Taking Lessons from
Thiamine
Catalytic Umpolung Reactivity of Aldehydes
Louis-Charles Campeau
University of Ottawa
Dept. of Chemistry
Center for Catalysis Research and Innovation
Taking Lessons From Thiamine
Millions of Years
of Evolution
O
O
NH
Ph
Et
Me
O OH
OH
Molecular Complexity
(azaspirene)
Efficient and
Stereo/RegioControlled Bond
Formation
Enzymes
Novel Methods
and Catalysts
2
Taking Lessons From Thiamine
Millions of Years
of Evolution
O
O
NH
Ph
Et
Me
O OH
OH
Molecular Complexity
(azaspirene)
Efficient and
Stereo/RegioControlled Bond
Formation
Enzymes
Novel Methods
and Catalysts
Understanding
Chemical Biology
3
Taking Lessons From Thiamine
O
O
O
(S)-Proline
O
O
O
O
O
OH
NH
Ph
Et
Me
O
-H2O
Millions of Years
of Evolution
O OH
OH
Molecular Complexity
(azaspirene)
Efficient and
Stereo/RegioControlled Bond
Formation
Aldolase
Proline Based
Catalysis
Organocatalysis
Understanding
Chemical Biology
4
Taking Lessons From Thiamine
Millions of Years
of Evolution
O
O
NH
Benzoin/Stetter
Reactions
Ph
Et
Me
O OH
OH
Molecular Complexity
(azaspirene)
Efficient and
Stereo/RegioControlled Bond
Formation
Transketolase
Carbene
Catalysis
Organocatalysis
Thiamine
Understanding
Chemical Biology
5
Overview

Umpolung Reactivity


Benzoin Reaction






Catalytic Cycle
Recent developments
O
O
R
R
H
1
R'
2
OH
Stetter Methodology


Aldehyde Umpolung
Catalytic Cycle
The Early Years: Hirsutic Acid C
HO2C 11
Recent developments
Conclusions
Acknowledgements
OH
H
3
2
9
O
H
6
Umpolung Reactivity
“Umpolung” is derived from German meaning “inverse


polarity”
Any process by which the normal alternating donor
and acceptor reactivity pattern of a chain is
interchanged, do to the presence of O or N
heteroatoms.

HO
R
This original meaning of the term has been extended to the reversal
of any commonly accepted reactivity pattern.
Nu
H
Nu
Umpolung
O
R
H
Electrophilic center
IUPAC Compendium of Chemical Terminology, 2nd Edition (1997).
O
O
E
R
R
E
Nucleophilic center
7
“Umpolung Chemistry” of
Aldehydes

Umpolung reactivity allows chemists to look at
bond disconnections in new ways
O
R
OH
3
1
O
R'
R
5
R'
R
1
O
R'
R
2
OH
1
4
R'
O
O
O
H
1
O
O
R'
R'
Aldol
OM
Michael
R
D. Seebach, Angew. Chem. Int. Ed., 1979, 18, 239
?
8
“Umpolung Chemistry” of
Aldehydes

Umpolung reactivity allows chemists to look at
bond disconnections in new ways
O
R
OH
3
1
O
R'
R
5
R'
R
Aldol
OM
R'
1
R
2
H
D. Seebach, Angew. Chem. Int. Ed., 1979, 18, 239
4
R'
O
R'
R'
Michael
R
1
O
O
R'
R'
O
OH
O
O
H
1
O
O
O
R
9
Stochiometric Methods

Cyanohydrins as aldehyde umpolung

Homologation and its reversal
1. HCN
2. Protection
O
R
NC OP Strong Base
R
H
H
NC OP
R
R'CHO
O
R'
R
OH
D. Seebach, Angew. Chem. Int. Ed., 1979, 18, 239
1) Deprotection
NC OP
R
2) Retro-Cyanation
R'
OH
10
Cyanohydrins as Aldehyde Umpolung
O
H
1) DIBAl-H
O
EEO
2) HCN, EtOH HO
3) 50% AcOH
H
HO
THF
H
CN
EEO
O
1) TsCl, Py
2) CH2CHOEt,
PPTS
O CN H
H
TsO
EEO
HO
H
EEO
H
2) L-Selectride
THF
H
H
1) 50% AcOH-THF
KHMDS, PhH
reflux (72%)
HO CN H
H
COOH
Me
HO
H
OH
Prostaglandine F2
G. Stork, T. Takahashi, I. Kawamoto, T. Suzuki, J. Am. Chem. Soc., 1978, 100, 8272
11
Stochiometric Methods

