Recent Advances in Asymmetric Transfer · PDF fileMeO MeO N H N Me H H HN OH tubulosine O N H...
Transcript of Recent Advances in Asymmetric Transfer · PDF fileMeO MeO N H N Me H H HN OH tubulosine O N H...
Recent Advances in Asymmetric Transfer Hydrogenation
Adam M. Azman8 March 2007
1
Chiral Secondary Alcohols and Amines• Chiral secondary alcohols and amines prevalent
• Important as intermediates
Me
Me Me
O
Me3Si
Me
Me Me
HO
Me3Si
Me
MeMe
HHHO H
or
Me
MeMe
HHH2C
(−)-β-cubebene(−)-cubebol
MeO
MeON
HN
MeH
H
HN
OH
tubulosine
O
NH
Me
CF3
HCl
fluoxetine hydrochloride(Prozac)
HO
OH
OMeMe
HN
NHCHO
(R,R)-formoterol
Fürstner, A.; Hannen, P. Chem. Eur. J., 2006, 12, 3006-3019.Hett, R.; Fang, Q. K.; Gao, Y.; Hong, Y.; Butler, H. T.; Nie, X.; Wald, S. Tetrahedron Lett., 1997, 38, 1125-1128.
2
Formation of Chiral Secondary Alcohols• Addition to aldehyde
– Organometallic Nucleophile
– Aldol
NO
• Epoxide opening • Asymmetric carbonyl/imine reduction
Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett., 1968, 18, 2199-2204.Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K.
J. Org. Chem., 2001, 66, 895-902.
R
S OMe
L3Ti
H
O
R1NO
R
S O OH
R1
"Evans Syn" Product
O MeLiMe
OH
Alexakis, A.; Vrancken, E.; Mangeney, P.; Chemla, F. J. Chem. Soc. Perkin Trans. I, 2000, 3352.3353.
Ph Me
O
Ph(S) Me
OH
[RuCl2(p-cymene)]2(1S,2S)-N -(p-toluenesulfonyl)-1,2-
diphenylethylenediamine
iPrOH, KOH
Hashiguchi, S.; Fujii, A.; Takehara, K.; Ikariya, T.; Noyori, R.J. Am. Chem. Soc., 1995, 117, 7562-7563.
• Asymmetric alkene oxidation– Hydroboration
– Dihydroxylation
OsO4NMO
O
OO
MeMe
OHO
OO
MeMe
OHOH
OH
O
O
O
O
MeMe
MeMe
H H
Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S.; Bennett, F.; Taylor, I. D.J. Chem. Soc. Perkin Trans. I, 1986, 5, 815-812.
Still, W. C.; Kempf, D.; Hauck, P. Tetrahedron Lett., 1986, 27, 2727-2730.
H
O
Rs
RL SnBu3
OH
Rs
RL
Felkin-Ahn ProductMe
OH
MeMe
OH
Me
OHMe
MeBH3•THF
3
Reduction of C=X π-Bond• Meerwein-Ponndorf-Verley Reduction
– Discovered in 1920s– Commonly aluminum or boron metal center– Metal-isopropoxide or -alkyl group as reducing agent
• Metal-based reductions– NaBH4 discovered in 1942 by Brown– LiAlH4 discovered in 1945 by Bond– Dissolving metal reduction
• Transition metal mediated reduction– Pioneered by Noyori
• Asymmetric Transfer Hydrogenation– Ru, Rh, Ir hydrides– η6-arene and diamine ligands– No hydrogen atmosphere– Isopropanol or formic acid/triethylamine as
stochiometric reducing agent
R R'
O O
H
Al
iPrO OiPr
R R'
O O
H
Al
iPrO OiPr
R R'
OH O Ph2P
PPh2
RuNH2
H2N Ph
Ph
Cl
Cl(S)-BINAP/(S,S)-DPEN-Ru(II) Catalyst
Ar R
OH2
Ru-catalyst
base Ar R
OH
Ponndorf, W. Z.; Angew. Chem., 1926, 39, 138. Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc., 1995, 117, 2675-2676.
Ph Me
O
Ph (S) Me
OH
[RuCl2(p-cymene)]2(1S,2S)-N-(p-toluenesulfonyl)-1,2-
diphenylethylenediamine
iPrOH, KOH
Hashiguchi, S.; Fujii, A.; Takehara, K.; Ikariya, T.; Noyori, R.J. Am. Chem. Soc., 1995, 117, 7562-7563.
Schlesinger, H. I.; Brown, H. C.; Hoekstra, H. R.; Rapp, L. R. J. Am. Chem. Soc., 1953, 75, 199.Finholt, A. E.; Bond, A. C. Jr.; Schlesinger, H. I. J. Am. Chem. Soc., 1947, 69, 1199.
Barton, D. H. R. J. Chem. Soc., 1953, 1027-1040.
