METAL CATALYZED ASYMMETRIC REDUCTION

1. For more presentations and information visit http://www.pharmaxchange.info METAL CATALYZED ASYMMETRIC REDUCTION For references please read abstract at http://pharmaxchange.info/presentations/mcar.html

2. For more presentations and information visit http://www.pharmaxchange.info 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.

3. For more presentations and information visit http://www.pharmaxchange.info Three approaches to asymmetric synthesis • Chiral pool synthesis • Chiralauxillaries • Asymmetric catalysis

4. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info THREE DIFFERENT KINDS OF CHIRAL CATALYST MOSTLY USED

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8. For more presentations and information visit http://www.pharmaxchange.info IRIDIUM CATALYZED ASYMMETRIC HYDROGENATION OF UNFUNCTIONALIZED ALKENES

9. For more presentations and information visit http://www.pharmaxchange.info Iridium based catalysts Iridium based catalysts are one of the most important homogeneous chiral catalysts for hydrogenation of hindered unfunctionalized alkenes .

10. For more presentations and information visit http://www.pharmaxchange.info ADVANTAGES OVER OTHER CATALYSTS • 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. For more presentations and information visit http://www.pharmaxchange.info HYDROGENATION OF TWO ALKENES USING1. Rh(PPh3)2(NBD).CB11H6Br52. Ir(Py)(PCy3)(Cod).PF6

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13. For more presentations and information visit http://www.pharmaxchange.info DIFFERENT Ir CATALYSTS Crabtree’s catalyst Ir(COD)L1L2 . PF6

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15. For more presentations and information visit http://www.pharmaxchange.info CHIRAL LIGANDS

16. For more presentations and information visit http://www.pharmaxchange.info N,P - LIGAND

17. For more presentations and information visit http://www.pharmaxchange.info Phosphino-oxazoline (PHOX) Ligands R - tBu CH2tBu iPr Ar - o-Tol Cy Ph

18. For more presentations and information visit http://www.pharmaxchange.info Phosphinite-oxazolineLigands Ar = Ph R1 = Ph o-Tol R2,3 = Bu R = tBu Ar = Ph, Cy iPr

19. For more presentations and information visit http://www.pharmaxchange.info Phosphine – ThiazoleLigand

20. For more presentations and information visit http://www.pharmaxchange.info COMPARISON BETWEEN LIGANDS

21. For more presentations and information visit http://www.pharmaxchange.info 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 carbeneligands are more thermostable than their phosphine analogues.

22. For more presentations and information visit http://www.pharmaxchange.info EXAMPLES

23. For more presentations and information visit http://www.pharmaxchange.info ALKENES AS SUBSTRATES

24. For more presentations and information visit http://www.pharmaxchange.info FUNCTIONALIZED AND UNFUNCTIONALIZED ALKENES UnfunctionalizedFunctionalized R = Alkyl CFG= Coordinating functional group CJKKLHJHH R1-3 = alkyl CFG = coordinating functional group

25. For more presentations and information visit http://www.pharmaxchange.info Ir-Mediated Hydrogenation of Trisubstituted alkenes

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29. For more presentations and information visit http://www.pharmaxchange.info • 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%

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32. For more presentations and information visit http://www.pharmaxchange.info PHOSPHANYL - OXAZOLINE LIGANDS 99% conversion 95% ee 99% conversion 96% ee

33. For more presentations and information visit http://www.pharmaxchange.info Mechanism Considerations for Asymmetric Ir-Mediated Hydrogenations

34. For more presentations and information visit http://www.pharmaxchange.info Different attempts to elucidate the mechanisms of asymmetric Ir-mediated hydrogenation via theoretical methods: • Brandt group • Hall group • Chen group • Pfaltz group

35. For more presentations and information visit http://www.pharmaxchange.info 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. For more presentations and information visit http://www.pharmaxchange.info 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

37. For more presentations and information visit http://www.pharmaxchange.info STEP 1

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39. For more presentations and information visit http://www.pharmaxchange.info STEP 3

40. For more presentations and information visit http://www.pharmaxchange.info STEP 4

41. For more presentations and information visit http://www.pharmaxchange.info STEP 5

42. For more presentations and information visit http://www.pharmaxchange.info STEP 6 STEP 1

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44. For more presentations and information visit http://www.pharmaxchange.info MECHANISTIC OVERVIEW

45. For more presentations and information visit http://www.pharmaxchange.info 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.

46. For more presentations and information visit http://www.pharmaxchange.info Schematic representation of electronically neutral trisubstituted olefin coordination to the catalyst.

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49. For more presentations and information visit http://www.pharmaxchange.info EFFECT OF DIFFERENT REACTION CONDITIONS

50. For more presentations and information visit http://www.pharmaxchange.info 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.