Molecular Design of Bifunctional Cp*Ru Catalysts for Asymmetric - PowerPoint PPT Presentation

Molecular Design of Bifunctional Cp*Ru Catalysts for Asymmetric Synthesis Masato Ito & Takao Ikariya IMCE. Kyushu University & Tokyo Tech. Nov. 12, 2009 @ IKCOC-11 (OP-28)

DIRECT HYDROGENATION OF POLARIZED C–O BONDs H O O catalyst + H 2 R Y R Y H unresolved substrates with a less electrophilic carbonyl O O O O EWG R H R R' R N R OR' R' aldehyde ketone imide ester O O O EDG R N RO OR' R 2 N NR' 2 R' amide carbonate urea now-resolved by Noyori’s catalysts (1995~)

EXPLORATION WITH Cp*M – BASED COMPLEXES H O O catalyst + H 2 R Y R Y H 1 2 H He 3 4 5 6 7 8 9 10 Li Be B C N O F Ne 11 12 13 14 15 16 17 18 Na Mg Al Si P S Cl Ar 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe 55 56 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 57~71 Cs Ba Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn 87 88 104 105 106 107 108 109 110 111 112 113 114 115 116 118 89~103 Fr Ra Rf Db Sg Bh Hs Mt Ds Rg Uub Uut Uuq Uup Uuh Uuo L L M M N N X X molecular orchestration R 1 R 1 H H at the ligand sphere of the central metal by judicious M = Fe II , Ru II , Co III , Rh III L = NMe 2 , , PPh 2 N choice of coordinating elements

PROTIC AMINE LIGANDS O Ph 2 R 1 TfOH P NHR 1 O N + Ph 2 P HPPh 2 –CO 2 M 2 equiv R 2 N X R 2 R 2 R 1 H O Li n L R 1 HCl (2 equiv) OH N M –H 2 O N X n n n R 1 NHR 1 NHR 1 H Organometallics , 2009 , 28 , 390

EXPLORATION WITH Cp*M – BASED COMPLEXES H O O catalyst + H 2 R Y R Y H 1 2 H He 3 4 5 6 7 8 9 10 Li Be B C N O F Ne 11 12 13 14 15 16 17 18 Na Mg Al Si P S Cl Ar 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe 55 56 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 57~71 Cs Ba Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn 87 88 104 105 106 107 108 109 110 111 112 113 114 115 116 118 89~103 Fr Ra Rf Db Sg Bh Hs Mt Ds Rg Uub Uut Uuq Uup Uuh Uuo L L Ru Ru N N X X molecular orchestration R 1 R 1 H H at the ligand sphere of the central metal by judicious L = NMe 2 , , PPh 2 N choice of coordinating elements

Ru & CHELATING PROTIC AMINE LIGAND H O O catalyst + H 2 R Y R Y H � Basic media-assisted heterolysis of H 2 � Chemoselective delivery of activated H 2 L L Ru Ru N N X X R 1 R 1 H H L = NMe 2 , , PPh 2 N

REDUCIBLE POLARIZED C–O BONDS WITH H 2 Me 2 N Cp*Ru(NN) Cp*Ru(PN) Ru aldehyde O O N Cl H 2 ketone O O imide X O N -acylcarbamate O X N lactone X O Ru O X ester N Cl H 2 lactam X X carboxamide X X Ph 2 P P H 2 = 1 –30 atm, cat. = Ru + base (1:1) [substrate] = 0.02 –1.0 M in alcohol Ru 30 –80 °C N Cl H 2 Chem. Commun. (Feature Article) , 2007 , 5134 J. Synth. Org. Chem., Jpn. , 2008 , 66 , 1042. Angew. Chem., Int. Ed. , 2009 , 48 ， 1324

HYDROGENATION OF IMIDE WITH Cp*Ru(PN) CATALYSTS O O Cp*RuCl(PN) Ph 2 KO t- Bu P + NHR N R H 2 2-propanol Ru 50 –80 ºC 30 atm N Cl O OH 1 –18 h H 2 Ru:KO t- Bu = 1:1 (1 –5 mol%) >99% yield [imide] = 0.02 –0.20 M Cp*RuCl(PN) O O O O O O NHR NHR R NHR R NH NHR RHNHO n n OH OH OH OH OH (n = 1 –4) (n = 1 –3) J. Am. Chem. Soc. , 2007 , 129 , 290.

