The Noyori Asymmetric Hydrogenation Reaction Chem 115

Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

Reviews: Mechanism:

1/n {[(R)-BINAP]RuCl2}n Noyori, R. Angew. Chem. Int. Ed. 2013, 52, 79–92. • Catalytic cycle: 2 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 OCH3 Original Report by the Noyori Group: O HCl CH3OH O [(R)-BINAP]RuHCl(CH3OH)2 CH3 H2 2 CH OH H2 (100 atm) 3 O O OH O RuCl2[(R)-BINAP] (0.05 mol %) OCH3 CH3 OCH3 CH3 OCH3 CH3OH, 36 h, 100 °C O [(R)-BINAP]RuCl(CH3O)(CH3OH)2 [(R)-BINAP]HClRu 96%, >99% ee O OCH 3 CH3 O

OCH3 HO O Noyori, R., Okhuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akuragawa, S. CH OH CH3 3 J. Am. Chem. Soc. 1987, 109, 5856–5858. [(R)-BINAP](CH3OH)ClRu 2 CH3OH 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,

prepared from the relatively inexpensive (±)-1,1'-bi-2-naphthol. pp. 56–82.

• 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

OH PPh2 PPh2 ruled out. + OH PPh2 PPh2

H2 (100 atm) O O OH O RuCl2[(R)-BINAP]–Ru (±)-1,1'-Bi-2-naphthol (R)-(+)-BINAP (S)-(–)-BINAP CH3 OCH3 CH OH, 23 °C CH3 OCH3 20% 20% 3 CH3 CH3 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

1 Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

• The use of a deuterated substrate provides further evidence that the reduction proceeds • 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 H2 (100 atm) OH O

O RuBr2[(R)-BINAP] O Cl OCH3 OCH3 P P D NHAc D NHAc Ru (R)-BINAP OH O O CH2Cl2 O O O H CH3 OCH3

CH3 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 Cl P P the phenyl rings attached to phosphorous to adopt the conformation depicted here (the napthyl Ru (R)-BINAP OH O rings are omitted for clarity). O O H CH3 OCH3

CH3O CH3 (S) !-hydroxy ester axial

P Ru P equatorial Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36–56.

Reaction Conditions: Ru(OCOCH3)2[(S)-BINAP]

• 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 4 atm/100 °C or 100 atm/23 °C.

• The two protruding equatorial P-phenyl groups allow a coordinating ligand access to only two DMF, 100 ºC 1 /2 [RuCl2(benzene)]2 + (R)-BINAP (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

2 Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

• The procedure involving in situ catalyst generation was found to be much more reliable. Also, • These conditions have been improved on even further, with milder reaction conditions and reactions with this catalyst were more enantioselective and required less catalyst. The lower catalyst loadings. following reaction was done on a 10-kg scale. Note the benzyl group is not removed.

H2 (50 psi), HCl (0.1 mol%) O O Ru–(R)-BINAP (0.05 mol %) OH O H2 (4 atm), (R)-BINAP O O OH O CH Ot-Bu CH Ot-Bu [C6H6RuCl]2 (0.05 mol %) 3 CH OH, 40 °C, 8 h 3 BnO BnO 3 OEt EtOH, 100 °C, 6 h OEt 97%, >97% ee (10.0 kg) (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 King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57, commercially available BINAP and RuCl2•cyclooctadiene has been published. The reaction 6689–6691. proceeds at a sufficiently low H2 pressure (50 psi) to avoid reduction of trisubstituted olefins, but not terminal olefins.

• Reduction of !-keto esters has been achieved at 1 atm of hydrogen using a catalyst H2 (50 psi) prepared in situ from BINAP, (COD)Ru(2-methylallyl)2, and HBr, all of which are O O Ru–(S)-BINAP (0.2 mol %) OH O commercially available. No special reaction apparatus is necessary for this procedure; CH3 CH3 OCH OCH3 3 CH3OH, 80 °C, 6 h however, the catalyst loading is unusually high.

