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Topic: Key concepts in catalysis
1
Reaction coordinate
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- Free energy, enthalpy and entropy are thermodynamic phenomena.
Boger’s Modern Organic Synthesis C.2
2
Transition state theory
2.1
Energy of activation
- Energy, enthalpy and entropy of activation are kinetic phenomena.
- 20 kcal/mol energy available at 25°C for free energy of activation (∆G‡).
- Increasing reaction temperature increases the rate of reaction but may decrease selectivity.
- R = the universal gas constant; kB = Boltzmann constant; and h = Planck's constant.
Boger’s Modern Organic Synthesis C.2
2.2
Rate determining step (rds)
- In a reaction involving more than one elementary step – that is more than one intermediates formed – there
is more than one energy barrier (more than one TS).
- The elementary step involving the highest energy barrier going to the TS is the rate-determining step (a).
- Note that pathway involving the highest energy TS is not necessarily the rate-determining step (b & c).
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7
1
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2.3
Kinetic and thermodynamic control
- In a reversible reaction, the majority of the product will be the thermodynamic product.
- In an irreversible reaction, the majority of the product may be the kinetic product.
Trost JOC 1965, 30, 1341
3
Catalysis
3.1
Catalyst definition and energy diagram
Boger’s Modern Organic Synthesis C. 2
4
Enantioselective catalysis
- Enantiomeric ratio is directly proportional to the relative rate of the enantiomeric products.
- Enantiomeric ratio is governed by differential activation parameters (∆∆G ‡, ∆∆H‡ and ∆∆S‡).
- R and S are chosen below arbitrarily.
Walsh and Kozlowski, Fundamentals of Asymmetric Catalysis, C.1
Some useful number to think about in enantioselective catalysis:
- ∆∆G‡ of 1.38 kcal/mol is needed to achieve 80% ee at room temp
- ∆∆G‡ of ~2.0 kcal/mol is needed to achieve 90% ee at room temp
- ∆∆G‡ of 2.60 kcal/mol is needed to achieve 98% ee at room temp
- ∆∆G‡ of 2.73 kcal/mol is needed to achieve 99% ee at room temp
- ∆∆G‡ of 1.80 kcal/mol is needed to achieve 98% ee at -78oC
Hartwig (Walsh) Organotransition Metal Chemistry, C.14
2
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4.1
Diastereomeric transition state
- Case 1: simple complex with a diastereomeric transition state
Shibassaki Adv. Synth. Catal 2004, 346, 1533
- Case 2: a more complicated TS involving complex with multiple catalysts
Blackmond and Jacobsen JACS 2004, 126, 1360
4.2
Transition state stabilization
Hiersemann & Strassner JOC 2007, 72, 4001
4.3
Microscopic reversibility
- The conversion of the product back to the reactant has to undergo through the same pathway with the
forward reaction, encountering the exact same intermediate(s) and transition state(s).
Blackmond ACIE 2009, 48, 2648
4.4
The Hammond postulate
- Activated complex (TS) most resembles the structure of adjacent reactant, intermediate, or product that is
closest in energy (thermodynamic factor).
- For example, in a highly exothermic reaction, the TS is closer in energy and in structure to the reactant than
the product (early transition state e.g. Grignard reagent addition to carbonyl compounds).
3
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R3COH
E
Bode Research Group
R
H+
C
R
R
Nu-
R3CNu
E
TS1
TS2
R
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C
R
CH2R
The transition states
resemble the geometry
of the carbocation
intermedate, not the
reactant nor the product.
R
CHR2
R3COH
The ralative stability of
carbocation:
the TS becomes more
stable as the reaction
becomes less endothermic.
CR3
R3CNu
reaction coordinate
reaction coordinate
Hammond JACS 1955, 77, 334
4.5
The CurtinHammett Principle
- In multistep reactions, there maybe an equilibrium between two diastereomeric intermediates.
- The overall enantioselection is determined by the difference in the relative heights of the turnover-limiting
barrier (∆∆G‡).
