Chiral Amines as Nucleophilic
Catalysts in Asymmetric
Synthesis
Stephen Greszler
University of North Carolina
March 9th, 2007
Asymmetric Synthesis
Transition
Metal Catalysis
Organocatalysis
Advantages
•
•
•
•
•
Diverse range of activity
Cost, availability of starting
materials
Moisture and air stability of catalysts
No metal byproducts or auxilliary
removal steps
Catalyst Recovery
Biocatalysis
Disadvantages
•
•
•
Catalyst loading
Competitive background reactions
ee’s > 99% still largely elusive
(pharmaceutical importance)
Outline
Acyl Ammonium Catalysis
•
•
kinetic resolution of alcohols/amines
C-acylation (quaternary centers)
Ammonium Enolate Reactions
•
•
•
•
β-lactone/lactam synthesis
α-halogenation
cyclopropanation
Baylis Hillman reactions
S
N
Achiral Nucleophilic Catalysts
S
N
Me2N
tBu
N
O
O
N
Ph
S
Fe
OH
Ph
Ph
H
H
N
Ph
Ph
O
N
N
CH3
Ph
H
Ph
CH3
N
N
N
N
N
N
N-methylimidazole
(NMI)
N,N-dimethylaminopyridine
(DMAP)
O
Me
OH
N
O
Me
O
N
H
O
HN
O
NH
BOC
N
N
O
N
NH
O
O
Me
O
Me
Me
N
NH
HN
R
1,4-diazabicyclo[2.2.2]octane
(DABCO)
H
N
H
N
HN
O
Me
Me
OMe
N
R
Mechanisms of Organocatalysis by Amines
Acyl Ammonium Catalysis
Iminium Ion Activation
N
O
N
H
O
R1
N
Nu
R
R2
O
C
N
H
R2
H
N
R1
-H2O
R2
R
X
Cl
aq/org
solvent
-HX
O
R
O
N
O
-HX
El
R
N
El
RO
R2
N
El
R
O
RO
N
2-Ammonium Enolate Catalysis
N
N
N
El
Phase Transfer Catalysis
O
R
1- Ammonium Enolate Catalysis
R2
Enamine Catalysis
R1
-X
Nu
R1
-H2O
O
X
O
R2
3-Ammonium Enolate Catalysis
O
R
O
N
El
R
N
Mechanisms of Organocatalysis by Amines
Acyl Ammonium Catalysis
Iminium Ion Activation
N
O
N
H
O
R1
N
Nu
R
R2
O
C
N
H
R2
H
N
R1
-H2O
R2
R
X
Cl
aq/org
solvent
-HX
O
R
O
N
O
-HX
El
R
N
El
RO
R2
N
El
R
O
RO
N
2-Ammonium Enolate Catalysis
N
N
N
El
Phase Transfer Catalysis
O
R
1- Ammonium Enolate Catalysis
R2
Enamine Catalysis
R1
-X
Nu
R1
-H2O
O
X
O
R2
3-Ammonium Enolate Catalysis
O
R
O
N
El
R
N
Kinetic Resolution Basics
OH
R
+
OH
catalyst *
Ac2O
+
R
R'
OAc
R'
Calculation of selectivity factor (s)
s=
kfast
kslow
s=
ln[(1-C)(1-ee)]
ln[(1-C)(1+ee)]
Where ee is enantiomeric excess of unreacted substrate
s=
ln[1-C(1+ee')]
ln[1-C(1-ee')]
Where ee is enantiomeric excess of product
Benchmark Values
s = 10…….....28% theoretical yield of unreacted substrate with ee > 99%
s = 60……….46% theoretical yield of unreacted substrate with ee > 99%
Vedejs, E.; Jure, M. Angew. Chem. Int. Ed. 2005, 44, 3974.
R
R'
Enzymatic Kinetic Resolution
Me
Me
O
+
OH
CH3(CH2)10
Me
lipase
OH
O
+
OH
O
(CH2)10CH3
() menthol
(95% ee)
15 days,
33% conversion
Advantages:
high regio-, stereo-, and enantioselectivity, mild reaction conditions
Disadvantages: lack of generality (defined substrate requirements), variable quantities of
water/buffer/other cofactors necessary, protein denaturation and inhibition
Langrand, G; Baratti, J; Buono, G; Triantaphylides, C. Tetrahedron Lett. 1986, 27, 29.
Pioneering Work by Evans and Vedejs
O
R
BrMg
N
O
O
O
+
Ph
O
O
1 equiv.
R
R
Ph
+
HO
Ph
R
N
10 equiv.
5-95% ee
NMe2
t-Bu
N
Cl3C
O
O
OMe
ZnCl2
R
+
HO
Ph
R
O
O
O
R
+
Ar
N
Cl
1 equiv.
Cl3C
1 equiv.
76-93% ee
Evans, D.; Anderson, J.C.; Taylor, M. Tetrahedron Lett. 1993, 34, 5563.
Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809.