4
Outline• Mechanism and scope of asymmetric transfer hydrogenation
• Pro-atropisomeric phosphine ligands
• Amino acid-based ligands
• Dendrimer-bound diamine ligands
• Asymmetric transfer hydrogenation in water
• Asymmetric transfer hydrogenation in ionic liquids
5
Mechanism of ATH• Several gas-phase computational studies indicate concerted pathway
NTsRu
H2N
R R
H
R1
O
R2
NTsRu
N
R R
H
O HH
R1
OH
R2*
NTsRu
HN
R R
OH
NTsRu
N
R R
H
O
R2R1
HH
O
NTsRu
H2N
R R
ClKOH
RuCl
Cl Cl
ClRu
(S)(S)
R
H2N NHTs
R
HCl HCl
Samec, J. S. M.; Bäckvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev., 2006, 35, 237-248.
Ph Me
O
Ph (S) Me
OH
[RuCl2(p-cymene)]2(1S,2S)-N-(p-toluenesulfonyl)-1,2-
diphenylethylenediamine
iPrOH, KOH
substrate:catalyst ~200:1
6
Mechanism of ATH• Solution phase computational study suggests role of solvent in reduction
Ru H
OHN
H CO
H
H
1.79 Å
1.32 Å
1.31 Å
1.04 Å 2.51 Å
Ru H
OHN
HC
O
H
H
H3C
O H
1.92 Å1.27 Å
1.34 Å1.40 Å
1.24 Å
2.02 Å
1.04 Å
RuH
OHN
HC
O
H
H
H3C
O H
2.06 Å
1.14 Å
1.42 Å1.02 Å
1.75 Å
1.65 Å
1.11 Å
RuH
OHN
HC
O
H
H
H3C
OH
H
O
CH3
1.14 Å
1.42 Å1.04 Å
1.28 Å
1.27 Å1.95 Å
1.06 Å
0.00 ps0.69 ps
0.99 ps
1.08 ps
Handgraaf, J.-W.; Meijer, E. J. J. Am. Chem. Soc. ASAP.
7
Sources of Hydrogen• Isopropanol
– Oxidation yields acetone– Transfer hydrogenation is reversible– After extended reaction times,
stereoselectivity erodes
• Formic acid/triethylamine– Oxidation yields carbon dioxide– Evolution of carbon dioxide renders
reaction irreversible– Allows for increase in reaction
concentration
Samec, J. S. M.; Bäckvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev., 2006, 35, 237-248. Koike, T. ;Ikariya, T. Adv. Synth. Catal., 2004, 346, 37-41.
NTsRu
H2N
R R
H
R1
O
R2
NTsRu
N
R R
H
OH
H
R1
OH
R2*
NTsRu
HN
R R
OH
NTsRu
N
R R
H
O
R2R1
HH
O
NTsRu
H2N
R R
H
R1
O
R2
NTsRu
N
R R
O
OH
H
R1
OH
R2*
NTsRu
HN
R R
HO
O
H
NTsRu
N
R R
H
O
R2R1
HH
CO
OH
8
Origin of Stereoselectivity• Some influence from chiral diamine ligand• Significant contribution from arene ligand
– CH-π interaction stabilizes otherwise more-congested transition state
H
RuO
NH
H RO
HH
H HH
H
H
H
RuO
NH
H O
R
HH
H HH
H
H
Addition to Siface of carbonyl
Addition to Reface of carbonyl
H H
Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem. Int. Ed., 2001, 40, 2818-2821.
vs.
9
Scope of ATH• Mainly aryl-alkyl ketones (alkyl-alkynyl ketones)
– Alkyl group• Large functional group tolerance (-Cl, -OH, -CN, -N2, -NO2, -NHBOC)• Not sterically bulky
– Aryl group• High oxidation potential prefered• o-Subtituted difficult• Electron withdrawing groups erode stereoselectivity• Heteroaromatic groups tolerated
Noyori, R.; Hashiguchi, S. Acc. Chem. Res., 1997, 30, 97-102.Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett., 2000, 41, 9277-9280.
Me
O
iPrOH - 53% yield, 72% eeHCOOH/NEt3 - >99% yield, 97% ee
MeO
n = 1iPrOH - 45% yield, 91% eeHCOOH/NEt3 - >99% yield, 99% ee
n = 2iPrOH - 65% yield, 97% eeHCOOH/NEt3 - >99% yield, 99% ee
O
nR
O
R = Me >99% yield, 98% eeR = Et 96% yield, 97% eeR = iPr 41% yield, 83% eeR = tBu <1% yield
Me
O
100% yield, 86% ee
O2N
Me
O
R = Me 53% yield, 91% eeR = OMe 24% yield, 89% ee
RN
Me
O
2-acetylpyridine99% yield, 91% ee
3-acetylpyridine99% yield, 89% ee
4-acetylpyridine99% yield, 92% ee
10
Scope of ATH• Diketones and β-keto esters
– 1,2-diketone: alkyl ketone preferential at low temp– 1,3-diketone: symmetrical anti-diol in high ee; unsymmetrical low ee– β-Keto ester: ketone reduced over ester
• Imines– Protic solvents not tolerated– Cyclic imines more selective than acyclic (except phosphinylimines)– More reactive than ketones
Ph
OPh
OPh
OMe
O
10 °C
87% yield92% ee
Ph
OMe
OH
40 °C
78% yield95% ee
Ph
OHMe
OH
anti :syn - 98.6:1.4100% yield, >99% ee
MeO
MeON
Me
>99% yield95% ee
NBn
Me
72% yield77% ee
N
Me
99% ee
PPh
OPh
Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikaria, T. Org. Lett., 1999, 1, 1119-1121.Koike, T.; Murata, K.; Ikariya, T. Org. Lett., 2000, 2, 3833-3836.
