18 noyori asymmetric hydrogenation reaction

Myers Chem 115 The Noyori Asymmetric Hydrogenation Reaction Reviews: Mechanism: Noyori, R Angew Chem Int Ed 2013, 52, 79–92 • Catalytic cycle: 1/n {[(R)-BINAP]RuCl2}n CH3OH Kitamura, M.; Nakatsuka, H Chem Commun 2011, 47, 842–846 Tang, W.; Zhang, X Chem Rev 2003, 103, 3029–3069 Noyori, R.; Ohkuma, T Angew Chem Int Ed 2001, 40, 40–73 [(R)-BINAP]RuCl2(CH3OH)2 H2 Original Report by the Noyori Group: OCH3 O HCl CH3OH O [(R)-BINAP]RuHCl(CH3OH)2 H2 CH3 CH3OH H2 (100 atm) O CH3 O OH O RuCl2[(R)-BINAP] (0.05 mol %) OCH3 OCH3 OCH3 CH3 CH3OH, 36 h, 100 °C O [(R)-BINAP]RuCl(CH3O)(CH3OH)2 96%, >99% ee [(R)-BINAP]HClRu O OCH3 CH3 O Noyori, R., Okhuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akuragawa, S J Am Chem Soc 1987, 109, 5856–5858 OCH3 HO O CH3 CH3OH CH3OH [(R)-BINAP](CH3OH)ClRu O CH3 • Both enantiomers of BINAP are commercially available Alternatively, both enantiomers can be Noyori, R Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1993, pp 56–82 prepared from the relatively inexpensive (±)-1,1'-bi-2-naphthol • The reduction of methyl 2,2-dimethyl-3-oxobutanoate proceeds in high yield and with high enantioselectivity, providing evidence that the reduction proceeds through the keto form of the !-keto ester However, pathways that involve hydrogenation of the enol form of other !-keto esters cannot be PPh2 PPh2 OH OH PPh2 PPh2 + ruled out H2 (100 atm) (±)-1,1'-Bi-2-naphthol O (R)-(+)-BINAP 20% O RuCl2[(R)-BINAP]–Ru OCH3 CH3 CH3 CH3OH, 23 °C (S)-(–)-BINAP 20% CH3 OH CH3 O OCH3 CH3 CH3 99%, 96% ee Takaya, H.; Akutagawa, S.; Noyori, R Org Synth 1989, 67, 20–32 Noyori, R.; Takaya, H Acc Chem Res 1990, 23, 345–350 Andrew Haidle Myers The Noyori Asymmetric Hydrogenation Reaction • The use of a deuterated substrate provides further evidence that the reduction proceeds Chem 115 • Of the two possible diastereomeric transition states for complexes with (R)-BINAP shown through the keto tautomer Enolization is rapid, so the deuterium is lost quickly However, below, the one leading to the (R) !-hydroxy ester allows the approach of the ketone at an when the reaction was stopped at 1.3% conversion, the hydroxy ester product retained unhindered quadrant (as represented by the light lower left quadrant of the circle) 80% of the deuterium at C-2, and no deuterium was incorporated at C-3 O O O O OCH3 D NHAc H2 (100 atm) OH O RuBr2[(R)-BINAP] O CH2Cl2 O OCH3 D NHAc P Cl P O O CH3 H CH3 OH O (R)-BINAP Ru OCH3 OCH3 (R) !-hydroxy ester Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H J Am Chem Soc 1989, 111, 9134–9135 • A crystal structure of Ru(OCOCH3)2[(S)-BINAP] revealed that the rigid BINAP backbone forces P the phenyl rings attached to phosphorous to adopt the conformation depicted here (the napthyl Cl P Ru O rings are omitted for clarity) CH3 H CH3O OH O (R)-BINAP O OCH3 (S) !