HO
Ar
Parallel Kinetic Resolution
NMe2
Entry
Ar
Yield A (ee)
1
2
3
1-naphthyl
2-naphthyl
o-tolyl
46% (88%)
49% (86%)
46% (83%)
Yield B (ee)
NMe2
tBu
N
OMe
49% (95%)
43% (93%)
46% (94%)
OBn
O
Cl3C O
(+)-Fenchyl
chloroformate
Cl
NMe2
NMe2
• Not catalytic
tBu
N
• Approaches enzymatic selectivity
tBu
N
Cl3C O
O
OMe
tBu
N
Cl
O
O
OBn
Cl
• Equivalent to having a selectivity factor >125
MgBr2
Et3N (3 eq)
CH2Cl2, 36 h
H3C
H
O
Ar
O
CCl3
O
A
Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584.
OH
H3C
+
Ar
H3C
H
O
Ar
O
O
B
Reactivity/Selectivity Dilemma
DMAP as an Esterification Catalyst
Reacts faster than alcohol
with acylating agent
(catalytic step)
Acylammonium species is a
better acylating agent than
anhydride (asymmetric induction step)
N
N
O
+
O
O
O
O
+
O
N
N
ROH
RO
-AcOH
N
N
O
ROH
~ rate enhancements on the order of 104 compared to the uncatalyzed reaction
Chiral Acylating Agent
NMe2
NMe2
O
N
t-Bu
+
Cl
X
O
R
HO
HO
R
Ph
O
t-Bu
N
OMe
R
Cl
OMe
-R''3NH
Cl
O
R
+
Ar
Ph
O
R
~preformation of acylating agent necessary
O
Ph
HO
Ar
Fu’s “Planar Chiral” Design
Void
Me2N
N
H
top
N
R
bottom
MLn
left
R'
Me2N
N
R'
Me2N
N
Fe R'
R'
right
R'
R'
R'
N
Fe R'
R'
R'
R'
R'
19-electron complex
R'
R'
R'
18-electron complex
A planar-chiral azaferrocene
Fe R'
18-electron complex
A planar chiral DMAP
Ruble, J.C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230.
Fu, G. C. Acc. Chem. Res. 2000, 33, 412.
Catalyst Synthesis
MeN
FeCl2
1) (C5Ph5)Li
2)
NMe2
racemic product
41% yield
resolve
N
Fe
Ph
Ph
Ph
Ph
N
Li
Ph
• Product stable to flash chromatography; enantiomers resolved via chiral HPLC
• Air/moisture stable; identical selectivities under air and inert atmosphere
• High % recovery of catalyst in most systems (98%)
Fu, G. C. Acc. Chem. Res. 2000, 33, 412.
Catalyst Evolution
Me2N
O
N
N
Fe
Me
Me
Me
Me
Me
Half-life (min)
Ph
O
5% catalyst
+
Me
Me
O
OH
Fe
O
Me
CD2Cl2, rt
O
Ph
Me
Me
Me
Me
Me
50,000
<3
O
Me2N
O
OH
N
O
Ph
Fe
Me
Me
O
Me
Me
Me
O
2% catalyst
+
NEt3
toluene, rt
Ph
Me
Me
S = 1.7
Me
Me
Me
O
Me2N
O
OH
O
Ph
N
Fe
Me
Me
O
Me
NEt3
toluene, rt
Ph
Ph
Ph
Ph
O
2% catalyst
+
Ph
Ruble, J.C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230.
Fu, G. C. Acc. Chem. Res., 2000, 33, 412.
Ph
Me
Me
S = 10
Enhancing Selectivity
O
O
OH
O
Ph
Me
Me
O
O
2% catalyst
+
Me
NEt3
toluene, rt
Ph
Me2N
N
Me
solvent
% conversion
after 1.0 h
s
DMF
CH3CN
CH2Cl2
Acetone
THF
EtOAc
Toluene
Et2O
t-amyl alcohol
6
10
14
8
4
6
13
8
36
3.4
3.6
7.0
8.7
9.6
11
11
13
27
Me
Fe
Ph
Ph
Ph
Ph
Ph
HO
Ruble, J.C.; Tweddell, J.; Fu, G.C. J. Am. Chem. Soc. 1998, 63, 2794.
Active Catalyst Structure
H
R
OH
N
N
Me
O
Fe
Ph
Ph
Ph
Ph
Ph
(SbF6- as counterion)
Fu, G.C.; Acc. Chem. Res., 2004, 33, 542.
Kinetic Resolution of Alcohols
OH
R
+
OH
1-2.5% catalyst
Ac2O
OAc
+
R'
NEt3
t-amyl alcohol, 0°C
R
R'
R
R'
Unreacted Enantiomer (selectivity factor)
OH
Me
Me
i-Pr
OH
OH
29
t-Bu
95
Me
Me
O
Me
Me
OH
n-Bu
OH
OH
Me
OH
12
Me
Me
64
43
20
Ph
Ruble, J. C.; Latham, H.A.; Fu, G.C. J. Am. Chem. Soc. 1997, 119, 1492.
Tao, B.; Ruble, J.C.; Hoic, D.A.; Fu, G.C. J. Am. Chem. Soc. 1999, 121, 5091.
