Journey from Lanthanide Triflate
to Metalloenzyme-Like Catalyst

2015.11.21 (Sat.)
KAJINO Hidetoshi(M1)Today's topic ~S. KOBAYASHI’s works~
1983 B. Sc.; The University of Tokyo (Professor T. Mukaiyama)
1987 Assistant Professor; Science University of Tokyo (SUT)1988 Ph. D.; The University of Tokyo (Professor T. Mukaiyama)
1991 Lecturer; Science University of Tokyo (SUT)1992 Associate Professor; Science University of Tokyo (SUT)1998 Full Professor, School of Medicine, The University of Tokyo
2007 Full Professor, School of Science, The University of Tokyo
Shu KOBAYASHIA leading chemist in the field of “water-tolerant Lewis acids”
1991 : Report that lanthanide and scandium triflates (Ln(Otf)3, Sc(Otf)3) is usable
as Lewis acid in water.
2015 : Development of metalloenzyme-like catalyst(Very Important Paper of Chem. Asian J.)

In this seminar, focus on up to development of metalloenzyme-like catalyst
from discovery of water-tolerant Lewis acids
1

Table of contents
1. Introduction
2. Lanthanide triflate as water-tolerant Lewis acids
3. Development of “LASC”
4. Asymmetric aldol reactions in aqueous media
5. Metalloenzyme-Like Catalyst
6. Summary2

1. Introduction

3Organic chemistry in waterOIntroduction

OHH

Me

Zn/CuI, cat. InCl
Na2C2O 4/H 2O

1+1R

R
R1 = CN, Br, Cl, H, CH3, CF 3, CH2O, HO
R2 = alkyl

NAcO

O

H

8h, r.t.

ONwatery. 14 - 85%

HOAcO
y. 81%

Barbier–Grignard typereaction in water

Organic reactions in watercat. Ru(OH)x/Al 2O3

NH2CNwater

MeO

R2+ R2I

Rate acceleration of Diels–Alder reactions
by water solvent.

Chem. Soc. Rev., 2006, 35, 68–82

O> 99%

Ru-catalyzed hydration of nitriles
to amides in water

Diels–Alder reaction in water・Advantage : safe, benign, environmentally friendly, and cheap

・Disadvantage : Most organic substances are insoluble in water.
Many reactive substrates, reagents, and catalysts are decomposed
or deactivated by water.
4Mukaiyama aldol addition

Introduction

Aldol addition is a powerful method for forming a C-C bond.

OTMS

O+R1

H

R3
R2OH1) Lewis acidOR12) desilylation

R3
R2

typical Lewis acids : TiCl4, SnCl4, BF3・OEt3
The Mukaiyama aldol addition is a type of aldol reaction
between a silyl enol ether and an aldehyde or formate.
These reactants allow for a crossed aldol reaction
between an aldehyde and a ketone or a different aldehyde
without self-condensation of the aldehyde.
Lewis acids undergo hydrolysis by water molecules,
so strict anhydrous conditions are needed in this reaction.

5

2. Lanthanide triflate as water-tolerant Lewis acids

6Use of Ln(OTf)3 as Lewis acid

Lanthanide triflate
as water-tolerant Lewis acids

Ln(OTf)3 is prepared from the corresponding lanthanide oxides (Ln2O3)
and trifluoromethanesulfonic acid in water.
H2OLnO3 + 6CF3 SO3 H

2Ln(OTf)3 + 3H2 O

Hydroxymethylation reactions by using Ln(OTf)3Ln(OTf)3(x%)

OSiMe 3+Ph

HCHO aq.
H2O/THF(1/4)
r.t.

Effect of Lanthanide Triflates in the Reactionof 1 with Commercial Formaldehyde Solution at r.t.

O
PhOH

Chem. Lett., 2187-2190 (1991)

In most cases,
the reactions proceeded smoothly.
Yb(OTf)3 is the most reactive catalyst.

7

Several examples ofhydroxymethylation reaction
Yb(OTf)3(10%)

OSiMe 3R

1R2 +HCHO aq.

H2O/THF(1/4)
r.t.

Lanthanide triflate
as water-tolerant Lewis acids
Reaction of Silyl Enol Ethers with Commercial
Formaldehyde Solution Catalyzed by Yb(OTf)3.

