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Recent Developments in Cascade Catalysis
MacMillan Group Meeting
July 7, 2010
Spencer Jones
Im Mt Ez
Organo-Cascade
Metallo-Cascade
Bio-Cascade
Defining Cascade Catalysis: Flowchart of One-Pot Processes
Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248 (21-24), 2365.
Are all precatalysts present at outset?
no yes
is >1 catalytic cycle required?
is a single catalyst / precatalyst used?
is a chemical trigger used to transform
the catalyst / change mechanism?
no yes
no yes
one-pot reaction
(multicatalytic)
domino catalysis
(cascade)
orthogonal
catalysis
no yes
auto-tandem
catalysis
assisted-tandem
catalysis
! Cascade catalysis: One or
more catalysts involved in at
least two distinct catalytic bond
forming steps in a one-pot process
! All of the one-pot processes
described by Fogg fulfil the
criteria for cascade catalysis
! Fogg discusses the relative
advantages of each of these
reaction types in ref. below
One Pot, Multicatalytic Reaction: Both Catalysts not Present at Outset
Me O
Ph
Im En anti:syn 17:1
99% ee
80% yield
NH
MeMe
RO2C CO2R
H H
O
H
F
PhS
NS
Ph
O O O O
F
Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051
N
NH
MeO
Me
Me
Me
catalyst
N
NH
MeO
catalyst
Me
Me
Ph
(5S)-iminium (2R)-enamine
(7.5 mol%) (30 mol%)
N
NH
MeO
Me
Me
Me
catalyst
N
NH
MeO
catalyst
Me
Me
Ph
(5S)-iminium (2S)-enamine
(7.5 mol%) (30 mol%)
catalyst combination A catalyst combination B
syn:anti 8:1
99% ee
79% yieldO
H
F
catalyst
combination A
Im En
catalyst
combination B
Me
Me
enamine catalyst and E
added after consumption of Nu
enamine catalyst and E
added after consumption of Nu
Defining Cascade Catalysis: Flowchart of One-Pot Processes
Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248 (21-24), 2365.
Are all precatalysts present at outset?
no yes
is >1 catalytic cycle required?
is a single catalyst / precatalyst used?
is a chemical trigger used to transform
the catalyst / change mechanism?
no yes
no yes
one-pot reaction
(multicatalytic)
domino catalysis
(cascade)
orthogonal
catalysis
no yes
auto-tandem
catalysis
assisted-tandem
catalysis
! Cascade catalysis: One or
more catalysts involved in at
least two distinct catalytic bond
forming steps in a one-pot process
! All of the one-pot processes
described by Fogg fulfil the
criteria for cascade catalysis
! Fogg discusses the relative
advantages of each of these
reaction types in ref. below
Domino Catalysis: Conjugate Addition/Aldol Cascade
Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125 (5), 1110.
O
Ph Me
O O
Ph
MeHO
Ph
Rh(acac)(C2H4)2
(R)-BINAP
PhB(OH)2
KOH, H2O
dioxane, 95 ºC 88%, 88% ee
PhPh
Me
OO
[Rh]
PhPh
Me
OO
[Rh]
[Rh]-Ph
O
Ph Me
O
Ph
[Rh]
! The rate of aldol cyclization is faster than rhodium enolate hydrolysis: single catalytic cycle
Defining Cascade Catalysis: Flowchart of One-Pot Processes
Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248 (21-24), 2365.
Are all precatalysts present at outset?
no yes
is >1 catalytic cycle required?
is a single catalyst / precatalyst used?
is a chemical trigger used to transform
the catalyst / change mechanism?
no yes
no yes
one-pot reaction
(multicatalytic)
domino catalysis
(cascade)
orthogonal
catalysis
no yes
auto-tandem
catalysis
assisted-tandem
catalysis
! Cascade catalysis: One or
more catalysts involved in at
least two distinct catalytic bond
forming steps in a one-pot process
! All of the one-pot processes
described by Fogg fulfil the
criteria for cascade catalysis
! Fogg discusses the relative
advantages of each of these
reaction types in ref. below
Orthogonal Catalysis: Multiple Catalysts Present from Outset
Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606
N
NH
Me O
Me
MeMe
N
NHBoc
SMe
O
NN
PMB
O
SBoc
N
PMB
N
R
RNH
N
PMB
ONH
SMe SMe
Boc BocX
Me
1-Nap
PMB
N
PMB
ONH
SMe
Boc
NR2
15 mol%
CBr3
O
HO
15 mol%
–NHR2 RCO2H
H+
–RCO2H
87%, 96% ee
! Both imium and Bronsted acid catalysts are present at the beginning of the reaction and catalyze separate steps
Et2O, –50 °C
Defining Cascade Catalysis: Flowchart of One-Pot Processes
Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248 (21-24), 2365.
Are all precatalysts present at outset?
no yes
is >1 catalytic cycle required?
is a single catalyst / precatalyst used?
is a chemical trigger used to transform
the catalyst / change mechanism?
no yes
no yes
one-pot reaction
(multicatalytic)
domino catalysis
(cascade)
orthogonal
catalysis
no yes
auto-tandem
catalysis
assisted-tandem
catalysis
! Cascade catalysis: One or
more catalysts involved in at
least two distinct catalytic bond
forming steps in a one-pot process
! All of the one-pot processes
described by Fogg fulfil the
criteria for cascade catalysis
! Fogg discusses the relative
advantages of each of these
reaction types in ref. below
Tandem Catalysis: Single Catalyst, Mechanistically Distinct Transformations
Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127 (43), 15051.
OMe
O
Cl
ClCl
Cl
Cl
Cl
N
NH
Me O
Me
MeMe
Ar
Ar = N-Benzyl Indole
Im En
20 mol%
O
Pr
O
Pr
Cl
OMe
74%, 13:1 dr, 99% ee
! Auto tandem catalysis: Single catalyst directly performs multiple catalytic transformations
Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4 (24), 4321.
Ph Br Br
PhPdBr2(NCPh)2 PdI2(PtBu3)2
Me
Me
OH
Ph
Me
Me
OH
tBu3P, CuI, HNiPr2
79%
DME, 0 °C
! Assisted tandem catalysis: Mechanistic change induced by addition of chemical trigger
Defining Cascade Catalysis: Flowchart of One-Pot Processes
Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248 (21-24), 2365.
