OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/

Chapter 2: Key concepts in catalysis

1 Reaction coordinate

- Free energy, enthalpy and entropy are thermodynamic phenomena.

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- Boger’s Modern C.2

2 theory 2.1 Energy of


- - 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 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 where one or more intermediates are 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 the pathway involving the highest energy TS is not necessarily the rate-determining step (b & c).

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Page 1 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 2.3 Kinetic and thermodynamic control - In a reversible reaction, the majority of the will be the thermodynamic product. - In an irreversible reaction, the majority of the product may be the kinetic product.

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Trost JOC 1965, 30, 1341 International

4.0 3 Catalysis 3.1 Catalyst definition and energy diagram

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Boger’s Modern Organic Synthesis C. 2

4 Enantioselective catalysis


- Enantiomeric ratio is directly proportional to the relative rates of formation of the enantiomeric products. - Enantiomeric ratio is governed by differential activation parameters (∆∆G‡, ∆∆H‡ and ∆∆S‡). - R and S are chosen below arbitrarily. Creative

This work is licensed under a 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 Chemistry, C.14

Page 2 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 4.1 Diastereomeric transition states - Case 1: simple complex with a diastereomeric transition state

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Shibasaki Adv. Synth. Catal 2004, 346, 1533

- Case 2: a more complicated TS involving a complex with multiple catalysts International


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NonCommercial - 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 proceed through the same pathway with the This work is licensed under a forward reaction, encountering exactly the 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 addition to carbonyl compounds).

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+ R R Nu- H C R3COH R3CNu R E

E TS1 TS 2 CH2R The transition states The ralative stability of resemble the geometry carbocation: R R CHR C of the carbocation 2 the TS becomes more

intermedate, not the stable as the reaction . R reactant nor the product. becomes less endothermic.


License reaction coordinate reaction coordinate

Hammond JACS 1955, 77, 334

4.5 The CurtinHammett Principle International

4.0 - In multistep reactions, there may exist an equilibrium between two diastereomeric intermediates.

- The overall enantioselectivity 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 the lower relative (∆∆G‡). ShareAlike - I1 gradually reverses back to the starting material (SM) then to I2 (SM, I1 and I2 are in equilibrium). NonCommercial - Attribution

Halpern Science 1982, 217, 401

Commons 4.6 Catalyst turnover

- Catalyst productivity: Turn Over Number (TON) = mol product/mol catalyst -1 Creative

- Catalyst : Turn Over Frequency (TOF) = (mol product/mol catalyst)/hour = TON/hour (unit of h ) - For example, 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 This work is licensed under a

Blaser Appl. Catal. A 2001, 221, 119

Page 4 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 4.7 Catalyst resting state

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Stoltz ACIE 2009, 48, 6840

4.8 Product inhibition International - Product inhibition occurs when the product binds better to the catalyst than the starting material. This is a 4.0

common problem in the catalysis of the Claisen reaction. ShareAlike -

NonCommercial - Yamamoto JACS 1990, 112, 316

4.9 Background rate

Attribution - The starting materials may react to form the product without the aid of the catalyst. If the background rate of

reaction is comparable to or faster than the catalyzed reaction, lower selectivity is obtained. (The background reaction is normally unfavorable and has to be avoided). Commons


Evans JACS 1999, 121, 7582

This work is licensed under a 5 Modes of binding

5.1 Single point binding

10 mol% (R)-BINOL O OH 10 mol% TiCl2(Oi-Pr) + Me TiL Me CF3 H CF3 O Me H CF3 OH L = 98% syn OH 96% ee H

Mikami Tetrahedron 1996, 52, 85 Page 5 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 5.2 Multiple points binding (tends to give higher selectivity because of a highly organized TS)

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Hiersemann ACIE 2001, 40, 4700

6 Types of catalysis

International BrØnsted catalysis 6.1


NMe2 NMe2 NMe2

NMe2 B

ShareAlike H - 2 mol% B-H O N , 1 d N O HN O H O N H Ar t-BuO C t-BuO2C H t-BuO2H2C Ar B 2 t-BuO2C H Ar H H Ar N N N N N N N N

9-anthryl NonCommercial B-H = - Ar = 4-FC H , 74% yield, 97% ee O O 6 4 P 4-PhC H , 71% yield, 97% ee O OH 6 4 4-MeOC6H4, 62% yield, 97% ee 9-anthryl

