Hybrid retrosynthesis : organic synthesis using Reaxys and SciFinder PDF
Preview Hybrid retrosynthesis : organic synthesis using Reaxys and SciFinder
Hybrid RETROSYNTHESIS Hybrid RETROSYNTHESIS Organic Synthesis using Reaxys and SciFinder JOHN D’ANGELO MICHAEL B. SMITH AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON NEWYORK(cid:129)OXFORD(cid:129)PARIS(cid:129)SANDIEGO SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO Elsevier Radarweg29,POBox211,1000AEAmsterdam,Netherlands TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK 225WymanStreet,Waltham,MA02451,USA r2015ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans, electronicormechanical,includingphotocopying,recording,oranyinformationstorageand retrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhowtoseek permission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandthe CopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightby thePublisher(otherthanasmaybenotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchand experiencebroadenourunderstanding,changesinresearchmethods,professionalpractices, ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgein evaluatingandusinganyinformation,methods,compounds,orexperimentsdescribedherein. Inusingsuchinformationormethodstheyshouldbemindfuloftheirownsafetyandthesafety ofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors, assumeanyliabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterofproducts liability,negligenceorotherwise,orfromanyuseoroperationofanymethods,products, instructions,orideascontainedinthematerialherein. ISBN:978-0-12-411498-2 BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary. LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress. ForInformationonallElsevierPublishingvisit ourwebsiteathttp://store.elsevier.com/ TypesetbyMPSLimited,Chennai,India www.adi-mps.com PrintedandboundintheUSA PREFACE Arguably, organic synthesis is one of the more difficult concepts for stu- dents to master in an organic chemistry course. Indeed, an advanced undergraduate course or a graduate-level course is often devoted to this single area of organic chemistry. One problem appears to be difficulty in learning and applying many different reactions. Another problem is learn- ing and applying the principles of retrosynthetic analysis, but this issue is often exacerbated by the first problem. There are certainly many books that discuss and teach organic synthesis, and many books using slightly different approaches to teach undergraduate organic chemistry. Why is another book necessary? Computersearchingtoolsareubiquitous,andseveralsearchenginesare currently available to an organic chemist. Two of them, Reaxys and SciFinder, provide the capability of finding a given compound, a specific reaction, or examples of a specific transformation, and total syntheses may befoundthathavebeenreportedintheliterature.Suchcomputersearches are less useful for assembling a total synthesis, although several computer programs have been developed to accomplish this task: LHASA,1 CHIRON,2 ArChem,3 SYNGEN, and MARSEIL/SOS, among others. Most of these programs are rather sophisticated and expensive, however, anddemandalevelofchemicalknowledgenotyetattainedafterthetypical undergraduatemainstreamorganiccoursesequence. This book presents a relatively simple approach to solving synthesis pro- blems, and a small library of basic reactions in Chapter 8, along with the computer searching capabilities of Reaxys and SciFinder. The idea is to use retrosynthesistofindadisconnectproductforwhichacomputersearchwill generatetheremainderoftheretrosynthesis. We term this approach a hybrid retrosynthesis approach since it uses the basics of retrosynthetic analysis to obtainaworking intermediatecompoundthatissubsequentlysearchedwith the computer. This book opens with an introduction to the retrosynthetic approach and a discussion of approaches for determining important bonds fordisconnection.Itendswithabriefdiscussionofmorecomplexmolecules andhowthissimpleapproachcanbeusedwiththosechallengingproblems. 1 SeeLee,T.V.ChemometricsandIntelligentLaboratorySystems1987,2,pp.259(cid:1)272. 2 Seehttp://osiris.corg.umontreal.ca/chiron.shtml 3 Seehttp://www.archemcalc.com vii viii Preface Finally, for selected chemical transformations, a sample experimental procedure and the source from which it was gleaned is provided as the final section of this book. This section is not intended to supplant litera- ture searching, but rather to provide a practical method for the reader to complete synthetic problems. In all cases, we strongly urge that the reader consult the primary literature found herein for the actual experimental protocol and also to search for additional examples that best meet his or her needs. The authors thank Dr. Adrian Shell, formerly of Elsevier, who proposed an early version of this book, and who was responsible for the early research that led