- From the graph below, I1 is more stable than I2 (from ∆∆G). But formation of I2 is more favorable because of
relative activation energy (∆∆G‡).
I1 gradually reverses back to the starting material (SM) then to I2 (SM, I1 and I2 are in equilibrium).
Halpern Science 1982, 217, 401
4.6
Catalyst turnover
- Catalyst productivity: Turn Over Number (TON) = mol product/mol catalyst
- Catalyst reactivity: Turn Over Frequency (TOF) = (mol product/mol catalyst)/hour = TON/hour (unit of h -1)
- For example, hydrogenation should have TON > 1000 for high value product and >50,000 for large-scale.
- For hydrogenation, TOF > 500 h-1 for small scale and TOF>10,000 h-1 for large scale
Blaser Appl. Catal. A 2001, 221, 119
4
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4.7
Catalyst resting state
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Stoltz ACIE, 2009, 48, 6840
4.8
Product inhibition
- Product inhibition occurs when the product binds better to the catalyst than the starting material. This is a
common problem in the catalysis of the Claisen reaction.
Yamamoto JACS 1990, 112, 316
4.9
Background rate
- The stating materials can react to form the product without the aid of the catalyst. If the background
reaction is faster than that the catalyzed reaction, lower selectivity is obtained. (The background reaction
normally, is unfavorable and has to be avoided).
Evans JACS 1999, 121, 7582
5
5.1
Modes of binding
Single point binding
10 mol% (R)-BINOL
10 mol% TiCl2(Oi-Pr)
O
Me
+
H
OH
CF3
CF3
Me
L* =
OH
OH
98% syn
96% ee
TiL*
O
CF3
Me
H
H
Mikami Tetrahedron 1996, 52, 85
5
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5.2
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Multiple points binding (tends to give higher selectivity because of a highly organized TS)
Hiersemann ACIE, 2001, 40, 4700
6
Types of catalysis
6.1
BrØnsted acid catalysis
NMe2
NMe2
NMe2
NMe2
B
2 mol% B-H
H
Ar
B-H =
N
O
Toluene, 1 d
H
t-BuO2C
N
O
H
H
H
t-BuO2C
N
N
N
Ar
N
N
N
N
O
H
Ar t-BuO H C
2 2
H
HN
B
t-BuO2C
O
Ar
N
N
9-anthryl
O
O
Ar = 4-FC6H4, 74% yield, 97% ee
4-PhC6H4, 71% yield, 97% ee
4-MeOC6H4, 62% yield, 97% ee
O
P
OH
9-anthryl
9-anthryl
Terada JACS 2005, 127, 9360
6.2
Lewis acid-base catalysis
Walsh and Kozlowski, Fundamentals of Asymmetric Catalysis, C.2
Denmark JACS 1999, 121, 4982
6
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6.3
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Transition metal catalysis
Trost Acc Chem Res, 1996, 29, 355
6.4
Organocatalysis
Barbas JACS, 2000, 122, 2395
6.5
Hydrogen bonding
O
Ph
CN
NH HN
N
HN
O
O
OH
2 mol%
H
CN
HCN
toluene, -20 oC
Ph
Ph
O
O H N
H
N
H
HN
H
NH
H
O
97% conv., 97% ee
Inoue JOC 1990, 55, 181
6.6
Ion-pair catalysis
Phase Transfer Catalysis (PTC) – (convenient for process chemists because of the ease of product isolation)
O’Donnell Acc. Chem. Res. 2004, 37, 506
7
Mode of activations
7.1
Electrophile activation
7
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Fu Acc. Chem. Res. 2000, 33, 412
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7.2
Nucleophile activation
O
NO2
+
H
R1
Ph
Ph
N
H
TMSO
10-20 mol%
Ph
Ph
TMSO
N
Hexanes
1-48 h
R2
activated nucleophile
R2
O
NO2
H
R1
Ph
Ph
TMSO
R2
N
O
N
Yield
(%)
R1
R2
Me
Me
Me
Et
i-Pr
Ph
n-Bu
Cy
Ph
Ph
R1
85
52
56
66
72
syn:anti
%ee
(syn)
94:6
84:16
96:4
93:7
93:7
99
99
99
99
99
O
R1
Hayashi ACIE 2005, 44, 4212
8
Ligand effect on catalysis
8.1
Ligand decelerated reaction
- A chiral reagent adds more quickly than the ligated adduct (faster background reaction).
