Retrosynthetic analysis

Describes disconnection approach and synthetic methodologies in organic synthesis.

1. 1
Retrosynthetic Analysis
Dr.Santosh L. Gaonkar, Professor,
Dept of Chemistry, Manipal Institute of Technology, Manipal

2. 2

3. 3

4. 4
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
•The idea of working backwards from final target molecule to
starting materials (usually via one or more intermediates) when
designing a synthesis.
•The development of this thought process is widely attributed toE.
J. Corey ofHarvardUniversity, who was awarded the 1990 Nobel
Prize in Chemistry.

5. 5
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

6. 6
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

7. 7
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

8. 8
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Retrosynthetic Analysis
It is exactly the reverse of chemical synthesis
Disconnection is reverse operation to a reaction: An imaginary
cleavage of a bond to break the molecule into starting materials
TM-Target molecule to be synthesized
FGI-Functional Group Interconversion
Reverse of Synthesis-The process of breaking down the TM
into available starting materials by FGI and disconnection
Synthon-Idealisedfragments resulting from disconnection,
Synthetic Equivalent ( reagents)-Actual substrates used for the forward synthesis
Synthon –An idealized fragment usually an ion or radical obtained by
disconnection. May or may not involve is actual reaction
Reagent –Actual comp (chemicals) used in practice for a synthesis e.g.-
Synthon-Me⁺Reagent-Me2SO4

9. 9
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Esters are easily made from acids. We should disconnect C-O bond
Now we should disconnect –NH2 or –COOH. But no good reactions

10. 10
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Synthesis
We have to write a reliable synthesis by adding reagents
and conditions

11. 11
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Synthon-Idealisedfragments resulting from disconnection
Retrosynthetic analysis

12. 12
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Retrosynthetic analysis

13. 13
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Retrosynthetic analysis

14. 14
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Retrosynthetic analysis
Synthesis
Undesired product
Better method

15. 15
Practice of Synthesis:
It involves two stages
Analysis
•Identify the functional groups/strategic bonds in the molecule
•Disconnect bonds using known and reliable reaction
•Repeat disconnection as necessary to reach starting materials
•Don’t compromise during the planning stage
•Evaluate all pathways and choose the most attractive route
Advantages of Analysis
•Readily available and inexpensive starting materials
•Efficient synthetic reactions
•Practical and convenient conditions
•Flexibility of modification in case of pitfalls
•Synthesis of analogues of natural products
•Quick and elegant route

16. 16
Practice of Synthesis:
It involves two stages
Synthesis
•Write all the possible retrosynthetic pathways
•Evaluate all the pathways and go ahead with the most attractive one
•Write the real synthesis with reagents and conditions
•Execute the Synthesis
•Modify the plan according to unexpected failures

17. 17

18. 18
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Retrosynthetic Analysis
FGI –Functional group interconversion usually written on
double arrow
This means substitution of functional group by another one
equivalent to it.

19. 19
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Retrosynthetic Analysis

20. 20
MainDisconnectingapproachesinretrosynthesis

21. 21

22. 22
Synthesis

23. 23
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Retrosynthetic Analysis

24. 24
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

25. 25
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
:Changing the polarity
Here we need electrophilic aromatic center and nucleophilic reagents. For this we
need leaving group on aromatic ring
SNAris difficult on aromatic ring. Some time activation ring is required. Done by
introducing EWG to accept the electron

26. 26
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Disconnection
Synthesis

27. 27
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Antidepressant drug intermediate
TM
Think mechanistically. Though F is worst leaving group. It becomes good leaving group when
ring is weakly activated
Alcohol is treated with NaHto generate oxyanion

28. 28
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Diazoniumsalts are unstable above 10
0
C. Nitrogen is eliminated and generates cation

29. 29
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Synthesis

30. 30
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

31. 31
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Saccharine is a cyclic imide, a double amide
Synthesis

32. 32
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Strategies used in retrosynthetic analysis
•Order of events
Guideline 1: Consider the effect of each functional group on the others. Add first the one
which increase the reactivity
Synthesis ?

33. 33
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Strait forward synthesis: Alkylation followed by acylation

34. 34
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Musksare aromatics used in perfumes to increase and retain fragrance
Guideline 2: Changing one functional group to another as per the requirement change
the reactivity drastically
Synthesis

35. 35
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
CCl3 group is m-directing, converted into o-and p-directing
Guideline 2: Consider the effect of each functional group on the others.
Synthesis

36. 36
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Guideline 3: Some substituents are difficult to add. In such case it is best start with them
present
Synthesis

37. 37
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Guideline 4: Some disubstitutedcompounds are difficult to synthesize. In such case it is
best start with them present
Synthesis
Ex

38. 38
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Guideline 5: Some groups are added by nucleophilic substitution are difficult to
synthesize

39. 39
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Guideline 6: In multistep synthesis, start with the one that gives single product
unambiguasouly.
Synthesis

40. 40
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Called one group C-X disconnection because we need to recognize only one group like ester,
ether, amide ete.
Here nucleophilic displacement of halide via S
N1 or S
N2
Reverse polarity

41. 41
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Ex. Insect repellent
Carbonyl derivatives

42. 42
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Reactivity of acid derivatives

43. 43
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Synthesis

44. 44
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Route a is preferred

45. 45
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Thiols are more acidic than alcohols
Sulfide anions are more nucleophilic than alkoxideanions
Synthesis is reaction of alkyl halide with Na2S

46. 46
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

47. 47
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
If a molecule has two reactive functional groups and we want to
react only one .
Ex.

48. 48
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Amines are more nucleophilic than phenol

49. 49
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Amines are more nucleophilic than phenol

50. 50
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

51. 51
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Amines are more nucleophilic than phenol

52. 52
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Classic example is amino acid chemistry: benzyl chloroformateis a good protecting
gpfor amines

53. 53
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Amines are more nucleophilic than phenol

54. 54
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
for thiols

55. 55
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Synthesis

56. 56
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Reduction is electron donation and EWG accelerates the reaction
When reactivity is equal use only one mole reagent to generate anion

57. 57
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
2 gpC-X disconnections
Synthesis

58. 58
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
2 gpC-X disconnections are better than one gp
Functional groups at 1 and 3-position called 1,3-diX relationship
which suggests conjugate addition

59. 59
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Sometime this method is problematic
Depends on the reactivity of electrophile
Highly reactive acid chlorides and aldehydes undergo direct addition

60. 60
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

61. 61
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
More examples
Synthesis

62. 62
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
More examples

63. 63
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
More examples

64. 64
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Consider

65. 65
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

66. 66
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

67. 67
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

68. 68
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Fluconazole-antifungal drug
How to make epoxide?

69. 69
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
2 functional groups on the same carbon
Synthesis

70. 70
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
Other method

71. 71

72. 72

73. 73
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

74. 74
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

75. 75
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

76. 76
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

77. 77
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

78. 78
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

79. 79
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal

80. 80
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal
1,5-diX relationship

81. 81
Retrosynthetic analysis
Dr. Santosh L. Gaonkar, Department of Chemistry, MIT, Manipal