Cossy, J.; Eustache, F.; Dalko, P. I. Tetrahedron Lett., 2001, 42, 5005-5007.
Everaere, K.; Morteux, A.; Carpentier, J.-F. Adv. Synth. Catal., 2003, 345, 67-77.Noyori, R.; Hashiguchi, S. Acc. Chem. Res., 1997, 30, 97-102.
Gladiali, S.; Alberico, E. Chem. Soc. Rev., 35, 226-236.
OO O
O
anti :syn = 95:585% yield
Ph
O O
Me
ant i:syn = 56:4279% yield
Ph
O O
OEt Me
O O
OtBu
99% yield94% ee
99% yield68% ee
11
Outline• Mechanism and scope of asymmetric transfer hydrogenation
• Pro-atropisomeric phosphine ligands
• Amino acid-based ligands
• Dendrimer-bound diamine ligands
• Asymmetric transfer hydrogenation in water
• Asymmetric transfer hydrogenation in ionic liquids
12
Pro-atropisomeric Phosphine Ligand• Noyori received 2001 Nobel Prize for H2 hydrogenation• Utilizes optically pure BINAP ligands
• BINAP can be resolved into pure (+) and (-) enantiomers due to high barrier of rotation about the aryl-aryl bond (atropisomeric)
Ph2P
PPh2
RuNH2
H2N Ph
Ph
Cl
Cl(S)-BINAP/(S,S)-DPEN-Ru(II) Catalyst
Ar R
OH2
Ru catalyst
base Ar Me
OH
(R)
PAr2
PAr2
(S)-BINAP
Noyori, R.; Asymmetric Catalysis: Science and Opportunities. Nobel Lecture, 8 December 2001.
13
Pro-atropisomeric Phosphine Ligand• BIPHEP and DPBP have significantly lower barriers of rotation (tropisomeric
or pro-atropisomeric)
– Optically pure isomers cannot be isolated in solution– Benzophenone (and derivatives) forms enantiomers in solid state
PAr2
PAr2
(S)-BINAP
PAr2PAr2
BIPHEP
OPAr2
PAr2
DPBP
PPh2
O PPh2
Ph2P
OPPh2
(P)-Conformation (M)-Conformation
Jing, Q.; Sandoval, C.; Wang, Z.; Ding, K. Eur. J. Org. Chem., 2006, 3606-3616.
14
(From M enantiomer)
Ru
Ph2P
NH2
Cl
HN
PPh2
Ph
Ph
O
Pro-atropisomeric Phosphine Ligand• Complexing DPBP to metal with diamine ligand forces single diastereomer
of metal complex
Jing, Q.; Sandoval, C.; Wang, Z.; Ding, K. Eur. J. Org. Chem., 2006, 3606-3616.
15
Pro-atropisomeric Phosphine Ligand• BINAP not conducive to ATH• Pro-atropisomeric DPBP successful for ATH – First pro-atropisomeric
phosphine used in ATH• Catalyst for alkyl-alkyl reductions?
Mikami, K.; Wakabayashi, K.; Yusa, Y.; Aikawa, K. Chem. Commun., 2006, 2365-2367.Noyori, R.; Hashiguchi, S. Acc. Chem. Res., 1997, 30, 97-102.
OO OO
Ligand = (R)-BINAP98 % conv. 72 % ee
Ligand = DPBP>99 % conv. 99 % ee
Ligand = (R)-BINAP61 % conv. 57 % ee
Ligand = DPBP99 % conv. 99 % ee
Ligand = (R)-BINAP97 % conv. 68 % ee
Ligand = DPBP95 % conv. 91 % ee
Ligand = (R)-BINAP96 % conv. 71 % ee
Ligand = DPBP97 % conv. 89 % ee
R Me
O
R Me
OHRh-catalyst, ligand, (S,S)-DPEN
KOtBu, iPrOH, rt, 24 h
Rh
Rh-Catalyst
PAr2PAr2
(R)-BINAP
OPAr2
PAr2
DPBP
(S)(S)
H2N Ph
PhH2N
+
SbF6-
(S,S)-DPEN
Noyori's Catalyst95% conv. 97% ee
Noyori's Catalyst53% conv. 91% ee
Noyori's Catalyst92% conv., 93% ee
NTsRu
H2N
Ph Ph
Cl
(R) (R)
Noyori's Catalyst
(R)
16
Outline• Mechanism and scope of asymmetric transfer hydrogenation
• Pro-atropisomeric phosphine ligands
• Amino acid-based ligands
• Dendrimer-bound diamine ligands
• Asymmetric transfer hydrogenation in water
• Asymmetric transfer hydrogenation in ionic liquids
17
Amino Acid-Based Ligands• Initially, amido-oxazoline ligands were targeted
• Poor yield, stereoselectivity in ATH• Noticed synthetic precursor provided better selectivity than target
N
O
O
N
HN
R1O
MeMe
OHN
R2
R1
R2
N
O
O
N
HN
R1O
MeMe
OHN
R2
R1
R2
R1
NHBoc
NH
O R2
OH
Pastor, I. M.; Västilä, P.; Adolfsson, H. Chem. Commun., 2002, 2046-2047.