- For example, ligand decelerated catalysis is a common problem in asymmetric catalytic Grignard addition.
This is usually overcome by using chiral reagents in stoichiometric fashion.
Cram JACS 1981, 103, 4585
8.2
Ligand accelerated catalysis
- This is a case where there is almost no background rate (the two starting materials do not react at 0oC).
- The binding of Et2Zn to the ligand DAIB increases the Lewis acidity of the central Zn and accelerates the
reaction rate. The product enantiomeric outcome is governed by the catalyzed pathway.
8
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Noyori JACS 1986, 108, 6071
8.3
Non-linear effect - (product enantiopurity doesn’t correlate with catalyst enantiopurity)
Me
Me
HO
R
Ph
Me
R = Et
cat %ee = 15
product %ee = 95
NMe2
OH
Me
O
O
homodimer formation
is reversible
Zn
Me
R
N
Me
R
Zn
Zn
R
Me
N
Me
Me
Khomo
Me
Me
Me
Me
Me
Me
O
O
H
N
R
Zn
PhCHO
Me
Me
N
Me
N
N
R2Zn
R Zn
Zn R
O
O
Me
Me
Me
+ enantiomer
Khetero
DAIB
Me
Me
% ee
product
N
R
Me
Zn
O
O
Me
Zn
R
N
Me
non-linear effect
linear effect
heterodimer is
"trapped" and slow to
reenter the catalytic cycle
Me
% ee of catalyst
Noyori JACS 1989, 111, 4028
8.4
Autocatalysis – product formed in the reaction acts as the catalyst
- The Soai reaction
9
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Soai Nature 1995, 378, 767 & Review: Soai Top. Curr. Chem. 2008, 284, 1
8.5
The Horeau principle
- A sequential multistep process on two (or more) prochiral centers on the same molecule that leads to a
high enantiomeric excess at the expense of diastereomeric ratio by means of statistical amplification.
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Review: Glueck Catal. Sci. Technol., 2011, 1, 1099
2nd order amplification
Ph
x2
Ph
OH O
O
Ph
O
N B
OMe
O
3
Ph
BH3.DMS
THF
Ph
(S)
OH OH
Ph
3 Ph
x(1-x)
x
x(1-x)
OH O
Ph (R) 3 Ph
Condition:
1-x
- A single catalyst performs all reactions
- no chiral recognition from the previous step
- no rate difference among the isomers on the same step
(1-x)2
(S)
(S)
Ph
3
OH OH
(S)
Ph
(R)
3 Ph
meso
OH OH
(R)
Ph
(R)
3
Ph
eep = xn-(1-x)n
xn+(1-x)n
Amplification:
A large part of minor
enantiomer formed in
the first step is diverted
into the meso compound
and suppresses the
formation of the product's
minor enantiomer.
17.2 dr
94.3% ee
Kagan JACS 2003, 125, 7490
Sherburn Angew. Chem. Int. Ed. 2013, 52, 8333
Higher order amplification
Sharpless Science 1993, 259, 64
9
Kinetics analysis
9.1
Rate law
- Rate order may be integral (0, 1, 2, etc) or partial (2/3, 1/2, etc).
- A complex rate law is not uncommon in catalytic systems with multiple substrates.
Reaction order
Zero-Order
First Order
Second-Order
Second-Order (two species)
Complex
Differential form
d[P]/dt = k
d[P]/dt = k [A]1
d[P]/dt = k [A]2
d[P]/dt = k[A][B]
d[P]/dt = k[A]m[B]n[C]p …
Integral form
[A] = kt + [A]0
ln[A] = kt + ln[A]0
1/[A] = kt + 1/[A]0
ln([A]0[B]/ [B]0[A]) = kt ([B]0-[A]0)
solving differential equations
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7
9.1.1 Initial rate kinetics
- In a complex reaction with multiple competing pathways, it’s possible to measure the rate by following the
10
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reaction to the first 5-10% (ideally no more than 20%) of the reaction. This is done by measuring the
concentration of the starting material or the product and plot that against time.
