Slide 1

METAL CATALYZED ASYMMETRIC REDUCTION 1 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info For references please read abstract at http://pharmaxchange.info/presentations/mcar.html Slide 2 What What is asymmetric synthesis? 2 Chemical synthesis of a pure enantiomer, or of an enantiomorphic mixture in which one enantiomer predominates, without the use of resolution. YEAR20061996 % OF CHIRAL DRUGS APPROVED BY USFDA 75%20% For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 3 3 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 4 ASYMMETRIC CATALYSIS 4 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 : Wilkinsons Catalyst For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 5 THREE DIFFERENT KINDS OF CHIRAL CATALYST MOSTLY USED 5 ASYMMETRIC CATALYSIS METAL LIGAND COMPLEXES CHIRAL ORGANOCATALYST BIOCATALYST For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 6 6 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 7 7 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 8 IRIDIUM CATALYZED ASYMMETRIC HYDROGENATION OF UNFUNCTIONALIZED ALKENES 8 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 9 9 Iridium based catalysts Iridium based catalysts are one of the most important homogeneous chiral catalysts for hydrogenation of hindered unfunctionalized alkenes. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 10 ADVANTAGES OVER OTHER CATALYSTS 10 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 11 HYDROGENATION OF TWO ALKENES USING HYDROGENATION OF TWO ALKENES USING 1. Rh(PPh 3 ) 2 (NBD). CB 11 H 6 Br 5 2. Ir(Py)(PCy 3 )(Cod). PF 6 11 ALKENES CATALYST TIME (h) YIELD (%) Rh CATALYST Ir CATALYST 5555 95 100 Rh CATALYST Ir CATALYST 24 16 68 95 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 12 12 DIFFERENT Ir LIGAND SYSTEMS DIFFERENT TYPE OF ALKENE SUBSTRATES MECHANISM For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 13 DIFFERENT Ir CATALYSTS 13 Crabtrees catalyst Ir(COD)L 1 L 2. PF 6 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 14 CENTRAL METAL ION A SUITABLE LIGAND 1,5- CYCLOOCTADIENE LIGAND A COUNTERION 14 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 15 CHIRAL LIGANDS 15 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 16 N,P - LIGAND 16 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 17 Phosphino-oxazoline (PHOX) Ligands 17 Ar - o-Tol Cy Ph R - t Bu CH 2 t Bu i Pr For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 18 Phosphinite-oxazoline Ligands 18 Ar = Ph R 1 = Ph o-Tol R 2,3 = Bu R = t Bu Ar = Ph, Cy i Pr For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 19 Phosphine Thiazole Ligand 19 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 20 COMPARISON BETWEEN LIGANDS 20 conv % ee%conv%ee%conv%ee% 999499 98 99 86999895 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 21 C,N-Ligands 21 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 22 EXAMPLES 22 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 23 ALKENES AS SUBSTRATES 23 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 24 FUNCTIONALIZED AND UNFUNCTIONALIZED ALKENES 24 Unfunctionalized Functionalized R = Alkyl CFG= Coordinating functional group CJKKLHJHH R 1-3 = alkyl CFG = coordinating functional group For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 25 Ir-Mediated Hydrogenation of Trisubstituted alkenes 25 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 26 HYDROGENATION OF TRISUBSTITUTED ALKENES 26 ALKENE Conversion % ee % Conversion % ee % 9996 (R)9999 (R) 9981 (R)10099 (R) 9763 (R)10092 (R) 9985 (S)9971(S) For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 27 Hydrogenation of Heteroaromatic alkenes 27 ALKENE Conversion % ee % Conversion % ee % 99 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 28 Hydrogenation of 1,1-disubstituted alkenes 28 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 29 29 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% For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 30 TETRASUBSTITUTED ALKENES 30 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 31 31 conversion%99%95% ee%79%82% For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 32 32 PHOSPHANYL - OXAZOLINE LIGANDS 99% conversion 95% ee 99% conversion 96% ee For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 33 Mechanism Considerations for Asymmetric Ir-Mediated Hydrogenations 33 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 34 34 Different attempts to elucidate the mechanisms of asymmetric Ir-mediated hydrogenation via theoretical methods: Brandt group Hall group Chen group Pfaltz group For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 35 MIGRATORY INSERTION 35 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 36 OXIDATIVE ADDITION 36 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 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 37 STEP 1 37 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 38 STEP 2 38 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 39 STEP 3 39 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 40 STEP 4 40 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 41 STEP 5 41 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 42 STEP 6 STEP 1 42 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 43 43 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 44 44 MECHANISTIC OVERVIEW For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 45 ENANTIOFACE SELECTIVITY MODEL 45 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 =H 2 or solvent. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 46 Schematic representation of electronically neutral trisubstituted olefin coordination to the catalyst Schematic representation of electronically neutral trisubstituted olefin coordination to the catalyst. 46 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 47 SELECTIVITY MODEL APPLIED TO DIPHENYL PROPENE 47 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 48 48 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 49 EFFECT OF DIFFERENT REACTION CONDITIONS 49 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 50 COUNTER ION EFFECT 50 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 PF 6 - salt exhibits a high reactivity with fast initial rates, however suffers from deactivation at low catalyst loading. Bulky lipophilic anion BAr f - prevents catalyst deactivation and gives high rate and full conversion even at low catalyst loading. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 51 51 PF 6 - 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 For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 52 SOLVENT EFFECTS 52 The best solvent was found to be dichloromethane Strongly coordinating solvents deactivate the catalyst Other solvents used include 1,2- Dichloroethane and toluene For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 53 Hydrogen consumption curves at different solvents 53 CH 2 Cl 2 1,2-Dichloroethane Toluene H 2 reservoir time For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 54 VARIATION OF HYDROGEN PRESSURE 54 Log[alkene] Log Vmax PF 6 - BARF - Influence of the hydrogen pressure, For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 55 VARIATION OF ALKENE CONCENTRATION 55 Log Vmax Log[alkene] Double log plot of the dependence of reaction rate on alkene concentration BARF - PF 6 - For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 56 CONCLUSION 56 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. For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info Slide 57 ACKNOWLEDMENT 57 Dr. Yan Zhang Kendra M. Haney Dr. Guo Li Orgil Elbegdorj For more presentations and information visit http://www.pharmaxchange.infohttp://www.pharmaxchange.info