Dithianes as aldehyde umpolung

Heteroatom exchange
O
R
SH
HS
H
BF3-Et2O
S
R
S
H
Strong Base
O
R
R'
OH
D. Seebach, Angew. Chem. Int. Ed., 1979, 18, 239
1) R'CHO
2) Dithiane
Removal
S
R
S
12
Dithianes as Aldehyde Umpolung
OH
O
OTBDPS
OTBDPS
CH2(CH2SH2)2
O
H
OTIPS
O
OMe O
TiCl4, DCM
O
O
S
S
O
H
i-Bu
OTIPS
Leucascandrolide A
then...
t
TIPSO
I
O
BuLi, HMPA
THF -78ºC
OTIPS
OTBDPS
i-Bu
1) PhI(O2CCF3)2
MeOH/H2O/THF
O
SS
TIPSO
OH
2) L-Selectride
THF
O
i-Bu
O
O
OTIPS
OTBDPS
TIPSO
P. Wipf and J.T. Reeves, Chem. Comm. 2002, 2066
13
Catalytic Methods

Introduction to the benzoin reaction

Nucleophilic acylation reactions catalyzed by
lyases (transketolase) in the presence of
coenzyme thiamine.
H2N
Umpolung
Catalyst
O
Ph
H
N
O
Ph
CH3
N
*
Ph
H3C
N
OH
Cl
S
HO
Thiamine
(vitamin B1)
D. U. Nilsson, L. Meshalakina, Y. Lindqvist, G. Schneider, J. Biol. Chem., 1997, 272, 1864
14
Nature’s Way
H2N
N
CH3
N
H3C
O
OH OH
HO
O PO3
Cl
S
HO
OH OH
N
O
Thiamine
OH
HO
O PO3
Sedoheptulose-7P
OH
Xylulose-5P
OH
OH OH
O
H
O PO3
OPO3
O
OH
Glyceraldehyde-3P
Ribose-5P
"
O
"
HO
Synthon
D. Enders & T. Balensiefer, Acc. Chem. Res, 2004, 37, 534
U. Nilsson, L. Meshalakina, Y. Lindqvist, G. Schneider, J. Biol. Chem., 1997, 272, 1864
15
Catalytic Vitamins
Ph
O
*
O
Ph
R2
R1
N
R3
S
Ph
H
OH
R2
R3
R1
O
N
S
-H
R1
N
R2
Ph
OH
Ph
R2
S
R3
R1
N
H
O
Ph
H
R3
R2
R1
OH
N
Ph
R3
S
S
R2
R1
N
R3
S
OH
R2
R1
N
S
R3
Breslow Intermediate
Ph
OH
Ph
O
Ph
R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719
T. Ukai, R Tanaka, T. Dokawa, J. Pharm. Soc. Jpn., 1943, 63, 296
O
Ph
H
16
Benzoin Reaction – Early Years
O
Ph
BzO
H3C
H
MeOH, Et3N
30ºC
CH3
N
S
N
Ph
*
Ph
OH
H3C
CH3
H3C
O
10 mol% catalyst
H3C
S
N
S
H3C
H3C
N
S
9% yield
12% yield
6.1% yield
78% yield
22.5% ee
0% ee
51.5% ee
7.8% ee
J.C. Sheehan, D.H. Hunneman, J. Am. Chem. Soc., 1966, 88, 3666
J.C. Sheehan, T. Hara, J. Org. Chem., 1974, 39, 1196
17
Triazolium Catalysts

