1. Improved Immobilization of Chiral Bisoxazolines on Silica: Application to Circulating Flow-Type Pack Bed Reactor
Su Seong Lee, Jaehong Lim, Jackie Y. Ying
Institute of Bioengineering and Nanotechnology
Singapore
The 12th Annual Green Chemistry and Engineering Conference (June 24-26, 2008) Washington, DC

2. Chiral Bisoxazoline Ligands
Privileged chiral catalyst
Yoon, T. P. & Jacobsen, E. N. Science 299,1691, 2003 R1 R2 R1 R2 R3 R2 R2
Cyclopropanation
Ene-Reactions
Diels-Alder Reactions
Allylic substitution
Aziridination reactions
Mukaiyama Aldol Reactions
Enantioselective Henry reaction
Enantioselective conjugate addition of carbamates
(synthesis of β-amino acids)

3. Causes of the low enantioselectivities?
Silica-Supported Chiral Bisoxazoline
Cyclopropanation of styrene
< 30% ee
Causes of the low enantioselectivities?
< 65% ee
J. Org. Chem., 66 (26), 8893, 2001
Silica
< 55% ee
Grafting on MCM
Chem. Commun. 1936, 2001

4. Spherical MCF Microparticles as a Silica Support
Spherical, micron-sized MCF particles
Packed beds for catalysis and separations
Conventional MCF
Conventional MCF
Advantages
Large pore size more than 20 nm  No diffusion problem
Easy control of the pore size
Excellent mechanical strength
Easy isolation of catalysts  Higher activity
Easy control of catalyst microenvironment
MCF = mesocellular siliceous foam
Conventional MCF
More efficient packed bed reactor
Spherical MCF

5. Asymmetric cyclopropanation of styrene
Interaction of Bisoxazoline with Silica Surface
MCF or
TMS-capped MCF
MCF + AzatBBOX:Cu(II) A C
PhNHNH2
Stirring, CH2Cl2
TMS-MCF + AzatBBOX:Cu(II) B D
Asymmetric cyclopropanation of styrene +
N2CH2CO2Et A B
Catalyst
Run
Yield (%)
Trans:Cis
Trans (ee%)
Cis (ee%) C 1 73
64:36 78 66 2 67
66:34 82 72 D
74:26 91 87
71:29 86 81
After two runs
Adv. Synth. Catal. 350, 1295, 2008

6. Asymmetric cyclopropanation of styrene
Influence of Postcapping M C F M C F
(HMDS)
Asymmetric cyclopropanation of styrene
% ee (for trans isomer)
Trans/cis ratio / /40
Chem. Commun. 3577, 2005
65% ee  71% ee  81% ee
Amount of TMS capping
Org. Lett. 3, 2493, 2001

7. Influence of PrecappingM C F M C F M C F
HMDS +
Cu(I) B
HMDS
toluene
Cu(I)
Vapor-phase grafting
Pre-capping A
Post-capping M C F M C F +
HMDS M C F
Cu(I) C
Asymmetric cyclopropanation of styrene
Catalyst
% Yield
Trans/Cis
% ee trans
% ee cis H 80
68/32 86 84 A 70
59/41 82 79 B 73
64/36 90 87 H C 80
65/35 95 92
Adv. Synth. Catal. 348, 1248, 2006

8. Asymmetric cyclopropanation of styrene
Influence of Precapping
MCF
Bare MCF
Post-capping
Cu(I)
TMS(0.8)-MCF
Pr-1
Post-capping
Cu(I)
Cu(I)
MCF
Bare MCF
MCF
HOMO-Me
Pr-2
Pr-3
Asymmetric cyclopropanation of styrene
Catalyst
Loading (mmolg-1)
Run#
% Yield
Trans:Cis
% ee trans
% ee cis
HOMO-Me 80
71:29 91 87
Pr-1
0.240 1 69
63:37 37 27 2 67 32
Pr-2
0.262 88 83 81
Pr-3
0.066 75
62:38 86 78
Adv. Synth. Catal. 350, 1295, 2008