Fu, G.C.; Acc. Chem. Res., 2004, 33, 542.
10
Fuji’s “Induced Fit” Catalyst
O
OH
O
O
H
H
H
N
OH
H
N
O
N
H
N
H
OH
H
N
O
N
H
Me2N
CH3
CH3
O OH
O
CH3
CH3
“Induced fit”-type catalysts are most
effective for resolution of cyclic diols
(e.g. deracemization of meso diols and
kinetic resolution of monoesters)
Kawabata, T.; Nagato, M.; Takusa, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169.
DHIP Catalysts
X
H
(R'CO)2O
N
N
R
O
R
N
R’
H
X
N
N
R
R'
H
X
N
O
H
Origin of Stereoselectivity
Disfavored
Favored
H
O
X
N
R2
R2
OH
R
N
O
X
N
Ph
H
OH
R
N
Ph
Birman, V.B.; Li, X.; Jiang, H.; Uffman, E.W.; Kilbane, C.J. J. Am. Chem. Soc., 2004, 126, 12226.
Birman, V.B.; Li, X.; Jiang, H.; Uffman, E.W. Tetrahedron, 2006, 62, 285.
Catalyst Synthesis and Reactivity
OH
H2N
X
2-bromopyridine,
DIEA, 165°C
Ph
X
Ph
N
1. SOCl2, CHCl3, reflux
OH
N
H
2. NaOH (aq)
N
N
Ph
40-55% overall
yield
X
S
N
N
S
N
N
N
Ph
N
Ph
Ph
DHIP
TA
BTA
DHIP = dihydroimidazo[1,2-a]pyridine
TA = tetramisole
BTA= benzotetramisole
OH
OH
Ar
R
Catalyst
Selectivity Factor
DHIP
s < 85
TA
s < 31
BTA
s < 355
R1
2
R
Selectivity Factor
s < 32
Birman, V.B.; Li, X.; Jiang, H.; Uffman, E.W.; Kilbane, C.J. J. Am. Chem. Soc. 2004, 126, 12226 .
Birman, V.B.; Guo, L. Org. Lett. 2006, 8, 4859.
Birman, V.B.; Li, X. Org. Lett. 2006, 8, 1351.
Peptides for Kinetic Resolution
O Me Me
O Me Me
N
H
N
BocHN
HN
N
H
N
O
Ac2O
BocHN
HN
Me
O
Me
O
O
N
N
N
N
O
Me
A
Selectivities using A
• Effective for cyclic and some acyclic
α-hydroxy amides
O
HO
NHAc
HO
NHAc
• Hydrogen bonding crucial in stabilizing
5% cat.
1 equiv Ac2O
O
Me
CHCl3, 0°C
NHAc
48% ee
s=3
transition state
• Imidazole is the active acylating portion
• β-hairpin turns are a common feature
OH
Me
No selectivity
Miller, S.J.; Copeland, G.T.; Papaiannou, N.; Horstman, T.E.; Ruel, E.M. J. Am. Chem. Soc. 1998, 120, 1629.
Stereochemical Model
Favored Approach
H
N
O
H
N
N H
O
O
OH
O
H Me Me
N
H N
H
N
H Me Me
N
O
O
O
R
O
Me
N
Me N
O
O
H
N
O
Me
N
Me N
Me
Me
OH
O
Disfavored Approach
N H
O
H
OMe
O
H N
R
O
H
OMe
t-Bu
t-Bu
O
s = 28
Vasbinder, M.M.; Jarvo, E.R.; Miller, S.J. Angew. Chem. Int. Ed., 2001, 40, 2824.
Representative Peptides
O
Me
N
N
H H
N
Boc
N
O
O
OMe
s = 28 for HO
O
Ph
Me
O
H
N
H
N
Me
H
H
O
HN
O
N
Me
Me
NH
O
HN
O
NH
NHAc
HN
O
O
Me
NH
Boc
N
Me
Me
Me
HN
O
N
s = 51 for
Me
OMe
HO
NHAc
O
Me
N
N
H H
N
O
O
N
NH
Boc
Cy
s = 9-50
for tertiary
α-hydroxy amides
O
HN
OMe
Me
R
OH
NHAc
~ some success in resolution of
secondary aryl alcohols using
alternative octapeptides
Jarva, E.R.; Evans, C.A.; Copeland, G.T.; Miller, S.J. J. Org. Chem. 2001, 66, 5522.
Vasbinder, M.M.; Jarvo, E.R.; Miller, S.J. Angew. Chem. Int. Ed., 2001, 40, 2824.
Resolution of Amines
O
NH2
Ph
acylating
agent
+
Me
acylating agent
O
O
R
O
10% catalyst
CHCl3
0°C
HN
Ph
1.0
• Limited progress relative to kinetic resolution of alcohols
O
X
1.0
O
Me
(no reaction)
• Cyclic amine derivatives allow for the best resolution
1.2
• Other methods of amine resolution involve the use of
stoichiometric quantities of a chiral acylating agent
O
MeO
O
OMe
• Nucleophilicity of amines is an issue
• Balance the reactivity of the catalyst with that of the amine
(complex acylating agents)
O
O
Me
selectivity factor
R
Cl
X
O
OMe
O
t-Bu
12
O
N
-Naphthyl
Arai, S.; Bellemin-Laponnaz, S.; Fu, G.C. Angew. Chem. Int. Ed., 2001, 40, 234.