90%, 98% ee

H H2 (1 atm) O O Ru–(S)-BINAP (2 mol %) OH O N CH CH 3 3 OCH OCH3 acetone, 50 °C, 3.5 h 3 CH3 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. Lenoir, J. Y. Tetrahedron Lett. 1995, 36, 4801–4804. Taber, D. F.; Deker, P. B.; Silverberg, L. J. J. Org. Chem. 1992, 57, 5990–5994. Andrew Haidle, Fan Liu

3 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 secondary alcohol with high yields and high enantioselectivities. NHBoc

H2 (100 atm) syn O O OH O OH RuBr2[BINAP] (0.18 mol %) X X X Ph OEt R R R NHBoc EtOH, 23 °C, 145 h OH O OH H2 O H2 OH Ph OEt R X (R)-BINAP–Ru R X (S)-BINAP–Ru R X NHBoc OH O OH X X X anti R R R

X = OR, NR2

conﬁguration of BINAP % yield syn : anti

• The authors propose that the heteroatom is necessary because the substrate must function as a R 98 >99:1

bidentate ligand for Ru. 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. X P • The (R)-BINAP case represents a stereochemically Ru O P OCH3 O matched case, while the (S)-BINAP catalyzed case H H • Example: has to override the inherent syn selectivity of the Bn NHBoc substrate: H

1. H2 (100 atm) proposed T.S.

RuCl2[(S)-BINAP] (0.1 mol%) O O EtOH, 30 °C, 100 h OEt CH3 O 2. AcOH, toluene, reﬂux O • Analysis of the results show that for this substrate, catalyst control is >32:1, while the H3C 94%, 99.5% ee substrate control is only 3:1.

Okhuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509–5512. Nishi, T.; Kitamura, M.; Okhuma, T.; Noyori, R. Tetrahedron Lett. 1988, 29, 6327–6330. Andrew Haidle, Fan Liu

4 Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

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 OH O OH O H (100 atm) O H (100 atm) OH O 2 2 CH OCH CH OCH CH OCH HO HO HO 3 3 3 3 3 3 RuCl2[(R)-BINAP] RuBr2[(R)-BINAP] CH3 CH3 CH3 CH3 CH3 CH3 EtOH 1 : 1 kS/kR = 64

50.5%, 92% ee 49.5%, 92% ee O O H (100 atm) HO O HO O 2 H H

OCH3 [RuCl(PhH)((R)-BINAP)]Cl OCH3 OCH3 • An inherent drawback to kinetic resolution is the fact that the maximum yield is 50% of (0.09 mol %) enantiopure material. 99 : 1 Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1993, pp. 56–82. • The preference for one diastereomer over the other can be rationalized by examining the likely • Epimerizing systems can give rise to a dynamic kinetic resolution, where the maximum theoretical transition states for carbonyl reduction. If the reduction of the !-amino compound, below right, is yield is 100%. carried out in methanol instead of dichloromethane, the diastereoselectivity drops from

99 : 1 to 82 : 18.

O O H2 (100 atm) OH O

RuBr2[(R)-BINAP] (0.4 mol %) CH3 OCH3 CH3 OCH3 X X P H C NHAc CH Cl , 15 °C, 50 h NHAc P 3 2 2 Ru O OCH Ru O P 3 P O H 99%, 98% ee O O H kS,R H H N CH3 kinv kinv CH3 H O H (100 atm) P,P = (R)-BINAP O O 2 OH O P,P = (R)-BINAP RuBr2[(R)-BINAP] (0.4 mol %) CH3 OCH3 CH3 OCH3 NHAc NHAc CH2Cl2, 15 °C, 50 h Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; 1%, >90% ee k R,R Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134–9135.

• To achieve yields approaching 100%, isomerization must be rapid relative to reduction • A detailed mathematical model of the dynamic kinetic resolution process has been (k > k and k . inv S,R R,R) published.

Noyori, R.; Ikeda, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144–152. Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134–9135. Andrew Haidle

5 Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

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 OCH reported by Noyori. 3

Ar2 Cl H2 P N H2 (60 psi) OCH3 O O OH O trans-RuCl2[(R)-xylbinap][(R)-diapen] = Ru (R,R)-i-Pr-BPE-RuBr (0.2 mol %) H 2 P N Ar Cl i-Pr CH3 OCH3 CH3 OCH3 2 H2 CH3OH : H2O (9 : 1), 35 ºC Ar = 3,5-(CH ) -C H 100%, 99.3% ee 3 2 6 3

H (8 atm) i-Pr i-Pr 2 (R, R)-Ru catalyst (0.05 mol %) (R,R)-i-Pr-BPE = P P O CH3 t-BuOK (0.8 mol %) OH CH3 N N i-Pr i-Pr 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

been developed. • This method allows for a practical synthesis of the antidepressent (R)-ﬂuoxetine without the need for any chromatographic separations.