1 (1.25mol%)
O
Ar
Triazolium catalysts give better yield and
selectivity
H
K2CO3, THF
22-72%
Proposed Transition State
O
Ar
Ar
Si face
OH
ee 20-86%
O
H
Ph
N N
HO
ClO4
N
Ph
O
Si attack
N N
N
Ph
O
O
O
1
D. Enders, K. Breuer, J.H. Teles, Helv. Chim. Acta, 1996, 79, 1217
Re attack
18
Alternative Catalysts
O
Ph
O
catalyst
Ph
H
* Ph
OH
Leeper
O
Rawal
TBSO
TBSO
Ph
Ph
N
N
N
N
S
S
34% yield
19.5% ee
20% yield
10.5% ee
Ts
N
O
S
50% yield
20.5% ee
R.L. Knight, F.J. Leeper, Tetraheron Lett., 1997, 38, 3611
C.A. Dvorak, V.H. Rawal, Tetrahedron Lett., 1998, 39, 2925
R.L. Knight, F.J. Leeper, Perkin Trans. 1, 1998, 1891
N
N
Ph
45% yield
80% ee
Ph
N
S
52% yield
48% ee
19
New Triazolium Catalyst
O
O
Ph
N N
3 Steps
NH
O
BF4
N
50% overall
Me3OBF4
DCM
quant.
a) HBF4, DCM, rt
b) HC(OMe)3, MeOH, 80ºC
65%
N NHPh
OMe
O
N
PhNHNH2, Et3N
O
NH
THF
77%
D. Enders, U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743
20
Catalyst Activity
cat. (10mol%)
KOtBu, THF
O
Ar
O
Ar
Ar
H
Ph
N N
8-83%
cat. =
N
O
OH
BF4
80-95% ee
Substrate
Loading (mol%)
Temperature (ºC)
10
18
81
83
10
0
61
91
H
10
18
8
95
H
10
18
83
90
Yield (%)
ee (%)
O
H
F
O
MeO
O
D. Enders, U. Kallfass, Angew. Chem. Int. Ed., 2002, 41, 1743
21
“Cross Benzoin” Reaction
O
O
O
R1
R2
H
O
R2
R1
H
R1
R1
OH
OH
O
catalyst
R2
Usually Observed!!
O
R1
R2
OH
Cross benzoin
adducts
R2
OH
Homo benzoin
adducts
X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534
22
Inefficiency of Cross-Benzoin
Methodology
R1
O
*
O
O
or
R2
R1
H
R2
C N
OH
O
H
R1
NC
H
O
NC
OH
R1
R2
NC
OH
Ph
OH
R1
NC
O
R2
O
O
or
R2
H
R1
H
23
Inefficiency of Cross-Benzoin
Methodology
O
O
or
R1
R1
O
R1
H
R2
C N
OH
O
H
R1
NC
O
NC
OH
R1
H
R1
There is a lack of
control because the
more electophilic
aldehyde reacts
first!!!
NC
OH
Ph
OH
R1
NC
O
R1
O
O
or
R1
H
R2
H
24
Silyl-Benzoin Reaction to the
Rescue!
O
O
R1
H
O
SiEt3
KCN/
[18]crown-6
(cat.)
OSiEt3
R1
R2
only one adduct!!
OSiEt3
OMe
O
Cl
R2
Cl
O
O
OSiEt3
OSiEt3
MeO
80% yield
80% yield
Me
Me
O
O
Me
OSiEt3
66% yield
Cl
85% yield
X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534
O
OSiEt3
75% yield
25
Catalytic Cycle of Silyl Benzoin
NC O
H
R1
Fast and Reversible
R1CHO
CN
O
R2
NC O
SiEt3
cyanation
R2
SiEt3
[1,2] Brook
rearrangement
Irreversible
N
C
CN
R2
OSiEt3
R2
OSiEt3
O
CN
NC O
O
R2
R1
R1
OSiEt3
retrocyanation
OSiEt3
R2
1,4-silyl
migration
R1
X. Linghu, J.S. Johnson, Angew. Chem. Int. Ed., 2003, 42, 2534
H
NC OSiEt3
O
R2
R1
26
Chiral Metallophites in Silyl Benzoin
O
O
Ph
phosphite (5mol%)
n-BuLi (5mol%)
H
SiEt3
Ph
THF, 0.5hrs
MeO
OSiEt3
O
P
EtO Li
EtO
Me
Me
100% conv.
*
O
P OLi
R2
SiEt3
[1,2] Brook
rearrangement
OMe
O
*
R2
Ar Ar
O O
O
P
O Li
O
Ar Ar
F
Ar =
100% conv.
90% ee
O
P O
Li
R1
H
*
OSiEt3
Chiral
Nucleophile
X. Linghu, J.R. Potnick, J.S. Johnson, J. Am. Chem. Soc., 2004, 126, 3070
O
P OSiEt3
OLi
R2
H R1
O
R2
R1
OSiEt3
27
TimeLine
Ph
BzO
Me
X
N
N
S
R
Sheehan
First Chiral
Carbenes
1966
1958
Breslow
Catalytic Cycle
R
N
OH
S
Ar
H
H
Leeper/Rawal
Bicyclic Cat.
1974
1997-98
1996
Enders
Triazolium
up to 86%ee
2002-04
Johnson
Cross-Benzoin
O
Ph
R
N N
N
Ph
O
O
SiEt3
Enders
90%ee Benzoin
O
N
N
N Ph
28
Back To The Future!!
Benzoin Methodology
1966
1958
Breslow
Catalytic Cycle
R
N
OH
S
Ar
1974
1976
1997-98
1996
2002-04
29
Other Electrophiles?

