Reversible Interaction between Substrate and Ligand
2010. 6. 9. Yohei Shimizu (D3)
HisSer271
OHOO
HNPOO

Lys229O-2

O3PO

HisHisZn2+OH

OH

H

O TyrOO
OPO32-H
OPO32-H
class 1 aldolase+

H3N Lys107

OH

OH

class 2 aldolase

Glu185
Asp211

CO2-CO2-

carboxypeptidase A

macrophomate synthase(Nature, 2003, 422, 185.)

High substrate selectivity(specific interaction in the active site)
Mimic active site of enzyme
with wide substrate generality.

EnzymeLow substrate generality

Contents
Reversible directing group with covalent bondNoncovalent bond interaction between substrate and ligand

Reversible directing group with covalent bond
Utilize aldehyde/imine equilibrium for temporal directing group.
Jun, C.-L. et al. J. Or g. Chem. 1997, 62, 1200.
DirectingGroupOfor catalytic hydroacylation
CH3CH3CH3H

N
N

N
Ph3P
Cl Rh

RN

H

NH2

H
2-amino-3-picoline
Reversible aldimine formation.

RN
PPh3 R

Suggs, J. W.
J. Am. Chem. Soc. 1979, 101, 489.
3: Rh(PPh3)3Cl 4: 2-amino-3-picoline
7: benzoic acid 8: aniline

Jun, C.-L. et al.
Angew. Chem. Int. Ed. 2000, 39, 3070.
Without 2-amino-3-picoline, decarbonylation was serious problem.
Benzoic acid accelerated imine formation.
Aniline accelerated imine formation via transimination.
Application of this catalyst to other reactions.
C-C bond activation
OnBu
15 eq.

PhRh(PPh3)3Cl (5 mol %)2-amino-3-picoline (20 mol %)toluene, 150 oC

Ph3P N
Cl Rh

RPhO
HPh

NnBu

Ph3P N
Cl Rh

H R

N

J. Am. Chem.
Soc, 1999, 121,880.

H RBuPhhydroacylation of alkynes

HCH3CH3N

PhnBu

98%

CH3Ph3P N
Cl RhORh(PPh3)3Cl (5 mol %)2-amino-3-picoline (40 mol %)benzoic acid (20 mol %)toluene, 80 oC
92%

OnBu

PhAngew. Chem. Int. Ed.
2002, 41, 2146.

Phosphite as reversible directing group(R1O)3P(R1O)2P(OR2)

R2OH

R1OH

Lewis, N. L. et al. J. Am. Chem. Soc. 1986, 108, 2728.
Ortho directed C-H activation
Ru cat. (6 mol %)OH
KOPh (9 mol%)
C2H4
THF, 177 oC(95 psi)

OH

OH
Et

Et

Et

P(OR )2P(OR1)2

M

M

HRu
P(OPh)3P(OPh)375%O
1O(PhO)2P

13%
KOPh facilitated the exchange of phenol on the phosphite.
OOP(OPh)2

O

P(OR1)2

OP(OR1)2M

M HHHPhosphite worked as temporal directing group.

Recent application of this type of reversible directing group.
Orthoarylation via directed C-H activation
OH

RhCl(COD)2 (5 mol %)ClPiPr2 (10 mol %)Cs2CO3 (1.7 eq)
t-Bu
toluene, reflux

Brt-Bu

COMe

OH

89%

1Phosphinite did the same work as phosphite.
To prevent contamination derived from phosphinite, substrate
derived phosphinite was generated in situ.

6COMe23Bedford, R. B. et al. Angew. Chem. Int. Ed. 2003, 42, 112.

Directed hydroformination

HOEt451) Rh(CO)2acac (1 mol %)Ph2P(OMe) (10 mol %)CO/H2 (1:1, 20 bar)
THF, MS4A, 40 oCO2) PCC/Al2O3
NaOAc, CH2Cl2, rt85%: =>99:<1OEt(PPh3: : =54:46)
Breit, B. et al Angew. Chem. Int. Ed. 2008, 47, 7346.

Ph2PO
Rh
HEt

Noncovalent bond interaction for molecular recognition
Eary works
organized space for specific substrate
lipid bilayer
Epoxidation occured only at the olefin of the side chain.
Steroid attached porphirin catalyst in phospholipid bilayer
organize rigid environmet which restrict the entrance ofsubstrates.
Low catalyst efficiency because of strong product binding.
Groves, J. T. et al. JACS, 1987, 109, 5045.

Early successful work by Breslow group.
Recognize hydrophobic group.
Fix substrate at appropriate position.
Release products (reversible interaction).

cyclodextrin

1 (10 mol %)PhIO (5 eq.)pyridine, H2O;
KOH aq.
no oxidation without binding groupno over oxidation to ketone

ca. 40%
only 4 turnover>2 cyclodextrin was necessary to fix the substrate.

Problem: oxidation of porphyrin core under the condition

perfluorination

addition of excess of pyridine
Coordinates to Mn. (like thiolate in P450 system)
Directs oxigen and substrates to the other side.

attachment of pyridine moiety on
porphyrin

oxidation resistent core

intramolecular
coordination of pyridine
0.1 mol% of cat. => 187 turnover
1 mol% of cat. => 95 turnover

0.02 mol% of cat. => 2000 turnover

Change the oxdation site.