Are all precatalysts present at outset?
no yes
is >1 catalytic cycle required?
is a single catalyst / precatalyst used?
is a chemical trigger used to transform
the catalyst / change mechanism?
no yes
no yes
one-pot reaction
(multicatalytic)
domino catalysis
(cascade)
orthogonal
catalysis
no yes
auto-tandem
catalysis
assisted-tandem
catalysis
Cascade catalysis: Transformation
! All of the one-pot processes
described by Fogg fulfil the
criteria for cascade catalysis
! No matter what classification is given, the advantage of
cascade catalysis is clear: Multiple transformations are
carried out in one pot, thereby eliminating the need for
separate work-up and isolation steps.
bond forming steps in a one-pot process
involved in at least two distinct catalytic
where one or more catalysts are
Selected Examples of Enantioselective Cascade Catalysis
Im En
Organocascade
Mt En
Organometallo Cascade
Mt Mt
Metallo Cascade
EzEn
OrganoBio Cascade
Mt Ez
MetalloBio Cascade
Ez Ez
Biocascade
N
N
O Me
R
N
N
O Me
R
N
NH
Ph
O Me
X-+
HX
N
NH
Me
imidazolidinone
! First step:
Iminium catalysis
! Second step:
Enamine catalysis
Ph Me
Merging LUMO-lowering and HOMO-raising with one catalyst
E+
O
MeMe
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
MeR
N
N
O Me
R
N
N
Ph
O Me
R
HX +
N
NH
Ph
O Me
N
N
Ph
O Me
+X-
R
X-+
Nu–
Nu O
Nu
Nu
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
MeMe
R
N
N
Ph
O Me
R
X-+
Nu
Me
MeMe
Ph
Ph
E
E
R O Nu O
R
E
First Cycle
(Im)
Second Cycle
(En)
Ph
O
R
HX +
Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051
Organocascade Catalysis: Before the Name
R O
CHCl3, –10 °C
(20 mol%)
NH
CO2H
MeS
Ph
OMe >19:1 dr
>89% ee
>67% yield
N CO2
Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240
R
Im
+cat –H2O
MeS
Ph
O MeN CO2
RS
Me
Me
Ph O
En
N CO2
CHO
R
O
Ph
H
RPh
O
–cat +H2O
! Indoline carboxylic acid facilitates the formation of cyclopropanes via iminium-enamine cascade catalysis
Double Organocascade Catalysis: Wang Group
DCE, rt
Wang, J.; Li, H.; Xie, H.; Zu, L.; Shen, X.; Wang, W. Angew. Chem.-Int. Ed. 2007, 46 (47), 9050.
NH
OTES
Ph
Ph
0.5 equiv NaOAc
10 mol%O
Ar
Ar = electron rich or electron poor
OMe
O
OMe
O
O
H
H O
Ar
MeO2CCO2Me
63–89% yield
91–97% ee
N
Ar
OTES
Ph
Ph
+cat –H2O
Im En
MeO
O
MeOONa
OH
Ar
conjugate addition aldol condensation
N
MeO2C CO2Me
OOTES
Ph
Ph N
Ar
MeO2CCO2Me
–H2O
TESO
PhPh
–cat +H2O
Triple Organocascade Catalysis: Jørgensen Group
Carlone, A.; Cabrera, S.; Marigo, M.; Jorgensen, K. A. Angew. Chem.-Int. Ed. 2007, 46 (7), 1101
NH
OTMS
Ar
Ar
toluene, rt
10 mol%O
R
R = alkyl or aryl
N
R
OTMS
Ar
Ar
+cat –H2O
Im
NC
conjugateaddition
2.2 equiv
PhCO2H
Ar = 3,5-(CF3)2-C6H3
NN
CN
– cat R
NC CN
N
R
OTMS
Ar
Ar
OHC Im
R
NC CN
R
O N
OTMS
Ar
Ar
conjugateaddition
En
–cat +H2O
aldol condensation
R
NC CN
R
O
57–89% yield
97–99% ee
Quadruple Organocascade Catalysis: Zhang Group
Zhang, F. L.; Xu, A. W.; Gong, Y. F.; Wei, M. H.; Yang, X. L. Chem. Eur. J. 2009, 15 (28), 6815
NH
OH
Ar
Ph
25 mol% PhCO2H
5 mol%O
N
OH
Ph
Ph
+cat –H2O
Im
conjugateaddition
– cat
En
Michaeladdition
Imconjugateaddition
Ph
O
41–57% yield
>99% ee
R
OH
R = alkyl or aryl
CHCl3, 0.5 M, 4 ºC
NO2
Ph
4 equiv 4 equiv 1 equivNO2
OR
OR
H
N
OH
Ph
Ph
RO
NO2
Ph
O
RO
Ph
NO2
N
OH
Ph
Ph
OOR
Ph
NO2
N
OH
Ph
Ph
En
aldol cond.
Iminium-Carbene Cascade Catalysis: Synthesis of Functionalized Cyclopentanones
Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131 (38), 13628
NH
OTMS
Ar
Ar
10 mol% NaOAc
20 mol%
CHCl3, rt
N
N NC6F5
10 mol%
Me
O
Me
O
O
Me
O
Me
Me
O MeHO
93%, 86% ee
85:15 dr
Ar=3,5-bisCF3-C6H3
BF4
Iminium-Carbene Cascade Catalysis: Synthesis of Functionalized Cyclopentanones
Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131 (38), 13628
Im
N
Me
OTMS
Ar
Ar
MeO
Me
O –cat
conjugateaddition
O
Me
O
O
Me
Me
N
N NC6F5
Me
O
O
Me
Me
O
Me
NH
OTMS
Ar
Ar
Me
O
Me
O
OH
N
N
NC6F5
Cb
N
N
NC6F5
Me
Me
O
OH
MeHONaOAc
–catMe
Me
O
OH
Me
O
B:
! Triazolium salt mediates Benzoin type cyclization to give functionalized cyclopentanones
Iminium-Carbene Cascade Catalysis: Synthesis of Functionalized Cyclopentanones
Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131 (38), 13628
NH
OTMS
Ar
Ar
10 mol% NaOAc
20 mol%
CHCl3, rt
N
N NC6F5
10 mol%
R
O O
O
R
O
Me
Me
O MeHO
Ar=3,5-bisCF3-C6H3
BF4
OMe
O MeHO
N
Bn
Boc
60% yield
OEtO
O MeHO
80% yield
O
Me
79% yield
O
Me
76% yield
Me
NBn
MeO2C
OHOH
MeO2C
90% ee
85:15 dr
93% ee
60:30:8:2 dr
94% ee
80:20 dr
90% ee
85:15 dr
Iminium-Carbene Cascade Catalysis: Synthesis of Functionalized Cyclopentanones
Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131 (38), 13628
NH
OTMS
Ar
Ar
10 mol% NaOAc
20 mol%
CHCl3, rt
N
N NC6F5
10 mol%
R
O O
O
R
O
Me
Me
O MeHO
Ar=3,5-bisCF3-C6H3
BF4
OMe
O MeHO
N
Bn
Boc
60% yield
OEtO
O MeHO
80% yield
O
Me
79% yield
O
Me
76% yield
Me
NBn
MeO2C
OHOH
MeO2C
90% ee
85:15 dr
93% ee
60:30:8:2 dr
94% ee
80:20 dr
90% ee
85:15 dr
NH
OTMS
Ar
Ar
10 mol% NaOAc
20 mol%
CHCl3, rt
N
N NC6F5
10 mol%
Me
O
Me
O
O
Me
O
Me
Me
O MeHO
65% yield
5:1 dr, 58% ee
Ar=3,5-bisCF3-C6H3
BF4
Me O
O O
MeMe
CHCl3, rt70%
(46% over two steps)
! Carrying out the cascade as separate reactions gives the product with lower yield and selectivity
Iminium-Carbene Cascade Catalysis: Synthesis of Functionalized Cyclopentanones
Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131 (38), 13628
NH
OTMS
Ar
Ar
10 mol% NaOAc
20 mol%
CHCl3, rt
N
N NC6F5
10 mol%
R
O O
O
R
O
Me
Me
O MeHO
Ar=3,5-bisCF3-C6H3
BF4
OMe
O MeHO
N
Bn
Boc
60% yield
OEtO
O MeHO
80% yield
O
Me
79% yield
O
Me
76% yield
Me
NBn
MeO2C
OHOH
MeO2C
90% ee
85:15 dr
93% ee
60:30:8:2 dr
94% ee
80:20 dr
90% ee
85:15 dr
NH
OTMS
Ar
Ar
10 mol% NaOAc
20 mol%
CHCl3, rt
N
N NC6F5
10 mol%
Me
O
Me
O
O
Me
O
Me
Me
O MeHO
65% yield
5:1 dr, 58% ee
Ar=3,5-bisCF3-C6H3
BF4
Me O
O O
MeMe
CHCl3, rt70%
(46% over two steps)
! Reaction of 2,4-pentanedione
with crotonaldehyde is reversible
! Optimal yields and selectivities are
obtained only when triazolium salt
is present to funnel off the conjugate
addition adduct to product
! Carrying out the cascade as separate reactions gives the product with lower yield and selectivity
Organocascade Catalysis Synthesis of Quinolizidine Derivatives
Franzen, J.; Fisher, A. Angew. Chem.-Int. Ed. 2009, 48 (4), 787.
Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352 (2-3), 499.
N
HN
H
Et
O
OMe
hirsutine
N
HN
H
Et
dihydrocorynantheine
N
H
Et
psychotrine
OMe
MeO
N
HO OMe
quilolizidine core
O
R O
HN
O
MeO
HN
Im H+
Michaeladdition
R
O
CO2Me
O
HN
HN
R
CO2Me
O
N
HN
HO H
R
CO2Me
O
N
HN
N
HN
H
O
CO2Me
R
MeO MeO
O
OMeN
H
alangine
OMe
HO
HO
kineticthermodynamic
cis quinolizidines trans quinolizidines
NH Et
R
H
NH
"kinetic" product
1,3-diaxial interaction
"thermodynamic" product
EtR
NH
H
Organocascade Catalysis Synthesis of Quinolizidine Derivatives
Franzen, J.; Fisher, A. Angew. Chem.-Int. Ed. 2009, 48 (4), 787.
Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352 (2-3), 499.
N
HN
H
Et
O
OMe
hirsutine
N
HN
H
Et
dihydrocorynantheine
N
H
Et
psychotrine
OMe
MeO
N
HO OMe
quilolizidine core
O
R O
HN
O
MeO
HN
Im H+
Michaeladdition
R
O
CO2Me
O
HN
HN
R
CO2Me
O
N
HN
HO H
R
CO2Me
O
N
HN
N
HN
H
O
CO2Me
R
MeO MeO
O
OMeN
H
alangine
OMe
HO
HO
kineticthermodynamic
cis quinolizidines trans quinolizidines
Organocascade Catalysis Synthesis of Quinolizidine Derivatives
Franzen, J.; Fisher, A. Angew. Chem.-Int. Ed. 2009, 48 (4), 787.
Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352 (2-3), 499.
NR
H
EO
N CO2Me
R
O
H
HN
R
H
EO
H
H
H
N
HO
CO2Me
R
O
R
O
HN
O
MeO
Nu
Im
H+
Michaeladdition
R
CO2Me
O
N
Nu
HO H
H+
R
CO2Me
O
N
R
CO2Me
O
N
kineticconditions
thermodynamicconditions
H
H
thermodynamic product
kinetic product
kinetic product thermodynamic product
! Kinetic product favored due to free
approach of aryl group onto iminium ion
! Thermodynamic product favored due to
all equitorial arrangement of substituents
Organocascade Catalysis Synthesis of Quinolizidine Derivatives
Franzen, J.; Fisher, A. Angew. Chem.-Int. Ed. 2009, 48 (4), 787.
Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352 (2-3), 499.
NR
H
EO
N CO2Me
R
O
H
HN
R
H
EO
H
H
H
N
HO
CO2Me
R
O
R
O
HN
O
MeO
Nu
Im
H+
Michaeladdition
R
CO2Me
O
N
Nu
HO H
H+
R
CO2Me
O
N
R
CO2Me
O
N
kineticconditions
thermodynamicconditions
H
H
thermodynamic product
kinetic product
kinetic product thermodynamic product
Kinetic method A: 20 mol% HCl, rt.
Thermodynamic method B: conc. TFA, 70 ºC
N
HN
H
Et
O
OMe
hirsutine
N
HN
H
Et
dihydrocorynantheine
MeO MeO
O
OMe
condition yield ee dr A:B
A 69% 94% 85:15
B 64% 94% 18:82
O
Ph O
HN
O
MeO
HN
N
HN
H
O
CO2Me
Ph
NH
Ph
Ph
OTMS
20 mol%
N
HN
H
O
CO2Me
Ph
CH2Cl2, 3 ºC
then cond. A or B
A B
! Kinetic cyclization induced by catalytic HCl gives rise to predominantly the cis isomer A
! Thermodynamic cyclization induced by excess TFA gives predominantly the trans isomer A
Organocascade Catalysis Synthesis of Quinolizidine Derivatives
Franzen, J.; Fisher, A. Angew. Chem.-Int. Ed. 2009, 48 (4), 787.
Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352 (2-3), 499.
