1. METAL CATALYZED ASYMMETRIC REDUCTION
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METAL CATALYZED ASYMMETRIC REDUCTION
For references please read abstract at

2. What is asymmetric synthesis?
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What is asymmetric synthesis?
Chemical synthesis of a pure enantiomer, or of an enantiomorphic mixture in which one enantiomer predominates, without the use of resolution.
YEAR
2006
1996
% OF CHIRAL DRUGS APPROVED BY USFDA
75%
20%

3. Three approaches to asymmetric synthesis
Chiral pool synthesis
Chiral auxillaries
Asymmetric catalysis
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ASYMMETRIC CATALYSIS
Small amounts of chiral, enantiomerically pure (or enriched) catalysts promote reactions and lead to the formation of large amounts of enantiomerically pure or enriched products. Eg : Wilkinson’s Catalyst

5. THREE DIFFERENT KINDS OF CHIRAL CATALYST MOSTLY USED
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THREE DIFFERENT KINDS OF CHIRAL CATALYST MOSTLY USED
ASYMMETRIC CATALYSIS
METAL LIGAND COMPLEXES
CHIRAL ORGANOCATALYST
BIOCATALYST

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8. IRIDIUM CATALYZED ASYMMETRIC HYDROGENATION OF UNFUNCTIONALIZED ALKENES
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IRIDIUM CATALYZED ASYMMETRIC HYDROGENATION OF UNFUNCTIONALIZED ALKENES

9. Iridium based catalysts
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Iridium based catalysts
Iridium based catalysts are one of the most important homogeneous chiral catalysts for hydrogenation of hindered unfunctionalized alkenes .

10. ADVANTAGES OVER OTHER CATALYSTS
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They do not require the presence of a coordinating group near the C=C bond, so even purely alkyl- substituted olefins can be hydrogenated with high enantioselectivity.
High activity in hydrogenation of hindered tetra- substituted alkenes also.
Comparitively cheaper by weight as compared to other metals like Rh.
Air and moisture stable.

11. HYDROGENATION OF TWO ALKENES USING 1. Rh(PPh3)2(NBD). CB11H6Br5 2
HYDROGENATION OF TWO ALKENES USING 1. Rh(PPh3)2(NBD).CB11H6Br5 2. Ir(Py)(PCy3)(Cod).PF6
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ALKENES
CATALYST
TIME
(h)
YIELD
(%)
Rh CATALYST Ir 5 95
100 Rh
Ir CATALYST 24 16 68

12. DIFFERENT Ir – LIGAND SYSTEMS
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DIFFERENT Ir – LIGAND SYSTEMS
DIFFERENT TYPE OF ALKENE SUBSTRATES
MECHANISM

13. DIFFERENT Ir CATALYSTS
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DIFFERENT Ir CATALYSTS
Crabtree’s catalyst
Ir(COD)L1L2 . PF6

14. 1,5-CYCLOOCTADIENE LIGAND
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CENTRAL METAL ION
A SUITABLE LIGAND
1,5-CYCLOOCTADIENE LIGAND
A COUNTERION

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CHIRAL LIGANDS

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N,P - LIGAND

17. Phosphino-oxazoline (PHOX) Ligands
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Phosphino-oxazoline (PHOX) Ligands
R - tBu
CH2tBu
iPr
Ar - o-Tol Cy Ph

18. Phosphinite-oxazoline Ligands
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Phosphinite-oxazoline Ligands
Ar = Ph R1 = Ph o-Tol R2,3 = Bu R = tBu Ar = Ph, Cy iPr

19. Phosphine – Thiazole Ligand
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Phosphine – Thiazole Ligand

20. COMPARISON BETWEEN LIGANDS
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COMPARISON BETWEEN LIGANDS
conv%
ee% 99 94 98 86 95

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C,N-Ligands
Electron-rich N-heterocyclic carbenes based on imidazolylidenes, imidazolinylidenes and 1,2,4-triazolylidiene have emerged as useful ligands. Complexes containing these carbene ligands are more thermostable than their phosphine analogues.

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EXAMPLES

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ALKENES AS SUBSTRATES

24. FUNCTIONALIZED AND UNFUNCTIONALIZED ALKENES
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FUNCTIONALIZED AND UNFUNCTIONALIZED ALKENES
Unfunctionalized Functionalized
R = Alkyl CFG= Coordinating
functional group
CJKKLHJHH
R1-3 = alkyl CFG = coordinating

25. Ir-Mediated Hydrogenation of Trisubstituted alkenes
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Ir-Mediated Hydrogenation of Trisubstituted alkenes

26. HYDROGENATION OF TRISUBSTITUTED ALKENES
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ALKENE
Conversion % ee 99
96 (R)
99 (R)
81 (R)
100 97
63 (R)
92 (R)
85 (S)
71(S)