OR1OHR2

1) In every case, the reactions proceeded smoothlyin high yield.
2) Di- and polyhydroxymethylated products
were not observed.
3) The absence of equilibrium allowed fora regiospecific hydroxymethylation reaction.
4) Only a catalytic amount of Yb(OTf)3 was required tocomplete the reaction.
5) Almost 100% of Yb(OTf)3 was quite easily recoveredfrom the aqueous layer after the reaction was completedand it couldbe reused (third use(93%yield)).
J. Org.Chem., 59, 3590-3596 (1994)

8

Screening of Ln(OTf)3
OSiMe 3O+Lanthanide triflate
as water-tolerant Lewis acids

Ln(OTf)3(10%)

OOH

H
H2O/THF(1/4)
r.t.

Effect of Lanthanide Triflates in the Reactionof 4 with Benzaldehyde at r.t. for 20 h in H2O-THF (1:4).

High reactivity : Nd-, Gd-, Yb-, Lu(OTf)3
Low reactivity : La-, Pr-, Tm(OTf)39

Several examples ofhydroxymethylation reaction 2OYb(OTf)3(10%)

OSiMe 3ROSiMe 3

R2 + H1

H2O/THF(1/4)
r.t.

OSiMe 3OSiMe 3Ph1(Z/E=>98/2)
OSiMe 32ZO

Lanthanide triflate
as water-tolerant Lewis acids

OH

R1
R2

Lanthanide Triflate-Catalyzed Aqueous Aldol
Reaction by Using Yb(OTf)3 (10 mol %)a).

2E

OSiMe 3OSiMe 3EtSPh

34181) In every case, the reactions proceeded smoothly
in high yield.
2) Diastereoselectivitieswere generally
good to moderate10Mechanistic study 1

Lanthanide triflate
as water-tolerant Lewis acids

Effect of Yb salts

The dissociation equilibrium equation

The Yb salts with
less-nucleophilic counter anions are more cationicand the high Lewis acidity promotes
the desired reaction.
Effect of additive

The results of screening of ligands,
only water was effective.
In the presence of other polar molecules,
the reaction proceeded very slowly.
11Mechanistic study 2Lanthanide triflate
as water-tolerant Lewis acids

Effect of water

In the absence or presence of small amount of water :THF predominantrly coodinates to Yb(OTf)3
Lewis acidity is low.
When the equivalents of water are gradually increased :Water is prone to coordinate to Yb(OTf)3
Lewis acidity is high.
There is a chance for an aldehyde activated.

When the amount of water is further increased :Hydrolysis of the silyl enol ether precedes
the desired aldol reaction
12

Short summary 1

Lanthanide triflate
as water-tolerant Lewis acids

Discovery of lanthanide triflate as water-tolerant Lewis acids
Problem◆ When the amount of water is further increased,
a competitive reaction precedes the desired aldol reaction.

3. Development of “LASC”◆ Lanthanide triflate could not be developed
into enantioselective asymmetric reactions.

4. Asymmetric aldol reactions in aqueous media
13

3. Development of “LASC”

14

Sc(OTf)3-SDS system

Development of “LASC”

Sc(OTf)3-catalyzed Mukaiyama aldol reactions have been successfully carried out
in aqueous solutions of surfactants.
Sc(OTf)3-SDS system

OSiMe 3

R1CHO +R

2R3

Sc(OTf)3 (0.1 eq.)
SDS (0..2 eq.)
H2O, r.t.

O

OH

R2

R1R3O

SDS =(Sodium dodecyl sulfate)

OSONaO

Not only aromatic, but also aliphaticand α, β-unsaturated aldehydes reacted withsilyl enol ethers to afford
the corresponding aldol adducts in high yields.

Tetrahedron Letters, Vol. 38, NO. 26, pp. 4559-4562, 199715

Lewis-Acid-Surfactant-Combined Development of “LASC”
Catalysts (LASC)LASC is more simplified catalyst than Sc(OTf)3-SDS system
1a-1f were prepared from ScCl3
and the corresponding SDS
or sodium alkanesulfonate.

1a : Sc(O3SOC12H25)3
1d : Sc(O3SC12H25) 3

Schematic representation of 1aOSiMe 31a(10 mol%)

PhCHO +Ph(1 equiv)(1.5 equiv)

H2Or.t., 4 hOHPhO

Effect of Solvents on LASC (1a)-Catalyzed Aldol Reactions
PhThe reaction in water afforded the productin high yield.
Low yield were observedin other organic solvents.
Tetrahedron Letters 39 (1998) 5389-5392
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7205

16

Substrate scope
R1CHO +(1 equiv)

Development of “LASC”

OSiMe 3
R23R

(1.5 equiv)

1a(10 mol%)
H2Or.t., 4 hOH

O

R1R3
R2LASC (1a)-Catalyzed Aldol Reactions in Water

Aromatic as well as aliphatic, α, β-unsaturated, and heterocyclic aldehydes worked well.
Silyl enol ethers, ketene silyl enol ethers, and an ester reacted well17
to give the corresponding adducts in high yields.