18
Amino Acid-Based Ligands• Boc group & free hydroxyl group crucial• Amino acid stereocenter more important than amino alcohol stereocenter• 1-amino-2-alcohols catalyze ATH with similar yield and ee
Pastor, I. M.; Västilä, P.; Adolfsson, H. Chem. Eur. J., 2003, 9, 4031-4045.Bøgevig, A.; Pastor, I. M.; Adolfsson, H. Chem. Eur. J., 2004, 10, 294-302.
(S) Me
OH
(S)Me
BocHNNH
O
(S)Ph
Me
ORu-catalyst, ligand
NaOH, iPrOH
RuCl
Cl Cl
Cl
Ru-Catalyst
Ru
91% Conversion, 94% ee
OH
(S)Me
BocHN
NH
O
(R)
Ph
OH
95% Conversion, 93% ee
19
Amino Acid-Based Ligands• Ru(II)(η6-arene) complexes known to facilitate peptide formation
• Provides template to form ligand in situ, form catalyst in situ, and conduct ATH in one pot
Ru
H2NCl O
O
H2NOMe
O
R2
-HCl
Ru
HNH2N O
OR2
OOMe
-MeOH
Ru
NH2N O
OR2
OR1R1 R1
RuCl
Cl Cl
ClRu
H2NOH
O
R1
-HCl
(S)
NHBoc
MeO
O
NO2
H2N (S)Me
OH
1) iPrOH, Δ, 1h
2) iPrONa, Ru-catalyst,ketoneiPrOH, rt, 1h
(S) Me
OH
Ketone (R=) Conversion (%) ee (%)
R
H 85 97m-Me 83 97o-F 90 92
m-OMe 86 973,5-OMe 82 97
3,4,5-OMe 45 99
RuCl
Cl Cl
ClRu
Ru-Catalyst
Haas, K.; Beck, W. Eur. J. Inorg. Chem., 2001, 2485-2488.
Västilä, P.; Wettergren, J.; Adolfsson, H. Chem. Commun., 2005, 4039-4041.
20
Amino Acid-Based Ligands• Mechanism elusive for several years• Key clues:
– Necessity of NHBoc, NHC(O)R, OH groups– 3 equivalents of base necessary– Additives
• Strong Lewis acid additives (Sc(OTf)3, Ti(OiPr)4) have negative effect on reactivity• NaCl or KCl additive - similar to nonadditive reactions• LiCl - higher stereoselectivity (also LiBr, LiI, LiClO4, LiOAc)
– Replacing NaOiPr with LiOiPr as base (no additive) increased stereoselectivity to the same extent as LiCl additive
– No additive effect of LiCl with traditional transfer hydrogenation systems
Västilä, P.; Zaitsev, A. B.; Wettergren, J.; Privalov, T.; Adolfsson, H. Chem. Eur. J., 2006, 12, 3218-3225.
R1
NHBoc
NH
O R2
OH
21
Amino Acid-Based Ligands• Proposed mechanism:
• Lithium ion activates and directs incoming ketone• Smaller lithium ion forms tighter transition state• Crown ethers erode stereoselectivity• CH-π interactions not as important
Ru
NO NH
MeO
HO
OtBuMe
OLi
H
O
Ph Ph
OHLiO
Ru
NH N
OMe
OH
O
OtBuMeLi
H H
O Li O
RuH
N
NMe
R HO
OtBuMe
O
Me
Västilä, P.; Zaitsev, A. B.; Wettergren, J.; Privalov, T.; Adolfsson, H. Chem. Eur. J., 2006, 12, 3218-3225.
22
Amino Acid-Based Ligands• Previously, other product stereoisomer obtained through un-natural amino acid ligand
• Modification from amide to thioamide, removal of alcohol reverses stereoselectivity
NHBoc(S) OH
O 1) N-methylmorpholinei-BuOC(O)Cl, -15 °C, 1h
2)
rt, 3 h, THF
BocHN(S) N
O
( S)
H
Lawesson's Reagent
THF, 60 °C, 8h BocHN(S) N
S
( S)
H
97%
77%H2N (S) Me
PhMe
Ph
Me
Ph
Pastor, I. M.; Västilä, P.; Adolfsson, H. Chem. Eur. J., 2003, 9, 4031-4045.Zaitsev, A. B.; Adolfsson, H. Org. Lett., 2006, 8, 5129-5132.