-hydroxy ester CH3 axial equatorial P Ru P Ru(OCOCH3)2[(S)-BINAP] Noyori, R.; Tokunaga, M.; Kitamura, M Bull Chem Soc Jpn 1995, 68, 36–56 Reaction Conditions: • Noyori has published conditions to prepare the active Ru-BINAP catalyst in one step from commercially available [RuCl2(benzene)]2, and it can be used without a purification step Also, the reaction can be run at atm/100 °C or 100 atm/23 °C • The two protruding equatorial P-phenyl groups allow a coordinating ligand access to only two 1/ [RuCl2(benzene)]2 + (R)-BINAP DMF, 100 ºC (R)-BINAP-Ru(II) quadrants on the accessible face of Ru (the other face is blocked by BINAP's napthyl rings) This situation is represented by a circle with two black quadrants where no coordination can occur Kitamura, M.; Tokunaga, M.; Okhuma, T; Noyori, R Org Synth 1993, 71, 1–13 Ohta, T.; Takaya, H.; Noyori, R Inorg Chem 1988, 27, 566–569 Andrew Haidle, Fan Liu Myers The Noyori Asymmetric Hydrogenation Reaction • The procedure involving in situ catalyst generation was found to be much more reliable Also, Chem 115 • These conditions have been improved on even further, with milder reaction conditions and lower catalyst loadings reactions with this catalyst were more enantioselective and required less catalyst The following reaction was done on a 10-kg scale Note the benzyl group is not removed H2 (50 psi), HCl (0.1 mol%) O H2 (4 atm), (R)-BINAP O O BnO OH O [C6H6RuCl]2 (0.05 mol %) OEt BnO CH3 OH O Ru–(R)-BINAP (0.05 mol %) Ot-Bu OEt EtOH, 100 °C, h (10.0 kg) O CH3OH, 40 °C, h CH3 Ot-Bu 97%, >97% ee (9.7 kg) 96%, 97–98% ee • The authors present kinetic data to show the dramatic increase in reaction rate that occurs in the presence of a catalytic amount of strong acid, and they suggest that failed reactions Beck, G.; Jendralla, H.; Kesseler, K Synthesis 1995, 1014–1018 may be a result of low levels of basic impurities Note that the acid-sensitive t-Bu ester is not cleaved under these conditions • A simplified, milder set of conditions that also features a catalyst available in one step from commercially available BINAP and RuCl2•cyclooctadiene has been published The reaction proceeds at a sufficiently low H2 pressure (50 psi) to avoid reduction of trisubstituted olefins, King, S A.; Thompson, A S.; King, A O.; Verhoeven, T R J Org Chem 1992, 57, 6689–6691 but not terminal olefins • Reduction of !-keto esters has been achieved at atm of hydrogen using a catalyst H2 (50 psi) O CH3 O OCH3 CH3OH, 80 °C, h prepared in situ from BINAP, (COD)Ru(2-methylallyl)2, and HBr, all of which are OH O Ru–(S)-BINAP (0.2 mol %) commercially available No special reaction apparatus is necessary for this procedure; CH3 OCH3 however, the catalyst loading is unusually high 90%, 98% ee H H2 (1 atm) O N CH3 CH3 O OH O Ru–(S)-BINAP (2 mol %) OCH3 CH3 acetone, 50 °C, 3.5 h OCH3 CH3 100%, 99% ee (–)-Indolizidine 223AB Genet, J P.; Ratovelomanana-Vidal, V.; Caño de Andrade, M C.; Pfister, X.; Guerreiro, P.; Taber, D F.; Silverberg, L J Tetrahedron Lett 1991, 32, 4227–4230 Taber, D F.; Deker, P B.; Silverberg, L J J Org Chem 1992, 57, 5990–5994 Lenoir, J Y Tetrahedron Lett 1995, 36, 4801–4804 Andrew Haidle, Fan Liu Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115 Substrates: • Chiral substrates: • !