Hartwig JACS 2008, 130, 5842
9.1.2 Pseudo rate order
- Used when one substrate is employed in large excess (usually >10 equiv).
- This greatly simplifies the rate law and rate constant determination.
d[P]/dt = k[A][B]
If [B] >> [A], then [B] is approximately constant, and k'  k[B]
d[P]/dt = k’[A]
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7
9.1.3 Steady state kinetics
- Use to simplify rate law in a reaction involving an intermediate that is approximated to be small in
concentration. Effectively the concentration of the intermediate is assumed to be constant.
Me Me
Me
Me
k1
rds
TiCp2
B
Me
Me
ROMP
P
k2
TiCp2
A
TiCp2
d[P]/dt = k2[I][B]
Steady state approximation: d[I]/dt = k 1[A] - k2[I][B] = 0  k2[I][B] = k1[A]
d[P]/dt = k1[A]
This explain the observed first order in the catalyst and zero order in substrate B.
Grubbs JACS 1986, 108, 733
9.1.4 Mechanistic studies
Analytical methods for mechanistic studies: NMR, UV-VIS, Calorimetry, IR, GC/MS, and HPLC.
Example 1: HPLC detection of nitrone intermediates. (for slow reactions)
11
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O
Ph
OH
O
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1
HO
Ph
N
H
CH3CN
O
Ph
Ph
N
H
3
Bode ACIE 2006, 45, 1248
Example 2: Reaction IR monitoring of the reaction of oxazolidinone A with nitrostyrene B to form C.
H
N
C
O
NO2
O
A
B
A
B
C
B
O
H
Ph
H
NO2
C
Seebach and Eschenmoser Helv. Chim. Acta 2007, 90, 425
9.1.5 Rate law determination
- “Power rate law” method. The rate orders are determined by measuring initial rates of each substrate over
a range of concentrations. The plot of ln[initial rate] vs. concentration affords the rate order.
12
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Denmark JACS 2009, 131, 11770 & JOC 2010, 75, 5558
- Reaction progress kinetics (RPK)
Alternative to the power rate law which involved performing multiple reactions, reaction progress kinetics
“employs in situ measurements and simple manipulations to construct a series of graphical rate equations
that enable analysis of the reaction to be accomplished from a minimal number of experiments. Such an
analysis helps to describe the driving forces of a reaction and may be used to help distinguish between
different proposed mechanistic models.” Reaction calorimetry is often a method of choice for RPK.
Blackmond ACIE 2005, 44, 4302
10
Mechanism determination
One can not prove a mechanism, but rather disprove one .
10.1 Activation parameter analysis (Eyring analysis)
- Determination of activation energy, enthalpy, and entropy (∆G‡, ∆H‡, ∆S‡) based on the following
relationship: ln(k/T) = -(ΔH‡/RT) + (ΔS‡/R) + ln(kB/h) where R = the gas constant; k B = Boltzmann constant;
and h = Planck's constant
H
0.5% Pd(NHC)(OAc)2(H2O)
R
OH
HOAc, O2
R
O
ln
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Sigman JACS 2004, 126, 9724
13
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10.2 Linear free energy relationship (LFER or Hammett analysis)
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- Substitution effect can be quantitatively studied using Hammett plots – a plot of log[ksubstituted/kno substitution] vs
sigma () values, characteristic for each substitution group and pattern.
- The slope of this plot is the rho () value.
- Negative  means positive change built up (or decrease in negative charge) in the rate-limiting step of the
reaction. Positive  means the opposite, and  = 0 means no substitution effect.