Can other electrophiles be used to give rise to
other umpolung products
OH
O
Ph
Ph
R2
X
Y
N
H
R1
Electrophile
O
Ph
E
R3
Breslow
Intermediate
30
Stetter Reaction
O
O
S
R2
N
R4
O
Ph
H
R3
O
OH
O
S
Ph
R2
N
Base
R4
O
R1
OR
R1
OR
*
Ph
R1
R
Ph
R1
R3
R1
R
*
O
O
CN
Ph
*
CN
R1
H. Stetter, H. Kuhlmann, Chem. Ber., 1976, 109, 2890
H. Stetter, Angew. Chem. Int. Ed., 1976, 15, 639
31
First Intramolecular Stetter



Trost & co-workers published the first
stereocontrolled synthesis of Hirsutic Acid C
Sesquiterpene with antibiotic
and antimitotic activity
7 chiral centers
H
Me
O
Me
HO2C 11
MeO2C
H
OH
H
TL, 1974, 3745
(Matsumoto)
3
2
9
O
H
Hirsutic Acid C
B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc., 1979, 101, 1284
32
OH
H
Hirsutic Acid C
HO2C 11
3
2
9
O
H
Hirsutic Acid C
O
O
H
CN
O
O
TMS
O
Br
LDA, -30ºC
THF
O
KOH, MeOH
88%
TMS
NC
2) CO2, then CH2N2
NC
NEt3 (8 equiv.)
PhMe, reflux, 12h
2.5% HCl (aq)
CO2Me
O
H
1) LDA, TMEDA
THF, -78C
O
O
PhH, reflux 6h
88%
NC
O
70%
NC
CO2Me
NC
2
11
NC
CO2Me
O H
B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc., 1979, 101, 1284
CO2Me
33
OH
H
Hirsutic Acid C
3
2
HO2C 11
9
O
H
Hirsutic Acid C
5% Pd, BaCO3
1 atm H2
NC
NC
NC
BrZn
CO2Et
H
O
H
CO2Me EtOH/EtOAc
80%
NC
NaOMe, MeOH
rt, 3hrs
77%
H
PhH, Et2O,
CO2Me reflux, 15min.
1)BH3-THF, 0ºC
THF
H
MeO2C
O
9
HOOC
2) Ac2O, Py, rt
89%
1) K2CO3, MeOH
0ºC, 2hrs
79%
NC
H
CO2Me
2) PCC, DCM
OAc
rt, 88%
NC
EtO2C
O
H
O
1)NBS, CCl4
reflux 30min
H
OAc
CO2Me
2) LiBr, Li2CO3,
DMF, 130ºC, 20min
NC
H
CHO
CO2Me
B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc., 1979, 101, 1284
34
Hirsutic Acid C
OH
H
3
2
HO2C 11
9
O
H
Hirsutic Acid C
S I
NC
Me
H
CHO
Me
H
Me
MeO2C
Me
Me
11
3
MeO2C
H
2
9
O
O
O
Me
H
O
MeO2C
NC
(2.3 eq.)
NEt3 (50eq.)
iPrOH, reflux
5h
67%
CO2Me
H
N
OH
Me
H
OH
HMe
O
Me
Me
MeO2C
O
TL, 1974, 3745
(Matsumoto)
B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc., 1979, 101, 1284
MeO2C
O
H
Hirsutic Acid C
35
Intramolecular Variant


Ciganek & co-workers reported the first
study of the intramolecular variant
Enders & co-workers reported the first
asymmetric intramolecular Stetter reaction
R
O
O
cat. (20mol%)
K2CO3, THF
CHO
CO2R
44-73%
Ph
N N
N
CO2R
R
O
ee = 41-74%
E. Ciganek, Synthesis, 1995, 1311
D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta, 1996, 79, 1899
cat. =
O
H3C
Ph
O
CH3
36
New Highly Enantioselective Catalyst
O
cat. (20mol%)
KHMDS (20mol%)
CHO
CO2Et
CO2Et xylenes, 25ºC, 24hrs
O
O
N
O
N BF4
N Ph
N
O
O
N Cl
N Ph
N
N BF4
N Ph
Ph
0% yield
27% yield
O
N
N
Cl
N Ph
85% yield
79% ee
O
N
90% ee
N BF4
N Ph
Ph
48% yield
80% ee
58% yield
M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298
95% ee
37
Catalyst Optimization