Me
ORu-catalyst, ligand
NaOH, iPrOHMe
OH
* RuCl
Cl Cl
ClRu
Ru-Catalyst
NH2
(S)MeO
NH
(R)
Ph
OH NH2
(R)MeO
NH
(S)
Ph
OH
Ligand A Ligand BLigand A - 95% yield, 93% ee (S)Ligand B - 91% yield, 93% ee (R)
23
Amino Acid-Based Ligands
R2
O
R1
Rh-catalyst, ligand
LiCl, iPrONa, iPrOHR2
OH
R1*
RhCl
Cl Cl
ClRh NHBoc
(S) NH
S
(S)
Ph
NHBoc(S)
MeNH
O
( R)
OH
RuCl
Cl Cl
ClRu
Ph
Me
O O O
Me
O
Me Me
Me MeOCatalyst A: 95% yield, 93% ee, (S)Catalyst B: 88% yield, 95% ee, (R)
Catalyst A: 91% yield, 95% ee, (S)Catalyst B: 88% yield, 96% ee, (R)
Catalyst A: 53% yield, 86% ee, (S)Catalyst B: 61% yield, 97% ee, (R)
Catalyst A: 63% yield, 95% ee, (S)Catalyst B: 56% yield, 91% ee, (R)
Catalyst A Catalyst B
Pastor, I. M.; Västilä, P.; Adolfsson, H. Chem. Eur. J., 2003, 9, 4031-4045.Zaitsev, A. B.; Adolfsson, H. Org. Lett., 2006, 8, 5129-5132.
24
Outline• Mechanism and scope of asymmetric transfer hydrogenation
• Pro-atropisomeric phosphine ligands
• Amino acid-based ligands
• Dendrimer-bound diamine ligands
• Asymmetric transfer hydrogenation in water
• Asymmetric transfer hydrogenation in ionic liquids
25
Recoverable Diamine Ligands• Recoverable systems important with expensive or toxic heavy metal
complexes• Immobilization on supporting apparatus can allow for recovery• For ATH, two classes of dendrimers initially tested
Chen, Y.-C.; Wu, T.-F.; Deng, J.; Liu, H.; Jiang, Y.-Z.-, Choi, M. C. K.; Chan, A. S. C. Chem. Commun, 2001, 1488-1489.Chen, Y.-C.; Wu, T.-F.; Deng, J.; Liu, H.; Xin, C.; Zhu, J.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. J. Org. Chem., 2002, 67, 5301-5306
(S)(S)
H2N HN SHN C
OO
O
O
O
O
O
O
On = 3
Ph
O
Me
Ru-catalyst, ligand
HCOOH/NEt3, CH2Cl2 Ph (S)
OH
Me
Run # t (h) Conversion (%) ee (%)1 20 98 96.52 20 92 96.63 25 87 96.84 30 85 96.75 40 73 96.36 40 52 87
RuCl
Cl Cl
ClRu
Ru-Catalyst
O
R2R1
Ru-catalyst, ligand
HCOOH/NEt3, CH2Cl2(R)
OH
R2R1
R1 t (h) Conversion (%) ee (%)
o-Cl 24 > 99 95.5p-tBu 55 98 96.3
R2
HH
H CH2C(O)Ph 72 70 >99H (CH2)4C(O)Ph 72 67 >99
RuCl
Cl Cl
ClRu
Ru-Catalyst
O
OO
OCCCH2NHO
HNO
O O
O
CCH2NH
OCCH2NH
CCH2NHO
NH
NH
NH
S
S
S
HNO
O
HNO
O
HNO
O
(R)Ph
( R)
Ph
H2N
(R)Ph
(R)
Ph
H2N
(R)Ph
(R)
Ph
H2NO
O
O
O
Ph
Ph
Ph
Ph
26
Recoverable Diamine Ligands• Late-stage tunability of ligand/dendrimer compatible with varying nature of
ketone substrates
• Recovery procedure:– Remove CH2Cl2 in vacuo– Precipitate dendrimer with MeOH– Filter
Liu, W.; Cui, X.; Cun, L.; Zhu, J.; Deng, J. Tetrahedron: Asymmetry, 2005, 16, 2525-2530.
