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The Career of Michael J. Krische
Hui-Wen Shih
MacMillan Group Meeting
June 19, 2010
Career: A Summary
B.S. Chemistry, University of California Berkeley
Fulbright Fellow, Helsinki University
PhD. Chemistry, Stanford University
Postdoctoral Fellow, Universite Louis Pasteur
1989
1990
1996
1999
Henry Rapoport
Ari M. P. Koskinen
Barry M. Trost
Jean-Marie Lehn
University of Texas, Austin
1999Assistant Professor of Chemistry
Professor of Chemistry 2004
Robert A. Welch Chair in Science 2007
Selected Awards: NSF CAREER, Camille Dreyfus Teacher-Scholar, ACS E.J. Corey,
Presidental Green Chemistry Challenge, Tetrahedron Young Investigator...
96 primary literature publications as primary investigator
Research Areas
Catalytic Conjugate Addition-Electrophilic Trapping Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Nucleophilic Catalysis via Phosphine Conjugate Addn Hydrogen Mediated C-C Bond Formation
Excludes: Supramolecular Chemistry
R
O
Electrophile
n
ER
O
nR'
MR' R
O
O
R'
H H
R
O
R'
O
seminal publication: JACS 2003, 125, 1110. seminal publication: JACS 2001, 123, 6716.
full article: JACS 2004, 126, 9448.
R
O
X
R'O
Bu3PR
O
X
R'O
n n
seminal publication: JACS 2002, 124, 2402.
Transfer Hydrogenation ACIE 2009, 48, 34. (review)
JACS 2000, 122, 5006.; JACS 2002, 124, 5074. (selected publications)
R
O
R'
ORh/Ir
H2
O
R
HO R'
reviews: Acc. Chem. Res. 2004, 37, 653.
Acc. Chem. Res. 2007, 40, 1394.
Research Areas
Catalytic Conjugate Addition-Electrophilic Trapping Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Nucleophilic Catalysis via Phosphine Conjugate Addn Hydrogen Mediated C-C Bond Formation
Excludes: Supramolecular Chemistry
R
O
Electrophile
n
ER
O
nR'
MR' R
O
O
R'
H H
R
O
R'
O
seminal publication: JACS 2003, 125, 1110. seminal publication: JACS 2001, 123, 6716.
full article: JACS 2004, 126, 9448.
R
O
X
R'O
Bu3PR
O
X
R'O
n n
seminal publication: JACS 2002, 124, 2402.
Transfer Hydrogenation ACIE 2009, 48, 34. (review)
JACS 2000, 122, 5006.; JACS 2002, 124, 5074. (selected publications)
R
O
R'
ORh/Ir
H2
O
R
HO R'
reviews: Acc. Chem. Res. 2004, 37, 653.
Acc. Chem. Res. 2007, 40, 1394.
