Chiral Amine Synthesis Methods, Developments and Applications Edited by Thomas C. Nugent Chiral Amine Synthesis Edited by Thomas C. Nugent Related Titles Blaser,H.U., Federsel, H.J.(eds.) Yamamoto, H.,Ishihara, K.(eds.) Asymmetric Catalysis on Acid Catalysis in Industrial Scale Modern Organic Synthesis Challenges,ApproachesandSolutions 2008 SecondEdition ISBN:978-3-527-31724-0 2010 Ricci, A.(ed.) ISBN:978-3-527-32489-7 Amino Group Chemistry Dunn,P.,Wells,A.,Williams,M.T.(eds.) FromSynthesistotheLifeSciences Green Chemistry in the 2008 Pharmaceutical Industry ISBN:978-3-527-31741-7 2010 Christmann, M.,Bräse, S.(eds.) ISBN:978-3-527-32418-7 Asymmetric Synthesis - Otera,J.,Nishikido, J. The Essentials Esterification 2008 Methods,Reactions,andApplications ISBN:978-3-527-32093-6 SecondEdition Hudlicky,T., Reed,J. W. 2010 ISBN:978-3-527-32289-3 The Way of Synthesis Kollár,L(ed.) EvolutionofDesignandMethods forNaturalProducts Modern Carbonylation 2007 Methods ISBN:978-3-527-32077-6 2008 ISBN:978-3-527-31896-4 Börner,A.(ed.) Phosphorus Ligands in Asymmetric Catalysis SynthesisandApplications 2008 ISBN:978-3-527-31746-2 Chiral Amine Synthesis Methods, Developments and Applications Edited by Thomas C. Nugent TheEditor AllbookspublishedbyWiley-VCHarecarefully produced.Nevertheless,authors,editors,and Prof.ThomasC.Nugent publisherdonotwarranttheinformationcontained JacobsUniversityBremen inthesebooks,includingthisbook,tobefreeof DepartmentofChemistry errors.Readersareadvisedtokeepinmindthat CampusRing1 statements,data,illustrations,proceduraldetailsor 28759Bremen otheritemsmayinadvertentlybeinaccurate. Germany LibraryofCongressCardNo.: appliedfor BritishLibraryCataloguing-in-PublicationData Acataloguerecordforthisbookisavailablefromthe BritishLibrary. Bibliographicinformationpublishedby theDeutscheNationalbibliothek TheDeutscheNationalbibliothekliststhis publicationintheDeutscheNationalbibliografie; detailedbibliographicdataareavailableonthe Internetathttp://dnb.d-nb.de. #2010WILEY-VCHVerlagGmbH&Co.KGaA, Weinheim Allrightsreserved(includingthoseoftranslationinto otherlanguages).Nopartofthisbookmaybe reproducedinanyform–byphotoprinting, microfilm,oranyothermeans–nortransmittedor translatedintoamachinelanguagewithoutwritten permissionfromthepublishers.Registerednames, trademarks,etc.usedinthisbook,evenwhennot specificallymarkedassuch,arenottobeconsidered unprotectedbylaw. ThecoverdesignwascreatedbyMichaelHolt Cover Formgeber,Eppelheim (Bremen,Germany). Typesetting ThomsonDigital,Noida,India PrintingandBinding StraussGmbH,Mörlenbach PrintedintheFederalRepublicofGermany Printedonacid-freepaper ISBN:978-3-527-32509-2 This book is dedicated to my twins, Kian and Helen, and their wonderful mother Elisa. VII Foreword A vast majority of drugs are amines or contain functional groups derived from amines, and an increasing number of these molecules are chiral and nonrace mic. Thus, the development of many biologically active molecules, whether derived from natural or synthetic sources, relies on the development of general and efficient methods to prepare chiral amines. With this need in mind, many researchers made the enantioselective synthesis of amines a focus of their research during the past decade. During the early 1990s, several groups illu strated that the asymmetric hydrogenation of imines was possible and that the asymmetric hydrogenation of enamides without the accompanying ester func tionality present in the reagent for the classic hydrogenation to form LDOPA could be achieved. However, this work also revealed many of the challenges faced by these types of hydrogenation. Further work on hydrogenation of heteroarenes illustrated both progress and additional challenges. Finally, meth ods to form chiral amines by C C and C N bond formation began to emerge. Again, progress was made, but this chemistry confronted many challenges. The asymmetric synthesis of amines is a difficult problem for many reasons describedinthismonograph.Althoughacomprehensivelistofchallengescannotbe provided here, I outline a few of them. First, acyclic imines can adopt E and Z isomers, and these isomers often lead to opposite enantiomers of the addition product, thereby reducing enanioselectivity. Second, both imines and amines can beligandsforatransitionmetal,andaminesoramidescanformmetal amideor metal amidatecomplexesinwhichtheproductbecomesapartofthestructureof the active or deactivated catalyst. Third, nitrogen protective groups are a particularly thorny component of any synthetic endeavor, and the most useful protectivegroupsforasyntheticsequence,duetotheirabilitytoberemovedunder mild conditions, need not be the substituents on nitrogen that lead to highly enantioselectivechemistrytoformaminederivatives. However, the creativity of a large number of synthetic chemists has led to tremendousprogresstowardaddressingthesechallengesandthedevelopmentof trulypracticalmethodstopreparechiralamines.Perhapsthebestillustrationofhow anopenmindcanleadtosignificantadvancestowardtheasymmetricsynthesisof aminesisthedevelopmentoftheprocesstomanufacturetheblockbusterdiabetes drugJanuviabytheasymmetrichydrogenationofanunstabilizedN Himine. ChiralAmineSynthesis:Methods,DevelopmentsandApplications.EditedbyThomasC.Nugent Copyright(cid:1)2010WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim ISBN:978-3-527-32509-2