Retrosynthesis: 123.312
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This is an experiment. It is NOT a presentation. It is meant to be an interactive pdf for students to work through/revise from at their own pace. For these features to operate I guess it needs to......

This is an experiment. It is NOT a presentation. It is meant to be an interactive pdf for students to work through/revise from at their own pace. For these features to operate I guess it needs to be downloaded first.

It is based on 123.312 lectures on retrosynthesis or the design of chemical syntheses.

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  • 1. .Retrosynthetic.analysis ©gareth j rowlands123.312 gareth j rowlands: massey university
  • 2. Retrosynthetic analysis ©gareth j rowlandsThis file does not contain my lecture notes.This filenot contain all the my lecture notes. lectures.It does does not contain information in myIt does not contain all the information in my lectures.Itisis not intended to be printed (so no complaints that it is 400 pages long).It not intended to be printed.
  • 3. Retrosynthetic analysis OHThe idea of this file is to allow you to look at the retrosynthesis of avariety of molecules at your own pace and for me to experiment withmethods of communicating the material. If you click on the arrow you’llget the general idea... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 4. Retrosynthetic analysis OHI have attempted to make various bonds (in this case adjacent to thealcohol) interactive thus allowing you to see potential disconnections. Itmay be helpful, it may not...we will have to wait and see.Funnily enough, I like to experiment... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 5. Retrosynthetic analysis general specific www.massey.ac.nz/~gjrowlan/teaching.htmlAll the information you need can be found from these sources.Of course, to actually pass the course, you need to understand thematerial... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 6. Terminology target molecule retrosynthetic analysis reverse step disconnection synthon synthetic equivalent functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 7. Terminology O The target molecule (TM) is the H2N goal, the target, the molecule you are trying to make... target molecule retrosynthetic analysis reverse step disconnection synthon synthetic equivalent functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 8. Terminology target starting precursor 1 precursor 2molecule materialRetrosynthetic analysis (or retrosynthesis) is the idea of workingbackwards, one step at a time, to simplify a molecule. It is the logicalapproach to planning a synthesis. Each precursor becomes the targetfor further analysis. -EXAMPLE- target molecule retrosynthetic analysis reverse step disconnection synthon synthetic equivalent functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 9. Terminology A logical backwards steps. This arrow effectively means “can be made from.” To be of any value, there must be a real reaction that corresponds to the forward reaction target molecule retrosynthetic analysis reverse step disconnection synthon synthetic equivalent functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 10. TerminologyA retrosynthetic (reverse) stepinvolving the breaking of a bond X Yto form two (or more) synthons. X Y X Y X YThe more reactions you know the X• Y•more possibilities you can invoke. target molecule retrosynthetic analysis reverse step disconnection synthon synthetic equivalent functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 11. Terminology X Y A synthon is an idealised fragment. It does not have to exist. It aids X Y thought/retrosynthesis. It should have a synthetic equivalent to be of any use. X• Y• -EXAMPLE- target molecule retrosynthetic analysis reverse step disconnection synthon synthetic equivalent functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 12. Terminology HThe synthetic equivalent is a real ≡compound that corresponds to thesynthon. Ideally, a commercially O Oavailable reagent (or the next target inyour retrosynthesis) ≡ Cl (& AlCl3) target molecule retrosynthetic analysis reverse step disconnection synthon synthetic equivalent functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 13. Terminology O O H2N FGI O2NThe imaginary conversion of one functional group into another in order toaid simplification, help planning or uncover a disconnection. There mustbe a good ‘forward’ (real) reaction. -EXAMPLE- target molecule retrosynthetic analysis reverse step disconnection synthon synthetic equivalent functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 14. .Retrosynthetic.analysis: planning ©Tom Coates@Flickr
  • 15. Guidelines O H2NWhere do we start when we plan a synthesis?Below are a set of guidelines to help you logically approachretrosynthesis or the planning stage. They are not rules, the only rule isthat you want to simplify the problem whilst using chemically allowabletransformations! identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 16. .....identify functional groups O ketone amine H2NFunctional groups are the signposts to retrosynthesis. Withoutfunctionality, we have a very limited range of reactions at our disposal.Frequently, they control where we can apply disconnections. identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 17. .....identify patterns O ketone amine H2N ortho/para meta directing directingThe pattern or connections between functional groups often revealwhich reactions you can employ. Learning to recognise patterns offunctional groups is very important for retrosynthesis. The pattern offunctional groups frequently indicates the order reactions should beapproached. identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 18. .....examine disconnections H2N O a O b O C–N a b C–C H2N H2NTo begin with, you need to examine all possible disconnections. Withpractice you will learn that some can readily be ignored. You must alsoremember not to look at backwards just one step but to go further back.Shortsightedness has ruined many a retrosynthesis. identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 19. .....identify problems route a route b H2N H2N o,p-directing, no synthetic NOT meta-directing equivalentAre all the disconnections chemically allowable? Will the reactionproceed with the correct regio-, stereo- or chemoselectivity? Does thedisconnection simplify the problem? Try and answer these questionsbefore you proceed. identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 20. .....consider FGI O O H2N FGI O2N reduction (note: I have written the forward reaction under the arrow; this shows the FGI is possible & highlights potential problems)Functional group interconversions do not simplify a structure, but theydo overcome problems and/or allow disconnections that will simply thetarget identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 21. .....repeat 1-5 (until you have simple SM) O O H2N FGI O2N reductionJust keep repeating the steps until C–Cyou have a commercially availablestarting material. Approached O2N Ologically, and with a good workingknowledge of reactions,retrosynthesis can be both fun & easy. -synthetic equivalents- identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 22. .....repeat 1-5 (until you have simple SM) O O H2N FGI O2N reduction C–C -finish retrosynthesis- O2N O Cl identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 23. .....repeat 1-5 (until you have simple SM) O O H2N FGI O2N reduction -Synthesis- C–C C–N O2N O O2N Cl identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 24. .....repeat 1-5 (until you have simple SM) O O H2N FGI O2N reduction Sn HCl C–C -Synthesis- AlCl3 C–N O2N O HNO3 Cl H2SO4 identify functional groups identify patterns examine disconnections identify problems consider FGI repeat terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 25. .Retrosynthetic.analysis: examples ©lennox_mcdough@Flickr
  • 26. .Retrosynthesis of a benzene derivativeThe synthesis of aromatic compounds is relatively simple; we have alimited number of reliable reactions and a well-defined set of guidingprinciples.Therefore, we will start here... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 27. .Simple retrosynthesis NH2 BrHow could you make this compound?Consider our guidelines... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 28. .Simple retrosynthesis amine NH2 o,p-directingidentify FG & patterns Which bond C–N or connecting them C–Br would you (guidelines 1 & 2) disconnect? bromide Br o,p-directing (just) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 29. .Simple retrosynthesis NH2 Br Choose a bond! I’m not doing all the work for you... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 30. .Simple retrosynthesis NH2 Br Are there any other approaches to this molecule? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 31. .Simple retrosynthesis NH2 NO2 FGI reduction Br Br Change order of events & perform FGI first. Do we disconnect C–N or C–Br next? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 32. .Simple retrosynthesis NH2 NO2 FGI reduction Br Br Now you are just being lazy. Choose a bond! terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 33. .Simple retrosynthesis NH2 Br Which route is best? Really depends on your definition of best... -next example- ©carbonNYC@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 34. .Simple aromatic retrosynthesis OH BrHow could you make this compound?Consider our guidelines... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 35. .Simple aromatic retrosynthesis secondary alcohol OH alkylbromide Br o,p-directing o,p-directing identify FG & patterns connecting them (guidelines 1 & 2). Which bond, C–Br or C–C would you disconnect first? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 36. .Simple aromatic retrosynthesis OH O FGI reductionBr Br FGI introduces a ketone. This aids simplification by permitting standard Friedel Crafts chemistry. Which bond, C–Br or C–C would you disconnect first? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 37. .Simple aromatic retrosynthesis OH O FGI reduction Br Br C–C C–Br O bromination Br Cl and the synthesis terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 38. .Simple aromatic retrosynthesis OH O FGI reduction Br Br NaBH4 C–C AlCl3 C–Br O bromination Br Cl Br2/Fe terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 39. .Retrosynthesis of a benzene derivativesAromatic chemistry limits your choices (but allows some very reliablereactions). It was a good place to start but now lets turn our attention tomore complex systems... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 40. .Retrosynthetic analysis:aliphatic examples ©Horia Varian@Flickr
