Fundamentals of Asymmetric Catalysis: Energetics and Principles

14. 1. General  Principles
14.1.1. Definition of a Catalyst
14.1.2. Energetics of Catalysis
14.1.3. Reaction Coordinate Diagrams of Catalytic Reactions
14.1.4. Origins of Transition State Stabilization
14.1.5. Terminology of Catalysis
14.1.6. Kinetics of Catalytic Reactions and Resting States
14.1.7. Homogeneous vs. Heterogeneous Catalysis
Organometallics Study Meeting
Chapter 14. Principles of Catalysis
2011/08/28 
Kimura
1
14. 2. Fundamentals of Asymmetric Catalysis
14.2.1. Importance of Asymmetric Catalysis
14.2.2. Classes of Asymmetric Transformations
14.2.3. Nomenclature
14.2.4. Energetics of Stereoselectivity
14.2.5. Transmission of Asymmetry
14.2.6. Alternative Asymmetric Processes:
            Kinetic Resolution and Desymmetrizations
2
14.2.4. Energetics of Stereoselectivity
 Δ
Δ
G
= 1.38 kcal/mol => 10:1 ratio of product (at rt.)
 
Δ
Δ
G
= 2 kcal/mol => 90%ee
3
14.2.4.1.1 Reaction with a Single Enantioselectivity-Determining Step
 simplest case:
  >direct reaction of catalyst. and prochiral substrate. 
  >
without coordination 
of subst. to cat. before enantioselectivity-determining step
 atom and group-transfer reactions  (epoxidation, aziridination etc.)
4
14.2.4.1.1 Reaction with Revesibility Prior to the Enantioselectivity-Determining
                
Step: The Curtin-Hammett Principle Applied to Asymmetric Catalysis
 Prochiral substrates bind to catalyst in a separate step from 
e
nantioselectivity-
  determining step (
EDS
)
1) 
interconversion of 
I
 and 
I’
 is slow relative to conversion to the product 
(Scheme 14.12.A)
     
EDS
 = binding to the prochiral olefin faces to the metal
2) 
interconversion of 
I
 and 
I’
 is significantly fast: 
(Scheme 14.12.B)
     
EDS
 = reaction to form the product (
Curtin-Hammett conditions
)
5
14.2.4.1.1 
The Curtin-Hammett Principle
 when competing reaction pathways 
begin from rapidly interconverting isomers
,
 ⇒ 
product ration is determined by the relative heights of the highest
      barriers leading 
to the two different products 
(

G
= G
I
-
 G
I’
)
 
enantioselectivity
 
is controlled 
by the relative energy of
 
the two 
diastereomeric
TSs 
(rather than the stabilities of the 
two diastereomeric intermediates)
R
S
6

G
14.2.4.1.3.2.1 
Curtin-Hammett : Example 1: Asymmetric Hydrogenation 1
Figure 14.13.
Mechanism of the asymmetric hydrogenation, illustrating a reaction meeting
the Curtin-Hammett conditions
7
14.2.4.1.3.2.1 
Curtin-Hammett : Example 1: Asymmetric Hydrogenation 2
8
14.2.4.1.3.2.2 
Curtin-Hammett : Example 2: Asymmetric Allylic Alkylation 1
 
dilute conditions will help to achieve Curtin-Hammett conditions
  (unimolecular v.s. bimolecular)
 Halide ions catalyze the 
isomerization
 reversed enantioselectivity in the presence/absence of additives
Figure 14.15.
Interconversion of the diastereomeric 
-allyls 
I
 and 
I’
 occurs via a
n 
1
-allyl. The enantioselectivity-
determining step depends on the 
relative rates of 

 isomerization and nucleophilic attack.
Interconversion occurs within 
the
coordination sphere of the metal center.
9
14.2.4.1.3.2.2 
Curtin-Hammett : Example 2: Asymmetric Allylic Alkylation 2
B. M. Trost, F. D. Toste  JACS, 1999, 121, 4545
 Halide anion + diluted condition => Curtin-Hammett conditions
 
Ammonium cation lowers phenol nucleophilicity?
10
14.2.5.1 Effect of C
2
 Symmetry
 it was often observed that C
2
-symmetric catalyst were most effective
 Kagan: smaller number of metal-substrate adducts and TSs available
Figure 14.15.
Interconversion of the diastereomeric 
-
allyls 
I
 and 
I’
 occurs via a
n 
1
-allyl. The
enantioselectivity-determining step
depends on the 
relative rates of 

isomerization and nucleophilic attack.
11
12
14.2.5.2 Quadrant Diagrams
 generic model for steric biasing
  of chiral metal-ligand adducts
 shaded: hindered
 white: less hindered
 stereogenic centers close to the metal: e.g.. Pybox 
(Fig. 14.18.A)
                                more distant from metal: e.g. Chiraphos 
(Fig. 14.18.B)
 chiraphos) Me: pseudo-equatorial
                  two phenyls: pseudo-axial (edge) + pseudo-equatorial (face)
14.2.6 Alternative Asymmetric Processes: 
           