NR
H
EO
N CO2Me
R
O
H
HN
R
H
EO
H
H
H
N
HO
CO2Me
R
O
R
O
HN
O
MeO
Nu
Im
H+
Michaeladdition
R
CO2Me
O
N
Nu
HO H
H+
R
CO2Me
O
N
R
CO2Me
O
N
kineticconditions
thermodynamicconditions
H
H
thermodynamic product
kinetic product
kinetic product thermodynamic product
N
HN
H
O
CO2Me
Ph
N
HN
H
O
CO2Me
Ph
A B
H+
H+
N
N
H
O
CO2Me
Ph
N
HN
H
OH
CO2Me
Ph
H
N
HN
O
CO2Me
Ph
N
N
OH
CO2Me
Ph
H
! Thermodynamic equilibration of the cis product to the trans product might go via regeneration of the acyl
iminium ion or via an intermediate 10-membered ring.
Organocascade Catalysis Synthesis of Quinolizidine Derivatives
Franzen, J.; Fisher, A. Angew. Chem.-Int. Ed. 2009, 48 (4), 787.
Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352 (2-3), 499.
NR
H
EO
N CO2Me
R
O
H
HN
R
H
EO
H
H
H
N
HO
CO2Me
R
O
R
O
HN
O
MeO
Nu
Im
H+
Michaeladdition
R
CO2Me
O
N
Nu
HO H
H+
R
CO2Me
O
N
R
CO2Me
O
N
kineticconditions
thermodynamicconditions
H
H
thermodynamic product
kinetic product
kinetic product thermodynamic product
O
4-MeO-Ph O
HN
O
MeO
N
H
O
CO2Me
4-MeO-Ph
NH
Ph
Ph
OTMS
20 mol%N
H
O
CO2Me
4-MeO-PhCH2Cl2, 3 ºC
then cond. A or B
condition yield ee dr A:B
A B
A 71% 89% 76:24
B 75% 89% 24:76
OMe
OMe
OMe
OMe
OMe
OMe
Method A: 20 mol% HCl, rt.
Method B: 40 mol% SnCl4, rt
N
H
Et
psychotrine
OMe
MeO
N
HO OMe
N
H
alangine
OMe
HO
HO! SnCl4 reaction does not achieve trans
selection by equilibration: aliquots at
low conversion still have 1:3 ratio
Organocascade Catalysis Synthesis of Quinolizidine Derivatives
Franzen, J.; Fisher, A. Angew. Chem.-Int. Ed. 2009, 48 (4), 787.
Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352 (2-3), 499.
NR
H
EO
N CO2Me
R
O
H
HN
R
H
EO
H
H
H
N
HO
CO2Me
R
O
R
O
HN
O
MeO
Nu
Im
H+
Michaeladdition
R
CO2Me
O
N
Nu
HO H
H+
R
CO2Me
O
N
R
CO2Me
O
N
kineticconditions
thermodynamicconditions
H
H
thermodynamic product
kinetic product
kinetic product thermodynamic product
O
4-MeO-Ph O
HN
O
MeO
N
H
O
CO2Me
4-MeO-Ph
NH
Ph
Ph
OTMS
20 mol%N
H
O
CO2Me
4-MeO-PhCH2Cl2, 3 ºC
then cond. A or B
condition yield ee dr A:B
A B
A 71% 89% 76:24
B 75% 89% 24:76
OMe
OMe
OMe
OMe
OMe
OMe
Method A: 20 mol% HCl, rt.
Method B: 40 mol% SnCl4, rt
N
H
Et
psychotrine
OMe
MeO
N
HO OMe
N
H
alangine
OMe
HO
HO! SnCl4 reaction does not achieve trans
selection by equilibration: aliquots at
low conversion still have 1:3 ratio
NAr
H
CO2MeO
NAr
HO
N
HO
CO2Me
Ar
Method A
Kinetic control
product A
Method B
Chelation
MeO
MeO
NAr
H
CO2MeOOMe
MeO
LnSnO O
Me
O
O
Sn
epimerization
chelation
product Bcontrol
N CO2Me
Ar
O
H
H
Selected Examples of Enantioselective Cascade Catalysis
Im En
Organocascade
Mt En
Organometallo Cascade
Mt Mt
Metallo Cascade
EzEn
OrganoBio Cascade
Mt Ez
MetalloBio Cascade
Ez Ez
Biocascade
Au
Brønsted Acid/Gold (I) Multicatalyst Cascade: Dixon Group
Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J., J. Am. Chem. Soc. 2009, 131 (31), 10796.
Au H+
R
R = alkyl
NH
NH2
NH
NO
R
Au
O
O
R
then
protonation
NH
NH2
OH
O
NH
NO
R
HOH+
NH
NO
R
A*AH*
! Gold catalysis facilitates !," unsaturated lactone via activation of the alkyne toward 5-endo-dig cyclization
! Brønsted acid catalyzed N-acyl iminium cyclization generates enantioenriched heterocycles
cyclization
#HA
Au
Brønsted Acid/Gold (I) Multicatalyst Cascade: Dixon Group
Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J., J. Am. Chem. Soc. 2009, 131 (31), 10796.
Au H+
R
R = alkyl
NH
NH2
NH
NO
R
Au
O
O
R
then
protonation
NH
NH2
OH
O
NH
NO
R
HOH+
NH
NO
R
A*AH*
! Gold catalysis facilitates !," unsaturated lactone via activation of the alkyne toward 5-endo-dig cyclization
! Brønsted acid catalyzed N-acyl iminium cyclization generates enantioenriched heterocycles
n-Pr
NH
NH2
NH
NO
n-Pr
OH
O
AuClPPh3, 0.5 mol%
AgOTf 0.5 mol%
toluene, rt, 1 hr
then tryptamine and cat A
80 ºC 24 hr, 110 ºC, 24 hr
R2 R2
R2
H
5-Br
7-Me
yield (%) ee (%)
79 84
77 89
96 95
O
OP
OH
O
SiPh3
SiPh3
cat A
! Organometallo cascade proceeds in good selectivity only at high temperatures.
Lower temperatures (i.e., rt to 50 °C gave around 30 to 50% ee.
! Bulky phosphoric acid catalyst required for good selectivity. Aryl substituted
Binol phosphoric acid catalysts gave < 55% ee.
Au
Brønsted Acid/Gold (I) Multicatalyst Cascade: Dixon Group
Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J., J. Am. Chem. Soc. 2009, 131 (31), 10796.