O
OO
Ph
Ph
NH2
NH2
O
OO
Ph
Ph
n
n
**
ArSO2Cl, (iPr)2NEt
CH2Cl2, 0 °C - rt
O
OO
Ph
Ph
NH
NH2
O
OO
Ph
Ph
n
n
**
SO2Ar
Ph
O
Me
Ru-catalyst, ligand
HCOOH/NEt3, CH2Cl2, rt Ph
OH
Me*
n ConfigurationAr time (h) Conversion (%) ee (%) Configuration
0 4-CH3C6H4 (R,R) 20 95 96.8 R1 4-CH3C6H4 (R,R) 20 >99 96.6 R2 4-CH3C6H4 (R,R) 20 97.1 96.1 R
(95.4, 90.2, 83.7, 71.2) (97.5, 97.2, 97.5, 97.0)3 4-CH3C6H4 (R,R) 20 75 94.6 R2 2,4,6-Et3-C6H2 (S,S) 20 93.0 91.7 S2 2,4,6-iPr3-C6H2 (S,S) 20 91.7 92.8 S2 1-naphthyl (S,S) 20 >99 96.3 S
RuCl
Cl Cl
ClRu
Ru-Catalyst
27
Recoverable Diamine Ligands• Minimize organic solvent – run ATH in water
– Switch to 1,2-diaminocyclohexane-based ligands and Cp* rhodium catalyst system
• Recovery procedure:– Add hexanes– Remove organic layer– Add HCOOH to pH ~7
(R)(R)
H2N SHN C
OO
O
O
O
HN
O
MeR
Catalyst, ligand
"H2"-source Solvent
Catalyst "H2"-source Solvent R Conversion (%) ee (%)
(R)
OH
MeR
Ru HCOOH/NEt3 CH2Cl2 H >99 94
Ru HCOONa H2O H >99 88
Rh HCOONa H2O H >99 96
Rh HCOONa H2O p-OMe 95 94Rh HCOONa H2O o-OMe >99 81
(>99, 98, 99, 85, 97) (96, 95, 94, 95, 95, 95)
O
99% Conversion97% ee
NMe
O
70% Yield91% ee
97% Yield72% ee
94% Yield52% ee
OEt
OO
Ph Me
ORu
Cl
Cl Cl
ClRu
Ru-Catalyst
RhCl
Cl Cl
ClRh
Rh-Catalyst
BnO
OBn
OBnBnO
Ligand
Jiang, L.; Wu, T.-F.; Chen, Y.-C.; Zhu, J.; Deng, J. Org. Biomol. Chem., 2006, 4, 3319-3324.
28
Outline• Mechanism and scope of asymmetric transfer hydrogenation
• Pro-atropisomeric phosphine ligands
• Amino acid-based ligands
• Dendrimer-bound diamine ligands
• Asymmetric transfer hydrogenation in water
• Asymmetric transfer hydrogenation in ionic liquids
29
ATH in Water• Increases atom economy and environmental friendliness
– Often no organic solvents during reaction
• Allows for ease of product separation, possibility of catalyst recyclability– Distillation or extraction
• Vigorously dried solvents and substrates not necessary
30
ATH in Water – Early Work• Bujoli group reported phosphonate-substituted diamine ligands with rhodium
metal-catalyzed ATH
• High conversions (~ 95%), moderate ee (34-60%), cosolvent needed, catalyst preparation under inert atmosphere
(R)(R)
NH
NH
Me
Me(HO)2P
(HO)2PO
O
(S)(S)
NH
NH
Me
Me(HO)2P
(HO)2PO
O
Maillet, C.; Praveen, T.; Janvier, P.; Minguet, S.; Evain, M.; Saluzzo, C.; Tommasion, M. L.; Bujoli, B. J. Org. Chem., 2002, 67, 8191-8196.
Me
ORh-catalyst, ligand
tBuOK, 1:1 H2O:iPrOH(S) Me
OH
95% yield46% ee
Rh ClCl Rh (R)(R)
NH
NH
Me
Me(HO)2P
(HO)2PO
ORh-Catalyst
Ligand
31
ATH in Water - Advances• Deng group developed o-sulfonated ligands with ruthenium catalyst and
HCOONa as hydrogen source
• Purification difficult
(R)(R)
NH2
NH2
1) 50% SO3 oleum0 °C - rt, 22 h
2) BaCO3
(R)(R)
NH2
NH2
SO3-
SO3-
Ba2+
TsCl, NaOH/SDSH2O/CH2Cl2, 0 °C - rt, 24 h
then Na2SO4(R)(R)
NHTs
NH2
SO3Na
SO3Na
C12H25OSO3NaSDS =
68% 72%
Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett., 2003,5, 2103-2106.
32
ATH in Water - Advances
• Recyclability possible – retention of stereoselectivity, loss of conversion (99% 75%)
• Surfactant required for satisfactory conversion
RuCl
Cl Cl
ClRu
O
R
R Yield (%) ee (%)p-Me 94 94p-F 88 92
O
n
n Yield (%) ee (%)1 66 832 21 98
O
R
R Yield (%) ee (%)87 9458 84
Br
HNO2
Ru-catalyst, ligand
H2O, HCO2Na, SDSR1 R2
O
R1 R2
OH
NHTs
NH2(R)(R)
SO3Na
SO3Na
Ru-Catalyst Ligand
C12H25OSO3Na
SDS
(R)
Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett., 2003,5, 2103-2106.