Kinetic Resolutions and Desymmetrizations
14.2.6.1. Kinetic Resolutions
14.2.6.2. Dynamic Kinetic Resolution
14.2.6.3. Dynamic Kinetic Asymmetric Transformations
14.2.6.4. Asymmetric Desymmetrizations
13
14.2.6.1. Kinetic Resolutions
Kinetic Resolution (KR)
 
reactions that occur at different rates with two enantiomers of a chiral substrate
 do not usually generate additional stereochemistry
 distinguish one enantiomer from another by creating new functionality
 maximum yield: 50%
 best option when racemate is inexpensive,
                            no practical enantioselective route is available
14
14.2.6.1.3.  Examples of Kinetic Resolutions
Figure. 14.26.
Kinetic resolution in the 
asymmetric allylic substitution
Trost,
 
B. M. et al. 
TL 1999, 40, 219
Schrock, R. R.. et al.
JACS
 1999 121 8251
15
14.2.6.2. Dynamic Kinetic Resolutions
Dynamic Kinetic Resolution (DKR)
 KR in a fashion that allows the conversion of both enantiomers of the reactant
  into a single enantiomer of the product
 KR with a rapid racemization of the chiral substrate thorough an achiral
  intermediate (=
I
) or transition state
In a typical DKR: 
k
rac
 
≥ k
fast
 
if substrate fully equbriuming and
k
fast
/k
slow
 ~ 20  => ee ~ 90%
16
14.2.6.2.1.  Examples of Dynamic Kinetic Resolutions
Noyori, 
R.
 et al. BCSJ 1995, 68, 36
17
14.2.6.3. Dynamic Kinetic Asymmetric Transformations
 
(DyKAT)
 Mechanism of stereochemical interconversion
s distinguishes DKR and DyKAT
 DKR
: catalyst that promotes racemization is achiral
                                                                   unrelated to resolution step
 
DyKAT
: interconversion of subst
. stereochemistry occurs on asymmetric cat.
              (epimerization)
18
DyKAT
KR
DKR
14.2.6.3.  Examples of DyKAT
19
D. S. Glueck et al. JACS 2002 124 13556
14.2.6.4. Desymmetrization Reactions
 differential reactivity of enantiotopic FGs of subst
. with chiral reagent or cat.
 catalyst differentiates between enantiotopic groups within single substrate
  (cf. 
KR
: differentiate between enantiomers of a racemic substrate)
Shibasaki, M. et al.
TL 1993, 34, 4219
Ito,
 Y. et al.
TL 1990, 31, 7333
Figure. 14.34. 
Desymmetrization of dienes by catalytic asymmetric hydrosilylation.
Oxidation of the product provides a valuable 1,3-diol
(14.19)
20
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Exploring the principles and energetics of asymmetric catalysis, this study delves into the importance, classes of transformations, stereoselectivity, and transmission of asymmetry. It discusses reaction coordination diagrams, transition state stabilization, and the terminology of catalysis. The Curtin-Hammett Principle is applied to asymmetric catalysis, revealing how competing reaction pathways and isomeric interconversions impact product ratios and enantioselectivity. Kinetic resolution and desymmetrizations are also explored.

  • Asymmetric catalysis
  • Energetics
  • Stereoselectivity
  • Catalytic reactions
  • Curtin-Hammett Principle

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  1. 2011/08/28 Kimura Organometallics Study Meeting Chapter 14. Principles of Catalysis 14. 1. General Principles 14.1.1. Definition of a Catalyst 14.1.2. Energetics of Catalysis 14.1.3. Reaction Coordinate Diagrams of Catalytic Reactions 14.1.4. Origins of Transition State Stabilization 14.1.5. Terminology of Catalysis 14.1.6. Kinetics of Catalytic Reactions and Resting States 14.1.7. Homogeneous vs. Heterogeneous Catalysis 1

  2. 14. 2. Fundamentals of Asymmetric Catalysis 14.2.1. Importance of Asymmetric Catalysis 14.2.2. Classes of Asymmetric Transformations 14.2.3. Nomenclature 14.2.4. Energetics of Stereoselectivity 14.2.5. Transmission of Asymmetry 14.2.6. Alternative Asymmetric Processes: Kinetic Resolution and Desymmetrizations 2

  3. 14.2.4. Energetics of Stereoselectivity G = 1.38 kcal/mol => 10:1 ratio of product (at rt.) G = 2 kcal/mol => 90%ee 3

  4. 14.2.4.1.1 Reaction with a Single Enantioselectivity-Determining Step simplest case: >direct reaction of catalyst. and prochiral substrate. >without coordination of subst. to cat. before enantioselectivity-determining step atom and group-transfer reactions (epoxidation, aziridination etc.) 4

  5. 14.2.4.1.1 Reaction with Revesibility Prior to the Enantioselectivity-Determining Step: The Curtin-Hammett Principle Applied to Asymmetric Catalysis Prochiral substrates bind to catalyst in a separate step from enantioselectivity- determining step (EDS) 1) interconversion of I and I is slow relative to conversion to the product (Scheme 14.12.A) EDS = binding to the prochiral olefin faces to the metal 2) interconversion of I and I is significantly fast: (Scheme 14.12.B) EDS = reaction to form the product (Curtin-Hammett conditions) 5