-Keto esters are typically the best substrates However, nearly any substrate that has an OH O ether or amine separated from a ketone by 1–3 carbons will be reduced to the corresponding Ph OEt NHBoc secondary alcohol with high yields and high enantioselectivities H2 (100 atm) OH O X R OH (R)-BINAP–Ru X H2 OH (S)-BINAP–Ru X R R RuBr2[BINAP] (0.18 mol %) OEt EtOH, 23 °C, 145 h NHBoc OH O Ph X R OEt NHBoc OH X R syn OH O X O Ph X R O H2 R OH X R O anti X R X = OR, NR2 • The authors propose that the heteroatom is necessary because the substrate must function as a bidentate ligand for Ru configuration of BINAP % yield syn : anti R 98 >99:1 S 96 9:91 Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R J Am Chem Soc 1988, 110, 629–631 • The (R)-BINAP case represents a stereochemically matched case, while the (S)-BINAP catalyzed case has to override the inherent syn selectivity of the • Example: substrate: RuCl2[(S)-BINAP] (0.1 mol%) OEt CH3 O 94%, 99.5% ee Okhuma, T.; Kitamura, M.; Noyori, R Tetrahedron Lett 1990, 31, 5509–5512 OCH3 H H Bn NHBoc H O EtOH, 30 °C, 100 h AcOH, toluene, reflux O O proposed T.S H2 (100 atm) O X P P Ru O • Analysis of the results show that for this substrate, catalyst control is >32:1, while the H3C substrate control is only 3:1 Nishi, T.; Kitamura, M.; Okhuma, T.; Noyori, R Tetrahedron Lett 1988, 29, 6327–6330 Andrew Haidle, Fan Liu Myers Chem 115 The Noyori Asymmetric Hydrogenation Reaction Dynamic Kinetic Resolution: • The stereochemistry of the secondary alcohol is determined by the choice of catalyst, but • Kinetic resolution of enantiomers occurs when the chiral catalyst reacts with one enantiomer much the stereochemistry at the !-position is substrate dependent more rapidly than the other O O HO OH H2 (100 atm) HO RuCl2[(R)-BINAP] CH3 O HO CH3 O CH3 OCH3 RuBr2[(R)-BINAP] CH3 CH3 OH O H2 (100 atm) CH3 OH O OCH3 CH3 OCH3 CH3 CH3 EtOH 1:1 kS/kR = 64 49.5%, 92% ee 50.5%, 92% ee O • An inherent drawback to kinetic resolution is the fact that the maximum yield is 50% of O H2 (100 atm) OCH3 HO H HO O H O OCH3 [RuCl(PhH)((R)-BINAP)]Cl OCH3 (0.09 mol %) enantiopure material 99 : Noyori, R Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1993, pp 56–82 • Epimerizing systems can give rise to a dynamic kinetic resolution, where the maximum theoretical yield is 100% • The preference for one diastereomer over the other can be rationalized by examining the likely transition states for carbonyl reduction If the reduction of the !