SLIDE 1 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)
SLIDE 2 DIRECT HYDROGENATION OF POLARIZED C–O BONDs
R Y O catalyst + H2 R Y O H H
aldehyde ketone imide ester amide carbonate urea
R N R' O EWG R OR' O R N R' O EDG RO OR' O R2N NR'2 O R H O R R' O
now-resolved by Noyori’s catalysts (1995~) unresolved substrates with a less electrophilic carbonyl
SLIDE 3 EXPLORATION WITH Cp*M–BASED COMPLEXES
R Y O catalyst + H2 R Y O H H
N
M X L N H R1 M X L N H R1 L = NMe2, , PPh2 M = FeII, RuII, CoIII, RhIII
2
He
5
B
8
O
9
F
10
Ne
11
Na
12
Mg
13
Al
14
Si
16
S
17
Cl
18
Ar
19
K
20
Ca
31
Ga
32
Ge
33
As
34
Se
35
Br
36
Kr
21
Sc
22
Ti
23
V
24
Cr
25
Mn
28
Ni
29
Cu
30
Zn
37
Rb
38
Sr
49
In
50
Sn
51
Sb
52
Te
53
I
54
Xe
39
Y
40
Zr
41
Nb
42
Mo
43
Tc
46
Pd
48
Cd
55
Cs
56
Ba
81
Tl
82
Pb
83
Bi
84
Po
85
At
86
Rn
57~71
72
Hf
73
Ta
74
W
75
Re
78
Pt
79
Au
80
Hg
87
Fr
88
Ra
113
Uut
114
Uuq
115
Uup
116
Uuh
118
Uuo
89~103
104
Rf
105
Db
106
Sg
107
Bh
108
Hs
109
Mt
110
Ds
111
Rg
112
Uub
1
H
4
Be
3
Li
47
Ag
7
N
15
P
6
C
26
Fe
27
Co
44
Ru
45
Rh
76
Os
77
Ir
molecular orchestration
at the ligand sphere of the central metal by judicious choice of coordinating elements
SLIDE 4 PROTIC AMINE LIGANDS
N O O R2 R1 + HPPh2 TfOH NHR1 Ph2P R2 2 equiv –CO2 Organometallics, 2009, 28, 390 N O R1 (2 equiv) Li NHR1 OH HCl NHR1
n n n
–H2O M X Ph2 P N H R1 R2 M X L N H R1
n
SLIDE 5 EXPLORATION WITH Cp*M–BASED COMPLEXES
R Y O catalyst + H2 R Y O H H
2
He
5
B
8
O
9
F
10
Ne
11
Na
12
Mg
13
Al
14
Si
16
S
17
Cl
18
Ar
19
K
20
Ca
31
Ga
32
Ge
33
As
34
Se
35
Br
36
Kr
21
Sc
22
Ti
23
V
24
Cr
25
Mn
28
Ni
29
Cu
30
Zn
37
Rb
38
Sr
49
In
50
Sn
51
Sb
52
Te
53
I
54
Xe
39
Y
40
Zr
41
Nb
42
Mo
43
Tc
46
Pd
48
Cd
55
Cs
56
Ba
81
Tl
82
Pb
83
Bi
84
Po
85
At
86
Rn
57~71
72
Hf
73
Ta
74
W
75
Re
78
Pt
79
Au
80
Hg
87
Fr
88
Ra
113
Uut
114
Uuq
115
Uup
116
Uuh
118
Uuo
89~103
104
Rf
105
Db
106
Sg
107
Bh
108
Hs
109
Mt
110
Ds
111
Rg
112
Uub
1
H
4
Be
3
Li
47
Ag
7
N
15
P
6
C
26
Fe
27
Co
44
Ru
45
Rh
76
Os
77
Ir
molecular orchestration
at the ligand sphere of the central metal by judicious choice of coordinating elements
N
Ru X L N H R1 Ru X L N H R1 L = NMe2, , PPh2
SLIDE 6 Ru & CHELATING PROTIC AMINE LIGAND
R Y O catalyst + H2 R Y O H H
Basic media-assisted heterolysis of H2 Chemoselective delivery of activated H2
N
Ru X L N H R1 Ru X L N H R1 L = NMe2, , PPh2
SLIDE 7 Me2 N Ru Cl Ph2 P N H2 aldehyde ketone lactone lactam carboxamide imide Cp*Ru(NN) Cp*Ru(PN) X X O X O X X O O O PH2 = 1 –30 atm, cat. = Ru + base (1:1) [substrate] = 0.02 –1.0 M in alcohol 30 –80 °C Ru Cl N N H2 Ru Cl N H2 N-acylcarbamate X O O O ester X X
REDUCIBLE POLARIZED C–O BONDS WITH H2
- Chem. Commun. (Feature Article), 2007, 5134
- J. Synth. Org. Chem., Jpn., 2008, 66, 1042.