5 (10 mol %)PhIO (5 eq.)pyridine, H2O;
NaOH aq.

Third binding groupeffeciently changed the regioselectivity.
Different binding groups also changed the regioselectivity.

1567

6 :7 :15 =1:3:1

6 :7 :15 =1:0:1

Flexible moving of binding group in CD resulted in low selectivity?

6 :7 :15 =1:1:2

Hydrogen bond based recognition
Crabtree, R. H.; Brudvig, G. W. et al. succeeded in developing effecient molecular recognitioncatalyst.
Science, 2006, 312, 1941.
recognition mode
(two point hydrogen bond)spacerKemp's triacid
recognition site

basic idea

terpyridine-Mn catalyst
originally developed for H2O oxidation catalyst
oxdation resistant frameworkhigh oxidation ability
Crabtree, R. H.; Brudvig, G. W. et al. Science, 1999,283, 1524.

potential problems

CO2H-CO2H hydrogen bonding => two point binding
inhibit the rotation of the substrate
Kemp's triacid U-turn motif => reasonably rigid
maintain low pKa condition => avoid calboxylate anion (potential ligand of center metal)
Ibuprofen as substratecondition
CH3CN, Oxone (5 eq.)terpy-Mn cat. (1 mol%)
1b: recognition cat.
1c: lacking Kemp's triacid
4123456789105

Competitive inhibitionof recognition. (4eq. AcOH)

Low cat. loading prevent
bimolecular selfoxidation of cat.

CD3CN is moreoxidation resistant.
High regioselectivity was achived by molecular recognition catalyst.

(4-methylcyclohexyl) acetic acid

High regioselectivity and stereoselectivity.
Low conversion...

Inhibition by 4-tert-butyl benzoic acid ~How was background reaction suppressed?~
ibuprofen methylester
MeO2CO

ibuprofen methylester as substrate

HOinhibitor
only 0.9% yield(without inhibitor: 30%)

uncompetitive inhibition

active site is sterically blocked
ibuprofen as substrate(c) reversal of inhibitioncat. (0.5 mol%)methyl ester (1 eq.)
inhibitor(0.3 eq.)

AcOH (2.25 eq.)

3 hr

3 hr
sampling
1.5% conversion

competitive inhibition

small enough toopen the active site

sampling
34% conversion

These result suggested thatcatalyst recognize carboxylic acidreversible binding
active site was sterically inhibitedH abstraction-rebound mechanism
DFT calculation
longer Mn-O bond (1.80~1.91 A compared to Mn=O: 1.60 A)
high spin dencity on O
reactive center has a MnIV-O character[(terpy)Mn(O)( -O)Mn(SO4)(terpy)]+

H abstraction step and rebound step
are exothermic.
Energy barrier is low.
(6.5 kcal/mol for H abstraction)hydrogen bondC-H

oxidized C-H bondis relatively far from active site

O-Mn

C-H can reach the active site
without losing recognition

The catalyst has enough flexibility enabling the approach of the substrate to the active site.
Feature of this catalyst
Suppresses the background reaction.
Catalyst has reasonable rigidity and flexibility.
Other than oxidation catalyst
Breit, B. et al. used similar approach to phosphine ligand.
hydrogenbondtarget reaction: hydroformination

recognize carboxylic acidLinear/branch selectivity could be observed using proper ligand.

LigandvL(rel)vB(rel)

PPh3

10.77

114.130.61

vL: rate of linear productvB: rate of branched product
Only the lenear selectivetransition state was accelerated
by the recognition catalyst.
HNO
PPh2N
10Ph2PN
NH2Ph2P

O
Ph2P

HN

N
N

Ph2P

N
H

N

21HN

H
N

HN

O

N
N

1922

NH2N
6

PPh2HN
N
H

16HN

Ph2P

N

H
N

N
7free guanidine > cyclic guanidine (1 vs 16)

NH2NH2NH2Ph2P

NH
8H2N

meta > ortho (7 vs 10)

OPh2PNH

HNN
17OON

1NN
20O

Ph2P

Ph2P

NNH2NH2Ar2P

HNO

N

Ar= pF-Ph
12N

NH2NH2pyridine ring > benzene ring (1 vs 7)

control experiments

entry3: Ligand moiety and recognitionmoity should be in the samemolecule.

entry4, entry5: Catalyst recognize thecarboxylic group. Itshould
be in the same moleculeas the substrate.

differenciation of two terminal olefins

Both terminal olefin reacted almost
same rate. Linear/branch selectivity
was poor.

0 hr

9.5 hr
25.3 hrReaction rate of each olefin was
significantly different (8.8:1).
And linear/branch selectivity wasalso excellent.
0 hr

Only the reaction at , -unsaturated
carboxylic group was accelerated by
the recognition catalyst.

4 hrThis system showed rate dependent
differenciation.

8.5 hr

DFT calculation of hydrometalation step
HO2C

Direction of hydrogenbond is desirable in TS.

2 Ligand 1Rh(acac)(CO)2H
N

HNONH

HHOOH
N
H

NH2NO

HRh

COCarboxylic acid formed hydrogen bond with both guanidine ligands.
Rotation of the alkene is the main cause of activation energy. (assisted by hydrogen bonding)
One point hydrogen bonding resulted in higher activation energy.

Molecular recognition catalyst still need to be investigated.
Substrate generality is still limited.
Reaction pattern is also limited.