H2 (8 atm) H2 (50 psi) O O OH O (S,S)-Ru catalyst (0.01 mol %) (S)-[2.2]-PHANEPHOS-Ru(TFA)2 (0.6 mol %) O OH t-BuOK (0.1 mol %) CH OCH CH3 OCH3 CH3 CH3 3 3 Bu4NI (5 mol %) N N CH3OH : H2O, –5 °C, 18 h CH3 i-PrOH, 25 °C, 5 h CH3

100%, 96% ee 96 %, 97.5 % ee

CF3 PPh2 (S)-[2.2]-PHANEPHOS = O PPh2 H N • HCl

CH3 Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510–6511. 39, 4441–4444. Andrew Haidle

6 Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

Other Ligands and Other Substrates: • Seminal reports on the use of ruthenium based catalysts for the asymmetric reduction of ketones 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 O F O F O Ru[(R)-Xyl-BINAP][(R)-diapen]Cl2 (0.1 mol%) [(S,S)-iPr-DuPhos Ru(TFA) ] (0.02 mol%) F O F OH O 2 O K2CO3, i-PrOH, THF H2 (150 psi), MeOH H OH OH S S O O N N OMOM OMOM i-Pr (R)-3-furoic acid F3C CF3 99% ee F3C CF3 P >98% ee i-Pr (S,S)-iPr-DuPhos = i-Pr P O i-Pr MeO OMe F O

P(Xyl)2 F O P(Xyl)2 N i-Pr NH2 S NH2 Johnson, N. B.; Lennon, I. C.; Moran, P. H.; Ramsden, J. A. Acc. Chem. Res. 2007, 40, 1291–1299. N (R)-Xyl-BINAP (R)-diapen OMOM F C CF • A reduction of an !,"-unsaturated cabroxylic acid using (R)-[2.2]-PHANEPHOS enabled the large- 3 3 scale synthesis of the integrin inhibitor JNJ-26076713: Chen, C.-Y.; Reamer, R. A.; Chilenski, J. R.; McWilliams, C. J. Org. Lett. 2003, 5, 5039–5042.

• A similar system was used in the production of the antidepressant, (S)-duloxetine.

O Ru[(S)-PhanePhos][(R,R)-DPEN] OH KOtBu, H2 (150 psi) S CO2Et S CO2Et N i-PrOH, 40 ºC N 1. Ru(COD)(CF2CO2)2 (0.1 mol%) CH3 CH3 (R)-[2.2]-PHANEPHOS 93.4% ee CO2H CO2H N H2 (10 bar), 40 ºC N Boc Boc N 86% ee, >99% conversion N 2. precipitation from toluene PPh Ph NH2 71%, >99% ee 2

Ph NH2 PPh2 O (S)-PhanePhos (R,R)-DPEN S NHCH3•HCl

Kinney, W. A.; Teleha, C. A.; Thompson, A. S.; Newport, M.; Hansen, K.; Ballentine, S.; Ghosh, S.; (S)-duloxetine Mahan, A. Grasa, G.; Zanotti-Gerosa, A.; Dinegen, J.; Schubert, C.; Zhou, Y.; Leo, G. C.; Hems, W.; Rossen, K.; Reichert, D.; Kohler, K.; Perea, J. J. US Patent 0272390, 2005 McComsey, D. F.; Santulli, R. J.; Maryanoff, B. E. J. Org. Chem. 2008, 73, 2302–2310. Joseph Tucker

7 Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115 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 RuCl2[(S)-BINAP] (0.1 mol %) OH O CH OEt CH OEt 3 Dowex-50 resin 3

H2 (110 atm) EtOH, 130 °C, 10 h O O OH O [RuCl2((S)-BINAP)]2•Et3N (0.2 mol %) 94%, 94% ee BnO Ot-Bu BnO Ot-Bu CH3OH, 45 °C, 24 h

76%, 96% ee CH3 S N(CH3)2 N O CH3 CH3 O OH CH3 O CH3 O HO H2N CH3 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.;

Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753–1765. Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237–12254.

H2 (50 psi) H (1500 psi) O O OH O 2 Ru–(S)-BINAP (0.2 mol %) O O [RuCl(PhH)((R)-BINAP)]Cl (0.09 mol %) HO O H OCH3 OCH3 CH3OH, 80 °C, 6 h OCH3 OCH CH2Cl2, 50 °C, 70 h 3

84%, 98% ee CH3 CH3 CH3 CH3 99%, 93% ee

CH3 O OH O H O O CH3 HO O CH3

CH3 H CH3

CH3 N (+)-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

8 Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

H (100 atm) O O 2 OH O L-DOPA: First Industrial Application of Asymmetric Hydrogenation Ru2Cl4[(S)-BINAP]•Et3N (1 mol %) PMBO OCH3 PMBO OCH3 CH3OH, 23 °C, 70 h OH OAc OAc 90%, >95% ee HO H3CO [Rh(cod)(R,R-dipamp)]BF4 H3CO

CH3O CH3 H OH NH CO H CH O AcNH CO H AcNH CO H 2 2 3 O O 2 2 L-DOPA H3C O N FK506 CH3 H O OH O H OCH O 3 CH CH H3CO P 3 3 OH

• Although the chirality of the "-hydroxy ester is lost in the ﬁnal product, it is used to set two other H3CO P stereocenters.