Resolution of Amine Derivatives
O
O
+
Ar
OMe
O
NH2
R
t-Bu
O
N
10% PPY catalyst
CHCl3, -50°C
-Naphthyl
HN
OMe
Catalyst
NH2
+
Ar
R
R
Ar
N
s = 11-27
N
O
OMe
O
+
R
t-Bu
N
H
Fe
5% PPY catalyst
O
N
-Naphthyl
Ph
Ph
R
N
Ac
1.5 equiv. LiBr
0.75 equiv. 18-crown-6
toluene, 0°C, 5 days
Ph
Ph
+
R
Ph
N
H
s = 9.8-31
O
HN
O
O
+
O
O
2% catalyst
0.75 equiv. DIEA
O
O
O
N
O
+
HN
S
O
CHCl3, 0°C, 24 h
R
R
R
s = 50-520
Arai, S.; Bellemin-Laponnaz, S.; Fu, G.C. Angew. Chem. Int. Ed. 2001, 40, 234.
Arp, F.; Fu, G.C. J. Am. Chem. Soc. 2006, 128, 14264.
Birman, V.B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E.W. J. Am. Chem. Soc. 2006, 128, 6536.
N
N
Ph
Silyl Ketene Acetals
O
R
O
O
OSiR3
+
R
R1
O
chiral catalyst
OR3
O
OR3
R
2
1
R
R2
R
O
common
O
O
R
OSiR3
X
nucleophilic
catalyst
R'
R'
O
rare
O
R'
R
O
OSiR3
TBAF
O
O
O
O
But…
X
Product when
X = Br, Cl, F
Wiles, C.; Watts, P.; Haswell, S.J.; Pombo-Villar, E. Tetrahedron Lett. 2002, 43, 2945.
Mermeria, A.H.; Fu, G.C.; J. Am. Chem. Soc. 2005, 127, 5604.
Product when
X = CN
Proposed Pathway for Nucleophile-Catalyzed Rearrangements
O
R
O
O
OSiR3
O
R1
R
OR3
O
OR3
R
R1 R2
R2
cat*
-cat*
OSiR3
O
R
R
O
1
OR3
cat*
O
R
-R3SiOCOR
O
O
R2
1
R
cat*
R
OR3
R2
-cat*
cat*
• Dual activation of both nucleophile
and electrophile
O
• Ion pairs are important
• E/Z mixtures of silyl ketene acetals
give identical enantioselectivities
O
R
1
R
OR3
R2
Black, T.H.; Arrivo, S.M.; Schumm, J.S.; Knobeloch, J.M. J. Am. Chem. Soc., Chem. Comm. 1986, 1524.
Mermeria, A.H.; Fu, G.C.; J. Am. Chem. Soc. 2005, 127, 5604.
Representative C-Acylations
O
R1 O
5% catalyst
OR
O
CH2Cl2, 35°C
X
Oi-Pr
R
N
N
N TBS
C
Fe
R
Ph
Ph
Ph
Ph
Et
Ph
Me
N
Ar
O
O
O
O
Ar
73-92% ee,
68-96% yield
R
O
N
69-83% ee,
52-93% yield
Me
88-91% ee,
93-95% yield
C
Et
Ph
R
RO2C
N
toluene, 0°C
Fu, G.C.; Acc. Chem. Res. 2004, 33, 542.
Mermerian, A.H.; Fu, G.C.; J. Am. Chem. Soc. 2005, 127, 5604.
Mermerian, A.H.; Fu, G.C. Angew. Chem. Int. Ed. 2005, 44, 949.
Oi-Pr
Et
2 % catalyst
OR
88-99% ee,
72-95% yield
O
Me
5% catalyst
1,2-DCE, rt
O
O
Ph
O
5% catalyst, Ac2O
toluene/CH2Cl2
rt
OR
O
X
R = CMe2(CCl3)
OSiMe3
Ar
R1
Ar
O
O
Mechanisms of Organocatalysis by Amines
Acyl Ammonium Catalysis
Iminium Ion Activation
N
O
N
H
O
R1
N
Nu
R
R2
O
C
N
H
R2
H
N
R1
-H2O
R2
R
X
Cl
aq/org
solvent
-HX
O
R
O
N
O
-HX
El
R
N
El
RO
R2
N
El
R
O
RO
N
2-Ammonium Enolate Catalysis
N
N
N
El
Phase Transfer Catalysis
O
R
1- Ammonium Enolate Catalysis
R2
Enamine Catalysis
R1
-X
Nu
R1
-H2O
O
X
O
R2
3-Ammonium Enolate Catalysis
O
R
O
N
El
R
N
Cinchona Alkaloids
OH
OH
N
N
N
N
R
R
Quinine (QN)
Cinchonidine (CD)
Cupreine (CPN)
R = OMe
R=H
R = OH
Quinidine (QD)
Cinchonine (CN)
Cupreidine (CPD)
• First used as an organocatalyst in the hydrocyanation of aldehydes in 1912
• Available in two pseudoenantiomeric forms
• Catalytic utility stems from the bifunctionality of quinuclidine core and C6 hydroxyl group; reactivity can be difficult to predict
• Approximate cost is $1/g of material
Marcelli, T.; van Maarseveen, J.H.; Hiemstra, H. Angew. Chem. Int. Ed. 2006, 45, 7496.