Attribution 9-anthryl

Terada JACS 2005, 127, 9360

6.2 Lewis acid- catalysis Commons


Walsh and Kozlowski, Fundamentals of Asymmetric Catalysis, C.2

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Denmark JACS 1999, 121, 4982

Page 6 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 6.3 catalysis


License Trost Acc. Chem. Res 1996, 29, 355





- Barbas JACS 2000, 122, 2395

6.5 bonding catalysis



NonCommercial N

- O HN Ph HN O OH H 2 mol% Ph NH O O H H CN N HCN H H N toluene, -20 oC H O Attribution 97% conv., 97% ee

Inoue JOC 1990, 55, 181


6.6 -pair catalysis Transfer Catalysis (PTC) – (convenient for process because of the ease of product isolation) Creative

O’Donnell Acc. Chem. Res. 2004, 37, 506

7 Modes of activation

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Fu Acc. Chem. Res. 2000, 33, 412 Page 7 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 7.2 Nucleophile activation

Ph Ph Ph N H Ph O NO2 TMSO N + 10 20 mol% TMSO Yield %ee H R1 R2 syn:anti Hexanes (%) (syn) 1 2 1 R R 1 48 h R Me Ph 85 94:6 99

activated nucleophile . Me n-Bu 52 84:16 99 Me Cy 56 96:4 99 Ph Et Ph 66 93:7 99 2 Ph 2 i-Pr Ph 72 93:7 99

License O R N R O


Hayashi ACIE 2005, 44, 4212 International

8 Ligand effect on catalysis 8.1 Ligand decelerated reaction 4.0 - 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 in stoichiometric fashion. ShareAlike - NonCommercial -

Attribution 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 0 oC). Commons - The binding of Et2Zn to the ligand DAIB increases the Lewis acidity of the central Zn and accelerates the . The product enantiomeric outcome is governed by the catalyzed pathway. Creative

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Noyori JACS 1986, 108, 6071

Page 8 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 8.3 Non-linear effect - (product enantiopurity does not correlate with catalyst enantiopurity)

Me Me Me Me N R N R Me Me HO Ph PhCHO Zn Zn O O O O R H homodimer formation Me Zn Me Zn is reversible R = Et R N R N cat %ee = 15 Me Me Me Me

. product %ee = 95 Khomo

Me Me Me Me Me Me N N License

R2Zn NMe2 Zn R R Zn OH Me O O + Me Me K DAIB hetero International

Me Me % ee N R

4.0 product Zn Me heterodimer is O O "trapped" and slow to reenter the Me Zn R N Me non-linear effect Me ShareAlike

- linear effect

% ee of catalyst

Noyori JACS 1989, 111, 4028

8.4 – the product formed in the reaction acts as the catalyst NonCommercial

- - The Soai reaction Attribution

Commons Soai Nature 1995, 378, 767 & Review: Soai Top. Curr. Chem. 2008, 284, 1

8.5 The Horeau principle

Creative - A sequential multistep process on two (or more) prochiral centers on the same that leads to a high enantiomeric excess at the expense of diastereomeric ratio by means of statistical amplification.

Review: Glueck Catal. Sci. Technol. 2011, 1, 1099 2nd order amplification

x2 OH OH Ph (S) (S) n n Ph eep = x -(1-x) OH O Ph Ph n n O 3 x +(1-x) N B Ph (S) 3 Ph x(1-x) O O OH OH Amplification: OMe x A large part of minor x(1-x) (S) (R) Ph Ph OH O Ph Ph enantiomer formed in 3 BH3.DMS 3 THF meso the first step is diverted Ph (R) Ph into the meso compound This work is licensed under a 3 Condition: (1-x)2 OH OH and suppresses the 1-x - A single catalyst performs all reactions (R) (R) formation of the product's - no chiral recognition from the previous step Ph 3 Ph minor enantiomer. - no rate difference among the on the same step 17.2 dr 94.3% ee Kagan JACS 2003, 125, 7490

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Sherburn Angew. Chem. Int. Ed. 2013, 52, 8333

Higher order amplification International


ShareAlike Sharpless , , 64

- Science 1993 259 9 Kinetic 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 Differential form Integral form NonCommercial - Zero-Order d[P]/dt = k [A] = kt + [A]0 1 First Order d[P]/dt = k [A] ln[A] = kt + ln[A]0 2 Second-Order d[P]/dt = k [A] 1/[A] = kt + 1/[A]0 Second-Order (two species) d[P]/dt = k[A][B] ln([A]0[B]/ [B]0[A]) = kt ([B]0-[A]0) Attribution Complex d[P]/dt = k[A]m[B]n[C]p … solving differential equations

