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Asymmetric Hydrogenations

Introduction to Asymmetric Hydrogenations. Asymmetric Hydrogenation of Enamides. Asymmetric Hydrogenation of Allylic and Homoallylic Alcohols. . Asymmetric Hydrogenation of Allylic and Homoallylic Alcohols. Asymmetric Hydrogenation of a,b-unsaturated carboxylic acids. Hydrogen pressure significantly affects the asymmetric induction. No trend or rationale was found for the observation. Each substrate has to be screened using a range of hydrogen pressures..

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Asymmetric Hydrogenations

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    1. Asymmetric Hydrogenations By Lisa Pattenden

    2. The Wilkinson’s catalyst was developed for the hydrogenation of olefins. Knowles developed chiral phosphine ligands for the specific hydrogenation of olefins.The Wilkinson’s catalyst was developed for the hydrogenation of olefins. Knowles developed chiral phosphine ligands for the specific hydrogenation of olefins.

    3. Asymmetric Hydrogenation of Enamides First report of asymmetric hydrogenation of Z-enamides with very good ee by Knowles et al, Noyori used a Ruthenium-binap catalyst instead to hydrogenate the enamide with 95-100%ee E-enamides are completely unreactive towards these conditions.First report of asymmetric hydrogenation of Z-enamides with very good ee by Knowles et al, Noyori used a Ruthenium-binap catalyst instead to hydrogenate the enamide with 95-100%ee E-enamides are completely unreactive towards these conditions.

    4. Asymmetric Hydrogenation of Allylic and Homoallylic Alcohols Previously in the synthesis of menthol they used a Rhodium binap complex to hydrogenate the olefin to give the enamide and then with hydroylsis and followed by reduction to give the chiral compound with alcohol functionality. Whereas with the catalyst developed by Noyori you can do the hydrogenation in 1 step by using the Ruthenium binap catalyst.Previously in the synthesis of menthol they used a Rhodium binap complex to hydrogenate the olefin to give the enamide and then with hydroylsis and followed by reduction to give the chiral compound with alcohol functionality. Whereas with the catalyst developed by Noyori you can do the hydrogenation in 1 step by using the Ruthenium binap catalyst.

    5. Asymmetric Hydrogenation of Allylic and Homoallylic Alcohols

    6. Asymmetric Hydrogenation of a,b-unsaturated carboxylic acids For the reduction of the olefin in the alpha, beta unsaturated carboxylic acid using Ruthenium-binap catalyst to give the chiral carboxylic acid with good %ee.For the reduction of the olefin in the alpha, beta unsaturated carboxylic acid using Ruthenium-binap catalyst to give the chiral carboxylic acid with good %ee.

    7. Catalytic Cycle

    8. Asymmetric Hydrogenation of a,b-unsaturated carboxylic acids Evidence for catalytic cycle Reactions in MeOD Addition across double bond-cis The reaction indicates that H is from the H2 whereas D comes from the MeOD

    9. Asymmetric Hydrogenation of a,b-unsaturated carboxylic acids

    10. Asymmetric Hydrogenation of Functionalised Ketones

    11. Asymmetric Hydrogenation of Functionalised Ketones The Ruthenium binap catalyst previously shown on my slides is reacted with 2 eq of HX to give a halogenated catalyst. However no one is particularly certain on the correct structure. This catalyst is then used to hydrogenate functionalised ketones with, oxygen, nitrogen or bromine in the y position.The Ruthenium binap catalyst previously shown on my slides is reacted with 2 eq of HX to give a halogenated catalyst. However no one is particularly certain on the correct structure. This catalyst is then used to hydrogenate functionalised ketones with, oxygen, nitrogen or bromine in the y position.

    12. Substrate Directed Ketone Hydrogenation Mechanism

    13. Dynamic Kinetic Resolution of 2-substituted-b-keto esters Diastereoselectivity shown in this DKR favours the syn productDiastereoselectivity shown in this DKR favours the syn product

    14. Dynamic Kinetic Resolution of 2-substituted-b-keto esters The carbonyl and the ester have to be almost eclipsing, so when you look at the way the Hydride is delivered (pre decided by the catalyst) it can tell that one way is slightly hindered so it equilibrates to give the syn diastereoisomer.The carbonyl and the ester have to be almost eclipsing, so when you look at the way the Hydride is delivered (pre decided by the catalyst) it can tell that one way is slightly hindered so it equilibrates to give the syn diastereoisomer.

    15. Dynamic Kinetic Resolution of 2-substituted-b-keto esters Mechm is thought to proceed through a Ru-monohydride species capable of coordinating the adjacent ester moiety.Mechm is thought to proceed through a Ru-monohydride species capable of coordinating the adjacent ester moiety.