33
ATH in Water – Recent Work• Shift to o-amine ligand and Cp* rhodium catalyst allows for increased yields,
stereoselectivities, and scope over previous work• Surfactant no longer necessary
R1 R2
O Rh-catalyst, ligand
HCOONa, H2O R1 R2
OH
NHTs
NH2(S)
(S)
NH2
NH2
LigandRh-catalyst
OR2
R1
R1 R2 Yield (%) ee (%)
p-OMe H 92 96o-OMe H 90 88
p-F H 94 95p-Br H 92 94
H Br 91 97p-NO2 Br 82 90
O
88% yield97% ee
SMe
O
90% yield98% ee
RhCl
Cl Cl
ClRh
(S)
Li, L.; Wu, J.; Wang, F.; Liao, J.; Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Green Chem., 2007,9, 23-25.
34
2-Bromo-1-arylethanols• Key intermediates in syntheses of β-adrenergic receptor agonists• Agonists used as bronchodilators in asthmatics• Non-aqueous synthesis by ATH previously hampered
OBr
(R)
OHBrRu-catalyst, ligand
HCOOH/NEt3, 28 °C
RuCl
Cl Cl
Cl
Ru-Catalyst
Ru NHTs
NH2(R)
(R)
Ligand
OOCHO
0% 73%
Cross, D. J.; Kenny, J. A.; Houson, I.; Campbell, L.; Walsgrove, T.; Wills, M. Tetrahedron: Asymmetry, 2001, 12, 1801-1806.
35
2-Bromo-1-arylethanols• Changing to aqueous system allows for reduction
Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org. Lett., 2003,5, 2103-2106.Wang, F.; Liu, H.; Cun, L.; Zhu, J.; Deng, J.; Jiang, Y. J. Org. Chem., 2005, 70, 9424-9429.
Li, L.; Wu, J.; Wang, F.; Liao, J.; Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Green Chem., 2007,9, 23-25.
(R)
OHBrR1
R2
R3
R1 R2 R3 Yield (%) ee(%)Surfactant
H H H SDS 87 94H H SDS 47 92OBn
H H H 2:1 SDS:CTAB 97 98H OMe H 2:1 SDS:CTAB 80 90
NO2 OBn 2:1 SDS:CTABH 87 93
H H H − 91 97H OMe H − 70 96
OBn H OBn − 82 95
OBrR1
R2
R3
catalyst, ligand
Surfactant, HCOONa, H2O
CH2Cl2cosolvent
RhCl
Cl Cl
ClRh
NHTs
NH2(R)
(R)
R4
R4
Ligand
Rh-CatalystCatalyst Ligand
RuCl
Cl Cl
Cl
Ru-Catalyst
C12H25OSO3Na
SDS
Ru
C16H33N
MeMe
Me
Br-
CTABA - R4 = SO3NaB - R4 = HC - R4 = NH2
Ru ARu A
Rh BRh BRh B
Rh CRh CRh C
36
(R,R)-Formoterol
• Long-acting, β2-agonist• Bronchodilator in treatment of patients with asthma and chronic bronchitis• (R,R)-enantiomer more active than other 3 possible stereoisomers
Wilkinson, H. S.; Tanoury, G. J.; Wald, S. A.; Senanayake, C. H. Org. Process Res. Dev., 2002, 6, 146-148.Li, L.; Wu, J.; Wang, F.; Liao, J.; Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Green Chem., 2007,9, 23-25.
OBr
BnO
BH3-diethylaniline,(R,S)-aminoindanol
THF(R)
OHBr
BnONO2 NO2
OBr
BnO
Rh-catalyst, ligand
2:1 SDS:CTAB, HCOONa, H2O(R)
OHBr
BnO
87% yield, 93% ee
2.3 kg, 80% yield, 88% ee RhCl
Cl Cl
ClRh NHTs
NH2(R)
(R)
LigandRh-Catalyst
NO2 NO2
HO
OH
OMeMe
HN
NHCHO
(R,R)-formoterol
37
(R,R)-Formoterol
OHBr
BnO
MeOH, aq NaOH
98%BnO
O
OMe
BnHN
Me
1) neat, 90 °C
2) PtO2, H23) HCOOH
BnO
OH
OMeMe
BnN
NHCHO
NO2 NO2
1) Pd-C, H2, EtOH
2) L-tartaric acid, iPrOH85% HO
OH
OMeMe
HN
NHCHO
(R,R)-formoterol
45%, 3 steps
+
Hett, R.; Fang, Q. K.; Gao, Y.; Hong, Y.; Butler, H. T.; Nie, X.; Wald, S. Tetrahedron Lett., 1997, 38, 1125-1128.