Catalytic Conjugate Addition-Electrophilic Trapping
Seminal Publication
Rh-catalyzed tandem conjugate addition-aldol cyclization
Ph
O O
Me
2.5 mol% [Rh(COD)Cl]27.5 mol% dppb ligand
2 equiv PhB(OH)2, KOH
H2O, dioxane, 95 C
Ph
O Me OH
87% IY, single diastereomer
Ph
Me
O Me OH
Ph
Ph
O Me OH
Nap
Ph
O
N
Me OH
Ph2- Ts
Ph
O
Ph
MeOH
73% Y 84% Y70% Y45% Y
BINAP ligand induces enantioselectivity
Ph
O O
Me
2.5 mol% [Rh(COD)Cl]27.5 mol% (R)-BINAP
2 equiv PhB(OH)2, KOH
H2O, dioxane, 95 C
Ph
O Me OH
Ph
88% IY, 88% ee
Scope: Aliphatic , -unsaturated ketones; 5 & 6 membered rings
J. Am. Chem. Soc. 2003, 125, 1110.
Catalytic Conjugate Addition-Electrophilic Trapping
Mechanism
Catalytic cycle
Ph
O O
Me
J. Am. Chem. Soc. 2003, 125, 1110.
LnRhICl LnRhIOH
LnRhIAr
Ph
OH O
Me
Ar
Ph
O
Ar
ORhILnMe
RhILn
ArB(OH)2
B(OH)3
Ph
O Me OH
Ar
Zimmerman-Traxler transition state via Z-enolate
O
RhIO
MePh
ArH
Ph
OH O
Me
Ar
RhILn
OOH
Me
ArH
Ph Me OH
Ph
O
Catalytic Conjugate Addition-Electrophilic Trapping
Improvements and Extensions
Rh-catalyzed tandem conjugate addition-aldol cyclization
Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5421
R
O 2.5 mol% [Rh(COD)OMe]27.5 mol% (S)-BINAP
2 equiv ArB(OH)2, KOH
H2O, dioxane, 95 C
65-87% Y, >99:1 de, 85-94% ee
O R''
R'
OMe
R'
R''
Ar
Me
OH
O
OR
nn
Improvements and extension of scope
Electron rich and electron poor aryl boronic acids
Acyclic, cyclic 5- and 6-membered diones
Applied to dione desymmetrization via kinetic resolution
Me
O
Me
O
O
Me
Me
2.5 mol% [Rh(COD)OMe]27.5 mol% (S)-BINAP
2 equiv ArB(OH)2, KOH
H2O, dioxane, 95 C
Ph
Me
OH
OMe
O
Me
MePh
Me
OH
OMe
O
MeMe
43% Y, >99:1 de>99% ee
41% Y, >99:1 de87% ee
[Rh(COD)OMe]2 is more stable to oxidation
Catalytic Conjugate Addition-Electrophilic Trapping
Improvements and Extensions
Cu-catalyzed tandem conjugate addition-aldol cyclization
J. Am. Chem. Soc. 2004, 126, 4528.
R
O
E+
2.5 mol% Cu(OTf)2
5 mol% P(OEt)3
1.5 equiv Zn(Et)2, CH2Cl2
73-99% Y, 2:1 to >95:1 dr
n
Electrophiles
Enantioselective using Feringa phosphoramidite ligand
R
O
E
nEt
R
O
nEt
R
O
nEt
R
O
nEt
OH
Me
O NH2
E+ = ketone E+ = ester E+ = nitrile
n=1,2
2.5 mol% Cu(OTf)2
5 mol% Feringa Ligand
1.5 equiv Zn(Et)2
Me
Ph O
O
O PhMe, 40 COMe
OHEt
Ph O
OMe
OHEt
Ph O
99% Y, 2.3:1 dr 80% ee 98% ee
O
OP N
Me
Ph
Ph
Me
Feringa ligand
Research Areas
Catalytic Conjugate Addition-Electrophilic Trapping Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Nucleophilic Catalysis via Phosphine Conjugate Addn Hydrogen Mediated C-C Bond Formation
Excludes: Supramolecular Chemistry
R
O
Electrophile
n
ER
O
nR'
MR' R
O
O
R'
H H
R
O
R'
O
seminal publication: JACS 2003, 125, 1110. seminal publication: JACS 2001, 123, 6716.
full article: JACS 2004, 126, 9448.
R
O
X
R'O
Bu3PR
O
X
R'O
n n
seminal publication: JACS 2002, 124, 2402.
Transfer Hydrogenation ACIE 2009, 48, 34. (review)
JACS 2000, 122, 5006.; JACS 2002, 124, 5074. (selected publications)
R
O
R'
ORh/Ir
H2
O
R
HO R'
reviews: Acc. Chem. Res. 2004, 37, 653.
Acc. Chem. Res. 2007, 40, 1394.
Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Seminal Publication
Colbalt-mediated diastereoselective [2+2] cycloaddition
Ph
O10 mol% Co(dpm)2
PhMeSiH2, DCE, 50 C
72% IY, single diastereomer
Scope
J. Am. Chem. Soc. 2001, 123, 6716p.
O
Ph H H
O
Ph
O
Ph
O
H H
O
Ph
O
Ph
NTs
H H
O
Ph
O
Ph
H H
O
Ph
O
Ph
OTBS
H H
O
Ph
O
Me
H H
O O
OO
69% Y 73% Y 65% Y 63% Y 65% Y
Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Mechanism
CoI is the active catalyst
J. Am. Chem. Soc. 2002, 124, 9448.
O
O
Co
O
O
t-Bu
t-Bu t-Bu
t-Bu
CoII(dpm)2
disproportionate
CoIII(dpm)3CoI(dpm)
CoII(dpm)2
Ph
O
O
Ph
Ph
O
O
PhCoIIILnCoIII
Ln
H H
O
Ph
O
Ph
H H
O
Ph
O
Ph
Ph
O
O
PhCoI
SET
Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Some Observations
Kinetic product is formed
H H
O
Ph
O
Ph HA
H H
O
Ph
O
Ph
E/Z isomers form same product
H H
O
Ph
O
Ph
Co-cordination is involved
Ph
O
O
Ph
Ph
O Ph
O
CoIII-enolates: rapid -facial interconversion
SET cyclopropane probe does not open
Ph
O
O
H H
O
Ph
O
42% Y
Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Some Observations in Support of Radical Anion
Cathodic reduction
H H
O
Ph
O
Ph0.9 V
Ph
O
O
Ph
MeCN, LiClO4H H
O
Ph
O
Ph
Org. Lett. 2002, 4, 611.
E1/2 = 1.2 V electron chain transfer 1:1.2
Benzoyl is crucial for radical anion stabilization
O
O
MeO
OMe
1.0 V
MeCN, LiClO4
E1/2 = 1.3 V
dimer and oligomer products
O
MeO
NO2
E1/2 = 1.0 V
0.8 V
MeCN, LiClO4
dimer and oligomer products only
H H
O
Ar
O
Ar
radical anion unstable
radical anion too stable = unreactive
O
Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Further Observations in Support of Radical Anion
Chemical SET reduction
H H
O
Ph
O
Ph
Ph
O
O
Ph
H H
O
Ph
O
Ph
J. Am. Chem. Soc. 2004, 126, 1634.
THF, 78 C
32% Y 9% Y
Increasing radical delocalization improves desired reaction
H H
O
Ph
O
Ph
Nap
O
O
Nap
H H
O
Ph
O
Ph
THF, 78 C
62% Y 0% Y
Electrostatic interactions between Na and C=O result in cis-product
Not catalytic radical chain process
Na+
Na+
Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Using Products to Probe Mechanism
Towards a mechanistic understanding of the Gilman Reagent
J. Org. Chem. 2004, 69, 7979.
(CH3)2CuLi-LiI
Cu complex followed bySET enone reduction
OLi X
Cu Me
Me
Li
reductive elimination
O
R R
O O
(CH3)2CuLi-LiI
THF, 0 CMe
O
R
R
O
H H
O
R
O
R
radical anion
productconjugate addition
electrophile trappingproduct
Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Using Products to Probe Mechanism
It is possible to form both products
J. Org. Chem. 2004, 69, 7979.
R R
O O(CH3)2CuLi-LiI
THF, 0 C Me
O
R
R
O
H H
O
R
O
R
radical anion
product
conjugate addition
electrophile trappingproduct
mol% (CH3)2CuLi
100 64 13
200 85 0
25 13 84
25, slow addition 0 91
R=4-biphenyl
Kinetic studies show dependence on concentration
Me
O
R
R
O
H H
O
R
O
R
alkylating reagent
cyclic dimer monomer
ET reagent
(CH3)2CuLiMe Cu Me
Li Li
Me Cu Me
Research Areas
Catalytic Conjugate Addition-Electrophilic Trapping Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Nucleophilic Catalysis via Phosphine Conjugate Addn Hydrogen Mediated C-C Bond Formation
Excludes: Supramolecular Chemistry
R
O
Electrophile
n
ER
O
nR'
MR' R
O
O
R'
H H
R
O
R'
O
seminal publication: JACS 2003, 125, 1110. seminal publication: JACS 2001, 123, 6716.
full article: JACS 2004, 126, 9448.