-amino compound, below right, is carried out in methanol instead of dichloromethane, the diastereoselectivity drops from 99 : to 82 : 18 O OCH3 NHAc CH3 kinv kinv O CH3 H2 (100 atm) O O OCH3 NHAc RuBr2[(R)-BINAP] (0.4 mol %) OH O CH3 CH2Cl2, 15 °C, 50 h kR,R Ru OH O CH3 P,P = (R)-BINAP O O H H2 (100 atm) CH2Cl2, 15 °C, 50 h P P 99%, 98% ee kS,R RuBr2[(R)-BINAP] (0.4 mol %) X OCH3 NHAc OCH3 X P Ru P H3C O O H O N H H CH3 H CH3 O P,P = (R)-BINAP OCH3 NHAc 1%, >90% ee • To achieve yields approaching 100%, isomerization must be rapid relative to reduction (kinv > kS,R and kR,R) Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H J Am Chem Soc 1989, 111, 9134–9135 Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H J Am Chem Soc 1989, 111, 9134–9135 • A detailed mathematical model of the dynamic kinetic resolution process has been published Kitamura, M.; Tokunaga, M.; Noyori, R J Am Chem Soc 1993, 115, 144–152 Andrew Haidle Myers Chem 115 The Noyori Asymmetric Hydrogenation Reaction Other Ligands: • Noyori has discovered a Ru–based catalyst, trans-RuCl2[(R)-xylbinap][(R)-diapen], that efficiently • Burk's 1,2-bis(trans-2,5-diisopropylphospholano)ethane (i-Pr-BPE) is a useful ligand for the reduces "-, !-, and #-amino ketones in a highly enantioselective fashion under mild conditions reduction of many !-keto esters, and the reaction conditions are milder than those originally OCH3 reported by Noyori H2 (60 psi) O O CH3 OCH3 CH3OH : H2O (9 : 1), 35 ºC trans-RuCl2[(R)-xylbinap][(R)-diapen] = OH O (R,R)-i-Pr-BPE-RuBr2 (0.2 mol %) Ar2 Cl H2 N P Ru P Cl N Ar2 H2 OCH3 CH3 OCH3 H i-Pr Ar = 3,5-(CH3)2-C6H3 100%, 99.3% ee i-Pr H2 (8 atm) i-Pr (R, R)-Ru catalyst (0.05 mol %) (R,R)-i-Pr-BPE = P P i-Pr O i-Pr CH3 N OH t-BuOK (0.8 mol %) CH3 N i-PrOH, 25 °C O O 96 %, 99.8 % ee Burk, M J.; Harper, T G P.; Kalberg, C S J Am Chem Soc 1995, 117, 4423–4424 • The mechanism of this reduction differs from the Ru-BINAP catalyst in that the adjacent nitrogen is believed not to ligate to the Ru center • Using the [2.2]-PHANEPHOS ligand, mild, neutral conditions for the reduction of !-keto esters have • This method allows for a practical synthesis of the antidepressent (R)-fluoxetine without the need been developed for any chromatographic separations H2 (8 atm) H2 (50 psi) O O CH3 OH O (S)-[2.2]-PHANEPHOS-Ru(TFA)2 (0.6 mol %) OCH3 Bu4NI (5 mol %) CH3 (S,S)-Ru catalyst (0.01 mol %) O OCH3 CH3OH : H2O, –5 °C, 18 h 100%, 96% ee CH3 N CH3 OH t-BuOK (0.1 mol %) CH3 N CH3 i-PrOH, 25 °C, h 96 %, 97.5 % ee CF3 PPh2 (S)-[2.2]-PHANEPHOS = PPh2 Pye, P J.; Rossen, K.; Reamer, R A.; Volante, R P.; Reider, P J Tetrahedron Lett 1998, 39, 4441–4444 O H • HCl N CH3 Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R J Am Chem Soc 2000, 122, 6510–6511 Andrew Haidle Myers Chem 115 The Noyori Asymmetric Hydrogenation Reaction • Seminal reports on the use of ruthenium based catalysts for the asymmetric reduction of ketones Other Ligands and Other Substrates: focused on the use of a chiral diamine in combination with BINAP derived bis-phosphine ligands • Ru catalysts have been applied to asymmetric reduction of acrylate derivatives • Application to the synthesis of a PDE-IV