Ligand Accelerated Catalysis (LAC)
Chris Borths
MacMillan Group Meeting
October 3, 2001
I. Definition
II. Oxidations
III. Reductions
IV. Alkylations
V. Lewis base catalysis
Reviews:
LAC: Berrisford, D.J.; Bolm, C.; Sharpless, K.B. Ang. Chem. Int. Ed. Engl. 1995, 34, 1059.
Non-Linear Effects: Girard, C.; Kagan, H.B. Angew. Chem. Int. Ed. Engl. 1998, 37, 2922. Blackmond, D.G. J. Am. Chem. Soc. 1997, 119,
12934.
Asymmetric Activation: Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto, Y.; Ueki, M.; Angelaud, R. Angew. Chem. Int. Ed. Engl. 2000, 112,
3532.
A Definition of LAC
catalyst
A+B
P
k0
catalyst + ligand
A+B
P
k1
! Ligand accelerated catalysis can be most simply defined as any reaction where
! Ligand acceleration effect (LAE) is defined by
!ML
>1
!M
k1Keq[ligand]
k0
! Useful levels of selectivity can be achieved when the LAE is 20 or higher.
! If ligand exchange occurs faster than or on the same time scale as the transormation,
asymmetric catalysis becomes viable at high levels of LAE.
Berrisford, D.J.; Bolm, C.; Sharpless, K.B. Angew. Cem. Int. Ed. Engl. 1995, 34, 1059.
Titanium-Catalyzed Asymmetric Epoxidation
OH
O
OH
! Titanium exhibits complex metal ligand association in solution.
Metal-ligand species detected in solution: Ti(OiPr)4 (M) and diisopropyl tartrate (L)
M1L0, M2L0, M2L1, M3L1, M2L2, M3L2, M3L3, M4L4
(evidence for existence based on NMR, MS, or XRD)
! Multiple metal-ligand species are active epoxidation catalysts
RO
RO
O
OR
OR
RO
Ti OR
OR
O
RO
Ti
RO
O
O
ER
Ti OR
O
O
O
RO
OR
Ti
RO
E
O
O
Ti
OR
OR
O
OR
E
solution fraction (1:1 M:L)
relative epoxidation rate
enantioselectivity
M1L0
~ 10%
1.4
none
M2L1
~ 10%
1.0
low
M2L2
~ 80%
3.6
high
! The standard SAE receipe calls for a 20% excess of tartrate, practically removing the unwanted epoxidation
catalysts from solution.
Berrisford, D.J.; Bolm, C.; Sharpless, K.B. Angew. Cem. Int. Ed. Engl. 1995, 34, 1059.
Titanium-Catalyzed Asymmetric Epoxidation
OH
O
E
OH
O
OR
RO
Ti
O
O
E
O
Ti
O
E
O
O
O
R
RO
! Sharpless system shows excellent enatioselectivity. (Ligand DET or DIPT)
R
R
R
OH
OH
R
OH
OH
R
ee ! 94
ee ! 80
ee ! 95
ee ! 91
R
R
OP
R
OP
ee ! 90
OP
OP
R
ee ! 92
ee ! 90
ee ! 86
Gao, Y.; Hanson, R.M.; Klunder, J.M.; Ko, S.Y.; Masamune, H.; Sharpless, K.B. J. Am. Chem. Soc. 1987, 109, 5765.
McKee, B.H.; Kalantar, T.H.; Sharpless, K.B. J. Org. Chem. 1991, 56, 6966.
Osmium-Catalyzed Dihydroxylation
OH OH
! This is the first reaction to show ligand acceleration by chincona alkaloids.
! The ligand acceleration effect has been demostrated to be greater than 15 and as high as 100 for stilbene at 0 °C.
