Asymmetric Synthesis

Asymmetric synthesis

1. Prepared By Dr. Krishnaswamy . G Faculty DOS & R in Organic Chemistry Tumkur University Tumakuru Asymmetric Synthesis For II M.Sc., III Semester DOS & R in Organic Chemistry Tumkur University Tumakuru

2. Asymmetric synthesis An asymmetric synthesis refers to a reaction which yields exclusively or predominantly only one of a set of chiral stereoisomers of compound by the action of a chiral reagent or auxiliary acting on heterotopic (enantiotopic or diastereotopic) faces, atoms or groups of a substrate. An asymmetric synthesis yields one of these 2 n stereoisomers predominantly or exclusively without involving any racemate resolution step. OR Asymmetric synthesis refers to the selective synthesis of one of the isomer of chiral product having a centre or a axis or helical chirality predominantly.

3. Achiral carbonyl compound in the presence of an achiral nucleophile

4. Chiral carbonyl compound in the presence of an achiral nucleophile

5. Achiral carbonyl compound with a chiral nucleophile

6. Enantiomeric Excess For non- racemic or Scalemic mixtures of enantiomers, one enantiomer is more abundant than the other. The composition of these mixtures is described by the  enantiomeric excess , which is the difference between the relative abundance of the two enantiomers. 

7. 50 % R 50 % S Racemic mixtures   Optically Inactive 20 % R 80 % S 60 % S 20 % R 20 % S Percentage of the enantiomers 60 % S Racemic mixtures Excess of S enantiomer 1 : 1 R & S Racemic mixtures Excess of S enantiomer OR Optically Active Enantiomeric excess tells us  how much more  of one enantiomer is present in the mixture. Racemic mixtures are optically inactive . This is a result of rotating the plane of the light by the two enantiomers to the same extent but opposite directions. 

8. What is the e.e . of a solution containing 90% (+) and 10% (–)? % ee = 90% - 10% % ee = 80% % R = 90 % % S = 10 %

9. What is the % ee of a solution with a specific rotation of –90 o where the pure solution rotates at –135 o ? [ α ] pure = –135 o Data Given [ α ] mixture = –90 o % ee = –135 o X 100 – 90 o = 0.66 X 100 % ee = 66%

10. A sample of a pure R- enantiomer has a specific rotation of -40 o . A mixture of R/S enantiomers has an observed optical rotation of +22 o . What is the % ee of the mixture? [ α ] pure = –40 o Data Given [ α ] mixture = +22 o % ee = – 40 o X 100 – 22 o = 0.55 X 100 % ee = 55 % R The sample contains 55% more of the (R) enantiomer . Thus, there is 55 % of (R) enantiomer + 45% of 1:1 mixture of (R = 22.5%) : (S=22.5%). Therefore, 77.5 % (R) enantiomer and 22.5 % (S) enantiomer in the mixture

11. If a sample is 55% ee of R stereoisomer. What is the % R in the mixture? % R = 2 55 50 + % S = 2 55 50 - % R = 27.5 50 + % R = 77.5 % S = 27.5 50 - % S = 22.5

12. What is the  ee  of a mixture containing 12.8 mol ( R )-2-bromobutane and 3.2 mol ( S )-2-bromobutane? % ee = 100 Moles of Major – Moles of Minor Moles of Major + Moles of Minor X % ee = 12.8 + 3.2 X 100 12.8 – 3.2 = 0.60 X 100 % ee = 60 %

13. Diastereomeric Excess

14. Asymmetric Induction / Enantio-induction Internal Asymmetric induction: refers to the control of stereoselectivity exerted by an existing chiral centre on the formation of a new chiral centre. Relayed Asymmetric induction: refers to the control of stereoselectivity exerted by chiral auxiliary on the formation of a new chiral centre. External Asymmetric induction: refers to the control of stereoselectivity exerted by chiral reagent / catalyst on the formation of a new chiral centre. Asymmetric induction is a Key element in Asymmetric synthesis CHIRAL POOL CHIRAL AUXILIARY CHIRAL REAGENT / CATALYST / LIGANDS Induction means Process of placing