  6. 14.2.4.1.1 The Curtin-Hammett Principle when competing reaction pathways begin from rapidly interconverting isomers, product ration is determined by the relative heights of the highest barriers leading to the two different products ( G = GI - GI ) G = Keq = [ ] I exp( ) [ ] ' I RT = = G R S enantioselectivity is controlled by the relative energy of the two diastereomeric TSs (rather than the stabilities of the two diastereomeric intermediates) 6

  7. 14.2.4.1.3.2.1 Curtin-Hammett : Example 1: Asymmetric Hydrogenation 1 Figure 14.13. Mechanism of the asymmetric hydrogenation, illustrating a reaction meeting the Curtin-Hammett conditions 7

  8. 14.2.4.1.3.2.1 Curtin-Hammett : Example 1: Asymmetric Hydrogenation 2 8

  9. 14.2.4.1.3.2.2 Curtin-Hammett : Example 2: Asymmetric Allylic Alkylation 1 Interconversion occurs within the coordination sphere of the metal center. Figure 14.15. Interconversion of the diastereomeric -allyls I and I occurs via an 1-allyl. The enantioselectivity- determining step depends on the relative rates of isomerization and nucleophilic attack. dilute conditions will help to achieve Curtin-Hammett conditions (unimolecular v.s. bimolecular) Halide ions catalyze the isomerization reversed enantioselectivity in the presence/absence of additives 9

  10. 14.2.4.1.3.2.2 Curtin-Hammett : Example 2: Asymmetric Allylic Alkylation 2 B. M. Trost, F. D. Toste JACS, 1999, 121, 4545 Halide anion + diluted condition => Curtin-Hammett conditions Ammonium cation lowers phenol nucleophilicity? 10

  11. 14.2.5.1 Effect of C2Symmetry it was often observed that C2-symmetric catalyst were most effective Kagan: smaller number of metal-substrate adducts and TSs available Figure 14.15. Interconversion of the diastereomeric - allyls I and I occurs via an 1-allyl. The enantioselectivity-determining step depends on the relative rates of isomerization and nucleophilic attack. 11

  12. 14.2.5.2 Quadrant Diagrams generic model for steric biasing of chiral metal-ligand adducts shaded: hindered white: less hindered stereogenic centers close to the metal: e.g.. Pybox (Fig. 14.18.A) more distant from metal: e.g. Chiraphos (Fig. 14.18.B) chiraphos) Me: pseudo-equatorial two phenyls: pseudo-axial (edge) + pseudo-equatorial (face) 12

  13. 14.2.6 Alternative Asymmetric Processes: Kinetic Resolutions and Desymmetrizations 14.2.6.1. Kinetic Resolutions 14.2.6.2. Dynamic Kinetic Resolution 14.2.6.3. Dynamic Kinetic Asymmetric Transformations 14.2.6.4. Asymmetric Desymmetrizations 13

  14. 14.2.6.1. Kinetic Resolutions Kinetic Resolution (KR) reactions that occur at different rates with two enantiomers of a chiral substrate do not usually generate additional stereochemistry distinguish one enantiomer from another by creating new functionality maximum yield: 50% best option when racemate is inexpensive, no practical enantioselective route is available 14

  15. 14.2.6.1.3. Examples of Kinetic Resolutions Figure. 14.26. Kinetic resolution in the asymmetric allylic substitution Trost, B. M. et al. TL 1999, 40, 219 Schrock, R. R.. et al. JACS 1999 121 8251 15

  16. 14.2.6.2. Dynamic Kinetic Resolutions Dynamic Kinetic Resolution (DKR) KR in a fashion that allows the conversion of both enantiomers of the reactant into a single enantiomer of the product KR with a rapid racemization of the chiral substrate thorough an achiral intermediate (=I) or transition state In a typical DKR: krac kfast if substrate fully equbriuming and kfast/kslow~ 20 => ee ~ 90% 16

  17. 14.2.6.2.1. Examples of Dynamic Kinetic Resolutions Noyori, R. et al. BCSJ 1995, 68, 36 17

  18. 14.2.6.3. Dynamic Kinetic Asymmetric Transformations (DyKAT) Mechanism of stereochemical interconversions distinguishes DKR and DyKAT DKR: catalyst that promotes racemization is achiral unrelated to resolution step DyKAT: interconversion of subst. stereochemistry occurs on asymmetric cat. (epimerization) DKR KR DyKAT 18

  19. 14.2.6.3. Examples of DyKAT D. S. Glueck et al. JACS 2002 124 13556 19

  20. 14.2.6.4. Desymmetrization Reactions differential reactivity of enantiotopic FGs of subst. with chiral reagent or cat. catalyst differentiates between enantiotopic groups within single substrate (cf. KR: differentiate between enantiomers of a racemic substrate) Figure. 14.34. Desymmetrization of dienes by catalytic asymmetric hydrosilylation. Oxidation of the product provides a valuable 1,3-diol Ito, Y. et al. TL 1990, 31, 7333 (14.19) Shibasaki, M. et al. TL 1993, 34, 4219 20

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