DHQ
Et
Et
N
RO
N
H
RL
RS
OR
H
MeO
OMe
N
DHQ
Ph
N
R'O
CO2R'
OR'
DHQD
N
DHQD
N
H
RM
R'O
OR'
IND
ee 20 - 80 %
PYR
PHAL
ee 30 - 97 %
PHAL
ee 90 - 99.8 %
PYR
PHAL
20 - 97 %
PHAL
ee 70 - 97 %
PHAL
ee 90 - 99 %
N
N
N
Ph
R=
PHAL
IND
PYR
THE CATALYSTS
Jacobsen, E.N.; Markó, I.; Mungall, W.S.; Schröder, G.; Sharpless, K.B. J. Am. Chem. Soc. 1988, 110, 1968.
Jacobsen, E.N.; Markó, I.; France, M.B.; Svendsen, J.S.; Sharpless, K.B. J. Am. Chem. Soc. 1989, 111, 737.
Sharpless, K.B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.; Kawanami, Y.; Lübben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita, T. J. Org. Chem. 1991, 56, 4585.
Kolb, H.C.; Van Nieuwenhze, M.S.; Sharpless, K.B. Chem. Rev. 1994, 94, 2483.
Multiple Catalytic Cycles Operate in the Osmium Dihydroxylation
! Slow addition of olefin substrate in presence of acetate can select against the second catalytic cycle.
! Use of K3Fe(CN)6 as the oxidant can eliminate the second catalytic cycle.
HO
L
OH
O
Ligand-Accelerated
Cycle
High ee
O
O
O
O Os O
O
O
H2O
O Os O
O
L
O
O
O
Os
L
Second Cycle
Low ee
O
O
[O]
O
O
Os
O
O
O
[O]
L
HO
81% ee in first cycle
OH
Os
O
O
O
H2O, L
-7% ee in second cycle
Wai, J.S.M.; Markó, I.; Svendsen, J.S.; Finn, M.G.; Jacobsen, E.N.; Sharpless, K.B. J. Am . Chem. Soc. 1989, 111, 1123.
Kwong, H.L.; Sarato, C.; Ogino, Y.; Chen, H.; Sharpless, K.B. Tetrahedron Letters 1990, 31, 2999.
Mechanism of Osmium Dihydroxylation
A concerted [ 3 + 2 ] mechanism is beleived to be correct
O
O
+L
Os O
O
-L
O
O Os O
O
L
O
[3+2]
O
O
Os
O
O
L
O
O
Os
O
L
[2+2]
O
O Os O
O
+L
O
-L
O
O
O
Os
L
! Hammett studies favor the existence of a concerted mechanism
! Frontier molecular orbital calculations favor a concerted [ 3 + 2 ] mechanism.
! Transition state models with chiral chelating dinitrogen ligands are inconclusive.
! Kinetic isotope effects match the predicted [ 3 + 2 ] calculations and do not match the predicted
[ 2 + 2 ] calculations.
! Quantum mechanical modelling based on the [ 3 + 2 ] mechanism (using MM3* calculations)
can predict the experimental enantioselectivities to within a few percentage points.
Norrby, P.O.; Becker, H.; Sharpless, K.B. J. Am. Chem. Soc. 1996, 118, 35.
Nelson, D.W.; Gypser, A.; Ho, P.T.; Kolb, H.C.; Kondo, T.; Kwong, H.L.; McGrath, D.V.; Rubin, A.E.; Norrby, P.O.; Gable, K.P.; Sharpless, K.B. J. Am. Chem. Soc. 1997, 119,
1840.
DelMonte, A.J.; Haller, J.; Houk, K.N.; Sharpless, K.B.; Singleton, D.A.; Strassner, T.; Thomas, A.A. J. Am. Chem. Soc. 1997, 119, 9907.
Norrby P.O.; Rasmussen, T.; Haller. J.; Strassner, T.; Houk, K.N. J. Am. Chem. Soc. 1999, 121, 10186.
Palladum-Catalyzed Oxidations
! Reaction rate accelerated by nitrogen ligands
O
5 mol % Pd(OAc)2
10 mol % ligand
OH
H
O2
Ligand
none
pyridine
2,6-lutidine
triethylamine
2,2'-bipyridine
pyridine with 3ÅMS
Conversion (2h)
5%
86 %
82 %
78 %
5%
quantitative
! Reaction rate shows a marked dependence on ligand concentration; efficient oxidations at 4 eq ligand / Pd
5 mol % Pd(OAc)2
20 mol % pyr
3ÅMS
OH
R
R
O
R
O2
R = alkyl, aryl, alkenyl,
H, keto, cyclic
R
yields ! 63 %
most ! 80 %
Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. Tetrahedron Letters 1998, 39, 6011.
Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750.
Palladum-Catalyzed Oxidations: Kinetic Resolution
! (-)-Sparteine is most selective ligand.
5 mol % Pd(II)
20 mol % (-)-sparteine
OH
R
R
O2
R
O
N
N
R
(-)-sparteine
OH
OH
OH
Me
Me
Et
MeO
krel = 17.5 / 23.1
krel = 11.6 / 14.8
OH
krel = 15.1 / 12.3
OH
Me
Me
F
krel = 12.2 / 14.4
krel = 10.1 / 47.1
(Note: first krel is from Sigman paper, second krel is from Stoltz paper)
Jensen, D.R.; Pugsley, J.S.; Sigman, M.S. J. Am. Chem. Soc. 2001, 123, 7475.
Ferreira, E.M.; Stoltz, B.M. J. Am. Chem. Soc. 2001, 123, 7725.
Zirconium-Catalyzed !"Cyanohydrin Synthesis
! Reaction shows significant ligand acceleration.
TMS
+
O
+
O
TMSCN
1) 20 mol % Zr catalyst
ClCH2CH2Cl
OH
2) KF, MeOH
CN
TMS
(BTSP)
Zr catalyst
time
yield (%)
Zr(OnBu)4
84 h
62
63 h
63
38 h
63
alone
15 h
68
+ Ph3PO
1.5 h
94
Zr(OiPr)4
Ph
Zr(OtBu)4
Ph
O
Zr(OtBu)2
O
Ph
Ph
! Mono-, di-, and tri-substituted olefins are good substrates for this reaction.
R
R
R
R
R
OH
R
CN
yields ! 53
Yamasaki, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 1256.
Zirconium-Catalyzed !"Cyanohydrin Mechanism
! Mechanism proposal based on Ti-catalyzed epoxidation and Yb-catalyzed epoxide opening
Zr(OtBu)4 + TMSCN + Ph3PO +
OH
OH
Ph3P
BTSP
Ph3P
O
O Zr CN
O
CN
TMSCN
TMSCN
TMSOTMS
OTMS
TMSCN
O TMS CN
O Zr O Zr OH
O
O
O
O
TMS
CN
NC
Ph3P
O
O Zr CN
O
O
O
Ph3P
Ph3P
O TMS CN
O Zr O Zr O
O
O
O
CN
TMS
O
O Zr CN
OTMS
O
TMS
Ph3P
O
O Zr CN
O
O
O
TMS
Ph3P
O
O TMS CN
O Zr O Zr O
O
O
O
NC
O
TMS
Yamasaki, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 1256.
Enantioselective Zr-Catalyzed !"Cyanohydrin Synthesis
! An enantioselective variant has been proposed and is under development.
1) Zr(OtBu)4 : ligand : H2O (1:1:1)
ClCH2CH2Cl
+ BTSP + TMSCN
OH
2) KF, MeOH
CN
85% yield
62% ee
Ph
Et
Et
Ph
O
OH
OH
O
Ph
Ph
LIGAND
Yamasaki, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 1256.
Platinum-Catalyzed Hydrogenation of Ethyl Pyruvate
O
Me
OH
Pt/Al2O3, H2
CO2Et
modifier
Me
CO2Et
! Chincona alkaloids have been shown to adsorb to Pt surfaces in an ordered pattern with uniformly shaped pores.
! Relative reaction rates from kinetic data suggest a ligand acceleration effect of !13.
Et
! Author's rendition of proposed transition states
Et
N
N
OMe
H
OH
H
Me
N
RO
N
N
ee 93%
ee 20%
H H
EtO
O
N
Me
O
Pt
Pt
Pt
R
HO
N
NH2
N
RO
H
H
EtO
Pt
Pt
ee 75%
O
O
Me
Pt
ee 82%
Pt Surface Modifiers
Blaser, H.U.; Jalett, H.P.; Lottenbach, W.; Studer, M. J. Am. Chem. Soc. 2000, 122, 12675.