Au H+
R
R = alkyl
NH
NH2
NH
NO
R
Au
O
O
R
then
protonation
NH
NH2
OH
O
NH
NO
R
HOH+
NH
NO
R
A*AH*
! Gold catalysis facilitates !," unsaturated lactone via activation of the alkyne toward 5-endo-dig cyclization
! Brønsted acid catalyzed N-acyl iminium cyclization generates enantioenriched heterocycles
NH
NH2
NH
NO
Me
O
O
Me CO2Me MeO2C
single diastereomer
cat AO
OP
OH
O
SiPh3
SiPh3
cat A
110 ºC
toluene
HN
HN O
O
Me
CO2Me
isolable
NH
NO
Me
MeO2C
isolable
HAHA
NH
NO
Me
MeO2C
NH
NO
Me
MeO2C
NH
NO
Me
MeO2C
NH
NO
Me
MeO2C
k1 k2
A A
! Because only a single diastereomer is formed, equilibration of 1, 2 must be fast relative to cyclization and k2>>k1.
1 2
Microencapsule Enabled Multicatalyst System
Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2006, 128 (49), 15586.
Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2007, 129 (29), 9216.
Im Ni
O
Me NO2
OO
OMeMeONO2
MeO2C CO2Me
Is it possible to use two incompatible catalysts for a tandem reaction?
NNH
NH2
x y
µ-Cap
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
BrN
NH
NH2
x y
Inactive
Dual Catalyst
System
Encapsulation
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
Br
Active
Dual Catalyst
System
Microencapsule Enabled Multicatalyst System
Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2006, 128 (49), 15586.
Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2007, 129 (29), 9216.
Im Ni
O
Me NO2
OO
OMeMeONO2
MeO2C CO2Me
Is it possible to use two incompatible catalysts for a tandem reaction?
NNH
NH2
x y
µ-Cap
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
BrN
NH
NH2
x y
Inactive
Dual Catalyst
System
Encapsulation
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
Br
Active
Dual Catalyst
System
Im
NO2
MeO2C CO2Me
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
Br
µ-Cap
NO2
H+NO2
NO2µ-Cap
NNH
NH2
x y
µ-Cap
O
Me NO2
OO
OMeMeO
Ni
Ni cat
Ni cat
Catalyst system Yield of malonate
µ-Cap and Ni cat 80%
µ-Cap alone
Ni cat alone
amine cat and Ni cat
2%
8%
5%
malonate
! Dinitro compound predominates
when no Ni cat is present
! In the absence of either one of the catalysts,
virtually no malonate addition product is formed
NO2
MeO2C CO2Me
Catalyst system Yield of malonate
µ-Cap and Ni cat 80%
µ-Cap alone
Ni cat alone
amine cat and Ni cat
2%
8%
5%
Microencapsule Enabled Multicatalyst System
Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2006, 128 (49), 15586.
Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2007, 129 (29), 9216.
Im Ni
O
Me NO2
OO
OMeMeONO2
MeO2C CO2Me
Is it possible to use two incompatible catalysts for a tandem reaction?
NNH
NH2
x y
µ-Cap
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
BrN
NH
NH2
x y
Inactive
Dual Catalyst
System
Encapsulation
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
Br
Active
Dual Catalyst
System
Im
NO2
MeO2C CO2Me
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
Br
µ-Cap
NO2
H+NO2
NO2µ-Cap
NNH
NH2
x y
µ-Cap
O
Me NO2
OO
OMeMeO
Ni
Ni cat
Ni cat
Catalyst system Yield of malonate
µ-Cap and Ni cat 80%
µ-Cap alone
Ni cat alone
amine cat and Ni cat
2%
8%
5%
malonate
! Dinitro compound predominates
when no Ni cat is present
! In the absence of either catalyst, virtually
no malonate addition product is formed
NO2
MeO2C CO2MeNO2 Ni cat
± µ-Cap
O O
OMe
OMe
significant rate enancement
when µ-Cap present
N
NO
H
H
O
O
N
R
O O
OMeMeO
Ni
! Encapsulating material is a polyurea made from a diisocyanate.
! H-bonding activation of the nitroolefin is responsible for rate acceleration
! The urea and not the NH groups of the catalyst were shown to be active
by exhasutive acetylation. The acetylated µ-Cap showed similar rates
Microencapsule Enabled Multicatalyst System
Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2006, 128 (49), 15586.
Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2007, 129 (29), 9216.
Im Ni
O
Me NO2
OO
OMeMeONO2
MeO2C CO2Me
Is it possible to use two incompatible catalysts for a tandem reaction?
NNH
NH2
x y
µ-Cap
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
BrN
NH
NH2
x y
Inactive
Dual Catalyst
System
Encapsulation
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
Br
Active
Dual Catalyst
System
NO2
MeO2C CO2Me
NH
NH
Bn
Bn
HN
HN
Bn
Bn
Ni
Br
BrN
NH
NH2
x y
µ-Cap Ni cat
6.8 mol% Ni cat
11.5 mol% µ-Cap
Me
Me O
1.5 equiv
MeNO2
10 equiv
MeO
O
OMe
O
1.0 equivMe Me
toluene, MeOH, rt
94% yield, 72% ee
Raney Ni
EtOH, H2
Me
Me NH
O
MeOO
96% yield
5 M HCl
115 °C
OH
O
NH2Me
Me
95% yield, 72% ee
Pregabalin
86% overall
! 92% ee and 74%
overall after one
recrystallization
Selected Examples of Enantioselective Cascade Catalysis
Im En
Organocascade
Mt En
Organometallo Cascade
Mt Mt
Metallo Cascade
EzEn
OrganoBio Cascade
Mt Ez
MetalloBio Cascade
Ez Ez
Biocascade
Tetrasubstituted Alkenes via Cooperative Rhodium and Silver Catalysis
Hojo, D.; Noguchi, K.; Tanaka, K. Angew. Chem. -Int. Ed. 2009, 48, 8129.
Hojo, D.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem. -Int. Ed. 2008, 47, 8129.
O
R
N
Me
O
O
Rh(ligand A)BF4 5 mol%
Fe
P
H
Me
P
Ligand A
R = cyclohexane
O
O
N
O
*
R
Me
84% yield, 93% eeF3C CF3
CF3
CF3
RhLn
O
R
RhLn
H
Insertion
migratory
insertion
RhLn
O
R
homo [4+2]
annulation
ketone
O
RhLn
O
RN
O
Me
reductive
elimination
Tetrasubstituted Alkenes via Cooperative Rhodium and Silver Catalysis
Hojo, D.; Noguchi, K.; Tanaka, K. Angew. Chem. -Int. Ed. 2009, 48, 8129.
Hojo, D.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem. -Int. Ed. 2008, 47, 8129.