HYDROGENATIVE DESYMMETRIZATION OF IMIDES O O Ph 2 Cp*RuCl(PN) P KO t- Bu * + NAr H 2 NHAr R n R n Ru 2-propanol N Cl 80 ºC, 24 h 30 atm H O OH n Ar = (3,4-OCH 2 O)C 6 H 3 Cp*RuCl(PN) Ru:KO t -Bu = 1:1 (10 mol%), [imide] = 0.20 M n = 1,2 CONHAr CONHAr O O R n NHAr CH 3 NHAr OH OH CH 2 OH CH 2 OH 91 – 99% ee 88% ee 97% ee 94% ee CONHAr CONHAr CONHAr CONHAr CH 2 OH CH 2 OH CH 2 OH CH 2 OH 94% ee 97% ee 92% ee 91% ee to be published

MOLECULAR STRUCTURES OF BICYCLIC IMIDES

HYDROGENATIVE DESYMMETRIZATION OF IMIDES O O Ph 2 Cp*RuCl(PN) P KO t- Bu * + NAr H 2 NHAr R n R n Ru 2-propanol N Cl 80 ºC, 24 h 30 atm H O OH n Ar = (3,4-OCH 2 O)C 6 H 3 Cp*RuCl(PN) Ru:KO t -Bu = 1:1 (10 mol%), [imide] = 0.20 M n = 1,2 CONHAr CONHAr O O R n NHAr CH 3 NHAr OH OH CH 2 OH CH 2 OH 91 – 99% ee 88% ee 97% ee 94% ee CONHAr CONHAr CONHAr CONHAr CH 2 OH CH 2 OH CH 2 OH CH 2 OH 94% ee 97% ee 92% ee 91% ee to be published

ASYMMETRIC SYNTHESIS OF PAROXETINE O H 2 / Cp*RuCl(PN) O N F 2-propanol O O O O 1) CBr 4 , PPh 3 4-FC 6 H 4 NHAr R 4-FC 6 H 4 NH 2) NaH 3) CAN OH >99% ee Ar = 3,4-(OCH 2 O)C 6 H 3 O O O steps 4-FC 6 H 4 NH 2 Cl Paroxetine (SSRI) Pure. Appl. Chem. , 2008 , 80 , 1047.

HYDROGENATION OF PHTHALIDE Cp*RuCl(isoprene) O Ligand NaOMe OH + H 2 O 2-propanol OH 100 ºC, 21 h 50 atm ester:Ru:Ligand:NaOMe = 100:1:1:25, [ester] = 1.0 M in 2-propanol Ph 2 P NH 2 Ph 2 P NMe Ph 2 P NMe 2 N NH 2 H >99% >99% <1% >99% Me 2 N NH 2 MeN NH 2 MeN NMe H 2 N NH 2 H H H 45% 83% 94% 81%

PRESSURE & TEMPERATURE EFFECT O Cp*RuCl(PyN) NaOMe OH + H 2 O 2-propanol OH 21 h ester:Ru:NaOMe = 100:1:25, [ester] = 1.0 M in 2-propanol 100 80 60 conv, % N 40 Ru 20 N Cl H 2 0 50 120 100 30 80 Cp*RuCl(PyN) 60 10 ℃ atm

SUBSTRATE SCOPE O OH Cp*RuCl(PyN) NaOMe N + O H 2 2-propanol Ru ( t -butanol*) 50 atm N Cl OH H 2 100 ºC, 21 –24h lactone:Ru:NaOMe = 100:1 –5:25, [lactone] = 1.0 –2.0 M Cp*RuCl(PyN) O O O O R O Ph OR PhCF 2 O t -Bu O R=Me* (5 mol%) R' R=C 2 H 5 >99% R=Ph R'=H O R=Bn R'=H R=H R'= n -C 5 H 11 CHF 2 OC 2 H 5 (0.1 mol%)