Anslyn and Dougherty, Modern Physical , C.7

Initial rate kinetics

Commons 9.1.1 - In a complex reaction with multiple competing pathways, it’s possible to measure the rate by following the 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. Creative

This work is licensed under a Hartwig JACS 2008, 130, 5842

9.1.2 Pseudo rate order - Used when one 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] remains approximately constant, and k' k[B] d[P]/dt = k’[A]

Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7

Page 10 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 9.1.3 Steady state kinetics - Use to simplify the 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 B Me Me k1 ROMP

P . rds k TiCp2 TiCp2 2 A TiCp2 License d[P]/dt = k2[I][B]

Steady state approximation: d[I]/dt = k1[A] - k2[I][B] = 0 k2[I][B] = k1[A]

d[P]/dt = k1[A]

International This explains the observed first order in the catalyst and zero order in substrate B.

4.0 Grubbs JACS 1986, 108, 733

9.1.4 Mechanistic studies Analytical methods for mechanistic studies: NMR, UV-Vis, , IR, GC/MS, and HPLC. ShareAlike - Example 1: HPLC detection of nitrone intermediates. (for slow reactions) NonCommercial - Attribution


Bode ACIE 2006, 45, 1248

Example 2: Reaction IR monitoring of the reaction of oxazolidinone with nitrostyrene to form .

Creative A B C

This work is licensed under a 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 slope of the plot of ln[initial rate] vs. ln[concentration] affords the rate order.

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NonCommercial - Denmark JACS 2009, 131, 11770 & JOC 2010, 75, 5558 - Reaction progress kinetics (RPK) Alternative to the power rate law, which involves performing multiple reactions, reaction progress kinetics

Attribution “employs 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.

Commons Blackmond ACIE 2005, 44, 4302

10 Mechanism determination Creative

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; kB = Boltzmann constant; and h = Planck's constant This work is licensed under a

Sigman JACS 2004, 126, 9724

Page 12 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 10.2 Linear free energy relationship (LFER or Hammett analysis)

- 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 transition state of 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




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Other kind of LFERs correlate the rate of a reaction with steric parameters, pKa values, etc

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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-, 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). This work is licensed under a • Secondary KIE: arises from the isotopic distribution remote from the bonds undergoing reaction. 3 2 • Normal Secondary KIE: kH/kD= 1.1-1.2 (the substituted changes hybridization from sp to sp ) 2 3 • Inverse Secondary KIE: : kH/kD = 0.8-0.9 (the substituted carbon changes hybridization from sp to sp )

Anslyn and Dougherty, Modern Physical Organic Chemistry, C.7

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Angelis Tet. Lett. 2001, 42, 3753

10.4 - “The discovery of several computational principles and algorithms — together with the development of fast International

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 4.0 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 ShareAlike

- (MM). Houk Nature 2008, 455, 309 NonCommercial - Attribution

Houk JACS 1986, 108, 554


10.5 Intermediate trapping - "Pentacoordinate species (ii) are proposed to be intermediates in the of RNA and DNA. Compound i can cyclize to give ii, although ii was never seen at room temperature. However, upon Creative adding to solution of i, both iii and iv are isolated." - Intermediate may be a part of the catalytic cycle even if it cannot be isolated.

Ramirez JACS 1978, 100, 5391 This work is licensed under a 10.6 Off-cycle intermediate - The detection of an intermediate species in any catalytic cycle must be interpreted with care. - Detectable intermediate may be stable but it may not be relevant for the resting state of the reaction.

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Me Me Me Me Me Me H H H H Me Ph P PPh Ph P 3 3 S Ph3P S 3 Me Rh Rh Rh Cl PPh Cl PPh 3 Cl PPh3 3 Ph3P Cl PPh3 Rh Rh Wilkinson's catalyst S Ph3P Cl PPh3 H This species has been detected. H2 2 H

However, it's not in the actual

. H Me Me catalytic cycle. H S Ph3P H Ph3P H Ph P H 3 Me Me Rh Rh Rh Cl PPh3 Cl PPh3 Cl PPh3

License PPh Me Me

3 S 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 intermediates that are International released before they recombine to give the product. It is usually used to determine if the reaction is intra- or

4.0 intermolecular.