38
ATH in Water - Imines• Noyori reported ATH of imines not conducive to protic solvents• Deng achieved reduction in water with o-sulfonated diamine ligands
– Acyclic imines unsuccessful
• Recovery procedure– Extract (3x) with 1:1 Et2O:hexanes– Add 1 eq. HCOOH– Ready for reuse
MeO
MeON
R
R Yield (%) ee (%)Me 97 95Et 68 92iPr 90 90
MeO
MeO SN
R Yield (%) ee (%)Me 97 65tBu 95 94
O O
R
97 949495
96 9485 94
RecycleExperiments
MeO
MeON+
RBn
R Yield (%) ee (%)Me 85 90Ph 94 95
N
R
Ru-catalyst, ligand, CTAB
HCOONa, H2O, 28 °C
NH
R
C16H33N
MeMe
Me
Br-
CTAB
NHTs
NH2(R)
(R)
SO3Na
SO3Na
Ru-Catalyst Ligand
RuCl
Cl Cl
ClRu
(S)
Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun., 2006,1766-1768.
39
Outline• Mechanism and scope of asymmetric transfer hydrogenation
• Pro-atropisomeric phosphine ligands
• Amino acid-based ligands
• Dendrimer-bound diamine ligands
• Asymmetric transfer hydrogenation in water
• Asymmetric transfer hydrogenation in ionic liquids
40
ATH in Ionic Liquids• Ionic liquid: salt of organic cation with melting point near
ambient temperature
• Can stabilize/immobilize transition metal catalysts• Negligible vapor pressure• Tunable miscibility• Easy recyclability
NN Me
BF4-
Me
[bmim][BF4] =butylmethylimidazolium tetraf luoroborate
41
ATH in Ionic Liquids• Synthesis of ionic liquid-supported precursor
H2NCl NHTs
PhPh
RuN NMe
Me
ClNNMe
Me
toluene, 110 °C
1)
2) NaBF4, CH2Cl2
N N
BF4-
MeMe
RuCl3
MeOH, 80 °C
BF4-
BF4-
RuCl Cl
ClRu
Cl
NNMe
Me Ph
NHTsH2N
Ph
DMF, rt
N NMe
Me
BF4-
Geldbach, T. J.; Dyson, P. J. J. Am. Chem. Soc., 2004, 126, 8114-8115.
42
ATH in Ionic Liquids
• Recovery procedure:– Extract – Et2O or hexanes– Wash – water– Dry in vacuo
H2NCl NHTs
PhPh
Ru
(R)
(R)
Me
Ocatalyst, [bmmim][PF6]
HCOOH/NEt3, 40 °C, 24 h(R) Me
OH
Cycle # Catalyst A(% yield,
% ee)
Catalyst B(% yield,
% ee)
1 >99%, 99% >99%, 99%2 >99%, 99% >99%, 99%3 >99%, 99% 80%, 99%4 99%, 99% 45%, 99%5 96%, 99%
H2NCl NHTs
PhPh
Ru
(R)
(R)BF4
-
N NMe
Me
Catalyst A Catalyst B
Cycle # R = Conversion (%) ee (%)
1 o-Me 72% 97%2 p-Cl 99% 95%3 H 99% 99%4 H 98% 99%
1 Acetophenone 99% 97%2 Tetralone 99% 97%3 Benzaldehyde 90% N/A
NNMe
Me
nBu
PF6-
[bmmim][PF6]
Geldbach, T. J.; Dyson, P. J. J. Am. Chem. Soc., 2004, 126, 8114-8115.
43
ATH in Ionic Liquids• Library of ionic liquids screened
– Hydrophilic ILs inhibit reaction– Hydrophobic ILs slow reaction, but good ee
Joerger, J.-M.; Paris, J.-M.; Vaultier, M. Arkivoc, 2006, 152-160.
Me
O
IonicLiquid
Cycle # Time (h) Conversion (%) ee (%)
[bmim][PF6] 1 31 97 962 50 92 953 95 46 89
[bmim][BF4] 40 <1 -[bmim][MeSO4] 48 19 85
[emim][OTf] 24 0 -
HydrophilicIonic Liquids
[bmim][NTf2] 1 27 98 962 21 58 96
[tmba][NTf2] 1 26 98 972 41 99 973 94 99 974 50 56 96
HydrophobicIonic Liquids
(S) Me
OHcatalyst, ionic liquid
HCOOH/NEt3
NNMe nBu
BF4-
[bmim][BF4]
NNMe Et
[emim][OTf ]
-O CF3SO
O
N+
Me
Me
Me
nBu
N-
CF3S
O
O
F3CS
O
O
[tmba][NTf2]
H2NCl NHTs
PhPh
Ru
(S)
(S)
Catalyst
44
Conclusions• Role of solvent in transition state may be significant• Pro-atropisomeric phosphine ligands can impart
stereocontrol• Ligands based on naturally-occurring amino acids
suitable for ATH• Catalyst can be recovered and reused• ATH can be run in water or ionic liquid
• Future directions:– Increase substrate:catalyst ratio– Expand scope– Improve recoverability further
45
AcknowledgmentsAcknowledgments
• Professor Crimmins• Crimmins Group Members• UNC Chemistry