- Angew. Chem., Int. Ed., 2009, 48，
1324
SLIDE 8
- J. Am. Chem. Soc., 2007, 129, 290.
HYDROGENATION OF IMIDE WITH Cp*Ru(PN) CATALYSTS
+ H2 2-propanol 50 –80 ºC 1 –18 h Cp*RuCl(PN) KOt-Bu Ru:KOt-Bu = 1:1 (1 –5 mol%) [imide] = 0.02 –0.20 M 30 atm Ru Cl Ph2 P N H2 Cp*RuCl(PN) N O O R NHR O OH NHR O OH NHR O OH NHR O OH R
n
>99% yield
n
(n = 1 –4) (n = 1 –3) NH R O OH NHR O OH O RHNHO
SLIDE 9 + H2 2-propanol 80 ºC, 24 h Cp*RuCl(PN) KOt-Bu 30 atm Cp*RuCl(PN) Ru:KOt-Bu = 1:1 (10 mol%), [imide] = 0.20 M Ar = (3,4-OCH2O)C6H3 NAr O O NHAr O OH Rn Rn NHAr O OH 91–99% ee NHAr CH3 O OH 88% ee CONHAr 97% ee Ru Cl Ph2 P N H n n = 1,2 92% ee 91% ee * Rn CH2OH CONHAr 94% ee CH2OH CH2OH CONHAr CH2OH CONHAr CONHAr CH2OH CONHAr CH2OH 94% ee 97% ee
HYDROGENATIVE DESYMMETRIZATION OF IMIDES
to be published
SLIDE 10
MOLECULAR STRUCTURES OF BICYCLIC IMIDES
SLIDE 11 HYDROGENATIVE DESYMMETRIZATION OF IMIDES
to be published
+ H2 2-propanol 80 ºC, 24 h Cp*RuCl(PN) KOt-Bu 30 atm Cp*RuCl(PN) Ru:KOt-Bu = 1:1 (10 mol%), [imide] = 0.20 M Ar = (3,4-OCH2O)C6H3 NAr O O NHAr O OH Rn Rn NHAr O OH 91–99% ee NHAr CH3 O OH 88% ee CONHAr 97% ee Ru Cl Ph2 P N H n n = 1,2 92% ee 91% ee * Rn CH2OH CONHAr 94% ee CH2OH CH2OH CONHAr CH2OH CONHAr CONHAr CH2OH CONHAr CH2OH 94% ee 97% ee
SLIDE 12 ASYMMETRIC SYNTHESIS OF PAROXETINE
NHAr 4-FC6H4 OH O 1) CBr4, PPh3 NH2Cl 4-FC6H4 Ar = 3,4-(OCH2O)C6H3
Paroxetine (SSRI)
2) NaH 3) CAN >99% ee 2-propanol H2 / Cp*RuCl(PN) NH 4-FC6H4 O O O O steps
R
F O O O O N
- Pure. Appl. Chem., 2008, 80, 1047.