Ketene Substrates: The Big Picture
O
LG
* RL
X RS
O
catalyst*
C
RL
X-LG
Product
Br-OR, Cl-OR, F-OR
RS
α-halo ester
Imine
β-lactam
Aldehyde/Ketone
β-lactone
O
LG
O
H-OR, H-NHR
chiral ester, amide
cat
RL
cat
* RL
RS
X RS
X-LG
determines
product identity
Early Work
Pracejus’s Chiral Ester Synthesis
OMe
N
N
OH
O
Me
Ph
Ph
NHR3
O
1-2% catalyst
C
Me
O
Ph
OMe
OMe
-110°C, MeOH
Me
• Bronsted Base catalysis
• Modest selectivities due
to high background reaction
99% yield
up to 76% ee
The Wynberg Method
H
C O
H
O
H
+
O
Cl3C
quinidine
-50°C, toluene
H
O
CCl3
90% yield
95% ee
• Original method required the
use of a ketene generator
• Limitations include the use of
a highly electrophilic aldehyde
Pracejus, H.; Matje, H. J. Prakt. Chem. 4. Reihe. 1964, 24, 195.
Wynberg, H.; Staring, E. J. Am. Chem. Soc. 1982, 104, 166.
Wynberg Modifications
O
R'
O
DIEA
Cl
10% AcQ
CH3CN, rt
O
R'
RCl2C
O
O
H
RCl2C
NR3
>90% ee
R'
AcQ
OMe
• Allows for in situ ketene generation
N
• Limitations still include the necessity of a highly electron deficient aldehyde
(overcome in intramolecular reactions with carboxylic acid activation)
CO2H
10% AcQ
+
n
COR2
N
Pr
Br
iPr2NEt, CH2CN
O
Me
• β –lactones undergo a variety of useful transformations
R1
N
O
O
R1
O
n 2
R
70-84% yield
91-98% ee for R2 = H
d.r.'s for ketone substrates
generally >19:1
Tennyson, Reginald; Romo, D. J. Org. Chem. 2000, 65, 7248.
Henry-Riyad, H.; Lee, C.; Purohit, V.C.; Romo, D.; Org. Lett. 2006, 8, 4363.
Utility of β-Lactones
O
N3
A
H
H
A
B
OH
A
OH
B

NaN3
O
O
O
R
A
B
R2CuMgBr
O
1.LDA
O
O
R
O
2. R-X
A
B
BnO
2. DIAD, PPH3
B
O
N
1. BnONH2
A
B
LAH
Nu
HOR
NEt3
HNR2
OH
A
OH
O
NR2
B
OH
A
A
O
B
OR
B
Yang, H.W.; Romo, D. Tetrahedron. 1999, 55, 6403.
Yang, H.W.; Romo, D. J. Org. Chem. 1999, 64, 7657.
France, S.; Guerin, D.J.; Miller, S.J.; Lectka, T. Chem. Rev. 2003, 103, 2985.
OH
β-Lactam Synthesis
The Staudinger Reaction
N
R1
O
C
X
+
H
R2
R1
R3
X
N
O
X
R3
R1
R2
H
O
N
R3
R2
electrophile
nucleophile
Nucleophilic Catalysis (Staudinger “Umpolung”)
O
C
R2
O
+
R3
cat*
3
cat*
R
R2
nucleophile
N
+
EWG
X
X
O
N
H
electrophile
Staudinger, H. Liebigs Ann. Chem. 1908, 356, 51.
EWG
R3
R2
Lectka’s “Shuttle Deprotonation” Strategy
• Ketene generated in situ from the corresponding acyl chloride
• Requires the use of a kinetically active, nucleophilic catalyst and
a thermodynamically active, non-nucleophilic base (proton sponge)
• Catalyst and base additive act in a tandem “shuttle deprotonation” mechanism
• Original methodology employed expensive phosphazene bases; recent improvements
allow for NaH and K2CO3
O
N
C
K2CO3
R
N
R
R
H
H
N
R'
R
O
R
N
Cl
X
H
N
O
N
R'
R
R
H
H
O
KHCO3 + KCl
X
H
cat.
R
Taggi, A.E.; Hafez, A.M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 6629.
Predicting Alkaloid Reactivity
Effect of the C6 Stereocenter on Facial Preference
Effect of the Quinoline Substituent on Facial Preference
N
re face
approach
0.0 kcal
N
PhCO2
H
O
OMe
Ph
si face
approach
6.69 kcal
proposed
ketene
adduct
re face
approach
0.13 kcal
N
N
PhCO2
H
O
Ph
proposed
ketene
adduct
N
si face
approach
0.0 kcal
N
PhCO2
re face
approach
0.0 kcal
H
O
OMe
proposed
ketene
adduct
Ph
Molecular Models
si face
approach
6.92 kcal
~ the configuration of the C6 stereocenter is unimportant
Molecular Models
~ an approximately racemic product results;
MeO group is critical
Taggi, A.E.; Hafez, A.M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 6629.