inhibitor: • Production of 3-furoic acid using (S,S)-i-Pr-DuPhos: O F [(S,S)-iPr-DuPhos Ru(TFA)2] (0.02 mol%) H2 (150 psi), MeOH O H F O OH O O O F OH S S N OMOM F3C CF3 (R)-3-furoic acid >98% ee P O N O i-Pr Ru[(R)-Xyl-BINAP][(R)-diapen]Cl2 (0.1 mol%) K2CO3, i-PrOH, THF O OH F OMOM F3C CF3 99% ee i-Pr i-Pr (S,S)-iPr-DuPhos = P O i-Pr MeO OMe P(Xyl)2 P(Xyl)2 O F i-Pr Johnson, N B.; Lennon, I C.; Moran, P H.; Ramsden, J A Acc Chem Res 2007, 40, 1291–1299 F N NH2 NH2 S N (R)-diapen (R)-Xyl-BINAP O OMOM F3C CF3 • A reduction of an !,"-unsaturated cabroxylic acid using (R)-[2.2]-PHANEPHOS enabled the large- Chen, C.-Y.; Reamer, R A.; Chilenski, J R.; McWilliams, C J Org Lett 2003, 5, 5039–5042 scale synthesis of the integrin inhibitor JNJ-26076713: • A similar system was used in the production of the antidepressant, (S)-duloxetine Ru[(S)-PhanePhos][(R,R)-DPEN] KOtBu, H2 (150 psi) i-PrOH, 40 ºC O S CO2H Boc N N Ru(COD)(CF2CO2)2 (0.1 mol%) (R)-[2.2]-PHANEPHOS H2 (10 bar), 40 ºC CO2Et N CH3 CO2Et N CH3 93.4% ee CO2H Boc OH S N 86% ee, >99% conversion precipitation from toluene 71%, >99% ee N PPh2 PPh2 Ph NH2 Ph NH2 O (S)-PhanePhos Kinney, W A.; Teleha, C A.; Thompson, A S.; Newport, M.; Hansen, K.; Ballentine, S.; Ghosh, S.; Mahan, A Grasa, G.; Zanotti-Gerosa, A.; Dinegen, J.; Schubert, C.; Zhou, Y.; Leo, G C.; McComsey, D F.; Santulli, R J.; Maryanoff, B E J Org Chem 2008, 73, 2302–2310 (R,R)-DPEN S NHCH3•HCl (S)-duloxetine Hems, W.; Rossen, K.; Reichert, D.; Kohler, K.; Perea, J J US Patent 0272390, 2005 Joseph Tucker Myers Chem 115 The Noyori Asymmetric Hydrogenation Reaction Examples in Total Synthesis: H2 (200 psi) • In all of the examples, the carbonyl carbon that is initally reduced is circled in the final product O O CH3 H2 (110 atm) O O BnO OEt CH3 OEt EtOH, 130 °C, 10 h BnO CH3OH, 45 °C, 24 h 94%, 94% ee Ot-Bu CH3 76%, 96% ee S N(CH3)2 N CH3 O CH3 O CH3 CH3 O OH O CH3 OH O Dowex-50 resin OH O [RuCl2((S)-BINAP)]2•Et3N (0.2 mol %) Ot-Bu RuCl2[(S)-BINAP] (0.1 mol %) H2N HO CH3 O O CH3 CH3 OH OH OH OH OH Pateamine A (–)-Roxaticin Romo, D.; Rzasa, R M.; Shea, H A.; Park, K.; Langenhan, J M.; Sun, L.; Akhiezer, A.; Liu, J O J Am Chem Soc 1998, 120, 12237–12254 Rychnovsky, S D.; Hoye, R C J Am Chem Soc 1994, 116, 1753–1765 O H2 (50 psi) O OCH3 CH3 H2 (1500 psi) OH O O Ru–(S)-BINAP (0.2 mol %) OCH3 CH3OH, 80 °C, h 84%, 98% ee CH3 CH3 CH3 [RuCl(PhH)((R)-BINAP)]Cl (0.09 mol %) O OCH3 HO CH2Cl2, 50 °C, 70 h H O OCH3 99%, 93% ee CH3 O H OH O O HO O CH3 H O CH3 CH3 CH3 N CH3 (+)-Brefeldin A (+)-Codaphniphylline Taber, D F.; Silverberg, L J.; Robinson, E D J Am Chem Soc 1991, 113, 6639–6645 Heathcock, C H.; Kath, J C.; Ruggeri, R B J Org Chem 1995, 60, 1120–1130 Andrew Haidle The Noyori Asymmetric Hydrogenation Reaction Myers O H2 (100 atm) O OCH3 PMBO L-DOPA: First Industrial Application of Asymmetric Hydrogenation OH O Ru2Cl4[(S)-BINAP]•Et3N (1 mol %) OCH3 PMBO CH3OH, 23 °C, 70 h OAc 90%, >95% ee CH3O H