to this book. We further thank Ms. Jill Cetel and Ms. Katey Bircher, who have worked with us to develop the manuscript in its present form, and who have made production of this book possible. Where there are errors, we take full responsibility. Please contact either of us if there are questions or errors. We hope that this book will be of value to both undergraduate organic chemistry students and first year graduate students taking an organic synthesis course. John G. D’Angelo Michael B. Smith Alfred University University of Connecticut May 2015 COMMON ABBREVIATIONS AIBN azo-bis-isobutyronitrile All Allyl Am Amyl (cid:1)CH (CH ) CH 2 23 3 aq Aqueous 9-Borabicyclo[3.3.1]nonyl B 9-BBN 9-Borabicyclo[3.3.1]nonane BINAP 2R,3S-2,20-bis- (diphenylphosphino)-1,10- binapthyl Bn Benzyl (cid:1)CH Ph 2 Boc t-Butoxycarbonyl O Ot-Bu Bu n-Butyl (cid:1)CH CH CH CH 2 2 2 3 Bz Benzoyl c- Cyclo- cat. Catalytic Cbz Carbobenzyloxy (cid:1)CO CH Ph 2 2 CIP Cahn-Ingold-Prelog COD 1,5-Cyclooctadienyl Cp Cyclopentadienyl Cy(c-C H ) Cyclohexyl 6 11 (cid:3)C TemperatureinDegrees Centigrade DABCO 1,4-Diazabicyclo[2.2.2]octane d Day(s) DBN 1,5-Diazabicyclo[4.3.0]non-5- ene DBU 1,8-Diazabicyclo[5.4.0]undec- 7-ene DCC 1,3-Dicyclohexylcarbodiimide c-C H (cid:1)N5C5N(cid:1)c- 6 11 C H 6 11 DCE 1,2-Dichloroethane ClCH CH Cl 2 2 %de %Diastereomericexcess DEA Diethylamine HN(CH CH ) 2 32 DEAD Diethylazodicarboxylate EtO C(cid:1)N5NCO Et 2 2 DET Diethyltartrate DIPT Diisopropyltartrate DMAP 4-Dimethylaminopyridine DME Dimethoxyethane MeOCH CH OMe 2 2 (Continued) ix x CommonAbbreviations (Continued) DMF N,N’-Dimethylformamide DMS Dimethylsulfide DMSO Dimethylsulfoxide e2 Electrolysis %ee %Enantiomericexcess Et Ethyl (cid:1)CH CH 2 3 EDA Ethylenediamine H NCH CH NH 2 2 2 2 EDTA Ethylenediaminetetraaceticacid Equiv Equivalent(s) GC Gaschromatography gl Glacial h Hour(hours) hν Irradiationwithlight HMPA Hexamethylphosphoramide (Me N) P5O 2 3 HMPT Hexamethylphosphorus (Me N) P 2 3 triamide 1HNMR ProtonNuclearMagnetic ResonanceSpectroscopy HPLC Highperformanceliquid chromatography i-Pr Isopropyl (cid:1)CH(Me) 2 IR Infraredspectroscopy LDA Lithiumdiisopropylamide LiN(i-Pr) 2 MCPBA meta-Chloroperoxybenzoic acid Me Methyl (cid:1)CH orMe 3 Mes Mesityl 2,4,6-tri-Me(cid:1)C H 6 2 min minutes Ms Methanesulfonyl MeSO (cid:1) 2 MS MolecularSieves(3A˚ or4A˚) NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NIS N-Iodosuccinimide Ni(R) Raneynickel NMO N-MethylmorpholineN-oxide Polymericbackbone P or PCC Pyridiniumchlorochromate PDC Pyridiniumdichromate PEG Polyethyleneglycol Ph Phenyl PhH Benzene PhMe Toluene Phth Phthaloyl PTSA para-Toluenesulfonicacid Pr n-Propyl (cid:1)CH CH CH 2 2 3 Py Pyridine (Continued) CommonAbbreviations xi (Continued) Quant Quantitativeyield rt Roomtemperature sBu sec-Butyl CH CH CH(CH ) 3 2 3 sBuLi sec-Butyllithium CH CH CH(Li)CH 3 2 3 s seconds TBAF Tetrabutylammoniumfluoride n-Bu N1F2 4 TBDMS t-Butyldimethylsilyl t-BuMe Si(cid:1) 2 TBHP(t-BuOOH) t-Butylhydroperoxide Me COOH 3 t-Bu tert-Butyl (cid:1)CMe 3 TFA Trifluoroaceticacid CF COOH 3 TFAA Trifluoroaceticanhydride (CF CO) O 3 2 Tf(OTf) Triflate (cid:1)SO CF 5((cid:1)OSO CF ) 2 3 2 3 THF Tetrahydrofuran THP Tetrahydropyran TMEDA Tetramethylethylenediamine Me NCH CH NMe 2 2 2 2 TMS Trimethylsilyl (cid:1)Si(CH ) 33 Tol Tolyl 4-(Me)C H 6 4 Tr Trityl (cid:1)CPh 3 Ts(Tos) Tosyl5p-Toluenesulfonyl 4-(Me)C H SO 6 4 2 UV Ultravioletspectroscopy SUMMARY OF REACTIONS IN CHAPTER 8 Reaction Page number number ACETALSandKETALS 80 01. FromAldehydesorKetones ACIDCHLORIDES 81 02. FromCarboxylicAcids ALCOHOLS 81 03. FromAcidDerivatives(acidchlorides,anhydrides,esters) 04. FromAlkenes 05. FromEthers 06. FromKetonesorAldehydes ALCOHOL-ALCOHOL.SeeDIOLS 85 ALCOHOLS-FUNCTIONALIZED 85 07. FromEpoxidesorAlkenes ALDEHYDESorKETONES 86 08. FromAcetals 09. FromAlcohols 10. FromAlkenes 11. FromAlkynes 12. FromDiols 13. FromNitriles ALKANES 91 14. FromAlkenes 15. FromAlkylHalides 16. FromKetonesorAldehydes ALKENES 93 17. FromAlkynes 18. FromHalides,SulfonateEsters,orAmmoniumSalts ALKYLHALIDES:SeeHALIDES,ALKYL 95 ALKYNES 95 19. FromAlkenylHalides (Continued) xiii xiv SummaryofReactionsinChapter8 (Continued) Reaction Page number number AMIDES 96 20. FromAcidDerivatives 21. FromNitriles AMINES 99 22. FromAzides,Imides,andHalides 23. FromNitriles 24. FromNitroCompounds ANHYDRIDES 101 25. FromCarboxylicAcidsandAcidDerivatives ARYLHALIDES:SeeHALIDES,ARYL 101 CARBOXYLICACIDS 101 26. FromAcidDerivatives(Acidchlorides,Anhydrides,Esters, Amides) 27. FromAlcohols 28. From1,3-DicarboxylicAcids 29. FromNitriles HydrolysisbyBase HydrolysisbyAcid DIENES 105 30. FromAromatics DIHALIDES.SeeHalides 106 DIOLS 106 31. FromAlkenes 32. FromEpoxides ENAMINES 108 33. FromKetonesorAldehydes EPOXIDES 109 34. FromAlkenes 35. FromHalohydrins ESTERS 110 36. FromCarboxylicAcidsandAcidsDerivatives 37. FromKetones (Continued)
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