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Bode JACS 2011, 133, 14082

A Case Study: Claisen rearrangements 11 Commons 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. J. Org. Chem. 2002, 9, 1461. (c) Hiersemann and Nubbemeyer The Claisen Rearrangment 2007, Wiley-VCH. Creative

11.1 Types of Claisen rearrangements

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Carreira and Kvaerno Classics in Stereoselective Synthesis, C.16.2

Page 15 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 11.2 Standard Claisen rearrangements: mechanistic and kinetics studies

- Based on the Hammond postulate, the high exothermicity of the aliphatic Claisen rearrangement implies an early-transition state (resembling the reactant with more bond breaking character) based on the observation of a secondary deuterium kinetic isotope effect. KIE data and the substitution effect data suggest a concerted, pericyclic mechanism (though not perfectly synchronous).

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Gajewski JACS 1979, 101, 2747 & 6693 International


ShareAlike - Carpenter JACS 1981, 103, 6983 - Catalyzed vs. uncatalyzed Claisen reaction energy profiles NonCommercial - Attribution



Hiersemann & Strassner JOC 2007, 72, 4001

11.3 Catalytic Claisen rearrangements 11.3.1

- Chorismate mutase catalyzes the only known sigmatropic rearrangement (a Claisen rearrangement) involved in primary . Rate accelerations on the order of 106 over background rate are observed. The study of this and the development of small molecule mimetics has been an area of considerable interest for the past 15–20 years. This work is licensed under a

Hilvert JACS 2003, 125, 3206

Page 16 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 11.3.2 Hydrogen-bonding catalysis - Chiral hydrogen-bonding organic catalysts are an area of intense interest at the moment where chiral phosphoric , thioureas, or are most widely used as the 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.


. Cat. k O O N O rel 1.0 equiv cat. H none 1.0 N Cat. A 22.4 80 oC O H Ar OMe OMe Cat. B 1.0 License MeO Cat. C 1.6

bis hydrogen bonding

CF CF CF CF 3 3 3 3 CF3

O O O C H O C N N CO C H C H O C N N CO C H 8 17 2 2 8 17 8 17 2 2 8 17 C8H17O2C N International H H H

Me Me Cat. A Cat. B Cat. C 4.0

Curran Tet. Lett. 1995, 36, 6647 ShareAlike -

NonCommercial Kozlowski Org. Lett. 2009, 11, 621 -

11.3.3 Lewis - Extensive efforts on chiral and achiral Lewis acid catalyzed Claisen rearrangements have been reported,

Attribution but these tend to suffer from poor substrate scope and lack of catalyst turnover.


Majumdar Tetrahedron 2008, 64, 597 Creative

This work is licensed under a Sharma Synlett 2000, 5, 615

Hiersemann Org. Lett. 2000, 3, 149

Page 17 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 11.4 Catalytic enantioselective Claisen rearrangement

- Although the enzymatic Claisen rearrangement has long been known from , there have been relatively few examples of a simple organic catalyst that provides significant rate accelerations and control of enantioselectivity.

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Kozlowski JACS 2008, 130, 16162




Jacobsen JACS 2008,130, 9228 & JACS 2011, 133, 5062 (mechanism)

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Jacobsen ACIE 2010, 49, 9753

Page 18 OC VI (HS 2015) Bode Research Group http://www.bode.ethz.ch/ 11.5 Enantioselective Claisen rearrangement by catalytic generation of a reactive intermediate

- Transition metal catalyzed enantioselective formal Claisen rearrangement via a metal-pi complex

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Nelson JACS 2010, 132, 11875

- We have 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 of unsaturated International that would give lactones as a means of catalyst turnover. A chiral NHC was used as the catalyst 4.0 for highly enantioselective Claisen rearrangments via the intermediacy of an α,β-unsaturated acyl azolium. ShareAlike - NonCommercial -

characterized by Attribution O NMR, UV-VIS Me and HRMS HO Me O N N ‡ O H = +15.30 kcal/mol O N O O Me O O Hc S‡ = – 25.50 cal/K.mol B O C OTBS N C -4 -1 H C 1 Ar kobs = – 3.41x10 s Commons 10 mol% 2 O 1 0.5 -0.5 rate = -k [B] [A] [C] Ar N Hd obs A N Ar OTBS Mes

Creative 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 azolium was catalytically generated via an oxidation of the Breslow intermediate instead of an internal reaction. This work is licensed under a

Bode Org. Lett. 2011, 13, 5378

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