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Useful Reviews:
! Fance, S.; Guerin, D. J.; Miller, S. J.; Leckta, T., Nucleophilic Chiral Amines as Catalysts in
37, 542-547.
Definitions
! Lewis base
A molecular entity (and the corresponding chemical species) able to provide a pair of electrons and thus
capable of coordination to a Lewis acid, thereby producing a Lewis adduct.
! Nucleophilic Catalysis
Catalysis by a Lewis base, involving formation of a Lewis adduct as a reaction intermediate. For example,
the esterification of anhydrides catalysed by DMAP:
IUPAC Compendium of Chemical
Terminology
Me
Me
Me
Me
OH
O
R
O
O
N
R
Lewis base
N
O
R1
O
R
R2
R3
R2
R3
Me
Me
Lewis base
R1
O
O
Me
Me
PPY
DMAP
Pyridine
Me
H
N
NMI
DABCO
Imidazole
! Common applications
! O-acylation - electrophile activation (pyridine, DMAP)
! O-silylation - electrophile activation (imidazole, DMAP)
! Baylis-Hilman reaction - nucleophile activation (DABCO, DMAP)
Me
picoline
Me
lutidine
Me
Me
Me
collidine
Et
Et
TEA
H
H
H
HO
HO
H
pseudoenantiomers
N
H
R1
R1
Cinchonidine (CD)
Quinine (QN)
R1 = H
R1 = OMe
Cinchonine (CN)
Quinidine (QD)
R1 = H
R1 = OMe
Moncure, R. MacMillan Group Meeting, 2003, web. contains a more fully discussion of cinchona alkaloids
site of modification
site of inversion of
configuration (epi alkaloids)
-pseudoenantiomers
OH
N
Quinidine
Pracejus (1964)
Wynberg (1983)
Simpkins (2001)
OMe
O
Et
N
N
benzoylquinine
Lectka (2000)
Et
Hatakeyama
MeO
(DHQD)2AQN
Deng
OMe
OMe
12 mol % quinidine
Ph
MeOH, 110 C
Me
Ph
selective
protonation
H
H
Quinidine
OMe
OMe
HO
Me
OH
+MeOH
Ph
up to 76% ee
NHR3
OMe
H-bond activation
Me
MeO
O
Bn
benzene, 78 C
Me3Si
H
Bn
SPh
79-93% ee
SiMe3
N
H
HO
MeO
selective
protonation
N
SPh
Bn
NR3
SiMe3
Blake, A. J.; Friend, C. L.; Outram, R. J.; Simpkins, N. S.; Whitehead, A. J. Tetrahedron Lett. 2001, 42, 2877.
OMe
O
R1
H
up to 95 % yield
45-98 % ee
O
H
NR3
R1 CCl R2
2
R1 = H, alkyl, aryl
R2 = Cl, alkyl
catalyst
(nucleophile)
Quinidine
Toluene, 50 C, 1 h
CCl2R2
OH
R1
CCl2R2
zwitterionic
intermediate
! Unprotected quinidine also catalyses its own acylation at OH
Me
Me
H
Me CH2
CCl3
O
Me
CCl3
CCl3
OR
O
O
O
Me
HC
MeO
Cl3C
! In the left TS, the ketene oxygen faces the methylene of the catalyst ring .The chloral approaches the catalyst
with the trichloromethyl group facing away from the methyl group of the catalyst to avoid steric strain.
! In the bottom TS, the ring is the dominant form of stereocontrol, and the CCl3 orients itself away from the ring
methylene protons.
Wynberg, H. J. Am. Chem. Soc. 1982, 104, 166.
Wynberg, H. J. Org. Chem. 1985, 50, 1977.
O
O
R1
Cl
PhMe, 25 C
Base: iPr2NEt
2 mol% cat.
CCl2R2
NR3
R1
R1 = H, alkyl, aryl
R2 = Cl, alkyl
O
R2Cl2C
Me
R1
R3N
cat.
N
H
Acyl-quinidine
! The use of pre-acylated catalyst stops unwanted acylation of the catalyst during the reaction.
! Applies a stoichiometric, non-nucleophilic base to turn over the catalyst.
! In situ ketene generation
! Solubility of the Hunigs salt may be crucial to catalyst turnover.
>90% ee
O
R1
Cl
Ts
N
10 mol% cat.
CO2Et
cat.
Ts
O
H
PhMe, 78 C
Base: proton sponge
or K2CO3 or NaH
Ts
EtO2C
R1
R1
EtO2C
45-65% yield
95-99% ee
25-99:1 dr
OMe
O
H
CO2Et
NR3
O
N
NR3
R1
R3N
cat.
Benzoyl-quinidine
Cl
O
O
10 mol% cat.
Cl
Cl
Cl
R1
Cl
Cl
Cl
Cl
THF, 78 C
Base: BEMP or
K2CO3 or NaH
But N
MeN
O
R1
Cl
Cl
Cl
Cl
OMe
65-85% yield
99% ee
NEt2
P
Cl
NMe
N
R1
Br
Br
Cl
Br
N
H
Benzoyl-quinidine
O
O
Br
10 mol% cat.