15. Strategies of Asymmetric Induction CHIRAL POOL CHIRAL AUXILIARY CHIRAL REAGENT CHIRAL CATALYST / LIGANDS To access enantiomerically pure molecules there is need for adoption of efficient strategies for asymmetric induction. Collection of enantiomerically pure molecules available in nature A chiral molecular unit that can be temporarily incorporated in an achiral substrate to guide selective formation of one of a possible pair of enantiomers. Starting material must have prochirality , then chiral reagent will be used to get single enantiomer Starting material must have prochirality , Chiral catalyst will be used to get single enantiomer Example Natural L-amino acids, α - hydroxy acids and Natural D-sugars Example Chiral oxazolidinones Example Alphine Borane BINAL-H Example (R, R) DIOP (S, S) CHIRAPHOS 1 st generation Asymmetric synthesis 2 nd generation Asymmetric synthesis 3 rd generation Asymmetric synthesis 4 th generation Asymmetric synthesis

16. BINAL-H is a chiral reagent Preparation

17. Asymmetric reduction of ketones (R)-BINAL-H gives the (R)- enantiomer of alcohol Application

18. (S)-BINAL-H gives the (S)- enantiomer of alcohol Example

19. Mechanism

20. Absolute configuration greatly influenced by Steric effect Various electronic factors Flexibility of molecule

21. Alpine borane is a chiral reagent Preparation

22. Asymmetric reduction of ketones also known as Midland Reduction Application Reaction proceeds through boat like TS

23. Example

24. (S)-2-PhenylButylMagnesium Chloride [ (S)- PBMgCl ] Sterically hindered Grignard reagent transfer a β -H to carbonyl group instead of undergoing nucleophilic addition reaction.

25. Enantioselective hydride transfer Highest enantioselection has been reported for isopropyl phenyl ketone (82%)

26. (-) – Isobornyloxy aluminium dichloride [ (-)- i BOAlCl 2 ] Used to reduce variety of carbonyl compounds with enantioselection ranging from moderate to high (30-90%)

27. Modified Meerwein-Verley-Ponndorf reduction

28. Chiral enantiopure ligand

29. Asymmetric Epoxidation / Sharpless Asymmetric Epoxidation (SAE) Enantioselective conversion of primary and secondary allylic alcohol into 2, 3-epoxy alcohol with stoichiometric amount of Titanium (IV) tetraisopropoxide (Ti( O i Pr ) 4 ) and chiral catalyst diethyl tartarate (DET) in presence of oxidizing agent terbutylperoxide (t- BuOOH ) in dichloromethane (CH 2 Cl 2 ) at -20 o C. Only one enantiomer is formed and it depends on the stereochemistry of catalyst. Reaction

30. General rule of thumb: Alcohol group right hand side with (+)-DET epoxide formed below (-)-DET epoxide formed above Alcohol group left hand side with (+)-DET epoxide formed above (-)-DET epoxide formed below

31. Example

32. Organophosphorus compound that is used as a chiral ligand DIOP   (2,3- O -isopropylidene-2,3-dihydroxy-1,4-bis( diphenylphosphino )butane) Preparation

33. Bidentate C2 symmetric chiral biphosphine catalyst with chirality in the carbon frame work

34. (-) - (R, R)- DIOP Rh-1, 5-cyclooctadiene tetrafluroborate complex Structural and electronic requirements in alkene

35. Asymmetric hydrogenation of (Z)- acetamido cinnamic acid / ester

36. Conformation of active form of catalyst Axial Axial Equatorial Equatorial Equatorial Axial Axial Equatorial M

37. Higher energy intermediate (Bad fit for catalyst and alkene)

38. Lower energy intermediate (Good fit for catalyst and alkene)

39. (S, S) – CHIRAPHOS (2S, 3S) – (-) – Bis ( diphenylphosphino ) butane Preparation

40. Asymmetric hydrogenation of (Z)- acetamido cinnamic acid / ester

41. CHIRAL AUXILIARY Chemical compound or unit that is temporarily incorporated into an organic synthesis so that synthesis is carried out asymmetrically with the selective formation one of two stereoisomers. Chiral auxiliaries are optically active compounds Qualities of a Good Chiral Auxiliary Needs to be available in both enantiomeric forms. Needs to be easy and quick to synthesize Must be readily incorporated onto an achiral substrate It should provide good levels of asymmetric induction leading to high enantiomeric excess ( ee ). Needs to be selectively cleaved from the substrate under mild conditions Must be recoverable and re-useable

42. Substrate Chiral Auxiliary Substrate Chiral Auxiliary Reaction to form new Chiral compound Product Chiral Auxiliary Chiral Auxiliary Product Cleavage of Chiral auxiliary Diastereoselective reaction

43. RAMP and SAMP auxiliaries used in asymmetric α -alkylation of aldehyde and ketones Oxazolidinone auxiliaries used in Evans aldol reaction

44. Asymmetric α -alkylation of aldehyde and ketones Carbon–carbon bond-forming reaction via SAMP / RAMP method Reaction occurs through formation of Azaenolates derived from N,N- dialkyl hydrazones an alternative to direct ketone and aldehyde enolate alkylations .

