168 4.5 Comparison of Analytical Methods 172 References 172 Chapter 5 Principles of Asymmetric Synthesis 180 5.1 Classification of Asymmetric Reactions 180 5.2 Kinetic and Thermodynamic Control 183 5.3 Asymmetric Induction 186 5.3.1 Control of Molecular Orientation and Conformation 189 5.3.2 Single and Double Stereodifferentiation 194 References 198 Chapter6 AsymmetricSynthesiswithStereodynamicCompounds:Introduction,Conversion and Transfer of Chirality 204 6.1 Asymmetric Synthesis with Chiral Organolithium Reagents 205 6.1.1 a-Alkoxy- and a-Amino-substituted Organolithium Compounds 207 6.1.2 Sulfur-, Phosphorus- and Halogen-stabilized Organolithium Compounds 212 6.2 Atroposelective Synthesis of Axially Chiral Biaryls 215 6.2.1 Intramolecular Atroposelective Biaryl Synthesis 217 6.2.2 Intermolecular Atroposelective Biaryl Synthesis 220 6.2.3 Atroposelective Ring Construction 224 6.2.4 Desymmetrization of Conformationally Stable Prochiral Biaryls 225 6.2.5 Asymmetric Transformation of Stereodynamic Biaryls 226 6.3 Nonbiaryl Atropisomers 231 6.4 Chirality Transfer and Interconversion of Chiral Elements 233
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