CH3O H3CO CH3 OH O O O CO2H AcNH CO2H NH2 CO2H FK506 O OH O H O CH3 CH3 OCH3 OH • Although the chirality of the "-hydroxy ester is lost in the final product, it is used to set two other stereocenters LDA (2.5 equiv) OH O PMBO H3CO P H3CO P (R,R)-DiPAMP allyl bromide (3.5 equiv) OCH3 HO [Rh(cod)(R,R-dipamp)]BF4 H3CO AcNH N H CH3 PMBO OH OAc L-DOPA H3C OH O Chem 115 OCH3 THF, –78 °C ! °C, h 90 % • (S)-3',4'-dihydroxyphenylalanine (L-DOPA) is used in the treatment of Parkinson's disease EtO • Chelation control and steric shielding explain the high diastereoselectivity of the allylation reaction H R O Li O X–R' Fráter, G.; Müller, U.; Günther, W Tetrahedron 1984, 40, 1269–1277 Seebach, D.; Aebi, J.; Wasmuth, D Org Synth 1984, 63, 109–120 H • This is the first successful industrial application of a homogeneous catalytic asymmetric hydrogenation • William Knowles had developed the Rh-catalyzed enantioselective hydrogenation using (R,R)- DiPAMP as a chiral ligand while working at Monsanto in the late 1970s PMBO O CH3 O SnPh3 (1.8 equiv) PMBO (4:1 trans:cis) H • Knowles was awarded the 2002 Nobel Prize in Chemistry for this discovery O CH3 BF3•OEt (1.1 equiv) I OH CH2Cl2, –78 °C, 100 I (5:1 diastereomeric mixture) 54%, >97% dr (67% maximum yield for major diastereomer) Knowles, W S Angew Chem Int Ed 2002, 41, 1998–2007 Knowles, W S Adv Synth Catal 2003, 345, 3–13 Nakatsuka, M.; Ragan, J A.; Sammakia, T.; Smith, D B.; Uehling, D E.; Schreiber, S L J Am Chem Soc 1990, 112, 5583–5601 Andrew Haidle, Danica Rankic The Noyori Asymmetric Hydrogenation Reaction Myers Chem 115 Application in Industry Mechanism: • (R)-Warfarin synthesis: A H X product P P * H Rh Sol Sol substrate with chelating group X X • An asymmetric hydrogenation was employed in the synthesis of (R)-warfarin, one of the most commonly prescribed oral anticoagulant drugs in North America • Enantiomeric excess could be improved from 88% to 98% ee by recrystallization solvate complex A A * P P Rh * H X Sol P P Rh X Rh(cod)OTf (0.1 mol%) O catalyst-substrate complex H Rh-catalyzed Hydrogenation (unsaturated mechanism) O O CH3 ONa Ph (S,S)-Et-DuPhos O MeOH, i-PrOH H2 (4 bar), 25 oC ONa Ph reductive elimination CH3 (R)-warfarin >98%, 88% ee H2 O O oxidative addition Robinson, A.; Li, H.-Y.; Feaster, J Tetrahedron Lett 1996, 37, 8321–8324 H A * P P Rh H X Sol H Rh-alkyl monohydride migratory insertion * P H Rh P A • Sitagliptin: X • Sitagliptin (Januvia!) is a potent and selective DPP IV inhibitor for the treatment of type diabetes mellitus dihydride complex • The second-generation process route involves the hydrogenation of an unprotected "- (amino)acrylamide • A catalytic amount of NH4Cl is required for high ee and turnover numbers • Evidence suggests that Rh-catalyzed hydrogenations operate through a mechanism by which • Hydrogenation occurs through the imine tautomer substrate chelation occurs prior to hydrogen oxidative addition, although recently, studies