Structural modifications were made to
improve the yield of the reaction
O
N
N
N
O
N
H
N
N
Cl
60% yield
91% ee
58% yield
95% ee
O
N
N
N
OMe
94% yield
94% ee
M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298
38
Scope of the Intramolecular
Stetter Reaction
cat. (20mol%)
KHMDS (20mol%)
CHO
R
X
CO2R
xylenes, 25ºC, 24h
O
CO2R
R
X
O
O
Me
O
CO2Et
CO2Et
CO2Et
O
O
O
Me
80% yield
97% ee
OMe
90% yield
84% ee
O
O
O
63% yield
96% ee
CO2Me
CO2Et
CO2Et
S
95% yield
87% ee
N
Me
64% yield
82% ee
M.S. Kerr, J.R. de Alaniz, T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298
N
CO2Me
72% yield
84% ee
39
Effect of the Michael Acceptor
O
N BF4
N N
O
(20mol%)
KHMDS (20mol%)
CHO
EWG
O
xylene, 25ºC, 24h
O
O
OEt
58% yield
95% ee
N
78% yield
75% ee
M.S. Kerr, T. Rovis, Synlett, 2003, 12, 1934
EWG
O
O
NH2
0% yield
95% recovered SM
O
H
0% yield
0% recovered SM
Et
90% yield
92% ee
only 1h!
NO2
0% yield
0% recovered SM
40
Quaternary Carbon Centers

Can we overcome the low reactivity when
forming quaternary carbon centers??
S I
CN
MeO2C
Me
N
OH
Me
NEt3 (50eq.)
iPrOH, reflux
5h
67%
CHO
CN
(2.3 eq.)
O
OH
H
HO2C
MeO2C
O
H
Hirsutic Acid C
B.M. Trost, C.D. Shuey, F. DiNinno Jr., S.S. McElvain, J. Am. Chem. Soc., 1979, 101, 1284
41
Catalytic Formation of Quaternary
Carbon Centers
O
cat. (20mol%)
KHMDS (20mol%)
Et
O
O
N
CO2Me
Et
CO2Me
PhMe, 25ºC, 24h
O
N BF4
N
O
N
O
O
N BF4
N
N
N
N
F
BF4
F
H
OMe
F
45% yield
99% ee
F
80% yield
99% ee
M.S. Kerr, T. Rovis, J. Am. Chem. Soc., 2004, 126, 8876
F
85% yield
99% ee
42
Aromatic Series : Scope
O
F
BF4
F
F
F (20mol%)
KHMDS (20mol%)
O
R
EWG
X
N F
N N
O
R
2 eq NEt3, PhMe, 25ºC, 24h
O
O
O
Et
O
Me
Et
CO2Me
S
96% yield
97% ee
CO2Et
CO2Me
95% yield
92% ee
O
95% yield
99% ee
O
Ph
O
O
Ph
Me
O
55% yield
99% ee
M.S. Kerr, T. Rovis, J. Am. Chem. Soc., 2004, 126, 8876
EWG
X
Me
O
43
Aliphatic Series: Scope
O
N F
N N
F
BF4
F
F
F (20mol%)
KHMDS (20mol%)
O
R
EWG
O
R
2 eq NEt3, PhMe, 25ºC, 24h
EWG
O
O
O
Me O
Me O
i-Bu
Ph
O
N
NO2
85% yield
96% ee
90% yield
84% ee
O
81% yield
95% ee
O
Me
O
Me
O
Me
81% yield
95% ee
M.S. Kerr, T. Rovis, J. Am. Chem. Soc., 2004, 126, 8876
Ph
63% yield
99% ee
44
Catalytic Cycle : Revisited
Ph
O
*
O
Ph
EWG
N
N
R
N
N
O
4
N
N
*
Ph
H
N
R
Ph
N
H
O
EWG
1
N
N
N
N
HO
*
Ph
Ph
N
3
N
Ph
OH
N
OH
2
R
EWG
J.R. de Alaniz, T. Rovis, submitted
N
N
R
EWG
45
Re-investigating the Mechanism

What is the rate limiting step?