R
O
X
R'O
Bu3PR
O
X
R'O
n n
seminal publication: JACS 2002, 124, 2402.
Transfer Hydrogenation ACIE 2009, 48, 34. (review)
JACS 2000, 122, 5006.; JACS 2002, 124, 5074. (selected publications)
R
O
R'
ORh/Ir
H2
O
R
HO R'
reviews: Acc. Chem. Res. 2004, 37, 653.
Acc. Chem. Res. 2007, 40, 1394.
Nucleophilic Catalysis via Phosphine Conjugate Addition
Seminal Publication
Intramolecular Rauhut-Currier Reaction
Ph
O 10 mol% Bu3P
EtOAc, 50 C
86% Y
Mechanism
J. Am. Chem. Soc. 2003, 125, 2402.
PhO
O
Ph
Ph
O
PBu3
Ph
OPhO
Ph
OPhO
Bu3P
O
Ph
Ph
O
Bu3P
O
Ph
Ph
O
Reaction is dependent on
Substrate electronics
Substrate sterics
Solvent polarity
more electrophilic enone preferred
less hindered enone preferred
more polar solvent improves reactivity
may lead to polymer products
Nucleophilic Catalysis via Phosphine Conjugate Addition
Seminal Publication
Steric effects
Ph
O 10 mol% Bu3P
EtOAc, 50 C
J. Am. Chem. Soc. 2003, 125, 2402.
MeO
O
Ph
Me
O
n
O
Me
Ph
O
O
Ph
Me
O
O
Me
Ph
O
1:1
rapidcyclization
7:1
slower cyclization allows for
preequilibrium
Me
OPhO
Me
Me
10 mol% Bu3P
EtOAc, 76 C
O
Me
Ph
O
O
Ph
Me
O
>95:5
rapidcyclization
Me
Me
MeMe
Electronic effects
Nucleophilic Catalysis via Phosphine Conjugate Addition
Summary
EWG
RR3P
EWGR
NO O
X X
R
O R'
O O
X
R
OSO2Ar
O
Ar
O
R O
O
EtO
R
R'
R
OH
H
O R'
O
R
R
O
EWG
R
PR3
catalyst
JOC 2006, 71, 7892.
JACS 2003, 125, 3682.
JACS 2004, 1256 5350.
JACS 2003, 125, 7758.JACS 2004, 126, 4118.
OL 2004, 6, 1337.
Synthesis 2004, 2579.
ACIE, 2004, 43, 6689.
JACS 2003, 125, 7758.
Nucleophilic Catalysis via Phosphine Conjugate Addition
Extensions
20 mol% Bu3P
CH2Cl2/tBuOH (9:1)
J. Am. Chem. Soc. 2004, 126, 5350.
-Arylation using hypervalent bismuth reagents
1 equiv BiPh3Cl2
93% Y
O
1 equiv iPrEtN
O
Ph
OBiAr3Cl
PBu3Cl
Substrates must be -substituted
Acyclic enones perform poorly
Nucleophilic Catalysis via Phosphine Conjugate Addition
Extensions
J. Am. Chem. Soc. 2004, 126, 5350.
-Arylation using hypervalent bismuth reagents
Enones and Enals
93% Y
OBr
OF
O
OMe
66% Y 71% Y
O
Ph
70% Y
O
Me
HPh
O
Me
H
MeO
Me
H
F
61% Y 49% Y 70% Y
O
Me
71% Y
F
20 mol% Bu3P
CH2Cl2/tBuOH (9:1)
1 equiv BiPh3Cl2
93% Y
O
1 equiv iPrEtN
O
Ph
Nucleophilic Catalysis via Phosphine Conjugate Addition
Extensions
Org. Lett. 2004, 6, 1337.