β-Lactam Products
N
EtO2C
O
C
Ts
+
H
H
Ts
10 % BQ
EtO2C
R
BQ
O
N
R
>95% ee,
25/1 - 99/1 dr,
36-65% yield
OMe
R = Ph, Et, Bn, CH2OPh, OR', CH2=CH2, N3, Br
N
N
• β-lactams are desirable targets because of their antimicrobial properties
O
O
Ph
• Subsequent manipulations are also possible
• Fu’s PPY catalyst has also been shown to be effective in catalyzing these reactions
O
Ph
O
Cl
1. cat
2. MeOH, 
cat
O
PhO
cat
Ph
N
H
O
63% yield
95% ee
14/1 d.r.
OMe
EtO2C
OPh
O
N
O
H
EtO2C
EtO2C
N
OPh
O
Ph cat
Cl
OH
Ph
MeO
NH2
O
N
H
OH
O
EtO2C
OPh
N
H
OMe
O
Taggi, A.E.; Hafez, A.M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 6629.
Dudding, T.; Hafez, A.; Taggi, A.; Wagerle, T.; Lectka, T. Org. Lett. 2002, 4, 390.
43% yield
95% ee
12/1 d.r.
Halogenations
*catalyst performs a dual
role as both a Lewis and
Bronsted base
OMe
OMe
N
N
N
N
OBz
OBz
O
R
Cl
catalyst
H
stoich. base
K2CO3
R
C O
catalyst
LG-Cl
R
O
H
cat
Cl
Cl
O
Cl
Cl
Cl
Cl
O
R
O
Cl
O
* esterification must
be fast enough to
avoid racemization
Cl
Cl
Cl
R
cat
Cl
Cl
O
Cl
Cl
Cl
Cl
Cl
Cl
France, S.; Wack, H.; Taggi, A.E.; Hafex, A.M.; Wagerle, T.R.; Shah, M.H.; Dusich, C.L.; Lectka, T. J. Am. Chem. Soc. 2004, 126,
4245.
Effect of the Halogenating Agent
Chlorination
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O
68% yield,
56% ee
Cl
Cl
O
Cl
Cl
65% yield,
91% ee
Cl
R H
O Nu
Bromination
Br
O
Br
Br
Br
Br
Br
Br
O
58-76% yield,
86-98% ee
*deterioration of yield
and ee at large scale
Br
41-68% yield,
>96% ee
*yield and ee consistent
on gram scale
France, S.; Wack, H.; Taggi, A.E.; Hafez, A.M.; Wagerle, T.R.; Shah, M.H.; Dusich, C.L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245.
Hafez, A.M.; Taggi, A.E.; Wack, H.; Esterbrook, J., Lectka T. Org. Lett. 2001, 3, 2049.
Dogo-Isonagie, C.; Bekele, T.; France, S.; Wolfer, J.; Weatherwax, A.; Taggi, A.E.; Lectka, T. J. Org. Chem. 2006, 71, 8946.
Halogenated Products
Cl
R
Cl
O
O
Cl
Cl
51-81% yield
80-99% ee
Cl
O
Cl
R = Ar, PhOCH2, Br, thiophenyl, allyl, propyl
R
Ar
O
Cl
Cl
Cl
Cl
62-90% yield
65-94% ee
R = Me, Et, i Bu, cyclopentyl
Br
R
Br
O
with PPY catalyst:
O
Br
41-68% yield
>95% ee
N
N
Fe
Br
R = Ar, nBu, Bn, PhOCH2
Ph
Ph
Ph
Ph
Ph
Lee, E.C.; McCauley, K.M.; Fu, G.C.; Angew. Chem. Int. Ed. 2007, 46, 977.
Dogo-Isonagie, C.; Bekele, T.; France, S.; Wolfer, J.; Weatherwax, A.; Taggi, A.E.; Lectka, T. J. Org. Chem. 2006, 71, 8946.
France, S.; Wack, H.; Taggi, A.E.; Hafez, A.M.; Wagerle, T.R.; Shah, M.H.; Dusich, C.L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245.
Mechanisms of Organocatalysis by Amines
Acyl Ammonium Catalysis
Iminium Ion Activation
N
O
N
H
O
R1
N
Nu
R
R2
O
C
N
H
R2
H
N
R1
-H2O
R2
R
X
Cl
aq/org
solvent
-HX
O
R
O
N
O
-HX
El
R
N
El
RO
R2
N
El
R
O
RO
N
2-Ammonium Enolate Catalysis
N
N
N
El
Phase Transfer Catalysis
O
R
1- Ammonium Enolate Catalysis
R2
Enamine Catalysis
R1
-X
Nu
R1
-H2O
O
X
O
R2
3-Ammonium Enolate Catalysis
O
R
O
N
El
R
N
Ammonium Ylide Cyclopropanations
NR3
O
OMe
R2
R1
NR3
O
O
N
Br
R1
OMe
N
OMe
N
O
OMe
NH2R3
NR3
Me
Br
R1
R2
R1
N
O
O
Cs2CO3
O
R1
N
Ph
O
MeO
O
N
N
O
N
CsHCO3
+ CsBr
R2
N
Ph
NR3
OMe
N
Bremeyer, N.; Smith, S.C.; Ley, S.V.; Gaunt, M.J.; Angew. Chem. Int. Ed. 2004, 116, 4641.
