Chiral Supramolecular Catalyst
for Asymmetric Reaction
2017/1/21 (Sat.)
Literature Seminar

Taiki Fujita (B4)1

Introduction

Rational design of chiral ligands
remains very difficult.

Conventional chiral ligands areconstructed with covalent bonds.

Numerous trial-and-error attempts
are needed.

Synthesis of chiral ligands require
multi-step operation and can becomplicated.

Optimizing ligands is time-and-energy consuming2Supramolecular Chiral Catalyst
Le second était de diviser
chacune des difficultés (...)

These attributes are induced by small components of supramolecular catalyst.
3Supramolecular Chiral Catalyst
What is the advantage of supramolecular chiral catalyst?

• Synthesis of each small component is much easier thancomplex conventional large ligand.
• The ligands can be tuned easily by changing each component.
• Combinatorial methods can be used for screening ligands

To date, some strategies
for supramolecular catalysts
have been developed.

4Supramolecular Catalysis Strategy 11)Zn-pyridine interactions

Zn-pyridine interaction is indeed selectiveFirst example of supramolecularbidentate ligands
N. H. Reek, et al. Chem. Commun. 2003, 89, 3446. 5

Supramolecular Catalyst Strategy 2
Achiral ligand upon chiral scaffold1) ion-paired chiral ligands

T. Ooi, et al. Nat Chem. 2012, 4, 473

Reaction Mechanism

Hydrogen bond is critical for enantio
selectivity.

co-solvent system is efficient?

T. Ooi, et al. Nat Chem. 2012, 4, 473 7

In Situ Generation and Deconvolution Method
In situ generation of chiral ligands enables us
to use combinatorial strategy much easier.

Just mixing reagent is enoughto evaluate ligand selectivity.

Only 16 experimentswere enough!
Ooi T, et al. Chem. Sci. 2014, 5. 3645

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Supramolecular Catalyst Strategy 3
In order to get higher ee, the reaction field should be bulkier
dissymmetrical environment. But such catalysts are often very
complicated and the synthesis of the catalysts is very laborious.

Using hydrogen bond, Lewis acid-base pair and selective
molecules interaction is attractive strategy to make better
dissymmetrical environment based on chiral scaffold.

9Early Attempt to Use Supramolecular Catalyst
Transmission of the chiral scaffold to other molecules

Catalyst1 is preparedfrom Yb(Otf)3, (R)-BINOL,
and a tertiary amine

TSThe axial chirality is transferred to the amine part,which work as a “wall” in the transition state toshield one side of the dienophile.
S. Kobayashi, et al. J. Am. Chem. Soc. 1994, 116, 4083.
Tetrahedron. 1994, 50, 11623. 10

The Effect of Tertiary Amine

The amine strongly influenced
the diastereo- andenantioselectivities.

S. Kobayashi, et al. Tetrahedron. 1994, 50, 11623.11

The Existence of Weak Interaction

10% eesluggishlyThis table indicate thatthe existence of aweak interaction.

S. Kobayashi, et al. J. Am. Chem. Soc. 1994, 116, 4083.
Tetrahedron. 1994, 50, 11623. 12

Additive is also Important Factor
S. Kobayashi, et al. Tetrahedron. 1994, 50, 11623.

Additive are effective not only instabilizing the catalyst, but also
in controlling the enantiofacialselectivity.

Both enantiomers could beprepared by the same chiralsource!!!!!

The enantioselectivities werecontrolled by the achiral ligands.
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Mechanism
substrate and additive areunder equilibrium condition.
Turnover…?

cat. A

substrate

additivecat. B
substrate

Negative non-linear effectadditiveS. Kobayashi, et al. J. Am. Chem. Soc. 1994, 116, 4083.
Tetrahedron. 1994, 50, 11623. 14

Supramolecular Catalyst Strategy31) Hydrogen bond + ion pair catalyst

catalyst 1a

Chiral tetraaminophosphonium cation ishydrogen-bonded via two
phenol molecules tophenolate.
The chirality ofaminophosphonium isrelayed over two achiralphenols.
T. Ooi, et al. Science. 2009. 326. 120.

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Analysis of Interaction
Single-crystal x-ray diffraction analysis

Ooi T, et al. Science. 2009, 326, 120.

Ooi T, et al. Angew. Chem. Int. Ed. 2011, 50, 3681 16

X-ray Crystal Analysis of Interaction

Ooi T, et al. Angew. Chem. Int. Ed. 2011, 50, 3681 17

The Effect of Phenol Derivative

T. Ooi, et al. Science. 2009. 326. 120.

18

The Importance of Phenols

Ooi T, et al. Angew. Chem. Int. Ed. 2011, 50, 3681 19

Supramolecular Catalyst Strategy 3
Subcomponents(=2B(C6F5)3 )act as abulky functional group to make a chiralcavity. And at once, they increase theactivity of catalyst center.

“anomalous” endo selective

99% (endo: exo= 83: 17)

Chiral cavity which consists of subcomponents iseffective for anomalous Diels-Alder reaction.
K. Ishihara, et al. Angew. Chem. Int. Ed. 2011, 71. 6474. 20

Enantio Selectivity VS endo/exo Selectivity

Covering the re or si face is enough toget enantiomer.