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.8
Bode ACIE 2011, 50, 1673
Other kind of LFERs correlate the rate of a reaction with steric parameters, pKa values, etc
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.8
Sigman PNAS 2011, 108, 2179
10.3 Labeling experiment
Kinetic Isotope Effect (KIE)
• Label tracking by analysis of the products (MS, 13C/17O-NMR, IR-spectroscopy, etc).
• Kinetic Isotope Effect (KIE): isotope distribution changes the reaction rate (k).
• Primary KIE: the X-D/X-H bond is broken in the rate determining step (primary KIE usually > 1.5).
• Secondary KIE: arises from the isotopic distribution remote from the bonds undergoing reaction.
• Normal Secondary KIE: kH/kD= 1.1-1.2 (the substituted carbon change hybridization from sp3 to sp2)
• Inverse Secondary KIE: : kH/kD = 0.8-0.9 (the substituted carbon change hybridization from sp2 to sp3)
Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7
14
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Angelis Tet. Lett 2001, 42, 3753
10.4 Computational chemistry
- “The discovery of several computational principles and algorithms — together with the development of fast
computers — has resulted in enormous leaps in the accuracy and speed of computational methods, and it is
now feasible to model many synthetic reactions …. [Computational techniques] provide information about
known catalytic reactions that is not available from experiments alone … [and] have become an invaluable
tool for predicting the behaviour of catalysts and have earned their place as a standard tool for the design of
catalysts.”
- Common techniques are Density functional theory (DFT), Hartree–Fock (HF),and Molecular mechanics
(MM).
Houk Nature 2008, 455, 309
Houk JACS 1986, 108, 554
10.5 Intermediate trapping
- "Pentacoordinate species (ii) are proposed to be intermediates in hydrolysis of RNA and DNA.
Compound i can cyclize to give ii, although ii was never seen at room temperature. However, upon
adding acetyl chloride to solution of i, both iii and iv are isolated."
- Intermediate can be a part of the catalytic cycle even if it can not be isolated.
Ramirez JACS 1978, 100, 5391
10.6 Off-cycle intermediate
- The detection of an intermediate species in any catalytic cycle must be interpreted with care.
- Detectable intermediate maybe stable but it may not be a relevant for the resting state of the reaction.
15
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Ph3P
Ph3P
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Ph3P
Cl
Rh
Cl
Rh
PPh3
PPh3
Rh
Cl
PPh3
Wilkinson's catalyst
S
http://www.bode.ethz.ch/
Ph3P
Cl
S
Rh
Me
Me
H
Me
Me
H
PPh3
Me Me
H
H
Me
Ph3P
Me
Rh
Cl
PPh3
S
PPh3
H2
H2
This species has been detected.
However, it's not in the actual
catalytic cycle.
H
Ph3P
Cl
Me
H
S
H
Rh
PPh3
PPh3
Ph3P
Cl
H
Rh
PPh3
S
H
Me
Ph3P
Me
Me
Cl
Me
Me
H
Rh
PPh3
Me
Me
Halpern Science 1982, 217, 401
10.7 Cross-over experiment
- A cross-over experiment is used to determine if a reactant breaks apart to form intermediate that are
released before they recombine to give the product. Usually, used to determine if the reaction is intra or
intermolecular.
Bode JACS, 2011, 133, 14082
A Case Study: Claisen rearrangements
11
There are a number of excellent reviews in the subject of the Claisen
rearrangements. For examples: (a) Ito Chem. Soc. Rev.. 1999, 28, 43. (b)
Hiersemann Eur. JOC. 2002, 9, 1461. (c) Hiersemann and Nubbemeyer The
Claisen Rearrangment 2007, Wiley-VCH.
11.1 Types of Claisen rearrangements
Carreira and Kvaerno Classics in Stereoselective Synthesis, C.16.2
11.2 Standard Claisen rearrangements mechanistic and kinetics studies
16
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- Based on the Hammond postulate, the high exothermicity of the aliphatic Claisen arrangement implies
early-transition state (resembled the reactant with more bond breaking character) based on the observation
of secondary deuterium kinetic isotope effect. KIE data and the substitution effect data suggested a
concerted, pericyclic mechanism (though not perfectly synchronous).