Papageorgiou, C.D.; Cubilla de Dios, M.A.; Ley, S.V.; Gaunt, M.J. Angew. Chem. Int. Ed. 2004, 43, 2735.
Proposed Stereochemical Model
Br
O
Me
Me
c-C6H11
O
N
O
H
O
H
N
O
H
C6H11
O
Me
Facial preference
For ylide attack
X-ray crystal structure of Me-MQD salt
Johansson, C.C.C.; Bremeyer, N.; Ley, S.V.; Owen, D.R.; Smith, S.C.; Gaunt, M.J.; Angew. Chem. Int. Ed. 2006, 45, 6024.
Substrate Scope
O
O
Ph
O
Cs2CO3, MeCN
+
OtBu
80°C, 24h
10-20% catalyst
Br
84% yield
71% ee
OtBu
Ph
• Increasing yield with increase
O
in size of cation
• Poor ee in intramolecular
reaction with Cl; significant
increases with Br
O
O
O
Cs2CO3, MeCN
+
tBuO
Ph
80°C, 24h
10-20% catalyst
Br
Ph
tBuO
96% yield
90% ee
O
O
H
O
Ot-Bu
t-BuO
H
50% yield
H
H
O
Me
68% yield (98%ee)
Me
O
O
O
O
NBoc2
OMe
90% yield (97%ee)
Me
N
O
Me
N
OMe
N
OMe
O
65% yield (96%ee)
O
H
O
O
t-BuO
O
84% yield (94%ee)
H
Ph
84% yield (97%ee)
O
96% yield (86%ee)
Bremeyer, N.; Smith, S.C.; Ley, S.V.; Gaunt, M.J.; Angew. Chem. Int. Ed. 2004, 116, 4641.
Johansson, C.C.C.; Bremeyer, N.; Ley, S.V.; Owen, D.R.; Smith, S.C.; Gaunt, M.J.; Angew. Chem. Int. Ed. 2006, 45, 6024.
Mechanisms of Organocatalysis by Amines
Acyl Ammonium Catalysis
Iminium Ion Activation
N
O
N
H
O
R1
N
Nu
R
R2
O
C
N
H
R2
H
N
R1
-H2O
R2
R
X
Cl
aq/org
solvent
-HX
O
R
O
N
O
-HX
El
R
N
El
RO
R2
N
El
R
O
RO
N
2-Ammonium Enolate Catalysis
N
N
N
El
Phase Transfer Catalysis
O
R
1- Ammonium Enolate Catalysis
R2
Enamine Catalysis
R1
-X
Nu
R1
-H2O
O
X
O
R2
3-Ammonium Enolate Catalysis
O
R
O
N
El
R
N
Baylis-Hillman Reactions
Reversibility of Michael addition
allows for selective reaction with the
more stable zwitterionic form (Z)
• Attractive reaction due to
R3N
O
NR3 +
R1
R3N
R1
R1
high functional density
generated
O
O
O
• Difficulties include substrate
racemization, low yields, and
side reactions
R2
H
• Catalysts exploit the
nucleophilicity and
hydrogen-bonding potential
of the cinchona alkaloids
R2 * OH
NR3 +
O
R1
R2 * O
R3N
O
R1
Stereoinduction
through metal ion
complexation or
hydrogen-bonding
in aldol step
Early Work
O2N
O
Et
N
O
+
H
H
H
OH
Ar
OH O
(10%)
R
10% NaBF4
MeCN, -40°C
Et
17-93% yield
21-72% ee
12-72 h
via
BF4
N
O
Na
H
Et
R
O
H
NO2
O
Barrett, A.G.M.; Cook, A.S.; Kamimura, A. Chem. Comm. 1998, 2533.
Hatakeyama’s ß-ICD Catalysts
OH
O
N
O
O
R
H
CF3
O
+
CF3
-ICD
N
R
OH O
(10%)
DMF, -55°C
R
O
+
OR
R
31-58% yield
91-99% ee
O
R
O
H
NR'Boc
+
CF3
O
CF3
OH
-ICD (10%)
R
O
O
0-25% yield
4-85% ee
O
BocR'N
R
O
O
CF3
O
CF3
+
R
O
DMF, -55°C
NR'Boc
11-83% yield
syn:anti = 94:6 to 100:0
>98% ee
NR'Boc
1-20% yield
syn:anti = 0:100 to 100:0
>98% ee
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
Nakano, A.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357.