Reductive condensation of -acyloxy butynoates
Allylic amination
120 mol% Ph3P
EtOAc, 110 C
60-91% Y
O OEt
R O
O
R'sealed tube
OEtO
O OR'
Ph3PR
EtO
O
R'
O
Ph3PO
R
O
O
EtO
R'
R
EtO
O
R'
O
R
EtO
O
O
R'
Ph3P
R
Ph3P=O
Ph3P
Ph3P
R
O OAc
R'
20 mol% PPh3
R
O
R'
Ph3P
4,5-dichlorophthalimide
R
N
Cl Cl
R
O OO
THF
J. Am. Chem. Soc. 2004, 126, 4118.
Nucleophilic Catalysis via Phosphine Conjugate Addition
Extensions
Ph
O 100 mol% Bu3P
tBuOH, 60 C
J. Am. Chem. Soc. 2003, 125, 7758.
The merger of phosphine and Pd-allyl catalysis
1 mol% Pd(PPh3)4
OPh
O
92% Y
O
OMe
Ph
O O
O
OMe
Bu3P
PBu3
LnPd0
CO2
MeO
Ph
O
Bu3P
LnPdII
Ph
O
Bu3P
LnPd
OMestrong base facilitates -elimination
polar solvent extends enolate lifetime
Nucleophilic Catalysis via Phosphine Conjugate Addition
Extensions
Ph
O 100 mol% Bu3P
tBuOH, 60 C
J. Am. Chem. Soc. 2003, 125, 7758.
The merger of phosphine and Pd-allyl catalysis
1 mol% Pd(PPh3)4
OPh
O
92% Y
O
OMe
Ph
O
64% Y
O
76% Y
O
81% Y
EtX
O
X= O
BzO
< 5% Y
S 73% Y
Scope
Nucleophilic Catalysis via Phosphine Conjugate Addition
Applications to Total Synthesis
Enyne [3+2] forms useful [3.3.0] bicycles
10 mol% Bu3P
EtOAc, 110 C
71-86% Ysealed tube
R
OO R'
R
OH
H
O R'
O R'
Bu3P
R
O
O R'
Bu3P
R
O
R
OH
H
O R'
Bu3P
H
Bu3P
Scope
MeO
OH
H
O Ph
MeO
OH
H
O Me
MeO
OH
H
O
MeO
O
O
H
H
O
J. Am. Chem. Soc. 2003, 125, 3683.
76% Y 77% Y 86% Y 75% Y
Nucleophilic Catalysis via Phosphine Conjugate Addition
Applications to Total Synthesis
Angew. Chem. Int. Ed. 2003, 42, 5855.
Formal synthesis of racemic hirsutene
H
H
H
Me
hirsutene
HO
Me Me
5 steps
21% overall yield
Me Me
MeO
OMe O
Me
E/Z 5.5:1
Me Me
MeO
OMe O
Me
10 mol% Bu3PEtOAc, 110 C
sealed tube
Me
Me
PBu3
CO2MeCOMe
Me
R
OH
H
O MeMe
88% Y
R
OH
H
O MeMe H
H
Me
H
O
HO
H
H
MeMe
HO
1. H2, Pd/C
2. LiAlH4
86% Y
1. Swern
2. KOH, Bu4NOH
74% Y
2 steps to hirsutene
Research Areas
Catalytic Conjugate Addition-Electrophilic Trapping Metal-Catalyzed/Anion Radical [2+2] Cycloaddition
Nucleophilic Catalysis via Phosphine Conjugate Addn Hydrogen Mediated C-C Bond Formation
Excludes: Supramolecular Chemistry
R
O
Electrophile
n
ER
O
nR'
MR' R
O
O
R'
H H
R
O
R'
O
seminal publication: JACS 2003, 125, 1110. seminal publication: JACS 2001, 123, 6716.
full article: JACS 2004, 126, 9448.
R
O
X
R'O
Bu3PR
O
X
R'O
n n
seminal publication: JACS 2002, 124, 2402.
Transfer Hydrogenation ACIE 2009, 48, 34. (review)
JACS 2000, 122, 5006.; JACS 2002, 124, 5074. (selected publications)
R
O
R'
ORh/Ir
H2
O
R
HO R'
reviews: Acc. Chem. Res. 2004, 37, 653.
Acc. Chem. Res. 2007, 40, 1394.
"...More than half of the chiral compounds produced industrially from
- OL 2006, 8, 519
the focus of research in our laboratory..."
