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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 be downloaded first.

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

Published in: Education

Retrosynthesis: 123.312

  1. 1. .Retrosynthetic.analysis ©gareth j rowlands123.312 gareth j rowlands: massey university
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 14. .Retrosynthetic.analysis: planning ©Tom Coates@Flickr
  15. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 25. .Retrosynthetic.analysis: examples ©lennox_mcdough@Flickr
  26. 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. 27. .Simple retrosynthesis NH2 BrHow could you make this compound?Consider our guidelines... terminology guidelines aromatics aliphatics two group patterns C–C bonds
  28. 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. 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. 30. .Simple retrosynthesis NH2 Br Are there any other approaches to this molecule? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  31. 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. 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. 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. 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. 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. 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. 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. 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. 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. 40. .Retrosynthetic analysis:aliphatic examples ©Horia Varian@Flickr
  41. 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. 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. 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. 44. .Simple retrosynthesis SH Cl Br Cl NaOEt Cl S Cl terminology guidelines aromatics aliphatics two group patterns C–C bonds
  45. 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. 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. 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. 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. 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. 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. 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. 52. .Retrosynthesis HN F3C fenfluramine neuroactive drug©alancleaver_2000@Flickr appetite surpressant terminology guidelines aromatics aliphatics two group patterns C–C bonds
  53. 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. 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. 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. 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. 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. 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. 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. 60. .Retrosynthesis O OMe N N F Ph Ocfentanil painkiller terminology guidelines aromatics aliphatics two group patterns C–C bonds
  61. 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. 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. 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. 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. 65. .Two group.disconnections
  66. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 83. .Retrosynthesis N O Ph atropine mimic ©shellgreenier@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  84. 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. 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. 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. 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. 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. 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. 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. 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. 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. 93. .C–C Bond Formation ©the albino@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  94. 94. .Retrosynthesis carnation perfume intermediate ©Somalia ya swan@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  95. 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. 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. 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. 98. .Retrosynthesis OH violet oil component ©{ pranav }@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  99. 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. 100. .Retrosynthesis b a OH FGIWhere would you start this retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  101. 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. 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. 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. 104. .Retrosynthesis O a b O FGIWhere would you start? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  105. 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. 106. .How would you make? OHPh ©vitroid@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  107. 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. 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. 109. .Retrosynthesis b OH Ph c aWhere would you start? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  110. 110. .Retrosynthesis OH Ph N Ph fenpiprane precursor (anti-histamine) ©jeffreyklassen.com terminology guidelines aromatics aliphatics two group patterns C–C bonds
  111. 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. 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. 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. 114. .Retrosynthesis Cl O precursor to chlophedianol (cough suppressant) ©tranchis@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  115. 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. 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. 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. 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. 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. 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. 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. 122. .Retrosynthesis O OHow would we make this compound?-retrosynthesis- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  123. 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. 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. 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. 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. 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. 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. 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. 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. 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. 132. .Retrosynthesis O industrial precursor©looseends@Flickr to β-carotene terminology guidelines aromatics aliphatics two group patterns C–C bonds
  133. 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. 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. 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. 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. 137. .1,3-diO.the aldol reaction
  138. 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. 139. .Retrosynthesis OH O OMe gingerol OH (hot flavour of ginger) ©itspaulkelly@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  140. 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. 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. 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. 143. .Retrosynthesis EtO2C HO MeO thromboxaneantagonist intermediate terminology guidelines aromatics aliphatics two group patterns C–C bonds
  144. 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. 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. 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. 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. 148. .α,β.the aldol condensation
  149. 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. 150. .Retrosynthesis O H oxanamide intermediate (tranquiliser) ©Thijs van Exel@Flickr terminology guidelines aromatics aliphatics two group patterns C–C bonds
  151. 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. 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. 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. 154. .Retrosynthesis O O NaOEt O H HSimple really!-example- terminology guidelines aromatics aliphatics two group patterns C–C bonds
  155. 155. .Retrosynthesis H N F O cinflumide (muscle relaxant) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  156. 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. 157. .Retrosynthesis a b H N F OWhere would you start your retrosynthesis? terminology guidelines aromatics aliphatics two group patterns C–C bonds
  158. 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. 159. .How would you make? ON O N doxpicomine (analgesic) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  160. 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. 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. 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. 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. 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. 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. 166. .1,3-aminoalcohols.nitrile chemistry
  167. 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. 168. .How would you make?MeO N HO Venlafaxine (anti-depressant) terminology guidelines aromatics aliphatics two group patterns C–C bonds
  169. 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. 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. 171. .1,3-aminoketones.the Mannich reaction

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