  • 41. .Simple retrosynthesis How would you make chlorbenside (anti-tick/mite)? Consider our guidelines... Cl S Cl©graftedno1@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 42. .Simple retrosynthesis chloride sulfide Cl chloride S Cl reactive benzylic positionIdentify FG & patterns connecting them (guidelines 1 & 2)C–heteroatom bonds are easy to identify & wide range of reactionsavailable to form them. These disconnections are our starting point... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 43. .Simple retrosynthesis d Cl b c S a ClWhich C–heteroatom bond would you disconnect first?Remember we want to simplify the problem & use reliable reactions. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 44. .Simple retrosynthesis SH Cl Br Cl NaOEt Cl S Cl terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 45. .Simple retrosynthesis O O OMe OH N H H O N O ICI-D7114©Peter Keyngnaert@Flickr (anti-obesity drug) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 46. .Simple retrosynthesisHow would you make this intermediate from the synthesis of ICI-D7114?Consider our guidelines... O Ph H Ph N O terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 47. .Simple retrosynthesis C–X no simple disconnections aromatic disconnections O Ph H Ph N O amine etherIdentify FG & patterns connecting them (guidelines 1 & 2)C–heteroatom (C–X) bonds are easy to identify.These disconnections are our starting point... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 48. .Simple retrosynthesis a O Ph d H c b Ph N OWhich C–heteroatom bond would you disconnect first?Remember we want to simplify the problem & use reliable reactions. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 49. .Remove reactive functionalityRemoving reactive functionality early limits side reactions & increasesthe chance of selectivity.The rest of the retrosynthesis... ©Alexandra Polido@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 50. .Simple retrosynthesis continued e O Ph f Br OWhich C–heteroatom bond should we disconnect next?Remember we want to simplify the problem & use reliable reactions. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 51. .Simple retrosynthesis OH OBn base BnCl HO HO excess base Br Br excess NHBn OBn Br OBn BnNH2 O OA simple understanding of basic reactions (& the principles behind them)allows a rapid synthesis of this precursor. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 52. .Retrosynthesis HN F3C fenfluramine neuroactive drug©alancleaver_2000@Flickr appetite surpressant terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 53. .Retrosynthesis amine HN F3C C–X disconnectionsIdentify FG & patterns connecting them (guidelines 1 & 2)C–heteroatom (C–X) bonds are easy to identify.These disconnections are our starting point... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 54. .Retrosynthesis HN C–N H2NF3C F3C ≡ ≡ NH2 Br F3CThe obvious disconnection does NOT work.Why?Think about the chemistry/reactivity of primary vs. secondary amines... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 55. .Problem NH2 Br HN F3C F3C more reactive Br N Br N BrF3C F3C MORE reactiveOver alkylation can be a serious problem.The solution to which is... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 56. .Solution O HN FGI HNF3C amide reduction F3C C–N amide NH2 O F3C Cl...Functional Group InterconversionAn amide is deactivated compared to an amine, so get single addition.The synthesis is... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 57. .Synthesis O HN FGI HNF3C amide reduction F3C LiAlH4 C–N base amide NH2 O F3C Cl...Functional Group InterconversionAn amide is deactivated compared to an amine, so get single addition.The synthesis is... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 58. .Solution HN FGI NF3C imine F3C reduction C–N imine O H2N F3CThere are many other FGI for the formation of amines.A common solution is given on the next page... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 59. .Synthesis HN FGI NF3C imine F3C reduction C–N NaBH4 or H+ imine NaBH3CN O H2N F3CAnd now for an example... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 60. .Retrosynthesis O OMe N N F Ph Ocfentanil painkiller terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 61. .Retrosynthesis amide ether O amine OMe C–N N amide N F Ph C–N amineIdentify FG & patterns connecting them (guidelines 1 & 2)C–N bonds are easy to identify.These disconnections are our starting point... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 62. .Retrosynthesis O OMe c a N b N F PhWhich C–heteroatom bond would you disconnect first?Remember we want to simplify the problem & use reliable reactions. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 63. .Retrosynthesis O O OMe OMe Cl N H C–N N N amide F N F Ph Ph FGI imine reduction O N N C–N N F Ph H2N amine condensation Ph F ...and the synthesis... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 64. .Retrosynthesis O O OMe OMe Cl N H C–N N N amide F N F Ph base Ph FGI NaBH3CN imine H+ reduction O N N C–N N F Ph H2N amine condensation Ph F terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 65. .Two group.disconnections
  • 66. .Two group disconnections OH O PhHow could you make this compound?Consider our guidelines... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 67. .Two group disconnections allyl ether group OH alcohol { O Ph C–X at centre of moleculeIdentify FG & patterns connecting them (guidelines 1 & 2)C–X bonds are easy to identify.These disconnections are our starting point... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 68. .Two group disconnections OH a b O PhWhich would be the better disconnection? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 69. .Two group disconnections OH OH O ≡ Br ≡ Ph Ph PhEpoxides are relatively stable.Epoxides are easy to prepare (and control stereochemistry)Therefore... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 70. .1,2-diX X2 1,2-diX X2 X 1 2 R2R R2 1 X1≠ (or =) X2= O, N, SForwards - 1 functional group gives 2 new ones.Backwards - look for two functional groups next to each other & weknow we can make them from a single functional group.So the synthesis is... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 71. .Retrosynthesis O OH OH ≡ b C–O O Ph OH O ≡ Ph Ph NaHlets look at an example... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 72. .Retrosynthesis O N H OH propranolol beta blocker stress relief ©non-partizan@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 73. .Retrosynthesis ether alcohol amine C–O 1 1phenolic 2 ether O N H OH 1,2-diX C–N amineIdentify FG & patterns connecting them (guidelines 1 & 2)C–X bonds are easy to form & our new 1,2-diX pattern is visible twice.These disconnections are our starting point... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 74. .Retrosynthesis a b ] O N H OHWhich C–X bond would you disconnect first? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 75. .Retrosynthesis O O N C–N O H OH H2N C–O Cl O ≡ O OH O ≡Looks good but can you see a potential problem? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 76. .There is a problem!stereochemistry!Don’t care? Go to next -retrosynthesis-Want to know what is going on? -here-©tibchris@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 77. .Retrosynthesis O H2N N O N O intermediate towards moxnidazole (anti-parasitic)©limowreck666@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 78. .Retrosynthesis hydrazone O carbamate H2N N O amine 2 x C–X 1 2 1 carbamate N O 2 x 1,2-diXIdentify FG & patterns connecting them (guidelines 1 & 2)C–X bonds & two possible 1,2-diX disconnections.These disconnections are our starting point... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 79. .Retrosynthesis O ab c H2N N O 1 2 d 1 O NWhere would you start? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 80. .Retrosynthesis H2N NH OH e 1 2 f 1 O NWhich order to we add the ‘amines’? (both are 1,2-diX disconnections) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 81. .Retrosynthesis O b c H2N 2 x C-X NH OHH2N e N O N O N O 1,2-diX O O O C–X H2N fCl NH2 O HN NHere is the complete retrosynthesis and here is the synthesis terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 82. .Retrosynthesis O b c H2N 2 x C-X NH OHH2N e N O O N O N O MeO OMe hydrazine Base 1,2-diX O O O C–X H2N fCl NH2 O HN NNow lets look at another useful pattern to identify terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 83. .Retrosynthesis N O Ph atropine mimic ©shellgreenier@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 84. .Retrosynthesis amine N O ketone 3 2 1 Ph 1,3-diXIdentify FG & patterns connecting them (guidelines 1 & 2)New pattern has heteroatoms three carbons apart (1,3-diX).Why is this a useful pattern? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 85. .1,3-diX C–X N N O O Ph Ph ≡ O Br O 3 Ph 2 1 ≡ Ph too reactiveConjugate addition is a reliable reaction. So the pattern is... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 86. .1,3-diXX O O ≡ O3 1 3 1 2 2Conjugate addition or Michael addition or 1,4-addition.Good disconnection as it is a reliable forward reaction and there aremany methods for the formation of the enone.so the synthesis would be... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 87. .1,3-diX O N O Ph N H Ph HOONote: the proton could be replace byother electrophiles to make morecomplex compoundsNote: in this case the mechanism is N Oprobably more complicated (look upiminium ion activation) PhRemember, it’s not just ketones that canactivate alkenes... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 88. .1,3-diXX .X .X ≡ .X3 1 3 1 2 2Conjugate addition or Michael addition or 1,4-addition.alkene can be activated by carbonyl group, sulfones, nitriles, nitrogroups or any strongly electron-withdrawing group.Lets look at an example terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 89. .Retrosynthesis O NH2How would you make this compound?Follow our normal thought process...Look for patterns terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 90. .Retrosynthesis ether amine 3 2 O 1 NH2 1,3-diXIdentify FG & patterns connecting them (guidelines 1 & 2)Two heteroatoms (1,3-diX) but neither are electron-withdrawing groups.Do we know any FGI that could convert one into a EWG? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 91. .Retrosynthesis FGI O NH2 O reduction N 1,3-diX OH ≡ O N NFGI allows amine to be converted to nitrile (reduction in a forwardreaction). Nitrile strong electron-withdrawing group & sets up 1,3-diX.-Synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 92. .Retrosynthesis FGI O NH2 O reduction N LiAlH4 1,3-diX base OH ≡ O N N1,3-diX disconnection is very useful. It allows molecules to be rapidlydivided.-Now the biggy- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 93. .C–C Bond Formation ©the albino@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 94. .Retrosynthesis carnation perfume intermediate ©Somalia ya swan@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 95. .Retrosynthesis alkyne C–C next to FGIdentify FG & patterns connecting them (guidelines 1 & 2)Only FG is alkyne.C–C bonds next to functional groups are good starting points.-Retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 96. .Retrosynthesis C–C ≡ ≡ H Br HAlkynes can be deprotonated with strong base and make goodnucleophiles.-Synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 97. .Retrosynthesis C–C ≡ ≡ i. NaNH2 ii. R–Br H Br HAlkynes can be deprotonated with strong base and make goodnucleophiles.-Lets try something harder- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 98. .Retrosynthesis OH violet oil component ©{ pranav }@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 99. .Retrosynthesis alkene alcohol OH C–C next to FGIdentify FG & patterns connecting them (guidelines 1 & 2)Two functional groups makes life a little easier but still some potentialproblems...-Retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 100. .Retrosynthesis b a OH FGIWhere would you start this retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 101. .Retrosynthesis OH FGI OH C–C OH H2 Lindlars i. NaNH2 catalyst NaNH2 ii. oxirane ≡ H C–C Br H H-another example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 102. .Retrosynthesis O O pea moth pheromone this is not a pea moth ©Dell’s Pics@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 103. .Retrosynthesis alkene ester O O C–C reactive next to FG functionalityIdentify FG & patterns connecting them (guidelines 1 & 2)-Retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 104. .Retrosynthesis O a b O FGIWhere would you start? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 105. .Retrosynthesis Na ( )7 OTHPBr O O i. NaNH2 ii. MeI Na(s), NH3(l) ( )7 OTHP ( )7 OTHP i. HO ii. AcCl O OIn the actual synthesis the THP protecting group was used.Make sure you understand each step (and know all the mechanisms)Next a -key disconnection- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 106. .How would you make? OHPh ©vitroid@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 107. .Retrosynthesis alcohol OH Ph C–C next to FGIdentify FG & patterns connecting them (guidelines 1 & 2)New pattern is called 1,1-C–C-1,1-C–C- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 108. .1,1-C–C OH 1,1-C–C OH R R R R ≡ ≡ O BrMg R RIf you see an alcohol, the first disconnection you should think about isthe addition of a nucleophile to a C=O bond (but not the only disconnection).-Retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 109. .Retrosynthesis b OH Ph c aWhere would you start? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 110. .Retrosynthesis OH Ph N Ph fenpiprane precursor (anti-histamine) ©jeffreyklassen.com terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 111. .Retrosynthesis alcohol OH amine 1 3 Ph 2 N Ph 1,1-C–C 1,3-diX next to FG (if we form C=O)Identify FG & patterns connecting them (guidelines 1 & 2)The alcohol group allows 1,1-C–C disconnections.two heteroatoms indicates that we should look to set up 1,3-diX (inother words this is going to influence the order of steps)-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 112. .Retrosynthesis OH a b Ph N PhSo, which way around should we perform the disconnections? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 113. .Retrosynthesis OH 2x OH 1,1-C–C Ph Ph N N Ph Ph ≡ 2 x Ph MgBr O MeO N mix together 1,3-diX O HN ≡ O N MeO MeONow that was easy. Want another example? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 114. .Retrosynthesis Cl O precursor to chlophedianol (cough suppressant) ©tranchis@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 115. .Retrosynthesis Cl O ketone aryl ring aryl ring 1,1-C–C next to FGIdentify FG & patterns connecting them (guidelines 1 & 2)Looks straightforward? No way I could be trying to trick you?-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 116. .Retrosynthesis Cl O Cl O 1,1-C–C ≡ ≡ Cl O BrMg OEt1,1-C–C disconnection removes aryl ring.Can you see why this will not work? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 117. .Problem Cl O Cl OH BrMg OEt Ph PhMultiple addition will occur (ketones normally more reactive than esters)Solution? Functional group interconversion terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 118. .Retrosynthesis Cl O Cl OH FGI oxidation 1,1-C–C Cl O Cl OH MgCl ≡FGI gives the precursor for a single addition (or 1,1-C–C disconnection)-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 119. .Retrosynthesis Cl O Cl OH MgCl Jones reagent Cl O How else could we make this compound (with reactions you have been taught)? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 120. .Retrosynthesis Cl O a bThink about aromatic substitution and the Friedel-Crafts reaction.Which side would you disconnect? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 121. .Retrosynthesis Cl O Cl O FeCl3 ClSynthesis is a simple Friedel-Crafts reaction.Now a more complex example involving the carbonyl group... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 122. .Retrosynthesis O OHow would we make this compound?-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 123. .Retrosynthesis (alcohol?) (acid?) 1,1-C–C next to FG lactone O O 1,1-C–C next to FGIdentify FG & patterns connecting them (guidelines 1 & 2)Technically only a lactone but this could be derived from an alcohol & anacid. Such a disconnection permits 1,1-C–C to be used.-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 124. .Retrosynthesis b c a O O e dWhich bond would you disconnect first?(please remember what I have just written) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 125. .Retrosynthesis FGI b c a CO2H OHWhich bond would you disconnect next?(think about selectivity and how easy it is form the nucleophile) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 126. .Retrosynthesis CO2H C–O FGI CO2H O O OH lactonisation reduction OH 1,1-C–C O C O O C OH 1,1-C–C ≡ O OH OHOnce the alkyne is installed the rest of the retrosynthesis is ok.-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 127. .Retrosynthesis i. 2 x BuLi HO O i. NaNH2 ii. CO2 ii. PrCHO iii. HOH H OH OH i. H2, Pd/C ii. HO O OThe synthesis is quite simple. Just note we need two equivalents ofbutyllithium for the second deprotonation due to the relatively acidicalcohol.-next pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 128. .Retrosynthesis Cl Et O ( )5 O Et O OMe arildone (anti-polio & herpes simplex virus) not the correct virus...©groovelock@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 129. .Retrosynthesis ether malonate (1,3-dicarbonyl) Cl Et O ( )5 O Et O OMe C–X next to FG (1,2-C–C)Identify FG & patterns connecting them (guidelines 1 & 2)The new pattern is 1,2-C–C and corresponds to enolate chemistry-pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 130. .1,2-C–C O 1,2-C–C OR R2 R R2 ≡ ≡ O Br R2 RA carbonyl group should always be one of the first places you look tosimplify a molecule, either by 1,1-C–C disconnections and oxidation or1,2-C–C disconnection.-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 131. .Retrosynthesis Cl Et a b O O Et O OMeWhich bond would you disconnect first? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 132. .Retrosynthesis O industrial precursor©looseends@Flickr to β-carotene terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 133. .Retrosynthesis alkene allylic ketone O allylic next to FG (activated (1,2-C–C) electrophile)Identify FG & patterns connecting them (guidelines 1 & 2)The new pattern is 1,2-C–C and corresponds to enolate chemistry-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 134. .Retrosynthesis 1,2-C–C O O ≡ ≡ O BrLooks fairly straight forward.Are there any problems with this in the forward sense?-yes- -no- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 135. .Retrosynthesis a O b FGISo where would you start your retrosynthesis?Disconnection or functional group interconversion? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 136. .Retrosynthesis Br NaOEt O O O CO2Et OEt NaOH H+ heat O O CO2HThe synthesis is quick and efficient.-next pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 137. .1,3-diO.the aldol reaction
  • 138. .1,3-diO (aldol) O OH O 1,3-diO OH 2 3R 1 R3 R R3 R2 R2 ≡ ≡ O OAs soon as you see an alcohol 1 Rcarbon from a carbonyl group you R3should think about the aldol reaction. R2-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 139. .Retrosynthesis OH O OMe gingerol OH (hot flavour of ginger) ©itspaulkelly@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 140. .Retrosynthesis alcohol OH O ketone OMe 1,3-diO OH (aldol)Identify FG & patterns connecting them (guidelines 1 & 2)The new pattern is 1,3-diO and corresponds to aldol chemistry-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 141. .Retrosynthesis OH O OMe a b OHSo, where would you start your retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 142. .Retrosynthesis O OTMS i. (TMS)2NLi OMe ii. TMSCl OMe OH OH hexanal TiCl4 OH O OMe OHReadily prepared by the Mukiayama aldol reaction.-another example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 143. .Retrosynthesis EtO2C HO MeO thromboxaneantagonist intermediate terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 144. .Retrosynthesis ester EtO2C allyl alcohol HO 1,2-C–C 1,3-diO (aldol) MeOIdentify FG & patterns connecting them (guidelines 1 & 2)Ester is key but remember the problem of self-condensation-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 145. .Retrosynthesis FGI a EtO2C b HO c MeOWhere would you start your retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 146. .Retrosynthesis CO2Et EtO2C b a HO MeOWhat would be the next step of the retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 147. .Retrosynthesis EtO2C CO2Et EtO2C CO2Et NaOEt Br NaOEt O MeO EtO2C CO2Et i. NaOH EtO2C ii. H+, heat HO HO MeO MeO-next example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 148. .α,β.the aldol condensation