Covering one of the faces doesn’t matter.

Completely different two strategies are necessary to get endo/exoenantio- selectivity.

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Prof. Ishihara’s Strategy

22Supramolecular Chiral Cavity

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The First Anomalous Diels-Alder Reaction

Catalyst covers around carbonylgroup and inhibit the “secondaryorbital interactions”.

Yamamoto H, et al. J. Am. Chem. Soc. 1994. 116. 4131. 24

The First Enantio and endo/exo Control

Heteroleptic complex coveres carbonyl group
and at once, makes enantiomeric reaction field.
Kündig, et al. Angew. Chem. Int. Ed. 2001, 40 4481. 25

The First Organic Catalyst

Maruoka K, et al. Org. Lett. 2006, 8. 2687.
Chem. Asian J. 2007 2 1161.

26

Mechanism

Maruoka K, et al. Chem. Asian J. 2007 2 1161. 27

Other Example

Hayashi Y, et al. Angew. Chem. 2008, 120. 6736.
Angew. Chem. Int. Ed. 2008, 47. 6634.

M. P. Sibi, et al. Synlett. 2008,2655

28

Epimerization

K. Ishihara, et al. Angew. Chem. Int. Ed. 2011, 71. 6474. 29

B(C6F5)3 Function as Bulky Groups and LLA
3421

Catalytic anomalous endselective enantioselective
Diels-Alder ractions with
α-substituted acroleins

P=O…B(C6F5)3 moieties are critical not only forbulky functional group, but also for LLA catalyst.
K. Ishihara, et al. Angew. Chem. Int. Ed. 2011, 71. 6474. 30

What is LLA?
LLA= Lewis acid assisted Lewis acid catalyst
LLA is one of the combined acid catalysis strategies.

Yamamoto H. and Futatsugi K, Angew. Chem. Int. Ed. 2005, 44. 1924 31

NMR and Intermediate

Ishihara K, et al. Chem. Commun. 2012, 48. 4273

32

Theoretical Calculation

In fact, the two flexible
subcomponents could have a syn
conformation.
It is more stable than the anti
conformation by 3.86 kcal/ mol.

K. Ishihara, et al. Angew. Chem. Int. Ed. 2011, 71. 6474.
Chem. Commun. 2012, 48. 4273.
33

Precedent Works and Results

E. J. Corey, et al. J. Am. Chem. Soc. 1991, 113. 8967.
Yamamoto H, et al. J. Org. Chem. 1989, 54. 1481.
Catalyst

K. Ishihara, et al. Angew. Chem. Int. Ed. 2011, 71. 6474.
Chem. Commun. 2012, 48. 4273. 34

Tuning for α-halo-acrolein

123

Is resonance effectimportant?

dihedral angle? Resonance effect?

Less selectivity

K. Ishihara, et al. Angew. Chem. Int. Ed. 2011, 71. 6474.
Chem. Commun. 2012, 48. 4273. 35

The Cavity can be Applied for Acrolein
Same strategy

Molecular recognition

Induced-fit ??????
K. Ishihara, et al. Angew. Chem. Int. Ed. 2011, 71. 6474.

36

Mechanism
methacrolein-catalyst complex
A chiral, narrow and deep cavity is assumed.

Theoretical calculations using Gaussian03 with
B3LYP/6-31G* basis set.

the B-O(Naph) moiety was
doubly coordinated with theC(=O)H and C(=O)H parts.

Ishihara K, et al. Chem. Commun. 2012, 48. 4273. 37

Endo-Selective Diels Alder
What is the difference between endo- and exo- selective catalyst ?

Acrolein-catalyst complex
A chiral, shallow and wide cavity.

Non-covalent amide-B(C6F5)3 moiety
turn outside the complex.

The amide has a less-hindered planarstructure.

Pseudo-tetrahedral phosphorus structure

K. Ishihara, et al. Angew. Chem. Int. Ed. 2011, 71. 6474.
Chem. Commun. 2012, 48. 4273. 38

Develop New Type Cavity

Excessive interaction between threebulky groups is the reason of low ee?
Ishihara K, et al. Synlett. 2016,227. 1061.

39

Substrate Scope

Ishihara K, et al. Synlett. 2016,227. 1061. 40

The Importance of Two B(C6F5)3

Low to high eeHigh ee

Ishihara K, et al. Synlett. 2016,227. 1061. 41

SummaryHydrogen bond, acid-base pair,selective interaction….
Deconvolution strategy….
Supramolecular strategy could develop a new field which conventional
catalysts are useless in it.
Chiral cavity strategy

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Future Prospect
Problems
Each component is still difficult to synthesize.
The search for non-covalent interactions is an important task.
To date, most supramolecular catalytic asymmetric reaction proceed evenwith conventional catalysts.

but!
Conformationally flexible catalysts are promising!
Induced-fit, tailor-made….

May supramolecular catalysis be beyond enzyme mimics?

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以下おまけ45

using Chiral phosphoric acid for diels-alderIshihara K, et al. J. Am. Chem. Soc. 2015, 137. 13472.

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PBP Rhodium Complex

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PBP Cobalt Complex

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PBP Cobalt Complex

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