Characterization ofthe colloidal particle

Development of “LASC”

・LASCs such as 1a and 1d do not dissolve in water.
・On the other hand, when the LASC was mixed
with organic substrates in water,a white turbid mixture formed through colloid formation.
Mixtures of LASC 1d in water (left) andLASC 1d and benzaldehyde (1:10) in water (right)

・Light microscopic observations of the colloidalparticles revealed their spherical shape.

・Finally, all of 1d formed
the spherical colloidal particles.
Mixture of LASC 1d and benzaldehyde as detected bylight microscopy.(a) 1d:benzaldehyde=1:10; (b) 1d:benzaldehyde
18=1:20; (c) 1d:benzaldehyde=1:100. In all cases,
the concentration of 1d was 16.7 mM.

Mechanism of catalytic reactions. Development of “LASC”

(a)
(b)
(c)

Without surfactants
With surfactants
A colloidal particle formed in a mixture in the presence of surfactants

Reaction mechanism
1) In the presence organic substrates, LASC molecules form stable colloidal particles.
(the surfactant moiety of the LASCs surrounds the organic substrates.)2) the countercations are attracted to the surface of the particles through electrostaticinteractions between the anionic surfactant molecules and the cations.
3) Although each Sc(III) cation is hydrated by several water molecules,
they can be readily replaced by a substrate.
4) The substrates to be activated move to the interface from the organic phase,coordinate to the cations, and then react with nucleophilic substances there. 19

4. Asymmetric aldol reactions in aqueous media

20

Chiral ligand for Ln(OTf)3Asymmetric aldol reactions
in aqueous media

Need to finding a chiral ligand which has strong binding ability
and does not significantly reduce the Lewis acidity of Ln(OTf)3.

Desirable ligand : chiral crown ether

・For the larger cations
such as La, Ce, Pr, and Nd,
both diastereo- and enantioselectivities were high.
・The smaller cations
such as Sc and Yb showed no enantioselection.
Org. Lett., 3, 165-167 (2001)21

Effect of chiral ligand

Asymmetric aldol reactions
in aqueous media

It should be noted that,
although 1 slightly decelerated the reaction,
sufficient reactivity still remained in the presence of 1.
Reaction profiles for the Pr(OTf)3-catalyzed aldol reactionof benzaldehyde with 2 in water/ethanol (1/9) at 0℃
in the absence and presence of 1.

✔

・The methyl groups of 1 are all in axial positions.
・one or two of the nitrate anions are dissociatedin aqueous media and that aldehydes
to be activated coordinate in place of the nitrate anion.

✔
✔
✔

22

5. Metalloenzyme-Like Catalyst23

1st generation :Asymmetric hydroxymethylation in water

Metalloenzyme-Like Catalyst
1st generation

・by using
2 mol% or 1 mol% of the catalyst (Conditions C and D)
led to the same range in yields and enantioselectivities
as those reactions employing 10 mol% of the catalyst.
Angew. Chem. Int. Ed. 2008, 47, 6909 –6911

24

2nd generation :Direct asymmetric aldol reaction in water.

Metalloenzyme-Like Catalyst
2nd generation

A cyclopentyl substituent
on the amide moiety (1 d)
was found to be the bestin terms of both yieldand enantioselectivity (entries 7–10).

Chem. Asian J. 2010, 5, 490 – 492

25

Substrate scope

Metalloenzyme-Like Catalyst
2nd generation

The addition of a catalytic amount of pyridine
enabled us to use ketones directly inasymmetric hydroxymethylation reactions.

26

3rd generation :Metalloenzyme-Like catalyst

Chem. Asian J. 2015, 10, 133 – 138

Metalloenzyme-Like Catalyst
3rd generation

27

Substrate scope

The addition of a catalytic amount of pyridine
enabled us to use ketones directly inasymmetric hydroxymethylation reactions.

Metalloenzyme-Like Catalyst
3rd generation

28

Reaction mechanismMetalloenzyme-Like Catalyst
3rd generation29

6. Summary30

Summary 1

Summary

Discovery of lanthanide triflate as water-tolerant Lewis acids
1991
Ln(OTf)3(x%)

OSiMe 3+Ph

HCHO aq.
H2O/THF(1/4)
r.t.

Asymmetric aldol reactions in aqueous media
2001

OPh

OH

Development of “LASC”
1998

31

Summary 2

Summary

Asymmetric aldol reactions in aqueous media
2001

Development of “LASC”
1998

Metalloenzyme-Like Catalyst
201532