  • 149. .α,β (the aldol condensation) O FGI O OH 1,3-diO O OR R" R R" R R" this is the same as O α,β O O aldol R R" condensation R R"Enones can readily be formed form the dehydration of 1,3-hydroxyketones (and related molecules)...Or we can perform the disconnection in one step...-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 150. .Retrosynthesis O H oxanamide intermediate (tranquiliser) ©Thijs van Exel@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 151. .Retrosynthesis enone { alkene O aldehyde H α,βIdentify FG & patterns connecting them (guidelines 1 & 2)Enone is key to simplifying this problem-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 152. .Retrosynthesis O OH O FGI H H dehydration 1,3-diO O O OH 2x H ≡ HFGI allows aldol reaction (or 1,3-diO)...Alternatively...-one step- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 153. .Retrosynthesis O O α,β O H H aldol condensationα,β disconnection gives us the two aldehydes in one go.It is the same thing but misses out some of the thought processes (sofor advanced students only?)-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 154. .Retrosynthesis O O NaOEt O H HSimple really!-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 155. .Retrosynthesis H N F O cinflumide (muscle relaxant) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 156. .Retrosynthesis α,β-unsaturated { H amide N F α,β O C–N amideIdentify FG & patterns connecting them (guidelines 1 & 2)Remove reactive functionality and then look at unsaturated system-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 157. .Retrosynthesis a b H N F OWhere would you start your retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 158. .Retrosynthesis heat HO2C CO2H OH O FF O SOCl2 H2N H N ClF F O OThe synthesis requires a malonate to prevent self-condensation.Otherwise, it is fairly straightforward.-another example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 159. .How would you make? ON O N doxpicomine (analgesic) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 160. .Retrosynthesis amine acetal O 2 x C–O acetal N O C–N NIdentify FG & patterns connecting them (guidelines 1 & 2)These are the obvious patterns but there is another we should consider.-hidden pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 161. .Retrosynthesis amine acetal O N O 2 1 3 NThe 1,3-diX relationship between heteroatoms suggests that we shouldconsider conjugate addition and hence formation of an α,β-system.-hidden pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 162. .Retrosynthesis O N O N OThe 1,3-diX relationship between heteroatoms suggests that we shouldconsider conjugate addition and hence formation of an α,β-system.-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 163. .Retrosynthesis O a e N O c b d NWhere would you start your retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 164. .Retrosynthesis EtO O c N O b N OEtWhich should be the next disconnection? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 165. .Retrosynthesis EtO O H EtO O EtO2C CO2Et N baseN N O N O O OEt N OEt LiAlH4 O OH CH2=O BF3 N O N OH N NAnd the complete synthesis.There are other ways of making amines as we shall see...-new pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 166. .1,3-aminoalcohols.nitrile chemistry
  • 167. .1,3-aminoalcohols (nitrile chemistry) OH NH2 OH NH2 1,3-aminoalcohol R R R" R" ≡ ≡ key: no substituent O N R R"Unsubstituted methylene amines can be readily prepared from nitriles-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 168. .How would you make?MeO N HO Venlafaxine (anti-depressant) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 169. .Retrosynthesis MeO amine alcohol HO 2 1 3 { N 1,3- aminoalcoholIdentify FG & patterns connecting them (guidelines 1 & 2)It contains 1,3-aminoalcohol pattern so we should know what to do...-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 170. .Retrosynthesis a MeO b e N HO c f dWhere would you start your retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 171. .1,3-aminoketones.the Mannich reaction
  • 172. .1,3-aminoketones (Mannich reaction) R R 1,3-aminoketone O R R O N N Mannich reaction R R R" R" ≡ ≡ O O O R R R R N N H ≡ R R" R R"Three-component coupling reaction to form 1,3-aminoketones-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 173. .How would you make? MeO O Ph N nisoxetine analogue (anti-depressant) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 174. .Retrosynthesis MeO ether O 1 2 3 Ph N amine { 1,3- aminoketoneIdentify FG & patterns connecting them (guidelines 1 & 2)Disconnections should lead to 1,3-aminoketone pattern-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 175. .Retrosynthesis MeO a b O c e Ph N d fWhere would you start your retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 176. .Retrosynthesis HNMe2 H2C=O O O H+ Ph N Ph NaBH4 OH MeO MeO Ph N SOCl2 HO Cl base O Ph NPh NSynthesis is quick and easy.-next pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 177. .1,3-diCO.the Claisen reaction
  • 178. .1,3-diCO (Claisen reaction) O O 1,3-diCO O O R R" Claisen reaction R R" ≡ ≡ O O R RO R"Formation of 1,3-diketones-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 179. .RetrosynthesisPh N Tazadolene(anti-depressant) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 180. .How would you make? O O Ph intermediate terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 181. .Retrosynthesis ketone O O ketone 1 3 2 Ph {Identify FG & patterns connecting them (guidelines 1 & 2)New disconnection is our 1,3-diCO-retrosynthesis- 1,3-diCO terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 182. .Retrosynthesis O O ab PhSo, which bond is it going to be? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 183. .Retrosynthesis O O O N O O H O N Ph Cl Ph BnNH2 H2(g) catalyst N NH2 NH2 OH (BrCH2CH2)2 dehydration Ph Ph Ph-next pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 184. .1,5-diO.conjugate addition
  • 185. .1,5-diO (conjugate addition) O O 1,5-diO O O 1 3 5R 2 4 R" R R" ≡ ≡ O O R R"Formation of 1,5-diketones-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 186. .How would you make? O NH Et N O rogletimide (sedative) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 187. .Retrosynthesis 2 3 1 O carbonyl 4 NH imide/ 5 amide Et N O 1,5-diOIdentify FG & patterns connecting them (guidelines 1 & 2)New disconnection is 1,5-diO so all other disconnections uncover this.-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 188. .Retrosynthesis O a c NH Et b c N OWhere would you start? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 189. .Retrosynthesis Et base CO2Et EtBr CO2Et N N base NH2 O O O base NH2 NH OEt Et Et N O NThe synthesis is relatively straight forward. Use of acrylamide instead ofethyl acrylate leads to a more practicable synthesis.-new pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 190. .C=C.alkene synthesis
  • 191. .C=C (α,β) O FGI O OH 1,3-diO O OR R" R R" R R" this is the same as O α,β O O aldol R R" condensation R R"Already seen this one.-more C=C- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 192. .C=C (Wittig reaction) R R" C=C R R" R R" Wittig R R" ≡ ≡ R R" PPh3 O R R"Wittig is a reliable method for forming C=C (but remember stereochemistry)There are many methods for the formation of alkenes: ring closingmetathesis or cross metathesis, Julia olefination, Peterson reaction,Tebbe’s reagent etc.-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 193. .Retrosynthesis Cl OH OH phenaglycol (tranquiliser) ©Tadeeej@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 194. .Retrosynthesis Cl diol OH OH { dihydroxylationIdentify FG & patterns connecting them (guidelines 1 & 2)Dihydroxylation will get us back to an alkene.-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 195. .RetrosynthesisCl Cl FGI OH dihydroxylation OHDihydroxylation will get us back to an alkene.At this point we have a lot of choices...-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 196. .Retrosynthesis Ar ≡ Ar PPh3 C=C Cl ≡ O Ar Ar O C=C ≡ ≡ Ph3PHere are two ways of using the Wittig reaction. Both get back to easilyprepared starting materials.We don’t even have to use the Wittig reaction...-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 197. .Retrosynthesis Ar O BrMg 1,1-C–CCl FGI 1,1-C–C Ar Ar BrMg dehydration OH O 1,1-C–C O BrMg ArThe alkene could also be formed by dehydration giving us this possibleroute or...-the following- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 198. .Retrosynthesis Ar MgBr 1,1-C–CCl O FGI Ar OH dehydration O 1,1-C–C Ar BrMg OEtEven with these seven possible routes, the industrial synthesis isdifferent...-industrial retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 199. .Retrosynthesis Cl Cl 1,1-C–C O OH OEt OH OH FGI hydrolysis Cl Cl O 1,1-C–C N OH NaCN...and it doesn’t even involve the formation of an alkene!-practice- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 200. .How would you make? OH Ph PhStart by identifying functional groups and patterns...-patterns- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 201. .Retrosynthesis alcohol 1,2-C–C OH FGI Ph Ph 1,1-C–C 1,1-C–CIdentify FG & patterns connecting them (guidelines 1 & 2)-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 202. .Retrosynthesis FGI OH 1 2 Ph Ph 3Where would you start? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 203. .Retrosynthesis practice! it is the only way to improve.Just pick any molecule and see how many different ways you can think of making it (with known reactions) -last slide- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 204. .Retrosynthesis Read: Stuart Warren - The Disconnection ApproachThe first edition was the book to read for retrosynthesis. I assume that the second edition is as good if not better... A good place to practice is this wonderful site from Arizona State University: http://www.asu.edu/courses/chm332/retrosynthesis.htmlThis pdf file was written whilst listening to a lot of music (it took a while to put this together) and I’ll just list a few: ...and you will know us by the trail of dead ‘tao of the dead’ black dog productions ‘bytes’ broadcast ‘ha ha sound’ swans ‘swans are dead’ mark kozelek ‘what’s next to the moon’ ©Gareth Rowlands (except the pictures, which are accredited to their rightful owners) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 205. Retrosynthetic analysis OHBreaking the left-hand bond could give you a nucleophilic benzenefragment. I would write more but this is only the demonstration. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 206. Retrosynthetic analysis OH CH3Disconnecting the right-hand bond gives the possibility of a nucleophilicmethyl fragment. Definitely possible. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 207. Retrosynthetic analysis: example O O H2N FGI O2N C–N O O C–C Cl AlCl3 We try to simplify the molecule with each step backwards. For this to work, we need to have an understanding of lots of simple chemical reactions. The more we known, the more options we have and the simpler synthesis is. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 208. synthon: example O C–C C–C O O Disconnection of a simple C–C bond gives two pairs of synthons. From your knowledge of carbonyl reactivity and simple aromatic chemistry you should be able to identify which pair of synthons relates to a known reaction. Choose one and see if you are correct... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 209. synthon: example Wrong choice! Aromatic rings are normally electron rich. They need a powerful electron withdrawing group as a substituent before you can attempt nucleophilic aromatic substitution (actually, you can perform nucleophilic aromatic substitution if you had a very good leaving groups, a diazonium ion but this leads us to the next problem). O The carbon of the carbonyl group is normally electrophilic not nucleophilic. Of course, we can reverse the inherent polarity of the carbonyl group and start discussing the concept of umpolung chemistry. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 210. synthon: exampleGood going!A benzene ring can be considered electron rich andhence nucleophilic (like an anion).The carbon of the carbonyl group is inherentlyelectrophilic (like a cation, hence the synthon) due tothe polarity of the C=O bond or the electronegativity Oof the oxygen.Now the question is, what would be the actualreagents or synthetic equivalents. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 211. functional group interconversion FGI: example NH2 A simple problem, how would we make aniline? -choose- the bond to disconnect first. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 212. functional group interconversion FGI: example NH2 C–N NH2Hopefully, the C–N bond looks the most promising, even withoutcovering the material on retrosynthetic analysis!This disconnection gives a nucleophilic benzene synthon and anelectrophilic ammonia synthon. Benzene is electron rich so can beconsidered to be the synthetic equivalent for the first synthon. There isno obvious synthetic equivalent for electrophilic ammonia.We must find a new approach -NEXT- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 213. functional group interconversion FGI: example NH2 X NH2 FGI NO2 Functional group interconversion FGI of the amine to a nitro group does not simplify our molecule (exactly the same number of atoms, just different ones). But, it does set the scene for a very simple undergraduate reaction, that of nitration, and thus makes the rest of the retrosynthetic analysis simpler. -NEXT- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 214. functional group interconversion FGI: example NH2 X NH2 FGI NO2 C–N O N OWe can now imagine the C–N disconnection. We get two synthons, thenucleophilic benzene ring & the nitronium cation. If you remember simplearomatic chemistry, this is the postulated intermediate in nitration & thushas a reliable forward reaction. We can now carry out the synthesis. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 215. functional group interconversion FGI: example NH2 X C–N NH2 FGI Sn HCl NO2 C–N O N O ≡ ≡ HNO3, H2SO4 Start retrosynthesis terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 216. .Simple retrosynthesis NH2 C–N NH2 Br Br bromobenzene would be No synthetic equivalent the synthetic equivalent this is a bad disconnection terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 217. .Simple retrosynthesis NH2 NH2 C–Br Br Br aniline is highly activated Br2/Fe towards electrophilic is the synthetic aromatic substitution equivalent now -identify problems- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 218. .Simple retrosynthesis NH2 NH2 Br Br Br2/Fe BrAmine of aniline is very effective at activating aromatic ring so we getmultiple additions.Will a FGI aid any disconnections? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 219. .Simple retrosynthesis NHAc NH2 NHAc Br2/Fe NaOH Br BrBromination of a aniline amide (acetanilide in this case) normally onlyoccurs once. The amide readily undergoes hydrolysis to regenerate thedesired amine. Thus FGI (amine to amide) overcomes the problematicmultiple bromination. Therefore, the retrosynthesis is... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 220. .Simple retrosynthesis NH2 NHAc NHAc FGI C–Br hydrolysis bromination Br Br FGI acetylation NO2 NH2 C–N FGI nitration reductionRemember: writing the process below the retrosynthesis makes it clearthat the steps you propose are possible. The synthesis would be... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 221. .Simple retrosynthesis NH2 NHAc NHAc FGI C–Br hydrolysis bromination Br NaOH Br Br2, Fe FGI acetylation Ac2O NO2 NH2 C–N FGI nitration reduction HNO3/H2SO4 Fe/HCl terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 222. .Simple retrosynthesis NO2 NO2 C–Br Br bromination Br Nitro group is meta-directing Br2/Fe is the (& strongly deactivating) synthetic equivalent Poor choice terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 223. .Simple retrosynthesis NO2 C–N NO2 nitration Br Br Bromide is activating and ortho/ HNO3/H2SO4 is the para-directing. So bromobenzene synthetic equivalent is the synthetic equivalent -full retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 224. .Simple retrosynthesis NH2 NO2 FGI reduction Br Br C–N nitration C–Br bromination Br and the -synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 225. .Simple retrosynthesis NH2 NO2 FGI reduction Br Sn/HCl Br C–N HNO3/ nitration H2SO4 C–Br bromination Br next Br2, Fe -example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 226. .Simple aromatic retrosynthesis OH OH C–Br Br brominationBr bromination with Br2/Fe ortho-directing with is known reaction activating alkyl group is promising identify potential -problems- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 227. .Simple aromatic retrosynthesis OH OH C–Br Br brominationBr NO regioselectivity activation would most likely lead to ortho & para-bromination try other disconnection terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 228. .Simple aromatic retrosynthesis OH C–C OH nucleophilic BrBr addition selective formation of nucleophile Good electrophilic synthon. (Grignard reagent) in presence on Synthetic equivalent is the bromide would be hard carbonyl group consider FGI as aid retrosynthesis terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 229. .Simple aromatic retrosynthesis O O C–Br Br brominationBr bromination with Br2/Fe ketone is meta-directing is known reaction and deactivates the ring poor choice try other disconnection terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 230. .Simple aromatic retrosynthesis O C–C O Friedel- BrBr Crafts acylation bromide is ortho,para- synthetic equivalent for directing & slightly electrophilic carbonyl is a activating carboxylic acid derivative look at the retrosynthesis in full terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 231. .Disconnection a or d X Cl b c S ClPoor choices. Neither disconnection simplifies the problem. In bothcases we still have the majority of the molecule to prepare. Eitherdisconnection b or c would be better as they split the molecule in half &lead to a convergent synthesis. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 232. .Convergent vs linear synthesis 33% 80% 80% B A+B A B A C 80% B B A C 80% A C 80% A B C F D D D E EA linear synthesis build a molecule up stepwise. Unfortunately, themaths is against you, even if you get 80% yield per step, in just threesteps you are down to a 33% yield. With a convergent synthesis... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 233. .Convergent vs linear synthesis 51% 80%A+B A B B 80% A C 80% DC+D C D B 80% 80% A CE+F E F F D EA convergent synthesis builds the molecule in units. Therefore thelongest linear sequence is far smaller & the mathematics allows a higheryield; at 80% per step, this convergent synthesis gives 51% yieldcompared to 33% by the linear sequence. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 234. .Disconnection b Cl b S Cl Cl ClCl S Cl S ≡ Br Cl no synthetic equivalentsCl HS no reliable reaction* terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 235. .alright, I lied... Pd(0), X phosphine, S base R HS RCurrently, the study of palladium(0)-catalysed reactions for the formationof C–C, C–N, C–O and C–S bonds is an area of intense study (NobelPrize this year (2010) went to Heck, Suzuki & Negishi for their work withPd). Formation of thiols has not seen as much research as the otherareas but there are still some good papers out there...But, we have not taught you this chemistry so cannot expect you toknow it, thus I’ll ignore it for the time being. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 236. .Disconnection c Cl c S Cl S Cl S ClCl Cl ≡ no good synthetic SH Cl equivalents Br Cl -synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 237. .Disconnection c Cl c S benzylic position is an Cl activated electrophile S Cl S ClCl Cl ≡ sulfur is a good nucleophile (lone pairs) SH Cl & a thiophenol is readily deprotonated Br Cl -synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 238. .Disconnection a NHBn a NHBn O Ph C–O O Ph O OHopefully, you are happy that the phenol portion should be thenucleophilic portion & the benzylic moiety should be the electrophile.There are two problems with this disconnection. The first is a minorquibble, it does not really simplify the problem.Can you see what the second, and more important problem is? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 239. .Disconnection a NHBn O Ph OChemoselectivity - there are two nucleophiles in this molecule & wecannot be certain where the electrophile would add (the oxygen asdesired or the nitrogen).You need to try another disconnection... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 240. .Disconnection bBnHN OBn C–O BnHN OBn b O OHopefully, you are happy that the phenol portion should be thenucleophilic portion, leaving a carbon-based electrophile.This disconnection is good because it cuts molecule in half, simplifyingthe synthesis considerably, but......there is a serious problem. Can you see what it is? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 241. .Disconnection b BnHN OBn OChemoselectivity - the electrophile has the chance to react with twonucleophiles and thus we have issues of selectivity.In fact, cyclisation (intramolecular attack of the amine on to theelectrophilic carbon) would give an aziridine, a potentially nastyfunctionality found/formed in mustard gases. On the other hand, aziridines, like epoxides, can be veryuseful in synthesis...Lets try again... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 242. .Disconnection dd H H N OBn C–N N OBnPh Ph O OVery poor choice!Firstly, this disconnection does not simplify the problem.Secondly, any subsequent disconnections will involve an alkylation inthe presence of an amine. This is bad.Go to the next slide to see why... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 243. .Disconnection d H2N O Ph O H2N OBn NH2 O Ph O O chemoselectivity chemoselectivity Two nucleophiles Two nucleophiles terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 244. .Always plan ahead... El laberinto del fauno ©PictureHouse ...it will avoid problems further down the sequence.... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 245. .Disconnection c H c OBn N OBn C–N HBn N Bn O O ≡ ≡ Br OBn NH2 Bn OGood choice!This disconnection may not split the molecule in half but it is chemicallypossible and it greatly simplifies the synthesis.This leads to another good guideline... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 246. .Disconnection e e Br O C–O Br O Ph Ph O O ≡ ≡ Br OH Br O PhPoor choice!Chemoselectivity is the issue. There are two electrophiles in twodifferent molecules. Hard to control which will react.Lets try the other disconnection... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 247. .Disconnection f Br OBn C–O Br OBn f O O ≡ ≡ Br OBn Br HOGood choice!Splits molecule in half. Whilst there are two electrophiles they are on thesame molecule, so if we use this reagent in excess statistics should giveus the product of a single addition.The full retrosynthesis is... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 248. .Retrosynthesis NHBn OBn Br OBn C–N BnNH2 O O C–O OH Cl O Br C–O Ph Ph HO HO BrThe starting material is a di-nucleophile but the functionality is in thesame molecule so once again we can employ the trick of using anexcess to ensure mono-benzylation.The full synthesis is... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 249. .Disconnection a O O OMe OMe a N N C–N N N F F Ph PhPoor choice!No reliable reaction (that we have taught you).Try again... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 250. .Disconnection b O OMe O N OMe C–N N N b N F Ph F PhNot the best choice!The forward reaction may be possible but potential problem ofchemoselectivity (N- vs. O-alkylation of amide) and possibility of amideacting as either a base or a nucleophile. There is a better disconnection.Try again... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 251. .Disconnection c O O OMe OMe c N C–N N N F N F Ph PhGood choice!The forward reaction is a simple amide formation. It simplifies theproblem by removing amide and ether functionality.What will the next disconnection be? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 252. .Retrosynthesis FGI d H a N N F PhWhich C–heteroatom bond would you disconnect first?Remember we want to simplify the problem & use reliable reactions. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 253. .Disconnection a H a H N N C–N N N F F Ph PhStill a Poor choice!No reliable reaction (that we have taught you).Try again... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 254. .Disconnection d d H N H C–N N N N F F Ph PhHello! What is this section about?The alkylation of amines is problematic; over alkylation can occur. Thisreaction might work, steric hindrance might prevent a second alkylationbut humour me and have another go...Try again... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 255. .FGI H N N FGI N N F F imine reduction Ph Ph C–NGood amineFGI prevents multiple alkylations condensationand simplifies the C–N bond Oforming step (condensations are H2Neasy reactions). NLets look at the whole Fretrosynthesis... Ph terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 256. .Disconnection a OH OH OH O ≡ HO a C–O Ph Ph O Ph Br ≡Possibly...But, can you see the potential problem with this reaction?If you can’t, the problem is shown here.Try again? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 257. .Problem a OH HO PhTwo nucleophilic alcohols; so chemoselectivity is an issue.Alkylation could occur on either.Try again? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 258. .Disconnection b O OH OH ≡ b C–O O Ph OH OH ≡ Br Ph PhGood...Splits molecule in half. But still have two alcohols that could causetrouble.Furthermore, the bromide is not stable...What could we use instead? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 259. .Disconnection a a N ≡ N H O H O N C–O OH H OH O OH ≡Possibly...Phenoxide is a good nucleophile. But there is a possible problem...If you can’t see the problem it is here.Try again? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 260. .Problem a OH N O HTwo nucleophiles; so chemoselectivity is an issue.Alkylation could occur on either.Try again? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 261. .Disconnection b b N ≡ H2N H O N C–N H OH O O O OH ≡Good...This disconnection removes the reactive functionality (the amine) first.Still haven’t got a simple starting material.More retrosynthesis is required. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 262. .Problem Cl Nuc OTwo electrophilesBut the reaction of both gives an almost identical product... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 263. .Problem Nuc Cl Nuc O O Cl Nuc Nuc O OBut isn’t this the same compound?Well, if you don’t care about stereochemistry it is...but for the rest of us... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 264. .Problem OH O base O Cl O OH O base O Cl OIf you start with a single enantiomer of the epoxide, the two differentmechanisms actually give the two different enantiomers of the finalproduct. terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 265. .Answer Cl Nuc ONormally, the epoxide reacts first.In fact, depending on the strength of the base you can isolate thealkoxide intermediate.-Next example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 266. .Disconnection a O H2NO N O O a N O H2N N O O N O H2NO N O N OWhy would you choose this? Have I taught you nothing?How many reactions do you know for making N–N bonds?How does this simplify the problem?-Try again- (or get a drink and come back to this later as you really aren’t thinking about it) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 267. .Disconnection d O O H2N H2N N O N O O N d N OPossiblyEasy bond to make. Removes an amine. You might go this route but...It does not make use of 1,2-diX disconnection which would simplify theproblem quicker.-Look for a route that will give you the 1,2-diX disconnection- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 268. .Disconnections b & c H2N N O O O b c N OH2N N O ≡ ≡ H2N O O NH OH N 1 2 O Cl Cl N 1Remove carbamate.Two simple C–X bonds that can be readily made in one step (& there aresafer reagents than phosgene, this is just to keep things simple)-Now we have the 1,2-diX precursor but one question still- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 269. .Disconnections fH2N H2N NH OH 1,2-diX NH OH f N O N O ? ≡ ≡NH2 O e O O Cl H2NHNNH2 HNDisconnection f is fine but...Can you see what is wrong with the subsequent disconnection?-problem- -try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 270. .Problem NH2 O Cl NH2 two two nucleophilic electrophilic centres centresMultiple additions could easily occur.Furthermore, if we add hydrazine early we have to carry the additionalreactive functionality through the entire synthesis-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 271. .Disconnections eH2N OH NH OH 1,2-diX e H2N NH O N O N ≡ ≡ O O C–XO H2N f Cl NH2 O HN NDisconnection e is goodRemoves reactive hydrazine functionality early (or adds late in synthesis).Minimises possibility of multiple additions-full retrosynthesis & synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 272. .Disconnection b C–C OH OH ≡ ≡ MgBr ODisconnection b is a poor choice.You remove one carbon, this hardly simplifies the problem.How would you make the necessary Grignard reagent (or its equivalent)?Whilst possible it would be better if -you tried again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 273. .Disconnection a C–C OH OH ≡ ≡ O ?Disconnection a could be a good choice.Split molecule in half and the epoxide is a good electrophile.But, stereoselective formation of the anion hard. Deprotonation is notselective. Formation of alkenyl halide or equivalent complex.Whilst possible it would be better if -you tried again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 274. .FGIUse of an FGI allows simple alkyne chemistry to be employed. OIn the forward sense the reactions is a stereospecificreduction. ≡Rest of retrosynthesis follows standard chemistry. OH FGI OH C–C OH reduction ≡ H C–C Br H H-Synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 275. .Disconnection a O a O C–C O ( )7 ODisconnection a is problematic.Deprotonation of an alkene is hard and stereoselectivity would be an issue.Whilst possible, it would be better if -you tried again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 276. .FGI O O FGI FGI reduction O OA good choice but to get the trans alkene we need to perform adissolving metal reduction and it is possible that the ester functionalitywill not survive.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 277. .Disconnection b O C–O ( )7 OH O FGI reduction H H C–C C–C ( )7 ( )7 OH OHBr ( )7 OHDisconnection b is good.Remove the reactive ester first. Then we can do our FGI to give us analkyne that allows C–C bond formation, twice!The actual synthesis is slightly different and shown -here- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 278. .Disconnection a OH 1,1-C–C OH Ph Ph Me ≡ ≡ O Ph BrMg MeDisconnection a is a good choice.Readily available starting materials & a reliable reaction.Now lets try a real example -here- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 279. .Disconnection b OH 1,1-C–C OH Ph Ph ≡ ≡ O Ph MgBrDisconnection b is a very good choice.Readily available starting materials, splitting the molecule in half & a reliablereaction.Now lets try a real example -here- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 280. .Disconnection c OH 1,1-C–C OH Me Ph Ph Me ≡ ≡ O BrMg Me Ph OMe BrMg MeDisconnection c is a very good choice.Readily available starting materials & a reliable reaction.Now lets try a real example -here- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 281. .Disconnection b OH C–X OH N Ph N Ph Ph PhDisconnection b is a poor choice.Whilst possible, it is a single group disconnection and would leave us havingto prepare the halide. Two group disconnections cause greatersimplification.How could we perform a two group disconnection on this molecule? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 282. .Disconnection a OH 2x OH 1,1-C–C Ph Ph N N Ph Ph ≡ ≡ O Ph MgBr MeO N Ph MgBr 1,3-diX O HN ≡ O N MeO MeODisconnection a is a good choice.The 1,2-C–C disconnection sets up the 1,3-diX disconnection.The full synthesis is -here- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 283. .Disconnection a Cl O Cl O C–C ≡ ≡ Cl O ClDisconnection a is not a good choice.It will make the product but only as a minor component.-What is the major product?--Try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 284. .Problem: regioselectivity Cl Cl O Cl O FeCl3 Cl Ph O Ph 88 : 11Problem: para substitution is favoured over ortho substitution.-the solution- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 285. .Disconnection b Cl O Cl O C–C ≡ ≡ Cl O ClDisconnection b is a good choice.There is no issue of regioselectivity during addition and the ketone willdeactivate product so no over addition.-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 286. .Disconnection a 1,1-C–C O O O ODisconnection a is a poor choice.Why? Why would you choose this bond? Whilst it is actually possible to godown this route, it is not obvious, it is not anything we have taught you & itcertainly does not follow on from the previous slides!-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 287. .Disconnection b 1,1-C–C O O O ODisconnection b is a poor choice.You cannot be serious! I admire your creativity but really, this isn’t helping(or following my hints). What are you going to use as an electrophile?Reverse the synthon and it is still looking hard.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 288. .Disconnection c 1,1-C–C O O O ODisconnection c is not the best choice.Whilst possible, this won’t be the simplest solution, there is one much easierbond to form. One bond which we teach you in the first year...-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 289. .Disconnection e C–X O O O ODisconnection e is a poor choice.Whilst there are a number of interesting ways this might be achieved, itcertainly isn’t straight forward. It ignores my hints and a very simple reaction.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 290. .Disconnection d C–X O O O O ≡ CO2H OHDisconnection d is a good choice.Esterification is a reliable reaction (& good at forming medium rings).The disconnection leaves an alcohol and an acid to use for furthersimplification.-next disconnection- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 291. .Disconnection a 1,1-C–C CO2H CO2H OH OH ≡ ≡ MgBr CO2H ODisconnection a is a poor choice.It would be hard to get selectivity in the addition of the Grignard reagent tothe aldehyde in the presence of the acid.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 292. .Disconnection b 1,1-C–C CO2H OH OH CO2H ≡ ≡ BrMg O CO2HDisconnection b is a poor choice.Formation of the Grignard reagent in the same molecule as an acid couldcause selectivity issues.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 293. .Disconnection c 1,1-C–C O CO2H OH OH OH ≡ ≡ MgBr O C O OHDisconnection c is not the best choice.Whilst it would be possible to form the Grignard reagent, there are betterways to achieve this. The use of carbon dioxide to form the acid is good.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 294. .Functional group interconversion CO2H FGI CO2H OH reduction OHFunctional group interconversion FGI is the best route. Byincorporating the alkyne we can now readily simplify the rest of themolecule-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 295. .Disconnection a Cl Et Cl a O C–X OH O Et O ether formation OMe OMeBr Br Et 1,2-C–C Br O O O Et Et Et O H HDisconnection a is ok but not the best choice...The problem is the alkylation of the diketone; we have a compound with 2 xelectrophilic carbons and 2 x acidic protons. Could get cyclisation.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 296. .Disconnection b Cl Et b O O O O 1,2-C–C Et Et Et O H H OMeBr Br Cl Cl C–X O OH Br ether formation OMe OMeDisconnection a is goodOnly potential problem arises with the dibromide (adding to phenols) butthis can be minimised by controlling the stoichiometry-next example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 297. .Problem: self-condensation WRONG!Why did you say no?Surely, by now you have realised that I won’t have asked the question ifthe answer had been no...-the problem- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 298. .Problem: self-condensation O OH O O BASE and/or OAcetone is prone to self-condensation (it adds to itself readily)-the solution- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 299. .Solution: functional group interconversion O O O ≡ OEtβ-Keto ester behaves like acetone then we can remove the unwantedester by decarboxylation-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 300. .Disconnection a 1,2-C–C O O The same as before! Really, that’s your choice...I give up...Why the f*$* have you chosen this disconnection?Did you read any of the previous slides?-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 301. .Functional group interconversion FGI O O decarboxylation CO2Et 1,2-C–C O O ≡ O Br OEt CO2EtFirst, we need the ester to prevent self-condensation.Then retrosynthesis is straightforward.-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 302. .Disconnection a OH O OMe OH 1,3-diO OH O OMe OH ≡ ≡ O O OMe OHDisconnection a leads to a quick simplification of the problem-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 303. .Disconnection b OH O OMe OH C–C OH O OH O OMe OMe OH OH ≡ ≡ ≡ ≡ O O ? ? X OMe OHWhy would you choose this bond in a section about the aldol reaction?-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 304. .Functional group interconversionEtO2C CO2Et EtO2C FGI HO HO decarboxylation MeO MeOFunctional group interconversion makes enolate formation easier. Thismakes subsequent disconnections easier.Prevents the self-condensation of ethyl acetate .-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 305. .Disconnection a CO2Et CO2Et EtO2C EtO2C 1,2-C–C HO HO MeO MeO ≡ ≡ H EtO2C CO2Et BrDisconnection a is problematic HOPotentially, we could alkylate thealcohol with the allyl bromide. MeO-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 306. .Disconnection b CO2Et EtO2C 1,3-diO CO2Et EtO2C HO HO MeO MeO ≡ ≡ EtO2C CO2Et EtO2C CO2Et 1,2-C–C O MeO BrDisconnection b is a good choiceReverse of the aldol reaction removes reactive alcohol & splits molecule intwo. Both halves readily prepared.-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 307. .Disconnection aEtO2C EtO2C 1,2-C–C HO HO MeO MeO ≡ ≡Disconnection a is badUnlikely to be able to controlchemoselectivity of allylation & EtO2C H Bryou will probably observe allylationof the alcohol. HOEven if this step worked the nextdisconnection would fail due to MeOself condensation!-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 308. .Disconnection b EtO2C 1,3-diO EtO2C HO HO MeO MeO ≡ ≡ EtO2C FGI O EtO2C CO2Et decarboxylation MeO 1,2-C–C Disconnection b seems ok Splits molecule in two. EtO2C CO2Et Need FGI to add ester & prevent self- Br condensation. Shows that there is more than one right answer! -my choice of synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 309. .Disconnection c EtO2C EtO2C 1,1-C–C HO HO MeO MeO ≡ ≡Disconnection c is a bad choice BrMgUnlikely to be able to control EtO2Cchemoselectivity of Grignardreaction; addition to either O MeOcarbonyl or deprotonation ofacidic malonate-like position.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 310. .Disconnection a α,β H H N NF aldol O condensation F O ODisconnection a might work but...Potentially the amide functionality could disrupt the condensation.Cyclopropane rings are often reactive (ring strain).-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 311. .Disconnection b H2N C–N H N F amide Cl O F O FGI OH O α,β OH F Knoevenagel condensation O O FDisconnection b betterRemove reactive functionality first then we can disconnection α,β-system.-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 312. .Disconnection a O O 1,1-C–C N O O N N N ≡ ≡ O O N MgBr NDisconnection a is problematicWhilst the addition of the Grignard is attractive, the iminium species willtautomerise to an enamine, which is not electrophilic.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 313. .Disconnection b O O C–N N O N N O N ≡ ≡ O H N O N ClDisconnection b is problematicI’m not sure if we would observe the desired substitution. It is likely that theamine would act as a base and cause elimination. If it didn’t how would wemake the chloride (and this is quite useful as it will lead us to a faster route)-further disconnections- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 314. .Disconnection b: next steps O O FGI N O N O Cl OH 1,1-C–C O O N O ≡ N O BrMg O OHHalide from alcoholAlcohol allows simple 1,1-C–C disconnection, which takes us back to analdehyde (good) and a strange Grignard reagent. How would we make this?-further disconnections- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 315. .Disconnection b: next steps O OH C–O N O N OH acetal OH formation OH FGI N CO2Et 1,2-C–C N O CO2Et OH EtO2C CO2EtMaking the Grignard would be hard but simple FGI allows us to use amalonate. Problem: competing Knoevenagel condensation but this isactually good and shows us how we should proceed...-Try again (using this knowledge)- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 316. .Disconnection c O 1,1-C–C O N O N O N N ≡ ≡ O N O BrMg NDisconnection c is ok-ishAddition to the iminium ion should work. The iminium is dervied from thealdehyde. Making the Grignard reagent is going to be tougher-further disconnections- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 317. .Disconnection c: the next steps O O C–O OH O ≡ O OH BrMg acetal formation FGI O CO2Et ≡ O CO2EtFGI will allow us to use a malonate instead of the difficult Grignard.Our biggest problem would be competing Knoevenagel condensationbut we could use to this to our advantage...