O
R
N
Me
O
O
Rh(ligand A)BF4 5 mol%
Fe
P
H
Me
P
Ligand A
R = cyclohexane
O
O
N
O
*
R
Me
84% yield, 93% eeF3C CF3
CF3
CF3
RhLn
O
R
RhLn
H
Insertion
migratory
insertion
RhLn
O
R
homo [4+2]
annulation
ketone
O
RhLn
O
RN
O
Me
reductive
elimination
O
R
N
Me
O
O
Rh(ligand A)BF4 5 mol%
O
O
N
O
*
R
Me
84%, 93% ee
CH2Cl2, rt
R = cyclohexane
R = 1-cyclohexenyl
O
O
N
O
Me
R
not detected
40%, 61% ee 60%, 85% ee
Fe
P
H
Me
P
Ligand A
F3C CF3
CF3
CF3
Fe
P
H
Me
P
Ligand B
F3C CF3
CF3
CF3
R = 1-cyclohexenyl(Ligand B)
OMe
MeMe
Me
Me
MeO
<1%, -- 99%, 95% ee
R = isopropenyl, alkyl, aryl "High" < 2%
! Only they cyclohexenyl
system gave the
tetrasubstituted olefin
Tetrasubstituted Alkenes via Cooperative Rhodium and Silver Catalysis
Hojo, D.; Noguchi, K.; Tanaka, K. Angew. Chem. -Int. Ed. 2009, 48, 8129.
Hojo, D.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem. -Int. Ed. 2008, 47, 8129.
O
R
N
Me
O
O
Rh(ligand A)BF4 5 mol%
Fe
P
H
Me
P
Ligand A
R = cyclohexane
O
O
N
O
*
R
Me
84% yield, 93% eeF3C CF3
CF3
CF3
RhLn
O
R
RhLn
H
Insertion
migratory
insertion
RhLn
O
R
homo [4+2]
annulation
ketone
O
RhLn
O
RN
O
Me
reductive
elimination
O
R
N
Me
O
O
Rh(ligand B)BF4 5 mol%
O
O
N
O
*
R
Me
84%, 93% ee
CH2Cl2, rt
R = cyclohexane
R = 1-cyclohexenyl
O
O
N
O
Me
R
not detected
40%, 61% ee 60%, 85% ee
Fe
P
H
Me
P
Ligand A
F3C CF3
CF3
CF3
Fe
P
H
Me
P
Ligand B
F3C CF3
CF3
CF3
R = 1-cyclohexenyl(Ligand B)
OMe
MeMe
Me
Me
MeO
<1%, -- 99%, 95% ee
R = isopropenyl, alkyl, aryl "High" < 2%
Rh
O
Rh
O
OR
N
O
MeRh
O
OR
N
O
Me
–Rh
Rh
H
C-H Insertion
Migratory
insertion
O
OR
N
O
Me
RhH
Reductive
Elimination
[4+2]
! Reason for the mechanistic change is not known. ! Model for the asymmetric induction has not been proposed.
Fe
P
H
Me
P
Ligand B
F3C CF3
CF3
CF3
OMe
MeMe
Me
Me
MeO
Tetrasubstituted Alkenes via Cooperative Rhodium and Silver Catalysis
Hojo, D.; Noguchi, K.; Tanaka, K. Angew. Chem. -Int. Ed. 2009, 48, 8129.
Hojo, D.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem. -Int. Ed. 2008, 47, 8129.
O
R
N
Me
O
O
Rh(ligand A)BF4 5 mol%
Fe
P
H
Me
P
Ligand A
R = cyclohexane
O
O
N
O
*
R
Me
84% yield, 93% eeF3C CF3
CF3
CF3
RhLn
O
R
RhLn
H
Insertion
migratory
insertion
RhLn
O
R
homo [4+2]
annulation
ketone
O
RhLn
O
RN
O
Me
reductive
elimination
O
R
N
O
ORh(ligand B)BF4 5 mol%
CH2Cl2, rt
O
O
N
O
Me
R
Fe
P
H
Me
P
Ligand B
F3C CF3
CF3
CF3
OMe
MeMe
Me
Me
MeO
R = alkyl, aryl, vinyl
5 mol% PPh3
10 mol% AgBF4Me
O
O
N
O
Me
Ph
96%, 96% ee
O
O
N
O
Me
Bu
72%, 94% ee
O
O
(CH2)3Cl
72%, 94% ee
O
! Role of silver is unknown. Initially it was suspected that it might act as a Lewis acid to enable cyclization
of the aldehyde onto the alkyne. However, subjection of the SM to silver did not produce any cyclization
derived products
Heterocycle Synthesis via Ruthenium and Palladium Cascade Catalysis
Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128 (20), 6745.
TMS
Nuc
nRu
O
NO2
Pd
Nuc
TMS
n
RuLn
RuTMS
Nucn
Ln
OAr
!-hydride elim.
reductive
elimination
H
cyclometallation
TMS
Nuc
n OAr
PdLn
PdLn
Nuc
TMS
n
! Key criterion: Ru catalyst must not be able to ionize allylic group (racemic pathway)
! Alkyne regioselectivity is dictated by the TMS group
! Allylic leaving group not present until after ene-yne coupling reaction
Heterocycle Synthesis via Ruthenium and Palladium Cascade Catalysis
Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128 (20), 6745.
TMS
NsHN
n OAr
NNs
TMS
n = 1-3
[RuCp(CH3CN)3]PF6
5 mol%, acetone, rt
then
Ar = p-NO2-C6H4
NH HN
OO
PPh2 Ph2P
Ligand
2 mol% [Pd(!3-C3H5)Cl]26 mol% Ligand
DBU, CH2Cl2, rt
90%, 91% ee
NNs
TMS
90%, 84% ee
NNs
TMS
37%, 13% ee
TMS
HO
n OAr
O
TMS
n = 1-3
[RuCp(CH3CN)3]PF6
10 mol%, acetone, rt
then
Ar = p-NO2-C6H42 mol% [Pd2(dba)3CHCl3
6 mol% Ligand
Et3N, CH2Cl2, 0 °C
84%, 76% ee
O
TMS
80%, 94% ee
O
TMS
0%, --! Alcohol nucleophiles gives products
with opposite sense of enantioinduction
Heterocycle Synthesis via Ruthenium and Palladium Cascade Catalysis
Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128 (20), 6745.
Pd
NsN
TMS
Pd
OH
TMS Pd
TMS
HO
NH HN
OO
PPh2 Ph2P
Ligand
TMS
NsHN
n OAr
6% ligand
DBU, CH2Cl2, rt
matched ionization
mismatched
ring closure
NNs
TMS
TMS
HO
n OAr
6% ligand
Et3N, CH2Cl2, 0 ºC
matched ionization
Ar = p-NO2-C6H4
Ar = p-NO2-C6H4
matched
O
TMS
! For nitrogen nucleophiles, ionization is the enantiodetermining step
! For oxygen nucleophiles, ring closure is the enantiodetermining step
! Oxygen nucleophiles are much slower to
add to the palladium !-allyl species and
hence, equilibration of the !-allyl occurs
to enable a matched ring closure
2% Pd(!-allyl)Cl)2
2% Pd2(dba)3CHCl3
Heterocycle Synthesis via Ruthenium and Palladium Cascade Catalysis
Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128 (20), 6745.