Gajewski JACS 1979, 101, 2747 & 6693
Carpenter JACS 1981, 103, 6983
- Catalyzed vs. uncatalyzed Claisen reaction energy profiles
Hiersemann & Strassner JOC 2007, 72, 4001
11.3 Catalytic Claisen rearrangements
11.3.1 Chorismate mutase
- Chorismate mutase catalyzes the only known sigmatropic rearrangement (a Claisen rearrangement)
involved in primary metabolism. Rate accelerations on the order of 106 over background rate are observed.
The study of this enzyme and the development of small molecule mimetics has been an area of considerable
interest for the past 15–20 years.
Hilvert JACS 2003, 125, 3206
17
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11.3.2 Hydrogen-bonding catalysis
- Chiral hydrogen-bonding organic catalysts are an area of intense interest at the moment,
chiral phosphoric acids, thioureas, or diols are most widely used as the hydrogen bond donors.
- An example below demonstrates that dual, rather than mono, hydrogen-bond activation plays an important
role in rate acceleration in the catalytic Claisen rearrangements.
O
O
H
1.0 equiv cat.
O
80 oC
OMe
OMe
Ar
N
H
O
N
Ar
MeO
krel
1.0
22.4
1.0
1.6
Cat.
none
Cat. A
Cat. B
Cat. C
bis-hydrogen bonding
CF3
CF3
CF3
C8H17O2C
N
H
CF3
CF3
O
O
N
H
CO2C8H17
N
Me
C8H17O2C
Cat. A
O
N
Me
Cat. B
CO2C8H17
C8H17O2C
N
H
Cat. C
Curran Tet. Lett. 1995, 36, 6647
Kozlowski Org. Lett. 2009, 11, 621
11.3.3 Lewis acid catalysis
- Extensive efforts on chiral and achiral Lewis acid catalyzed Claisen rearrangements have been reported,
but these tend to suffer from poor substrate scope and lack of catalyst turnover.
18
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11.4 Catalytic enantioselective Claisen rearrangement
- Although the enzymatic Claisen rearrangement has long been known from biosynthesis, there has been
relatively few examples of a simple organic catalyst that provides significant rate accelerations and control of
enantioselectivity.
Hiersemann ACIE 2001, 40, 4700
Kozlowski JACS. 2008, 130, 16162
19
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Jacobsen JACS 2008, 130, 9228 & JACS 2011, 133, 5062 (mechanism)
Jacobsen ACIE 2010, 49, 9753
11.5 Enantioselective Claisen rearrangement by catalytic generation of a reactive intermediate
- Transition metal catalyzed enantioselective formal Claisen rearrangement via a metal-pi complex
Nelson JACS 2010, 132, 11875
- We devised a catalytic Claisen reaction that overcomes the limitation of slow catalyst turnover by
considering an enantioselective variant of the Coates-Claisen reaction of enols and acetals of unsaturated
aldehydes that would give lactones as a means of catalyst turnover.” A chiral NHC was used as the catalyst
for highly enantioselective Claisen rearrangments via the intermediacy of α,β-unsaturated acyl azolium.
characterized by
NMR, UV-VIS
and HRMS
Me
Me
N
O
O
H
Ar
A
N
N
Me
10 mol%
B
O
N
O
C1
O
HO
O
O
Hc
C2
Hd
N N
Mes
C
O
O
OTBS
Ar
O
Ar
OTBS
DH‡ = +15.30 kcal/mol
DS‡ = – 25.50 cal/K.mol
kobs = – 3.41x10-4 s-1
rate = -kobs [B]1[A]0.5[C]-0.5
Bode JACS 2010, 132, 8810 & ACIE 2011, 50, 1673
- An aza-Claisen variant of the above reaction has also been achieved. Here, the key α,β-unsaturated acyl
20
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Update to 2013
Bode Research Group
http://www.bode.ethz.ch/
azolium was catalytically generated via an oxidation of the Breslow intermediate instead of an internal redox
reaction.
Bode Org. Lett. 2011, 13, 5378
21