45. Four Step synthesis of SAMP S- Proline Nitrosoamine Intermediate SAMP

46. R- Glutamic acid Nitrosoamine Intermediate RAMP Six Step synthesis of RAMP

47. Formation of hydrazone by reaction of SAMP with Aldehydes Formation of hydrazone by reaction of SAMP with Ketones

48. Hydrazone reaction with LDA to form Azaenolate

49. Alkylation reaction of Azaenolate

50. Auxiliary removal – Two approaches Ozonolysis (O 3 ) Quaternization with MeI followed by hydrolysis with HCl

51. BELOW ABOVE Overall Alkylation reaction

52. EXAMPLE

53. Alkylation reaction using Chiral PTC In a reaction a substrate in an organic phase is reacted chemically with a reagent in another phase which is usually aqueous or solid. Since these phases are mutually insoluble, the concentrations of the two reactants in the same phase are too low for convenient reaction rates. One way to overcome this difficulty is to use a solvent that will dissolve both the species. Another way is to use a transfer agent or catalyst which is capable of solubilizing or extracting the reagent into the organic phase or conversely, the substrate into the aqueous phase. Such an agent is termed a phase transfer catalyst , and the whole process is referred to as phase transfer catalysis.

54. Phase Transfer Catalysis can be defined as being concerned with accelerating or making possible reactions between chemical species residing in phases which are mutually insoluble.

55. Two types of Phase Transfer catalysts ( i ) Onium salts or Quats Onium salts or ' quats ' are quaternary ammonium, phosphonium , sulfonium or arsonium salts. They consist of ion pairs with a positively charged quaternary centre Q + and a counter ion X - . (ii) Crown ether group of catalysts. Crowns are defined as macroheterocycles usually containing the basic unit (-Y-CH 2 -CH 2 ) n where Y is 0, S or N.

56. Asymmetric synthesis using Chiral Phase Transfer Catalysts 1 st Generation Chiral PTC - Ephedrine alkaloid salts – primarily based on ephedrine. 2 nd Generation Chiral PTC - Cinchona Alkaloids - The most intensely studied group of catalysts has been those prepared by quaternization of cinchona alkaloids.

57. 3 rd Generation Chiral PTC - Anthracenylmethyl Cinchona Alkaloid Quats 4 th Generation Chiral PTC - Maruoka Chiral Phase-Transfer Catalyst

58. One of the most impressive uses of chiral PTC involves the alkylation of 6,7-dichloro-5-methoxy-2-phenyl-1-indanone with methyl chloride with chiral catalyst. Through a systematic study of reaction conditions, kinetics and reaction mechanism, a 92% ee of adduct was obtained.

59. Aldol reaction When an aldehydes or ketone having atleast one α -hydrogen are treated with dilute base gives β - hydroxy aldehydes (Aldehyde + Alcohol = Aldol) or β - hydroxy ketones (Ketone + Alcohol = Ketol )

60. There will be formation of two stereogenic centers in the aldol product and hence it leads to formation of four stereoisomers.

61. Asymmetric Aldol reaction In order to achieve stereoselectivity in aldol reaction formation of enolate plays crucial role. E or Z - enolate are produced stereoselectively using hindered bases such as LDA or dialkylborontriflate . In ketones cis-enolate favoured if R is large but trans- enolate favoured if R is small.