Ar = p-NO2-C6H4
NNs
TMS
73%, 2:1 dr
80%, 97:3 dr
OAr
Ru Pd
R,R-Ligand for Pd
Ru Pd
S,S-Ligand for Pd
80%, 97:3 dr
TMS
Ar = p-NO2-C6H4
OAr
Ru Pd
R,R-Ligand for Pd
Ru Pd
S,S-Ligand for Pd
NsHN
Me
Me
NNs
TMS
68%, 99:1 drMe
NH HN
OO
PPh2 Ph2P
R,R-Ligand
NH HN
OO
PPh2 Ph2P
S,S-Ligand
O
TMS
heptyl
TMS
HO
Me
7
O
TMS
heptyl
Heterocycle Synthesis via Ruthenium and Palladium Cascade Catalysis
Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128 (20), 6745.
O O
O O
HO MeMe
OH
Me
Me
OH H
O
OHMe
CO2Me
MeO2C
O
OMe
OH
Bryostatin 2
O
OH
PMBCl, NaH
78%
O
OPMB
Li TMS
BF3OEt2
60%
OPMB
OHTMS
Ru Pd
Ar = p-NO2-C6H4
OArO
TMS
OPMB
NH HN
OO
PPh2 Ph2P
S,S-Ligand
2% Pd2(dba3)
6% S,S-ligand
10% [RuCp(CH3CN)3]PF61. NIS
52%
2. 9-BBN, H2O2
3. Pd2(dba3)
50%
CO, MeOH
O
MeO2C
OPMB
OH
Selected Examples of Enantioselective Cascade Catalysis
Im En
Organocascade
Mt En
Organometallo Cascade
Mt Mt
Metallo Cascade
EzEn
OrganoBio Cascade
Mt Ez
MetalloBio Cascade
Ez Ez
Biocascade
OrganoBio Cascade Catalysis: !-Hydroxy Ketone Synthesis
Edin, M.; Backvall, J. E.; Cordova, A. Tetrahedron Lett. 2004, 45 (41), 7697.
O
Me Me
O (S)-prolineOH
Me
O
OH
NPh
MeOOH
50% yield, 64% ee
OH
Me
O Amano I = Pseudomonas
racemic
vinyl acetate, 4 Å MS, rt
OAc
Me
O
51% yield, 97% ee
O
Me Me
O
OAc
Me
O
31% yield, 99% ee
En
OH
Me
O
Ez
(S)-proline Amano I lipase
vinyl acetate
4 Å MS, rt
OH
Me
O
37% yield, 99% ee
or
(R)-proline
OH
Me
O
64% ee
64% ee
cepacia lipase
64% ee 81%, 99% ee
40% over
two steps
MetalloBio Cascade Catalysis: Dynamic Kinetic Resolutions
Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.; Harris, W. Tetrahedron Lett. 1996, 37 (42), 7623.
R
OH
R'
racemic
EzR
OAc
R' R
OH
R'
Mt
Ph
OH
Me
racemic
Ph
OAc
Me
2 mol% Rh2(OAc)4
Pseudomonas fluorescens Lipase
6 mol% o-phenanthroline
1.0 equiv PhCOMe
2:1 vinyl acetate:cyclohexane
(Oppenauer oxidation)
rt, 72 hr
60%, 98% ee
max. theoretical ee: 67%
Ph
O
MeH Ph
O
Me
M
Ph
O
MeHPh
O
Me
M
Ph
OH
Me Ph
OH
Me
MetalloBio Cascade Catalysis: Dynamic Kinetic Resolutions
Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.; Harris, W. Tetrahedron Lett. 1996, 37 (42), 7623.
R
OH
R'
racemic
EzR
OAc
R' R
OH
R'
Mt
Ph
OH
Me
racemic
Ph
OAc
Me
2 mol% Rh2(OAc)4
Pseudomonas fluorescens Lipase
6 mol% o-phenanthroline
1.0 equiv PhCOMe
2:1 vinyl acetate:cyclohexane
(Oppenauer oxidation)
rt, 72 hr
60%, 98% ee
max. theoretical ee: 67%
Ph
O
MeH Ph
O
Me
M
Ph
O
MeHPh
O
Me
M
Ph
OH
Me Ph
OH
Me
Larsson, A. L. E.; Persson, B. A.; Backvall, J. E. Angew. Chem.-Int. Ed. Eng. 1997, 36 (11), 1211.
Ph
OH
Me
racemic
Ph
OAc
Me
2 mol% Ru Complex
50 mg CALB
1.0 equiv PhCOMe
t-BuOH, 70 ºC, 87 hr
(Oppenauer oxidation)
92%, >99.5% ee
O
Ph
Ph
Ph
Ph
RuOC
OC
O
Ph
Ph
Ph
Ph
RuCO
CO
H
H
Ru Complex2 mmol
Cl
OAc
acetate donor
CALB = Candida antarctica lipase B
MetalloBio Cascade Catalysis: Dynamic Kinetic Resolutions
Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.; Harris, W. Tetrahedron Lett. 1996, 37 (42), 7623.
R
NH2
R'
racemic
EzR
NHAc
R' R
NH2
R'
Mt
Ph
OH
Me
racemic
Ph
OAc
Me
2 mol% Rh2(OAc)4
Pseudomonas fluorescens Lipase
6 mol% o-phenanthroline
1.0 equiv PhCOMe
2:1 vinyl acetate:cyclohexane
(Oppenauer oxidation)
rt, 72 hr
60%, 98% ee
max. theoretical ee: 67%
Ph
O
MeH Ph
O
Me
M
Ph
O
MeHPh
O
Me
M
Ph
OH
Me Ph
OH
MeRu
Paetzold, J.; Backvall, J. E. J. Am. Chem. Soc. 2005, 127 (50), 17620.
Ph
NH2
Me
racemic
Ph
NHAc
Me
4 mol% Ru Complex
CALB, Na2CO3
toluene, 90 ºC, 3 days
90%, 98% ee
O
R
R
R
R
RuOC
OC
O
R
R
R
R
RuCO
CO
H
H
Ru Complex
CALB = Candida antarctica lipase B
Thalen, L. K.; Zhao, D. B.; Sortais, J. B.; Paetzold, J.; Hoben, C.; Backvall, J. E. Chem. Eur. J. 2009, 15 (14), 3403.