C-C Bond formation – Ketones Were Faster…
O
Bn
D
O
N BF4
N N Ph
O
H
CO2Et
20mol%
CO2Et
KHMDS 20mol%
PhMe
O
H
CO2Et
D
H
H
O
H
O
dr = 3:1
kH/kD = 3.8

Primary Kinetic Isotope Effect Observed

Indicates C-H or X-H Bond Cleavage at the rate
determining step
J.R. de Alaniz, T. Rovis, submitted
46
Catalytic Cycle : Reloaded
Ph
*
O
O
D
Ph
EWG
N
N
R
N
N
O
4
N
N
*
Ph
D
D
N
R
Ph
N
D
O
EWG
1
Could be Rate-Limiting
N
N
Could be Rate-Limiting
N
N
DO
*
Ph
Ph
N
J.R. de Alaniz, T. Rovis, submitted
N
Ph
OD
N
OD
2
R
EWG
3
N
N
R
EWG
47
Deuterium NMR Studies
O
Bn
N BF4
N N Ph
D
O
CO2Et
H
H
Bn
N
N Ph
CO2Et
O
H
J.R. de Alaniz, T. Rovis, submitted
CO2Et
TMS
H
+
CO2Et
D
H
PhMe
H
+
D
O
20mol%
D
O
O
PhMe
N
CO2Et
D
KHMDS 20mol%
O
O
O
20mol%
O
O
H
N
D
TMS
CO2Et
H
+
D
O
48
Diastereoselective Protonation
TMS
N
H N
N
N
TMS
O
TMS
N
DH
TMS
H
O
H
N
N
D
OEt
O
H

O
TMS
H
N
N
O
D H
O
OEt
OEt
O
O
O
H
HH
O
O
N
N
O
D N
OEt
O
TMS
DH
O
OEt
H
O
major diastereomer
Accounts for presence of D-HMDS and less
than 100% deuterium incorporation
J.R. de Alaniz, T. Rovis, submitted
49
Diastereoselective Protonation
TMS
N
H N
N
N
TMS
O
TMS
N
D H
TMS
H
O
N
N
O
N
OEt
D H
D N
N
TMS
O
J.R. de Alaniz, T. Rovis, submitted
O
O
OEt
O
dr = 3:1
N
H D
OD
OEt
H
OEt
TMS
N
N
DH
O
H
H
O
OEt
O
O
O
TMS
H
N
N
O
HH
O
TMS
D
O
H
D N
OEt
O
H
N
O
TMS
N
N
N
TMS
O
H D
O
H
OEt
O
50
Diastereoselective Protonation
N
N
N
O
Absence of
KHMSD
D
OEt
O
H

O
N
N
N
O
O
D H
O
OEt
O
H
H
O
DH
OEt
O
dr = 9:1
Potential for generating two contiguous chiral
centers with one catalytic reaction !!!
J.R. de Alaniz, T. Rovis, submitted
51
Setting Contiguous Stereocenters
O
CO2Et
O
20 mol% cat.
H
CO2Et
Me
Me
PhMe, 24h, 25ºC
O
Entry
Catalyst
1
Yield (%)
ee (%)
dr (%)
85
90
3:1
N
N BF
4
N Ph
N
N
N
80
90
15:1
N
N
N
94
92
30:1
Bn
2
Base
O
KHMDS
Bn
3
Bn
J.R. de Alaniz, T. Rovis, submitted
CF3
52
Contiguous Stereocenters via
Asymmetric Stetter Reaction
O
CO2Et
Bn
N
N N pCF Ph
3
O
20 mol%
H
CO2Et
Bn
Bn
PhMe, 24h, 25ºC
O
O
O
O
Bn
N
N N pCF Ph
3
O
80% yield
89% ee, 20:1 dr
O
20 mol%
PhMe, 24h, 25ºC
O
O
Bn
O
O
J.R. de Alaniz, T. Rovis, submitted
N
N N pCF Ph
3
20 mol%
PhMe, 24h, 25ºC
H
O
H
O
O
95% yield
90% ee, 10:1 dr
O
H
O
H
O
94% yield
99% ee, 50:1 dr
53
Conclusion
O
H2N
N
N
CH3
N
N Ph
O
N
H3C
Enders
Ar
N
Johnson
S
HO
Breslow
O
Ar
Ar
OH
OH
H
SiR3
O
Stetter
HO2C
O
H
Trost
Bn
O
R'
Ph
R
N
CO2Et
R
O
N
N Ar
H
O
N
O
N
N
N
O
N
N Ar
D H
O
H
Rovis
OEt
O
54
Acknowledgements

Prof. Keith Fagnou

Prof. Tom Rovis

Fagnou Research Group








... And you!!
Mathieu Parisien
Marc Lafrance
Mélissa Leblanc
Valérie Charbonneau
Irina Dessinova
Julien Dugal-Tessier
Praew Thansandote
Nicole Blaquiere
55