Inspired by this prospect, hydrogen-mediated C-C bond formation has become
This suggests an equally powerful approach to reductive C-C bond formation...
prochiral substrates are made via asymmetric hydrogenation.
Hydrogenation
Background
J. Am. Chem. Soc. 2002, 124, 15156.
Rhodium(I) Iridium(I)
heterolytic hydrogen activation
5s04d8 6s04f145d8
LnM X
H2
LnM X
H
H
baseLnM H
Motivation
H2 is completely atom economical
No waste is generated
On rhodium and iridium
weak -donor stronger -donor due to relativisitic effects
Hydrogenation
Seminal Publication
Reductive aldol
Ph
O10 mol% Rh(COD)2OTf
24 mol% (p-CF3Ph)P ligand
1 atm H2, 30 mol% KOAc
DCE, 25 C
Ph
O
71% Y, syn:anti 24:1
J. Am. Chem. Soc. 2002, 124, 15156.
O H OH
Ph
O5 mol% Rh(COD)2OTf
12 mol% (p-CF3Ph)P ligand
1 atm H2, 50 mol% KOAc
DCE, 25 C
Ph
O
Me
92% Y, syn:anti 1.8:1
H
O
NO2
OH
NO2
Scope
Ph
O
OHPh
O
Me
OH
OMe
Ph
O
Me
OH
Me
75% Y, syn:anti 1.7:1 44% Y, syn:anti 2:189% Y, syn:anti 10:1
Me
O
Me
OH
NO2
70% Y, syn:anti 2:1
Hydrogenation
Mechanism
Proposed mechanism
J. Am. Chem. Soc. 2002, 124, 15156.
Ph
O
O
LnRhI
LnRhI(H)2
Ph
OH
O
H
Ph
O
H
RhILn
H2
H
H
O
RhIII
Ln H
H
Ph
O
OH
adding base slows
down conjugate reduction
Phosphine ligand affects reactivity
Ln yield
PPh3 59%
P(p-CF3Ph)3 89%
Increasing Lewis acidity of Rhimproves aldehyde coordination
Triaryl phosphines do not add to substrate
Baylis-Hillman cyclization-conjugatereduction is not observed
Hydrogenation
Improvements
syn-Selectivity improved for intermolecular reaction
J. Am. Chem. Soc. 2002, 124, 15156.
Me
O5 mol% Rh(COD)2OTf
12 mol% ligand
1 atm H2, Li2CO3
CH2Cl2, 25 C
Me
O
Me
92% Y, syn:anti 1.8:1
H
O
NO2
OH
NO2
ligand yield dr
(p-CF3Ph)3P 70 2:1 *from prev work
Ph3P 31 3:1
(2-Fur)Ph2P 24 6:1
(2-Fur)2PhP 52 15:1
(2-Fur)3P 74 19:1
increasing
-acidity
OO
Stereochemical rational for anti-Felkin model
MeRhLn
Me
R
H
Z-enolate is kinetic Zimmerman-Traxler TS
enolization and aldolization are irreversible
ORhLn
MeMe
Org. Lett., 2006, 8, 519.
Hydrogenation
Enantioselective Reductive Aldol
Development of a chiral ligand
J. Am. Chem. Soc. 2008, 130, 2746.
Me
O5 mol% Rh(COD)2OTf
12 mol% ligand
1 atm H2, Li2CO3
CH2Cl2, 25 C
O
MeH
OOH
MeN
O
O
N
O
O
Commercially available chiral ligands are too -acidic: only trace amount of product observed