-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 318. .Disconnection d O O C–O N O N O N NDisconnection d is rubbishThere is no reason to choose this disconnection. It does not simplify theproblem. It does not have useful synthetic equivalent. If you honestlychose this there is a good chance you are going to fail...-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 319. .Disconnection e O OH 2 x C–O N O N OH acetal formation N N FGI reduction EtO ODisconnection e is a good choiceIn the introduction to this molecule, I said N Othat the 1,3-diX disconnection would beuseful. So the first thing we need to do isadd the carbonyl group so that we set up N OEtthe correct pattern-next step- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 320. .Disconnection c EtO O EtO O 1,2-C–C N O N O N OEt N OEt ≡ ≡Disconnection c is a possibility EtO OThis might work. Should be able to Nget addition to iminium ion and Ohopefully, elimination of the amine Nwill not be a problem but a more OEtreliable route exists-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 321. .Disconnection b EtO O EtO O 1,3-diX N O N O OEt N OEt N ≡ N EtO O α,β H N O N O O O OEt EtO OEtDisconnection b is the best choiceAll reliable reactions that will lead to the desired product.-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 322. .Disconnection a why?Why would you choose this disconnection? It does not simplify theproblem and there is no reliable method of making this bond. You aregoing to fail...-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 323. .Disconnection b MeO N MeO HO N HO ≡ ≡ MeO N O MgBrDisconnection b is ok-ishCuts molecule in half, which is good. Might have trouble opening theepoxide but certainly worth considering...Except this is a section on 1,3-aminoalcohols so use that disconnection!-try again- (for practice, work out how to make the epoxide...) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 324. .Disconnection cMeO MeO HO N HO N ≡ ≡ MeO O N BrMgDisconnection c is a bad choiceI can see where you are coming from but NO! How are you going to makethe Grignard reagent (or anion)?-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 325. .Disconnection d why?Why would you choose this disconnection? It does not simplify theproblem and there is no reliable method of making this bond. You aregoing to fail...-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 326. .Disconnection e MeO MeO N N HO HO ≡ ≡ MeO Cl HN HODisconnection e is a bad choiceDoesn’t simplify the problem anddoesn’t even set-up the disconnectionwe have been discussing!-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 327. .Disconnection f MeO MeO 2 x C–N N NH2 HO HO FGI reduction MeO MeO N N 1,3-aminoalcohol HO ODisconnection e is a good choiceThe initial disconnection may only remove methyl groups from the end of themolecule but it sets-up the 1,3-aminoalcohol disconnection.How would you make the nitrile? -new pattern- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 328. .Disconnection a why?Why would you choose this disconnection? It does not simplify theproblem and there is no reliable method of making this bond. You aregoing to fail...-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 329. .Disconnection b why?Why would you choose this disconnection? It does not simplify theproblem and there is no reliable method (that we have taught you) ofmaking this bond. You are going to fail...-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 330. .Disconnection c MeO MeO C–O O Ph N O Ph N ≡ ≡ Cl MeO Ph N HODisconnection c is a good choiceRemoved large part of molecule and one step closer 1,3-aminoketonepattern. How would we make this pattern from here?-next step- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 331. .Disconnection c Cl OH FGI Ph N Ph N FGI O reduction Ph 1,3-aminoketone O O Ph N Mannich reaction H H H NThe chloride can easily be taken back to the required ketone and thuswe can use the Mannich disconnection.-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 332. .Disconnection d MeO O MeO Ph N O MeO Ph N O Ph NDisconnection d...really?Do any of these look like plausible synthons?-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 333. .Disconnection e MeO MeO O O Ph N Ph NDisconnection e not the best choiceYes, the disconnection works but it doesn’t simplify the problem or aid insimplifying the problem. It is a waste of time.Unless you were looking at an asymmetric synthesis and required anallylic alcohol (look at Sharpless’s synthesis of the related molecule, Prozac)-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 334. .Disconnection f MeO MeO MeO 2 x C–O FGI O O O reduction N Ph N Ph NH2 Ph C–O O 1,1-C–C OH FGI Cl MeO Ph N N N Ph Ph HODisconnection f not the best choiceWe can complete the synthesis as shown...but it is long dull synthesis.No advantages to this route, it just shows there is more than one answer.-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 335. .Disconnection a O O O O 1,3-diCO Ph Ph ≡ O O OEt PhDisconnection a is not good...Chemoselectivity is going to be an issue; which side will form theenolate & which site is the better electrophile-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 336. .Disconnection b O O O O 1,3-diCO Ph Ph ≡ ≡ O O Cl PhDisconnection b worksNo issue of chemoselectivity. I hope you can see why I only choose oneset of synthons...-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 337. .Disconnection a O O NH NH N Et EtN O ODisconnection a is not good...We have not taught you any reaction to make the requisite C–aryl bond(this is potentially a way of doing it but that is for a more advanced class)-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 338. .Disconnection b O O O 1,2-C–C NH NH NH ≡ Et N ON O N O Et Et IDisconnection b is ok...Removing the ethyl group is possible. It does not simplify our problem buton the plus side, the late stage addition of this substituent would allow thesynthesis of analogues. I will not go through this route but you willhopefully see its similarity to the completed route (just swap two steps).-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 339. .Disconnection c y O CO2Et 2 x C–N x NH NH3 CO2Et Et Et N O NDisconnection c is goodRemoving the nitrogen sets up the 1,5-diO disconnection.But which bond, x or y, is it? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 340. .Disconnection y CO2Et CO2Et 1,5-diO CO2Et CO2Et Et Et N N ≡ ≡ ? CO2EtDisconnection y is not your best choiceWhilst it is possible, it can’t proceed by a 1,5-diO disconnection and thus Idon’t think you have been paying much attention...-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 341. .Disconnection x CO2Et 1,5-diO CO2Et CO2Et CO2Et Et Et NN ≡ ≡ Et Br Et 1,2-C–C CO2Et CO2Et CO2Et N NDisconnection x is goodMolecule can simply be prepared by enolate chemistry.-synthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 342. .Disconnection 2 OH Ph OH Ph 1,1-C–C Ph Ph OH Ph PhDisconnection 2Which is the correct set of synthons? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 343. .Disconnection 2 No! OH Ph OH Ph 1,1-C–C Ph Ph OH Ph PhYou want an electrophilic carbon on alcohol so that you can use analdehyde...its the most standard reaction, please learn it (or you will fail)Disconnection 2-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 344. .Disconnection 2 OH Ph OH Ph 1,1-C–C Ph Ph OH Ph Ph ≡ ≡ O BrMg Ph PhDisconnection 2Simple one step synthesis.-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 345. .Disconnection 1 OH 1,1-C–C OH PhPh Ph Ph ≡ ≡ O Ph MgBr PhDisconnection 1This is the only set of synthons for this disconnection (unless you do anFGI first) and leads to a simple one step synthesis.-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 346. .Disconnection 3 OH Ph OH Ph 1,2-C–C Ph Ph OH Ph PhDisconnection 3Which is the correct set of synthons?-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 347. .Disconnection 3 OH ok Ph PhDisconnection 3Possible but needs some work (protecting alcohol for instance)-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 348. .Disconnection 3 OH Ph OH Ph 1,2-C–C Ph Ph OH Ph Ph ≡ ≡ O BrMg Ph PhDisconnection 3The epoxide gives yet another good route. So many ‘correct’ answers...-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 349. .Functional Group Interconversion OH FGI O a b cPh Ph reduction Ph PhFunctional Group InterconversionOpens up another useful collection of disconnections.Which one would you choose? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 350. .Disconnection c O Ph O Ph 1,3-C–C Ph Ph O Ph PhDisconnection cWhich set of synthons is best?-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 351. .Disconnection c O Ph Ph terminology No!How would you make the nucleophile (hint: you could not start with ahalide, it would be unstable).-try again- guidelines aromatics aliphatics two group patterns C–C bonds
  • 352. .Disconnection c O Ph O Ph 1,3-C–C Ph Ph O Ph Ph ≡ ≡ O BrMg PhDisconnection c PhConjugate addition is a good method for the formation of this molecule.But, from a practical point of view you would probably need some copperpresent to encourage 1,4 over 1,2-addition.-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 353. .Disconnection b O Ph O Ph 1,2-C–C Ph Ph O Ph PhDisconnection bWhich set of synthons is best?-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 354. .Disconnection b O No! Ph PhHow would you get chemoselectivity in the nucleophilic addition to acompound containing a carbonyl group?-try again- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 355. .Disconnection b O Ph O Ph 1,2-C–C Ph Ph O Ph Ph ≡ ≡ O Br Ph PhDisconnection bSimple enolate chemistry offers the best route for this disconnection.-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 356. .Disconnection a O Ph O Ph 1,1-C–C Ph Ph O Ph PhDisconnection aWhich set of synthons is best?-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  • 357. .Disconnection a O Ph terminology No!Really, you that was the best choice? So what is your nucleophile andelectrophile going to be? Do you remember any aromatic chemistry?-try again- guidelines aromatics aliphatics two group patterns Ph C–C bonds
  • 358. .Disconnection a O Ph O Ph 1,1-C–C Ph Ph O Ph Ph ≡ ≡ O PhH Cl PhDisconnection aTo be honest, I don’t think that Friedel Crafts will work here. Cyclisation(or intramolecular Friedel Crafts) is going to compete...-try a different disconnection- -finish- terminology guidelines aromatics aliphatics two group patterns C–C bonds