27. Hydrogenation of Heteroaromatic alkenes
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ALKENE
Conversion % ee 99

28. Hydrogenation of 1,1-disubstituted alkenes
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Hydrogenation of 1,1-disubstituted alkenes

29. However enantioselectivity varies substrate to substrate.
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So far only 2-Aryl-1-butenes and allylic alcohols have been tested using Ir complxes as catalysts.
Being less hindered as compared to trisubstituted, conversions are excellent.
However enantioselectivity varies substrate to substrate.
conv 99%
ee 88%

30. TETRASUBSTITUTED ALKENES
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TETRASUBSTITUTED ALKENES

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conversion%
99%
95%
ee%
79%
82%

32. 99% conversion 99% conversion 95% ee 96% ee
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PHOSPHANYL - OXAZOLINE LIGANDS
99% conversion
95% ee
99% conversion
96% ee

33. Mechanism Considerations for Asymmetric Ir-Mediated Hydrogenations
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Mechanism Considerations for Asymmetric Ir-Mediated Hydrogenations

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Different attempts to elucidate the mechanisms of asymmetric Ir-mediated hydrogenation via theoretical methods:
Brandt group
Hall group
Chen group
Pfaltz group

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MIGRATORY INSERTION
A migratory insertion reaction is when a cisoidal anionic and neutral ligand on a metal complex couple together to generate a new coordinated anionic ligand.

36. two new anionic ligands
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OXIDATIVE ADDITION
In oxidative addition, a metal complex with vacant coordination sites and a relatively low oxidation state is oxidized by the insertion of the metal into a covalent bond(X-Y).
two new anionic ligands

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STEP 1

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STEP 2

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STEP 3

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STEP 4

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STEP 5

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STEP STEP 1

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MECHANISTIC OVERVIEW

45. ENANTIOFACE SELECTIVITY MODEL
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ENANTIOFACE SELECTIVITY MODEL
Generalized iridium (III) dihydride complex with bound olefin (left), and a view of the sterics about iridium from the perspective of the olefin ligand (right).
R1 = smallest olefin substituent; NR= chiral N-containing ligand (frequently oxazoline); YXn = strong trans-influence ligand (phosphine, carbene, etc.); Z =H2 or solvent.

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Schematic representation of electronically neutral trisubstituted olefin coordination to the catalyst.

47. SELECTIVITY MODEL APPLIED TO DIPHENYL PROPENE
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SELECTIVITY MODEL APPLIED TO DIPHENYL PROPENE

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49. EFFECT OF DIFFERENT REACTION CONDITIONS
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EFFECT OF DIFFERENT REACTION CONDITIONS

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COUNTER ION EFFECT
Counter ion of cationic Iridium complex plays a crucial role in catalytic cycle.
Halides and weakly coordinating group triflate were found to completely deactivate the catalyst.
The PF6- salt exhibits a high reactivity with fast initial rates, however suffers from deactivation at low catalyst loading.
Bulky lipophilic anion BArf -prevents catalyst deactivation and gives high rate and full conversion even at low catalyst loading.

51. PF6- Complex BARF Complex
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PF6- Complex
slower hydrogenation
relative to catalyst deactivation
BARF Complex
non-specific contacts with cation,
does not compete with the alkene,
stabilizes complex and accelerates hydrogenation

52. SOLVENT EFFECTS The best solvent was found to be dichloromethane
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SOLVENT EFFECTS
The best solvent was found to be dichloromethane
Strongly coordinating solvents deactivate the catalyst
Other solvents used include 1,2- Dichloroethane and toluene

53. Hydrogen consumption curves at different solvents
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Toluene
H2 reservoir
CH2Cl2
1,2-Dichloroethane
time
Hydrogen consumption curves at different solvents

54. VARIATION OF HYDROGEN PRESSURE
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VARIATION OF HYDROGEN PRESSURE
PF6-
BARF-
Log Vmax
Log[alkene]
Influence of the hydrogen pressure,

55. VARIATION OF ALKENE CONCENTRATION
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VARIATION OF ALKENE CONCENTRATION
PF6-
Log Vmax
BARF-
Log[alkene]
Double log plot of the dependence of reaction rate on alkene concentration

56. CONCLUSION
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Ir catalyst with chiral N,P ligands are emerging as a new class of highly efficient catalyst for asymmetric hydrogenation.
They are able to hydrogenate a large variety of subtrates for which no catalyst are available.eg. Tetrasubstituted alkenes
They are easy to synthesize and form moisture, air stable complexes.

57. ACKNOWLEDMENT Dr. Yan Zhang Kendra M. Haney Dr. Guo Li Orgil Elbegdorj
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ACKNOWLEDMENT
Dr. Yan Zhang
Kendra M. Haney
Dr. Guo Li
Orgil Elbegdorj