Catalyst development based on TADDOL scaffold
O
P
OO
O
R
R
R R
R R
Ar
monodentate ligand
independent modification sites
Hydrogenation
Enantioselective Reductive Aldol
TADDOL-like phosphonite ligand evolution
J. Am. Chem. Soc. 2008, 130, 2746.
O
P
OO
O
Me
Me
Me Me
Me Me
Ar
O
P
OO
O
R
R
Me Me
Me Me
Ar
O
P
OO
O
Me
Me
R R
R R
Arketal aryl carbinol
O
O
S
O
O
Me
Me
O
O
Et
Et
O
O
i-Pr
i-Pr
O
Me Me
O
Et Et
O
Ph Ph
64% Y, 66% ee
75% Y, 75% ee
76% Y, 69% ee
90% Y, 59% ee
64% Y, 66% ee
65% Y, 86% ee
64% Y, 66% ee
32% Y, 66% ee
15% Y, 30% ee
Hydrogenation
Enantioselective Reductive Aldol
TADDOL-like phosphonite ligand: optimized structure
J. Am. Chem. Soc. 2008, 130, 2746.
O
P
OO
O
Et
Et
Me Me
Me Me
S
90% Y, 92% ee
optimized
ligand
Enantioinduction results from C2-symmetric catalyst: Rh(COD)Ln2OTf: crystal structure
top front side
Hydrogenation
Reductive Rh-Alkyne Coupling
Reductive 1,3-diyne coupling to carbonyls
5 mol% Rh(COD)2OTf
10 mol% Ph3P
1 atm H2, DCE, 25 C
79% Y
J. Am. Chem. Soc. 2003, 125, 11488.
Ph
Ph
Ph
O
O
H
Ph Ph
OH
O
Ph
Enantioselective with chiral ligand
5 mol% Rh(COD)2OTf
10 mol% (R)-Cl-OMe-BIPHEP
1 atm H2, DCE, 25 C
74% Y, 91% ee
Ph
Ph
Ph
O
O
H
Ph Ph
OH
O
Ph
MeO
Cl
MeO
Cl
PPh2
PPh2
(R)-Cl-OMe-BIPHEP
Hydrogenation
Reductive Rh-Alkyne Coupling
Selectivity
J. Am. Chem. Soc. 2003, 125, 11488.
5 mol% Rh(COD)2OTf
10 mol% (R)-Cl-OMe-BIPHEP
1 atm H2, DCE, 25 C
R
R'
Ph
O
O
H
R R'
OH
O
Ph
Org. Lett. 2006, 8, 3873.
Me Ph
OH
O
Ph
Ph Me
OH
O
Ph
t-Bu Ph
OH
O
Ph
n-Pr Ph
OH
O
Ph
Ph n-Pr
OH
O
Ph
Ph t-Bu
OH
O
Ph
80% Y, 5.2:1 64% Y, 4:1 57% Y, >99:1
Hydrogenation
Reductive Rh-Alkyne Coupling
Reductive acetylene coupling: the effect of counterions
5 mol% Rh(COD)2SbF6
5 mol% BIPHEP
1 atm H2, DCE, 25 C
J. Am. Chem. Soc. 2006, 128, 16041.
O(CH2)2Ph
O
O
H
OH
O
O(CH2)2PhHC CHPh3COOH, Na2SO4
counterion yield
0
OTf 32
41
51
noncoordinating
ligands
Cl
BF4
SbF6
Enantioselective using chiral ligand5 mol% Rh(COD)2SbF6
5 mol% (R)-OMe-BIPHEP
1 atm H2, DCE, 25 CO
H
OH
OTBDPSHC CHPh3COOH, Na2SO4
OTBDPS
77% Y, 89% ee
RhIIILnRhIIILn
O
OR
Hydrogenation
Reductive Rh-Alkyne Coupling
Enyne coupling
J. Am. Chem. Soc. 2003, 125, 11488.
2 mol% Rh(COD)2OTf
2 mol% (R)-Xylyl-WALPHOS
1 atm H2, DCE, 60 oC
R
OR"
O
O
R'
R O
OR'
Org. Lett. 2006, 8, 3873.
R' OH1 mol% PH3CCO2H
FeH
PAr2
Me
PAr2Ar = 3,5-xylyl
WALPHOS
Ph O
OMe
Me OH
O
OMe
Me OH
BocHNO
Me OH
O
O
OMe
Me OH
Scope
n-C4H9
O
OMe
Et OH
AcOO
OMe
OH
AcOO
OMe
Ph OH
AcO
92% Y, 92% ee 88% Y, 90% ee 80% Y, 91% ee 96% Y, 91% ee
97% Y, 86% ee 85% Y, 88% ee 73% Y, 91% ee
Hydrogenation
Reductive Rh-Alkyne Coupling
How are over-addition and over-reduction avoided?