SUBSTRATE SCOPE O OH Cp*RuCl(PyN) NaOMe N + O H 2 2-propanol Ru ( t -butanol*) 50 atm N Cl OH H 2 100 ºC, 21 –24h lactone:Ru:NaOMe = 100:1 –5:25, [lactone] = 1.0 –2.0 M Cp*RuCl(PyN) OH R OH OH Ph OH PhCF 2 OH OH R=Me, >99%* >99% (5 mol%) R=C 2 H 5 , >99% R' >99% R=Ph R'=H, >99% R=Bn R'=H, >99% R=H R'= n -C 5 H 11 , 76% CHF 2 OH 660 TON (0.1 mol%)

ASYMMETRIC HYDROGENATION VIA DKR O Cp*RuCl(chiral diamine) Ph Ph KO t -Bu OH + H 2 O 2-propanol OH 80 ºC, 48 h 50 atm lactone:Ru:KO t -Bu = 100:2:25, [lactone] = 1.0 M 94 –97% yield Ph Ph MeN NMe N NH 2 H H H 34% ee 29% ee Ph Ph H 2 N NH 2 MeN NMe H H 20% ee 54% ee 67% ee (10 mol%, 60 ºC, 90 h)

EFFECT OF SUB-STOICHIOMETRIC BASE condition A with condition B with Cp*Ru(PN) any Cp*Ru(LN) N -acylcarbamate O O lactone O O ester O O lactam X O carboxamide X O A: P H 2 = 30 atm, cat. = Ru + base (1:1), 80 °C B: P H 2 = 50 atm, substrate + base (4:1), 100 °C Me H Ph 2 N P N Ru Ru Ru N Cl N N Cl Cl H 2 H 2 Me H

HYDROGENATION OF N -Ph- γ -LACTAM O OH Cp*RuCl(LN) NaOMe H + H 2 N N t -butanol 100 ºC, 90 h 50 atm lactam:Ru:NaOMe = 100:10:30, [lactam] = 1.0 M Ph 2 P N Ru Ru N N Cl Cl H 2 Me H 66% yield 82% yield

SUBSTRATE SCOPE O OH Cp*RuCl(PyN) NaOMe + N H 2 t -butanol R n 100 ºC, 90 h 50 atm HN R n lactam:Ru:NaOMe = 100:10:30, [lactam] = 1.0 M O O O O R N N N N R R n H n n=0, 83% R=F, 83% R=4-CF 3 , 90% R=C 6 H 5 , 99% n=1, 82% R=CF 3 , 90% R=3,5-(CF 3 ) 2 , 93% R=CF 2 C 6 H 5 , 99% n=2, 91% R=OMe, 56% (48 h) n=3, 74%

ACKNOWLEDGEMENT Co–workers Mr. Makoto Hirakawa Ms. Mariko Sugizawa Dr. Akihide Osaku Dr. Sachiko Kitahara Ms. Ayaka Sakaguchi Mr. Kensuke Yamamoto Ms. Miho Ashiarai Ms. Hiroko Komatsu Dr. Akira Shiibashi Dr. Yoshinori Endo Mr. Yuji Shibata Mr. Masahiro Yamamura Ms. Chika Kobayashi Ms. Noriko Tejima Mr. Kentaro Yamaguchi Mr. Akio Himizu Ms. Lee-Wei Koo Mr. Akira Watanabe Mr. Takashi Otsuka Ms. Takako Noguchi Ms. Yasuko Oosawa Mr. Ryo Watari Mr. Naoki Sakamoto Financial Support JSPS Kakenhi Kawakami Memorial Foundation Taisho Pharmaceutical Co. Ltd The Asahi Glass Foundation