9. Fabrication of Immobilized Catalysts
Complexation
Immobilization
Post-capping
Pre-capping
Cu+
: Si-OH
: Si-OTMS
: Si-O L

10. Asymmetric cyclopropanation of styrene
Influence of Linker Group
TMS(0.8)-MCF
Post-capping
MCF MP
MCF
Pr-3
HOMO-MP
Asymmetric cyclopropanation of styrene
Catalyst
Loading amount (mmol/g)
Run#
Yield (%)
Trans:Cis
Trans
ee%
Cis
Pr-2
0.120 1 68
70:30 64 2 40
67:33 38 MP
0.148 55
72:28 84 80 58 88
Pr-3
0.066 75
62:38 86 78
HOMO-MP 82
74:26 93 90
Adv. Synth. Catal. 350, 1295, 2008

11. Blank test by mixing of MCF with Cu(OTf)2
(no ligand)
Support = 100 mg, Cu(OTf)2 = 3.6 mg (0.01 mmol)
Catalyst
Run #
Styrene/EDA
Yield (%)
Trans:Cis
MCF:Cu(I) 1
1.5 58
57:43
TMS(0.8)-MCF:Cu(I) 35
63:37 2 53 3 49
67:33
Silanol or siloxane-coordinated cooper can give cyclopropanation products
Incomplete complexation
Low enantioselectivity
Adv. Synth. Catal. 350, 1295, 2008

12. Influence of Catalyst Loading Amount
Loading amount (mmol/g)
0.120
0.262
Trans ee (%)
68 (40)a
88 (91)a
Cis ee (%)
64 (38)a
83 (87)a Pr
MCF
a result from the 2nd run
Loading amount (mmol/g)
0.148
0.245
Trans ee (%) 84 93
Cis ee (%) 80 91 MP
MCF
Catalyst
Loading amount (mmol/g)
Reaction time (min)
Run#
Yield (%)
Trans/Cis
Trans
ee%
Cis MP
0.507
420 1 81
69/31 94 90 2 77
68/32
180 61
70/30 93 91 63
0.245 75 82
72/28 83 35 4 79 5
Adv. Synth. Catal. 350, 1295, 2008

13. Packed Bed Reactor Continuous flow reaction Circulating flow reaction
Circulating at a high flow rate (5 ml/min) N2
mix
Flow rate: 0.2 ml/min
MCF
Packed Bed Reactor
(50 mm  4.6 mm I.D.)
Adv. Synth. Catal. 350, 1295, 2008

14. Circulating Flow-Type Reactor
Conditions
Reactor = 50 mm x 4.6 mm, Catalyst ~ 240 mg (0.03 mmol)
Flow rate = 5.0 ml/min
Reaction time per cycle = 75 min
Turn over number (TON) per cycle = 100
Total TON = 2000 (20 cycles)
Decrease the amount of the reaction medium
Trans ee
Yield
Trans ratio
Adv. Synth. Catal. 350, 1295, 2008

15. Synthesis of Useful Chiral Ingredient+ *
Cilastatin (dehydropeptidase)
MCF
Run #
Catalyst (mol%)
% Yield
% ee 1
0.1 90 92 2
Adv. Synth. Catal. 348, 1248, 2006
Run #
Catalyst (mol%)
% Yield
% ee 1a
0.1 90 92 2a
86c 3a 91 4b 5b
MCF
a Dripping of EDA for 5 hr at 0C and then warm to RT over 14 hr
b Dripping of EDA for 5 hr at 5C, stirring at 10C for 90 min, and
then warm to RT over 30 min
c Overall yield from run #2-5
Adv. Synth. Catal. 350, 1295, 2008

16. Summary
Selectivity and recyclability of silica-supported chiral bisoxazoline-copper(I) were greatly improved by pre-capping, post-capping and a rigid linker group
Circulating flow-type reaction system was developed for gas-generating catalytic reactions

17. Acknowledgments Dr. Jaehong Lim, Dr Han Yu, Ms. Siti Nurhanna Riduan
Members of the Nanobiotechnology Group
IBN Staff
Facilities and Administration Staff
IBN, BMRC and A*STAR