62. Z- enolates (Thermodynamic) gives predominantly syn aldol products E- enolates (Kinetic) gives predominantly anti aldol products

63. Most aldol reactions take place via a highly order transition state know as the Zimmerman– Traxler transition state. Zimmerman– Traxler Transition state

64. Zimmerman– Traxler Transition state

65. Why Z- enolate / Cis-enolate favours syn product because there is no steric repulsion in the favoured transition state

66. Why E- enolate / Trans- enolate favours anti product because there is no steric repulsion in the favoured transition state

67. Asymmetric Intramolecular Aldol reaction

68. MECHANISM Transition state is controlled and stabilised by OH---O hydrogen bonding

69. Michael reaction Michael reaction is a 1,4-addition (conjugate addition) of Nucleophile to an alpha-beta unsaturated alkene. Nucleophile – Michael Donor α - β unsaturated alkene – Michael Acceptor

70. CASE - 1

71. CASE - 2

72. CASE - 3 SYN ANTI

73. Asymmetric Michael reaction Example for Prochiral Acceptor reaction with Nucleophile

74. Polymer bound Chiral Catalyst in Asymmetric Induction Homogenously catalysed reactions have major practical limit Difficulty in separating product from the catalyst or in removing product. Expensive transition metal and chiral ligand are not readily recovered. Hence to overcome these difficulties homogenous catalyst have been attached to a variety of heterogeneous supports. By doing this, the catalyst retains the selectivity of homogeneous catalyst, still function under mild condition but acquires essential property of insolubility.

75. Cave and D’Angelo have prepared polymer-supported Cinchona alkaloid for use in asymmetric Michael addition reaction. 2-methoxy-indan-1-one and methyl vinyl ketone to get Michael product in 85% yield and 87% ee . Polymer-supported Cinchona Alkaloid (R)

76. Merrifield-supported (S)-4-(4-hydroxybenzyl)oxazolidin-2-one Solid-supported Evans’ syn -aldol reaction Rachel Green et al, Solid-phase asymmetric synthesis using a polymer supported chiral Evans’-type oxazolidin-2-one Nature protocols, 8, 2013

77. Asymmetric Induction Internal Asymmetric induction: refers to the control of stereoselectivity exerted by an existing chiral centre on the formation of a new chiral centre. 1, 2 - Asymmetric Induction α-C atom adjacent to the prochiral carbonyl group is a C* Diastereoselective reaction: one diastereomer formed preferentially

78. Cram’s Model

79. Large group SYN to C=O then attack from Medium group Large group ANTI to C=O then attack from Small group Major Major

80. Felkin-Ahn Model

81. Addition of Allylmetals to Carbonyl compounds Addition of achiral allylmetals to α-chiral carbonyl compounds Addition of chiral allylmetals to prochiral carbonyl compounds Metal = B, Sn , Ti Metal = B, Sn , Ti

82. Addition of achiral allylmetals to α-chiral carbonyl compounds

83. Addition of chiral allylmetals to prochiral carbonyl compounds

84. Addition of achiral 2-allyl-4,4,5,5-tetramethyl-1,3-dioxaborolane to (R)-2-methylbutanal Acyclic TS

85. Cyclic TS

86. Z- allylboranes give Syn product E- allylboranes give Anti product

87. 1, 4 - Asymmetric Induction Addition reaction of prochiral carbonyl group of ketone placed at 4 th position to the existing chiral centre will generate chiral centre. Prelog's Rule An extension of Cram's idea of reactive conformation to chiral esters of  α - ketoesters ( pyruvates )

88. Small group above the plane nucleophile (Ph - ) attack from above the plane α - Ketoacid Chiral alcohol α - Ketoester

89. Small group below the plane nucleophile (Ph - ) attack from below the plane α - Ketoacid Chiral alcohol α - Ketoester

90. Asymmetric synthesis of α – hydroxyacids Assigning the configuration of secondary and tertiary alcohols Application

91. 1, 3 - Asymmetric Induction In 1983, Reetz and Jung reported the reaction of chiral β- alkoxy aldehydes, unsubstituted at the α-position, with Lewis acidic compound CH 3 TiCl 3 through a half-chair chelated transition state model ( CramReetz chelate model), which would lead to a chair-like intermediate, to account for the diastereoselectivity .

92. Cram- Reetz Chelate Model Half-chair chelated transition state

93. Distereoselection in Cylic System

94. Selective reduction of 4- tert -butylcyclohexanone to a mixture of trans- and cis-4- tert -butylcyclohexanol by LiAlH 4  is an example of diastereoselectivity , reflecting a preference for hydride attack at the more hindered axial face of the carbonyl group.  Formation of axial and equatorial alcohols

95. Selectivity can be reversed by using a larger hydride reagent, such as Li(sec-butyl) 3 BH; in which case severe hindrance to axial approach diverts the reaction to the equatorial face.

96. Formation of cyclic alcohols Endo product Exo product

97. Catalytic hydrogenation

98. Diastereoselective Oxidation