Thomas, J.M. Angew. Chem. Int. Ed. Engl. Adv. Mater. 1989, 28, 1079.
Garland, M.; Blaser, H.U. J. Am. Chem. Soc. 1990, 112, 7048.
Ruthenium-Catalyzed Transfer Hydrogenation
20 mol % RuCl2(PPh3)3
26 mol % ligand
O
Me
OH
Me
iPrOH / iPrOK
Ligand
none
time
conversion
20 h
5%
6h
93 %
(94% ee)
Ph
N
Fe PPh3 O
A
! Only aryl ketones are reduced enantioselectively.
20 mol % RuCl2(PPh3)3
26 mol % A
O
Ar
R
OH
Ar
iPrOH / iPrOK
R
yields ! 75 %
ee (%)
! 84
96 (Ar = Ph)
88 (Ar = Ph)
R
Me
Et
iPr
Sammakia, T.; Strangeland, E.L. J. Org. Chem. 1997, 62, 6104.
Copper-Catalyzed Enolsilane Amination
! Evidence for LAC: Use of excess Cu(OTf)2 (50 mol %) relative to ligand (2 & 10 mol %) shows no significant
decrease in enantioselectivity (99 % vs. 96 % ee).
2+
Me Me
O
O
N
X
O
O
OTMS
R
+
2 OTf-
N
tBu
O
N
N
O
Troc
CF3CH2OH
X = Ar, pyrrole, StBu
R = Me, Et, iPr, tBu, Ph, Bn
Ph
Troc
Ph
N
L2Cu
N
O
N
H
N
O
OTMS
R
O
N
N
O
O
yield ! 64
ee ! 96
OTMS
R
R
X
tBu
1-10 mol %
N
Troc
Cu
Troc
N
O
N
ROH
O
O
N
O
ROTMS
proposed intermediates
! Amination reaction allows access to chiral building blocks: protected chiral hydrazines, hydrazino alcohols,
and oxazolidones.
Evans, D.A.; Johnson, D.S. Org. Lett. 1999, 1, 595.
Conjugate Additions of Dialkylzinc Reagents
! Diamines and amino-alcohols accelerate the reaction of dialklzinc reagents with aldehydes.
! Without catalyst, no product is generated under reaction conditions.
OH
Et
NMe2
98 % ee
OH
Me
Me
O
Catalyst
OH
99 % ee
(using (C5H11)2Zn)
O
R
H
2 mol % catalyst
+ Et2Zn
Me
OH
96 % ee
Me
Me
O
Me
Me2
O
N
Zn
RH
R Zn
R
OH
90 % ee
OH
Ph
proposed T.S.
Me
Me
61 % ee
Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382, 19.
Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley and Sons, Inc.: New York, 1994.
Titanium-Catalyzed Enantioselective Alkylation of Aldehydes
! Catalytic ligand loading can be used with stiochiometric titanium
! Taddol prevents titanium oligomerization.
Ph
O
Ph
H
+
Et2Zn
OH
20 mol% B
1.2 equiv Ti(OiPr)4
Ph
Me
Et
96% yield
98% ee
Me
Ph
O
O
O
O
Ti(OiPr)2
Ph
Ph
! Diamine ligand increases titanium's Lewis acidity.
O
R1
OH
R2Zn, Ti(OiPr)4
H
R1 = alkyl, !,"-unsat, aryl
8 mol% cat
R1
Tf
N
R
56-95% yield
68-98 %ee
Ti(OiPr)2
N
Tf
Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473.
Rozema, M.J.; Sidduri, A.; Knochel, P.; J. Org. Chem.; 1992; 57; 1956.
Rozema, M.J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P.; Tet. Lett.; 1993; 34; 3115.
Lewis Base-Catalyzed Aldol Reactions
! Phosphoramide ligands greatly increase the reactivity of silicon as a Lewis acid.