SLIDE 13
HYDROGENATION OF PHTHALIDE
+ H2 2-propanol 100 ºC, 21 h Cp*RuCl(isoprene) Ligand NaOMe ester:Ru:Ligand:NaOMe = 100:1:1:25, [ester] = 1.0 M in 2-propanol 50 atm O O OH OH Ph2P NH2 >99% Ph2P NMe >99% Ph2P NMe2 <1% Me2N NH2 45% MeN NH2 83% MeN NMe 94% N NH2 >99% H2N NH2 81% H H H H
SLIDE 14 120 100 80 60 10 30 50 20 40 60 80 100 conv, % ℃ atm
PRESSURE & TEMPERATURE EFFECT
+ H2 2-propanol 21 h Cp*RuCl(PyN) NaOMe ester:Ru:NaOMe = 100:1:25, [ester] = 1.0 M in 2-propanol O O OH OH Ru Cl N N H2 Cp*RuCl(PyN)
SLIDE 15
SUBSTRATE SCOPE
+ H2 2-propanol (t-butanol*) 100 ºC, 21 –24h Cp*RuCl(PyN) NaOMe lactone:Ru:NaOMe = 100:1 –5:25, [lactone] = 1.0 –2.0 M 50 atm O O OH OH O O (0.1 mol%) R=Me* R=C2H5 Ph OR O CHF2 OC2H5 O R R=Ph R'=H R=Bn R'=H R=H R'=n-C5H11 (5 mol%) PhCF2 Ot-Bu O R' O O >99% Ru Cl N N H2 Cp*RuCl(PyN)
SLIDE 16
SUBSTRATE SCOPE
+ H2 2-propanol (t-butanol*) 100 ºC, 21 –24h Cp*RuCl(PyN) NaOMe lactone:Ru:NaOMe = 100:1 –5:25, [lactone] = 1.0 –2.0 M 50 atm O O OH OH 660 TON (0.1 mol%) R=Me, >99%* R=C2H5, >99% Ph OH CHF2 OH R R=Ph R'=H, >99% R=Bn R'=H, >99% R=H R'=n-C5H11, 76% >99% (5 mol%) PhCF2 OH OH >99% Ru Cl N N H2 Cp*RuCl(PyN) OH OH R' OH
SLIDE 17
ASYMMETRIC HYDROGENATION VIA DKR
+ H2 2-propanol 80 ºC, 48 h Cp*RuCl(chiral diamine) KOt-Bu lactone:Ru:KOt-Bu = 100:2:25, [lactone] = 1.0 M 50 atm O O Ph OH OH Ph 94 –97% yield MeN NMe 34% ee H2N NH2 20% ee H H Ph Ph Ph Ph MeN NMe 54% ee 67% ee (10 mol%, 60 ºC, 90 h) H H N NH2 29% ee H
SLIDE 18
EFFECT OF SUB-STOICHIOMETRIC BASE
N lactone lactam carboxamide condition A with Cp*Ru(PN) A: PH2 = 30 atm, cat. = Ru + base (1:1), 80 °C B: PH2 = 50 atm, substrate + base (4:1), 100 °C Ru Cl N N H2 Ru Cl N N-acylcarbamate O O O ester H H Me Me O O O X X O O condition B with any Cp*Ru(LN) Ru Cl Ph2 P N H2
SLIDE 19
HYDROGENATION OF N-Ph-γ-LACTAM
+ H2 t-butanol 100 ºC, 90 h Cp*RuCl(LN) NaOMe lactam:Ru:NaOMe = 100:10:30, [lactam] = 1.0 M 50 atm N O N OH H 82% yield Ru Cl Ph2 P N 66% yield H Me Ru Cl N N H2
SLIDE 20 SUBSTRATE SCOPE
+ H2 t-butanol 100 ºC, 90 h Cp*RuCl(PyN) NaOMe lactam:Ru:NaOMe = 100:10:30, [lactam] = 1.0 M 50 atm N O HN OH R=C6H5, 99% R=CF2C6H5, 99% Rn Rn N O n=0, 83% n=1, 82% n=2, 91% n=3, 74%
n
N O R=F, 83% R=CF3, 90% R=OMe, 56% R N O H N O R R=4-CF3, 90% R=3,5-(CF3)2, 93% (48 h) Rn
SLIDE 21 Co–workers
JSPS Kakenhi
Financial Support
- Mr. Makoto Hirakawa
- Dr. Akihide Osaku
- Ms. Ayaka Sakaguchi
- Ms. Miho Ashiarai
- Dr. Akira Shiibashi
- Mr. Yuji Shibata
- Ms. Chika Kobayashi
- Mr. Kentaro Yamaguchi
- Ms. Lee-Wei Koo
- Mr. Takashi Otsuka
- Ms. Yasuko Oosawa
- Mr. Naoki Sakamoto
Kawakami Memorial Foundation
- Ms. Mariko Sugizawa
- Dr. Sachiko Kitahara
- Mr. Kensuke Yamamoto
- Ms. Hiroko Komatsu
- Dr. Yoshinori Endo
- Mr. Masahiro Yamamura
- Ms. Noriko Tejima
- Mr. Akio Himizu
- Mr. Akira Watanabe
- Ms. Takako Noguchi
- Mr. Ryo Watari
Taisho Pharmaceutical Co. Ltd
ACKNOWLEDGEMENT
The Asahi Glass Foundation