with bulky diphosphines have shown that oxidative addition can occur prior to substrate association F Gridnev, I D.; Imamoto, T Acc Chem Res 2004, 37, 633 F F NH2 O • The solvate complex, catalyst-substrate complex, and Rh-alkyl monohydride complexes have all been observed and characterized F [RhCl(cod)]2 (0.15 mol%) N N N N CF3 (S,R)-tBu-JOSIPHOS (0.155 mol%) H2 (17 bar), NH4Cl MeOH, 50 oC • Enantioselectivity is highly dependent on temperature and H2 pressure F NH2 O N N F N N CF3 98%, 95% ee (>99.9% ee after recrystalization) • Curtin-Hammett kinetics is operating under the reaction conditions: the minor diastereomer of the catalyst-substrate complex undergoes hydrogenation to afford the major enantiomer of product Halpern, J Science 1982, 217, 401–407 Desai, A A Angew Chem Int Ed 2011, 50, 1974–1976 Hansen, K B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.; Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.; Spindler, F.; Malan, C.; Grabowski, E J J.; Armstrong, J D J Am Chem Soc 2009, 131, 8798–8804 Danica Rankic 10 The Noyori Asymmetric Hydrogenation Reaction Myers Chem 115 • Pregabalin: • Pregabalin (Lyrica!) is an anti-convulsive agent marketed for the treatment of a number of nervous system disorders, including epilepsy, neuropathic pain, anxiety and social phobia [Rh(cod)((S)-TCFP)]BF4 (0.0037 mol%) CN i-Pr CO2– H2 (3.5 bar) MeOH, 25 oC H3N t-Bu 98%, 98% ee t-Bu t-Bu P P t-Bu H3C (S)-TCFP NH2 CN i-Pr i-Pr CO2– CO2H H3N t-Bu Lyrica! • Rh-catalyzed asymmetric hydrogenation replaced an enzymatic resolution (lower cost of reagents, waste reduction and higher throughput) • Trichickenfootphos (TCFP) is a P-chiral phosphine designed and developed at Pfizer that allowed for high turnover numbers (> 27000) and high ee Hoge, G.; Wu, H.-P.; Kissel, W S.; Pflum, D A.; Greene, D J.; Bao, J J Am Chem Soc 2004, 126, 5966–5967 • Anti-tumor antibiotic L-azatyrosine: • An N-oxide was found to be necessary to prevent catalyst inhibition through pyridine coordination O N BnO CO2CH3 [Rh(cod)((R,R)-Et-DUPHOS)]BF4 (5 mol%) H2 (3 bar), MeOH, 48 oC, 80% NHCbz O N CO2CH3 NHCbz BnO 83% ee (>96% ee after recrystalization) Zn, aq NH4Cl THF, 92% N BnO CO2CH3 NHCbz LiOH, THF, H2O H2, Pd/C aq HCl, MeOH 82% N HO CO2H NH2 L-azatyrosine Adamczyk, M.; Akireddy, S R.; Reddy, R E Org Lett 2001, 3, 3157–3159 Danica Rankic 11 ... M.; Okhuma, T; Noyori, R Org Synth 1993, 71, 1–13 Ohta, T.; Takaya, H.; Noyori, R Inorg Chem 1988, 27, 566–569 Andrew Haidle, Fan Liu Myers The Noyori Asymmetric Hydrogenation Reaction • The... Kitamura, M.; Tokunaga, M.; Noyori, R J Am Chem Soc 1993, 115, 144–152 Andrew Haidle Myers Chem 115 The Noyori Asymmetric Hydrogenation Reaction Other Ligands: • Noyori has discovered a Ru–based... H.; Noyori, R J Am Chem Soc 2000, 122, 6510–6511 Andrew Haidle Myers Chem 115 The Noyori Asymmetric Hydrogenation Reaction • Seminal reports on the use of ruthenium based catalysts for the asymmetric