R = p-MeO-C6H4
OAc
Me
Me
acetate donor
Ph
NH2
Me
O
OC
OCPh
NH
Me
H
Ru
O
OC
OCPh
N
Me
H
Ru
O
OC
OCPh
NH
Me
H
Ph
NH2
Me
H
!-hydride
elim.
re-
additionRu –Ru
MetalloBio Cascade Catalysis: Dynamic Kinetic Resolutions
Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.; Harris, W. Tetrahedron Lett. 1996, 37 (42), 7623.
R
NH2
R'
racemic
EzR
NHAc
R' R
NH2
R'
Mt
Ph
OH
Me
racemic
Ph
OAc
Me
2 mol% Rh2(OAc)4
Pseudomonas fluorescens Lipase
6 mol% o-phenanthroline
1.0 equiv PhCOMe
2:1 vinyl acetate:cyclohexane
(Oppenauer oxidation)
rt, 72 hr
60%, 98% ee
max. theoretical ee: 67%
Ph
O
MeH Ph
O
Me
M
Ph
O
MeHPh
O
Me
M
Ph
OH
Me Ph
OH
MeRu
Paetzold, J.; Backvall, J. E. J. Am. Chem. Soc. 2005, 127 (50), 17620.
Ph
NH2
Me
racemic
Ph
NHAc
Me
4 mol% Ru Complex
CALB, Na2CO3
toluene, 90 ºC, 3 days
90%, 98% ee
O
R
R
R
R
RuOC
OC
O
R
R
R
R
RuCO
CO
H
H
Ru Complex
CALB = Candida antarctica lipase B
Thalen, L. K.; Zhao, D. B.; Sortais, J. B.; Paetzold, J.; Hoben, C.; Backvall, J. E. Chem. Eur. J. 2009, 15 (14), 3403.
R = p-MeO-C6H4
OAc
Me
Me
acetate donor
Ph
NH2
Me
O
OC
OCPh
NH
Me
H
Ru
O
OC
OCPh
N
Me
H
Ru
O
OC
OCPh
NH
Me
H
Ph
NH2
Me
H
!-hydride
elim.
re-
additionRu –RuMeMe
NHAc
85%, 93% ee
Me
NHAc
88%, 97% ee
NHAc
70%, 99% ee
S
NHAc
Me
85%, 99% ee
NHAc
Me
O2N
70%, 99% ee
MetalloBio Cascade Catalysis: Dynamic Kinetic Resolutions
Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.; Harris, W. Tetrahedron Lett. 1996, 37 (42), 7623.
R
NH2
R'
racemic
EzR
NHAc
R' R
NH2
R'
Mt
Ph
OH
Me
racemic
Ph
OAc
Me
2 mol% Rh2(OAc)4
Pseudomonas fluorescens Lipase
6 mol% o-phenanthroline
1.0 equiv PhCOMe
2:1 vinyl acetate:cyclohexane
(Oppenauer oxidation)
rt, 72 hr
60%, 98% ee
max. theoretical ee: 67%
Ph
O
MeH Ph
O
Me
M
Ph
O
MeHPh
O
Me
M
Ph
OH
Me Ph
OH
MeRu
Paetzold, J.; Backvall, J. E. J. Am. Chem. Soc. 2005, 127 (50), 17620.
Ph
NH2
Me
racemic
Ph
NHCbz
Me
4 mol% Ru Complex
CALB, Na2CO3
toluene, 90 ºC, 3 days
90%, 93% ee
O
R
R
R
R
RuOC
OC
O
R
R
R
R
RuCO
CO
H
H
Ru Complex
CALB = Candida antarctica lipase B
Thalen, L. K.; Zhao, D. B.; Sortais, J. B.; Paetzold, J.; Hoben, C.; Backvall, J. E. Chem. Eur. J. 2009, 15 (14), 3403.
R = p-MeO-C6H4
OBn
O
BnO
carbonate donor
Ph
NH2
Me
O
OC
OCPh
NH
Me
H
Ru
O
OC
OCPh
N
Me
H
Ru
O
OC
OCPh
NH
Me
H
Ph
NH2
Me
H
!-hydride
elim.
re-
additionRu –RuMeMe
NHCbz
89%, 90% ee
Me
NHCbz
92%, 96% ee 64%, 99% ee 74%, 97% ee
NHCbz
Me
F
72%, 99% ee
NHCbzNHCbz
Me
MeO
Deracemization of Secondary Alcohols via Biocascade Catalysis
Voss, C. V.; Gruber, C. C.; Kroutil, W. Angew. Chem.-Int. Ed. 2008, 47 (4), 741.
R
OH
R'
EzR
OH
R'
R
OH
R'
racemic
S
RR
O
R'
R
OH
R'S
R-selective
Ez
S-selective
oxidation reduction
high ee
Me
OH
intact cells of
Alcaligenes faecalis
DSM 13975, O2
Me
OH
racemic Me
O
pH 7.5 buffer, 30 ºC
Me
OH
alcohol dehydrogenase
NADH NAD+
Glucose
from Rhodococuss
erythropolis (RE-ADH)
dehydrogenase
100 mM glucose
0.5 mM NAD+
>99%, >99%ee
Me
OH
n-octyl
>99%, >99% ee
O
OH
>99%, 30% ee
OEt
OOH
>99%, 96% ee
Me
Me
Me
OH
>99%, >99% ee
! When lysed cells were used, racemization of enantiopure secondary alcohols was observed
! They concluded that the oxidation and reduction cycles must be separated: intact cell membrane
Deracemization of Secondary Alcohols via Biocascade Catalysis
Voss, C. V.; Gruber, C. C.; Kroutil, W. Angew. Chem.-Int. Ed. 2008, 47 (4), 741.
R
OH
R'
EzR
OH
R'
R
OH
R'
racemic
S
RR
O
R'
R
OH
R'S
R-selective
Ez
S-selective
oxidation reduction
high ee
Me
OH
intact cells of
Alcaligenes faecalis
DSM 13975, O2
Me
OH
racemic Me
O
pH 7.5 buffer, 30 ºC
Me
OH
alcohol dehydrogenase
NADH NAD+
Glucose
from Rhodococuss
erythropolis (RE-ADH)
dehydrogenase
100 mM glucose
0.5 mM NAD+
>99%, >99%ee
Me
OH
n-octyl
>99%, >99% ee
O
OH
>99%, 30% ee
OEt
OOH
>99%, 96% ee
Me
Me
Me
OH
>99%, >99% ee
Ph
OH
Me
>99%, 10% ee