    16. Note: Limitations of DKR with a-substituted-b-keto esters Genet and co workers were working on the synthesis of dolaproine and they wanted to apply Noyori’s DKR. So they thought that they’d get the syn product. However, they found that in the DKR of the alpha-substituted-beta-ketoester, the ligand in Ru controls the stereochemistry of the ketone being reduced but…the diastereoselectivity is controlled by the SUBSTRATE. SO… only one of syn or anti relationships between the 2 centres can be accessed reliably. So they yielded the two anti productsGenet and co workers were working on the synthesis of dolaproine and they wanted to apply Noyori’s DKR. So they thought that they’d get the syn product. However, they found that in the DKR of the alpha-substituted-beta-ketoester, the ligand in Ru controls the stereochemistry of the ketone being reduced but…the diastereoselectivity is controlled by the SUBSTRATE. SO… only one of syn or anti relationships between the 2 centres can be accessed reliably. So they yielded the two anti products

    17. Asymmetric Hydrogenation of Ketones Reversal in chemoselectivity Suzuki used a Ru catalyst with halogen and phosphine ligands in benzene to yield the hydrogenation of the ketone, then went on to try the conditions on the ketone with alkene functionality and this hydrogenated the least substituted olefin. So Noyori tried these conditions but with base and a diamine which yielded the hydrogenation of the ketone over the least substituted olefin. The BASE-is thought to promote heterolytic cleavage of hydrogen to form the catalytically active Ru monohydride species. The DIAMINE-is thought to be responsible for the reversal in chemoselectivity. Suzuki used a Ru catalyst with halogen and phosphine ligands in benzene to yield the hydrogenation of the ketone, then went on to try the conditions on the ketone with alkene functionality and this hydrogenated the least substituted olefin. So Noyori tried these conditions but with base and a diamine which yielded the hydrogenation of the ketone over the least substituted olefin. The BASE-is thought to promote heterolytic cleavage of hydrogen to form the catalytically active Ru monohydride species. The DIAMINE-is thought to be responsible for the reversal in chemoselectivity.

    18. Asymmetric Hydrogenation of Simple Ketones Ru-H formed acts as a “bulky hydride” Can think of the hydrogenation as a Metal hydride which can either attack axial or equatorial to give trans and cis products respectively. This attack can be thought of as a bulky hydride totally down to sterics therefore Anti-cieplak. Li in ammonia goes via cieplak theory down to stereoelectronic effects of thew donation of C-H sigma bond into the Can think of the hydrogenation as a Metal hydride which can either attack axial or equatorial to give trans and cis products respectively. This attack can be thought of as a bulky hydride totally down to sterics therefore Anti-cieplak. Li in ammonia goes via cieplak theory down to stereoelectronic effects of thew donation of C-H sigma bond into the

    19. Asymmetric Hydrogenation of Ketones 1,2-Diamine is a ligand for the Ru Noyori used this Ru catalyst containing binap, chlorine and dmf, alongside base and diamine to yield the alcohol. He tried the (S,S) diamine which gave excellent %ee, then the (R,R) diamine was used which only yielded the R enantiomer in 14%ee. Also tried a non chiral diamine which yielded the alcohol in only 57% ee.Noyori used this Ru catalyst containing binap, chlorine and dmf, alongside base and diamine to yield the alcohol. He tried the (S,S) diamine which gave excellent %ee, then the (R,R) diamine was used which only yielded the R enantiomer in 14%ee. Also tried a non chiral diamine which yielded the alcohol in only 57% ee.

    20. Catalytic Cycle for the Asymmetric Hydrogenation of ketones An x-ray crystal has been made of the Complex in top left hand corner (trans dihydride complex) if this is kept under Hydrogen it is yellow. However if this is placed under Argon, nitrogen or vacuum it slowly loses hydrogen in its solid state to produce dark-red Ruthenium hydridoamido complex (bottom right hand corner). Studies with Deuterium to prove that the exchange with Hydrogen is reversible from trans dihydride complex to the hydridoamido complex.An x-ray crystal has been made of the Complex in top left hand corner (trans dihydride complex) if this is kept under Hydrogen it is yellow. However if this is placed under Argon, nitrogen or vacuum it slowly loses hydrogen in its solid state to produce dark-red Ruthenium hydridoamido complex (bottom right hand corner). Studies with Deuterium to prove that the exchange with Hydrogen is reversible from trans dihydride complex to the hydridoamido complex.

    21. Proposed Mechanism for the Asymmetric Hydrogenation of Ketones

    22. Asymmetric Transfer Hydrogenation of Imines and Ketones

    23. Asymmetric Transfer Hydrogenation of Ketones

    24. Asymmetric Transfer Hydrogenation of Ketones Proposed mechanism 1

    25. Asymmetric Transfer Hydrogenation of Ketone

    26. Asymmetric Transfer Hydrogenation of Ketones

    28. Asymmetric Transfer Hydrogenation Left hand Si-TS looks more sterically hindered but has been calculated to be 8.6kcal more stable than the Re-TS on the right hand side. This could be because the Si-TS is stabilized by the C-H/pi attractive interaction between a C(sp2)H substituent on the benzene ligand of the Ru complex and the pi system of the aryl gp on the substrate. C-Hd+ of the benzene is enhanced by binding to the metal…resulting in its increased ability to act as CH donor to the electron rich pi system of the aryl gp on the substrate.Left hand Si-TS looks more sterically hindered but has been calculated to be 8.6kcal more stable than the Re-TS on the right hand side. This could be because the Si-TS is stabilized by the C-H/pi attractive interaction between a C(sp2)H substituent on the benzene ligand of the Ru complex and the pi system of the aryl gp on the substrate. C-Hd+ of the benzene is enhanced by binding to the metal…resulting in its increased ability to act as CH donor to the electron rich pi system of the aryl gp on the substrate.

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