OSiCl3
O
MeO
H
O
CD2Cl2, -80 °C
+
OSiCl3
MeO
tBu
Additive
time
tBu
Conversion
none
2h
50 %
10 mol % HMPA
<3 min
100 %
! Enantioselective methyl ketone aldol reactions:
OSiCl3
O
R1
OH
R1
CH2Cl2, -78 °C
R2
H
O
5-10 mol % catalyst
+
Me
R2
N
yields ! 79%
R1
nBu
nBu
nBu
Me
tBu
Ph
R2
(E)-CH=CHPh
c-C6H11
tBu
Ph
Ph
Ph
O
P
N
ee (%)
84
89
92
87
52
49
N
Me
CATALYST
Denmark, S.E.; Stavenger, R.A. Acc. Chem. Res. 2000, 33, 432.
Lewis Base-Catalyzed Aldol Reactions
! Geometry of enolate controls stereochemical outcome of reaction.
OSiCl3
O
O
+
H
OH
10 mol % catalyst
R
R
yields !90
R
aryl
CH=CHPh
CMe=CHPh
C!CPh
syn/anti
1 / !61
<1 / 99
<1 / 99
1 / 5.3
ee (%)
!93
88
92
82
Me
N
O
P
N
N
Me
O
OSiCl3
Ph
Me
+
H
O
15 mol % catalyst
OH
Ph
R
R
CATALYST
Me
yields ! 89%
R
aryl
CH=CHPh
CH=CHMe
C!CPh
syn / anti
!3 / 1
9.4 / 1
7.0 / 1
1 / 3.5
ee (%)
!84
92
91
10*
* anti ee
Denmark, S.E.; Stavenger, R.A.; Wong, K.T.; Su, X. J. Am. Chem. Soc. 1999, 121, 4982.
Denmark, S.E.; Stavenger, R.A. Acc. Chem. Res. 2000, 33, 432.
Lewis Base-Catalyzed Aldol Mechanism
Me
! Kinetics and a demonstrated non-linear relationship between catalyst ee and product ee
N
suggest two phosphoramide molecules involved in the transition state.
O
P
! Exerimental evidence suggests chloride dissociation is involved in the reaction.
N
N
! Kinetics of a more sterically encumbered catalyst suggest an alternate mechanism involving
Me
only one phosphoramide molecule.
CATALYST
P(NR2)3
Cl-
O Si O
Cl
Cl
2 (R2N)3PO
O
PhCHO
O
Ph
P(NR2)3
OPR3
OPR3
Si
Cl
Cl
O
H O
OSiCl3
Ph
-2 (R2N)3PO
Cl-
anti
Chair-like T.S.
high selectivity
OSiCl3
H
(R2N)3PO
Cl-
O
O
P(NR2)3
Ph
Si Cl
Cl
PhCHO
Cl-
O
Cl
O Si OPR3
Cl
O
OSiCl3
Ph
-(R2N)3PO
syn
Boat-like T.S.
low selectivity
Denmark, S.E.; Stavenger, R.A. Acc. Chem. Res. 2000, 33, 432.
Silicon-Catalyzed Allylation and Propargylation of Aldehydes
! Variation in catalyst linker length affects reaction efficiency and selectivity. This supports a mechanism involving 2
phosphoramides in the transition state.
OH
O
R
H
5 mol % catalyst
SnBu3
+
R
110 mol % SiCl4
yields ! 65%
R
aryl
cinnamyl
C!CPh
furyl
ee (%)
!83
65
22
62
N
Me
O
P
N
N
(CH2)5
Me Me
2
H
O
R
H
OH
5 mol % catalyst
+ H
SnBu3
110 mol % SiCl4
H
CATALYST
R
H
R
Ph
cinnamyl
2-naphthyl
ee (%)
97
87
93
yield (%)
81
90
95
Denmark, S.E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199.
This is my Summary Slide
! Most ligand accelerated processes exhibit non-linear effects (rate and ee).
! LAC allows for highly selective transformations by selecting against an undesired pathway.
! LAC lends itself well to the development of asymmetric transformations.
! The discovery of more ligand-accelerated transformations will be a fruitful field in asymmetric catalysis.