Selectivity Model
O
N+
O-
N
H
CF3
CF3
O
OH
si face
attack
O H
H
N
re face
attack
O
H
O
X
H
O
+
N
O
Y
CO2R'
H
O-
N
N+
N
N
O H
R
O
H
O
H
H
O-
CF3
CF3
O H
H
H
O
CF3
CF3
R
R
CF3
OH O
R
O
CF3
O
R
R
O
CF3
OH O
O
R
O
CF3
O
R
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
O
O
Aza-Baylis-Hillman
OH
O
N
N
N
Ar
O
PPh2
CF3
O
+
CF3
O
H
N
Ts
10% catalyst
1:1 MeCN/DMF
-30°C, 24h
15% catalyst
O
O
+
Ar
H
TsNH2
+
O
Ph
CF3
O
NH
10% catalyst
OMe
H
NH
CF3
42-90 (32-57) % yield,
54-73 (93-100) % ee
(recrystallized)
Ts
O
+
Ar
DMF, -55°C
O
Ph2P
Ph
4Å mol. sieves
THF, r.t.
OMe
54-89% yield,
46-99% ee
OMe
78-95% yield,
49-74% ee
Ts
NH
Ti(OiPr)4, 2%
OMe
O
Ph
O
Kawahara, S.; Nakano, A. Esumi, T; Iwabuchi, Y.; Hatakeyama, S., Org. Lett. 2003, 5, 3103.
Shi, M.; Xu, Y.-M.; Shi, X.-L, Chem. Eur. J. 2005, 11, 1794.
Adolfsson, H.; and Balan, D., Tetrahedron Lett. 2003, 44, 2521.
Conclusions
• In the growing field of asymmetric organocatalysis, amines have played
a prominent role through their ability to function as both nucleophiles
and Bronsted bases.
• Tertiary amines have proven viable nucleophilic organocatalysts
in a variety of synthetically useful transformations
• Nucleophilic organocatalysis complements the well-established
enamine and iminium ion modes of catalysis provided by secondary amines;
Fu’s DMAP catalysts and cinchona alkaloid-based catalysts have been shown to
be effective catalyst designs for general use.
• Although a century-old concept, organocatalysis has seen a surge
in research in the past decade that should only continue to increase in the years to come.
Acknowledgements
Dr. Jeff Johnson
Johnson Group
Catalytic Fluorination
OAc
R
Selectfluor (1.2 equiv.)
NaOAc (2.0 equiv.)
O
catalyst (0.1 equiv.)
CH2Cl2, rt, 2-4 days
*
F
Cl
OAc
N
• ee’s up to 91% when
N
a stoichimetric quantity of
alkaloid is used
F
H
N
BF4
R
OR
H
AcONa
O
• better results have been
achieved with secondary
amine organocatalysts and
aldehydes
BF4
17-88% yield
3-53% ee
R
Cl
N
N
N
F
2BF4
Selectfluor

H
F
R
*
OR
H
Ac2O + NaBF4
Catalyst
Fukuzumi, T.; Shibata, N.; Sugiura, M.; Nakamura, S.; Toru, T. J. Fluor. Chem. 2006, 127, 548
Peptide Screens
HO
NHAc
AcO
NHAc
2.5 mol% catalyst
Ac2O
toluene, 25°C
N
O
N
O
OMe
Non-Fluorescent
H
OAc
OMe
Fluorescent
Jarva, E.R.; Evans, C.A.; Copeland, G.T.; Miller, S.J. J. Org. Chem. 2001, 66, 5522
(iPrCO)2O
iPrCOOS
R2N
S
NR2 O
N
Bu
R1
R2
R1
N
O
O
O
Ph
R2
Ph
OH
OCOiPr
+
O
tBu
t
OH
R2N
N
S
N
N
NMR Evidence
S
R2
tBu
S
S
OH
+
R1
N
R1
R2
A
Yamada, JOC, 2006, 71, 6872-6880
B
Related Catalysts
N
O
MeO2C
N
H
S
N
N
O
S
O
N
O
N
H
N
tBu
N
MeO2C
O
N
O
N
O
HO
Ar Ar
Yamada, JACS, 2002, 8184
Fuji, Tet. Lett., 2003, 1545
Connon, Org. Biomol. Chem, 2006, 4, 2785-2793
Yamada, JOC, 2006, 71, 6872-6880
N
O
Ph
Ph
O
Summary of Kinetic Resolution
Me2N
O
N
Me
O
Me
O
H
NH
N
H
N
H
O
HN
S
Fe
Me
Me
Ph
Ph
N
Ph
Ph
O
Ph
OH
Ph
NH
H
HN
O
O
Me
NH
BOC
N
O
N
Me
HN
H
B
N
O
N
D
CH3
H
CH3
Me
OMe
C
A
OH
OH
OH
i-Pr
1
Ar
Catalyst
R
s
R
R2
OH
R
s
X
NH2
R
Ar
R
%ee
s
s
< 51 (X = N)
< 52
< 20
< 64
C
D
O
HO
R
A
B
OH
R
s
< 99%
< 65%
< 355
< 32
< 23
N
< 27
< 12 (X = O)