J. Am. Chem. Soc. 2004, 126, 4664.
5 mol% Rh(COD)2OTf
5 mol% BIPHEP
1 atm H2, DCE, 25 C
Ph
Ph
Ph
O
O
H
R R'
OH
O
Ph
RhIR'
OH
O
Ph
R
RhIIIR O
Ph
R' OH
RhIR O
OR'
R' OH
R
R
RhIII
Competition experiments
pre-equilibrium/exchange of -unsaturated substrates prior to C-C bond formation
1 equiv1 equiv
Ph
1 equiv
Ph
Ph Ph
OH
O
Ph
Ph O
PhPh
OH
not formed
59% Y
5 mol% Rh(COD)2OTf
5 mol% BIPHEP
1 atm H2, DCE, 25 C
Ph
O
O
H
1 equiv1 equiv
Ph
1 equiv
Ph
Ph O
PhPh
OH
not formed
46% Y
PhPh
Ph O
PhPh
OH
Hydrogenation
Reductive Rh-Alkyne Coupling Mechanism
LnRhI LnRhIHBH R
R'
R
R'
HLnRhI
R'
R
RhIIILnH
R'
R
RhIIILn
H
O
O
R"
O
R''
O
H
R'
R
RhIIILn O
O
R"
H
O
O
H
R
R'
R
RhIIILn OH
O
R"
O
OH
H
R
HO R
O
R'
R
RhIIILn OH
O
R"
H2
H
R'
R
RhIIILn OH
O
R"
O
OR
H2
acid
slow
catalyzed
protonolysis
hydrogenolyticcleavage
R'
R
H OH
O
R"
Hydrogenation
Reductive Rh-Alkyne Coupling
Reductive acetylene coupling
5 mol% Rh(COD)2SbF6
5 mol% BIPHEP
1 atm H2, DCE, 25 C
J. Am. Chem. Soc. 2006, 128, 16041.
O(CH2)2Ph
O
O
H
OH
O
O(CH2)2PhHC CHPh3COOH, Na2SO4
RhIIILn
RhIIILn
O
ESI-MS
O OR
Hydrogenation
Reductive Ir-Alkyne Coupling
Iridium catalyzed reductive coupling of alkyl-substituted alkynes
2 mol% Ir(COD)2BARF
2 mol% DPPF
1 atm H2, PhMe, 60 C
J. Am. Chem. Soc. 2007, 129, 280.
OR'
O
O
R Et
O
OR'Et Et
2 mol% Ph3CCOOH
Et
HO R
PPh2
PPh2
Fe
DPPF
Stronger backbonding due to relativistic effects allows Ir to coordinate to less reactive substrates
Reaction is regioselective
82-93% Y
5 mol% Ir(COD)2BARF
5 mol% BIPHEP
1 atm H2, DCE, 80 C
OR'
O
O
R Ph
O
OR'R Me
5 mol% Ph3CCOOH
Me
HO R
78-97% Y
Ph
O
OEt
Me
HO R
93% Y
O
OEt
Me
HO p-OMePh
78% Y, 15:1
Me
MePh
O
OEt
Me
HO p-NO2Ph
78% Y, 15:1
Scope
A Sneak Peek at Transfer Hydrogenation
Seminal Publication
Strategy
5 mol% RuBr(CO)3( 3-C3H5)
15 mol% t-BuPPh2
4 equiv i-PrOH
PhMe, 75 C 61-87% Y
Org. Lett, 2008, 10, 2705.
R
R'
O
HH
MLnOH
R'''R"H OH
H
R R'H2 source
The formation of homoallylic alcohols
R
R'
(CHO)n
or RCHO
OH
R
R R'
For more, read on...
Review article: "Catalytic Carbonyl Addition through Transfer Hydrogenation" ACIE 2009, 48, 34.