LDA (2.5 equiv) OH O OH O allyl bromide (3.5 equiv) (R,R)-DiPAMP PMBO OCH3 PMBO OCH3 THF, –78 °C ! 0 °C, 4 h

90 %

EtO • (S)-3',4'-dihydroxyphenylalanine (L-DOPA) is used in the treatment of Parkinson's disease. O • Chelation control and steric shielding explain the Li H R high diastereoselectivity of the allylation reaction. O • This is the first successful industrial application of a homogeneous catalytic asymmetric H hydrogenation. Fráter, G.; Müller, U.; Günther, W. Tetrahedron 1984, 40, 1269–1277. X–R' Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1984, 63, 109–120. • 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.

CH SnPh (1.8 equiv) PMBO O 3 3 PMBO OH • Knowles was awarded the 2002 Nobel Prize in Chemistry for this discovery. (4:1 trans:cis) O H O BF3•OEt (1.1 equiv) CH3 I I CH2Cl2, –78 °C, 100 min (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

9 Myers The Noyori Asymmetric Hydrogenation Reaction Chem 115

Mechanism: Application in Industry

• (R)-Warfarin synthesis:

H A • An asymmetric hydrogenation was employed in the synthesis of (R)-warfarin, one of the most X substrate with P Sol product Rh X chelating group X commonly prescribed oral anticoagulant drugs in North America. H * P Sol • Enantiomeric excess could be improved from 88% to 98% ee by recrystallization. solvate complex A P X A Rh Rh(cod)OTf (0.1 mol%) * P O CH O CH P X H O O 3 (S,S)-Et-DuPhos O O 3 * Rh P Sol catalyst-substrate MeOH, i-PrOH H complex o ONa Ph H2 (4 bar), 25 C ONa Ph Rh-catalyzed Hydrogenation (R)-warfarin (unsaturated mechanism) >98%, 88% ee H reductive 2 oxidative addition elimination Robinson, A.; Li, H.-Y.; Feaster, J. Tetrahedron Lett. 1996, 37, 8321–8324.

H A H A • P X Sitagliptin: Rh P X * P Rh • Sitagliptin (Januvia!) is a potent and selective DPP IV inhibitor for the treatment of type 2 diabetes H Sol mellitus. H migratory * P dihydride insertion • Rh-alkyl monohydride 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 F Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633. F NH2 O F [RhCl(cod)]2 (0.15 mol%) NH2 O N N N N t N • The solvate complex, catalyst-substrate complex, and Rh-alkyl monohydride complexes have all F N (S,R)- Bu-JOSIPHOS N (0.155 mol%) F N been observed and characterized. CF3 H2 (17 bar), NH4Cl CF3 o MeOH, 50 C 98%, 95% ee • Enantioselectivity is highly dependent on temperature and H2 pressure. (>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. 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.; Halpern, J. Science 1982, 217, 401–407. 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 Myers The Noyori Asymmetric Hydrogenation Reaction 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)]BF NH CN 4 CN 2 (0.0037 mol%) i-Pr i-Pr i-Pr

– – CO2 H2 (3.5 bar) CO2 CO2H MeOH, 25 oC H N t-Bu H3N t-Bu 3 98%, 98% ee Lyrica!

• Rh-catalyzed asymmetric hydrogenation replaced an enzymatic resolution t-Bu t-Bu (lower cost of reagents, waste reduction and higher throughput) P P t-Bu H3C • Trichickenfootphos (TCFP) is a P-chiral phosphine designed and developed at Pfizer that allowed for high turnover numbers (> 27000) and (S)-TCFP 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 [Rh(cod)((R,R)-Et-DUPHOS)]BF4 O N CO CH 2 3 (5 mol%) N CO2CH3 o NHCbz H2 (3 bar), MeOH, 48 C, 80% NHCbz BnO BnO

83% ee (>96% ee after recrystalization)

Zn, aq. NH4Cl N CO2CH3 1. LiOH, THF, H2O N CO2H

THF, 92% NHCbz 2. H2, Pd/C NH2 BnO aq. HCl, MeOH HO 82% L-azatyrosine

Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 3, 3157–3159. Danica Rankic