THF, 78 C
Base: BEMP or
K2CO3 or NaH
O
R1
Br
Br
O
Br
Br
55-80% yield
>90% ee
Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.; Lectka, T. J. J. Am. Chem. Soc. 2001, 123, 1531.
Hafez, A. M.; Taggi, A. E.; Wack, H.; Esterbrook, J.; Lectka, T. J. Org. Lett. 2001, 3, 2049.
Taggi, A. E.; Wack, H.; Hafez, A. M.; France, S.; Lectka, T. J. Org. Lett. 2002, 4, 627.
O
R1
OH
15 mol% catalyst
R2
OMe
R1
up to
45% ee
R2
THF, 30 C, 34 h
cat.
O
O
O
R2
O
R1
R2
NR3
R3N
quinidine
R1
OH
R2
R3N
O
R1
CF3
O
OH
CF3
15 mol% catalyst
R1
CF3
O
CF3
OH
31-58% yield
91-99% ee
THF, 30 C, 34 h
Me
N
N
quinidine analogue
Ph
CF3
O
CF3
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatekeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
Et
Et
N
H
Ph
O
H
N
MeO
O
H
OMe
Ph
catalyst
! Cyanation
O
O
R1
O
R2
NC
cat.
R3N
R1
52-78% yield
87-97% ee
OEt
R2
R3N
CN
NC
CHCl3, 12 to 24 C
0.5 - 7 days
NC
OEt
R1
R2
R1
O
R2
O
R3N
OEt
O
R
( )n
MeOH
OH
( )n
OMe
70-99% yield
90-98% ee
OMe
H
OH
Et
O
N
Hatakeyama
MeO
(DHQD)2AQN
Deng
BocHN
OH
Me N Me
Me
N
H
Et
Quinine
Wynberg
Ph
N
Me
Fe
Ph
H
Ph
Ph
Ph
N
N
Fu (1998-current)
N
Miller
Synthetic chiral imidazole equivalents
OMe
O
O
P
O
ADP
O
N
OH OH
NH
O
P
P
O
O
O
NDP3
NH
fast
NH
OH OH
NTP4
P
O
O
O
NO2
NO2
H2O
fast
NH
NH
HOPO32
NH
!
!
!
!
First in vitro example of imidazole participating in phosphoryl transfer from ATP analogues.
N-nucleophiles found to react 30-100 fold faster than O-nucleophiles at physiological temperatures.
Carried out in vitro experiments on ATP.
Supports proposed enzymatic mechanism.
Admiraal, S. J.; Herschlag, D.; J. Am. Chem. Soc., 1999, 121, 5837-5845
O Me
N
H
OH
H2N
BocHN
O Me
Me
N
H
O
N
Me
Ac2O
BocHN
Me
O
N
Me
N
N
N
OAc
O
Me
acyl imidazolium
! Modularity of peptide-based systems allows for the rapid synthesis and screening of many analogues.
! Initial designs drew heavily from the peptide design literature in order to generate a relatively rigid !-turn structure
Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630.
O Me
Me
N
H
BocHN
O
N
Me
N
N
Me
1.0 equiv
OH
anti, racemic
10 equiv
catalyst
O
Me
5 mol% catalyst
0 C
NHAc
NHAc
O
OH
OAc
OAc
O
Me
CH3CN = 12% ee
CH2Cl2 = 40% ee
PhMe = 84% ee (S = 12.6)
Me
O
O
1.0 equiv
OH
anti, racemic
10 equiv
Me
5 mol% catalyst
0 C
OH
PhMe
= 14% ee
Me
Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630.
Me
O
O
1.0 equiv
OH
Me
5 mol% catalyst
0 C
anti, racemic
10 equiv
NHAc
NHAc
O
OH
Me
L-Pro
H
BocHN
D-Pro
O Me
N
H
H
Me
O
N
N
O
Bn
N
O
N
Me
OMe
O Me
Boc
Me
N
H
H
O
N
Bn
O
OMe
N
Me
S = kRR / kSS = 28
! What is the mechanism of binding and role of the peptide backbone structure?
Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 4306.
Harris, R. F.; Nation, A. J.; Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2000, 122, 11270.
Me
O
O
1.0 equiv
OH
Me
5 mol% catalyst
0 C
NHAc
NHAc
O
OH
Me
! Mechanistic postulate
Me
O
N
N
H
O
Boc
krel = 28
N
H
H
N
O
OH
Me
Me
Me
Me
OH
Me
H
Me
Ph
OMe
O
O
H
O
OtBu
O
H
N
Ph
Me
Me
N
H
Me
Me
Me
O
Boc
H
OMe
Larger rate acceleration than using DMAP - NMI is usually less activating?
Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J. Angew. Chem. Int. Ed. 2001, 40, 2824-2827.
krel = 1
N
H
O
Ph
OMe
Me
O
O
1.0 equiv
OH
NHAc
O
NHAc
Me
OH
catalyst
AcOH
Me
reaction byproduct
AcOH
N
O
N
O
OMe
Non-Fluorescent
H
OAc
OMe
Fluorescent
Me
N
N
Boc
OH
O
N
N
H
OH
NHAc
Me
Me
krel = >50
krel = 40
NHAc
NH
nucleophilic
Me
OMe
OH
H
N
BocHN
O
Me
N
H
Me
Me
Me
H
N
Ph
O
N
H
H
N
O
NTrt
BuOt
Me
N
H
Me
Me
H
N
O
OH
Me
Ph
OMe
Me
Me
krel = >50
krel = >50
HO
PhO
PhO
OH
BnO
O
OBn
Cl
HO
BnO
OBn
2 mol% catalyst
OH
Ph
OH
PhO
PhO
OH
BnO
PhO
Cl
O
H
OBn
O
OH
PhO
Et3N, PhMe
OBn
BnO
2 mol% catalyst
OH
OBn
OH
>98% ee
H
N
O
HN
Ph
N
N
N
H
Me
N
Me
Boc
HO
NH
O
OPh
>98% ee
Ph
Ph
OBn
OPh
Et3N, PhMe
OBn
O
Boc
O
N
H
O
OBu
NH
O
But
NH
Me
Ph
OMe
O
OMe
! Two very different peptides give very highly enantioselective phosphorylation in opposite enantioseries
Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc.. 2001, 123, 10125.
OMe
OH
Et
N
N
Hatakeyama
MeO
(DHQD)2AQN
Deng
BocHN
OH
Me N Me
Me
N
H
Et
Quinine
Wynberg
Ph
N
Me
Fe
Ph
H
Ph
Ph
Ph
N
N
Fu (1998-current)
N
Miller
Synthetic chiral imidazole equivalents
OMe
Me
R2
OH
Me
racemic
Me
Me
Me
S = 11-53
R1
R2
R1
R2
Me
Me
Cl3C
N
O
tBu
Cl
O
OMe
OH
Me
Me
O
O
O
OH
Me
O
Me
Me
OBn
S = 1.8
Me
2 mol% catalyst
Et3N, THF, 78 C
Catalyst
OH
Me
Pr
O
O
O
OH
Pr
2 mol% catalyst
Et3N, THF, 78 C
OBn
O
Me
Pr
Me
cat. a
S = 7.6
cat. b
S = 29
MeN
Catalyst a
NEt2
Catalyst b
OH
H
H
N
Bui
0.7 equiv
OH
syn, racemic
catalyst
O
iBu
5 mol% catalyst
toluene, rt, 2-5 h
OCOR
OCOR
O
OH
iBu
81->94% ee
68-72% conv.
! Induced-fit Mechanism
OH
O
Bui
HO
H
H
H
N
O
O
H
iBu
H
N
O
Me
N
H
H
N
open conformation
Me
Nu
reactive, closed conformation
! Take advantage of charged Lewis adduct
! Cation-p interaction holds transition state rigid
Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169-3170.
Fe
N
Me
Me
Me
Me
N
Fe
Me
N
Me
Me
Me
Me
Fe
Me
Me
Me
Me
Me
pyridine
analogues
Me N Me
Me
N
Fe
Me
OSiR3
Me
Me
N
Ph
N
Fe
Ph
N
Ph
Ph
Ph
Fe
Ph
Ph
Ph
Me
Ph
Ph
pyrroles
analogues
DMAP
analogues
PPY
analogues
! In general best results were obtained with DMAP and PPY derivatives
France, F.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985-3012.
Fu, Gregory C. Acc. Chem. Res. 2004, 37, 542-547.
Me
R2
racemic
O
O
Me N Me
N
OH
Me
R1
2 mol% catalyst
Et3N, t-amyl alcohol
O
R2
R1
Me
Ph
Fe
Ph
Ph
R2
Ph
Ph
catalyst
OH
Me
99% ee
55% conv.
OH
OH
Cl
tBu
99% ee
55% conv.
99% ee
55% conv.
OH
Me
OH
Me
OH
Me
Me
Me
99% ee
55% conv.
99% ee
55% conv.
99% ee
55% conv.
Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492-1493.
Ruble, J. C.;Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794-2795.
99% ee
55% conv.
Me N Me
Fe
O
Me
Ph
H
Ph
Ph
Fe
Me
Ph O
Ph
Ph
H
Ph
Ph
Ph
Favoured rotamer
Disfavoured rotamer
Me N Me
Nu
N
Ph
Fe
O
Me
Ph
Nu
Ph
Ph
Ph
! Acetyl rotamer consistent with minimization of sterics between the methyl R group and ferrocene.
! Selectivity increases as the size of the alkyl group R increases.
! Nucleophile approaches from the top face of the DMAP catalyst.
N
NH2
Ar
O
But
Me
racemic
OMe
NH2
10 mol% catalyst
CHCl3, 50 C
Ar
HN
Me
Ar
Me
Ph
Ph
Me
Ph
Ph
Ph
catalyst
!-naph
NH2
Me
s=12
Fe
Me
s=27
NH2
MeO
NH2
Me
Me
s=22
s=16
Arai, S.; Laponnaz-Bellemin, S.; Fu, G. C. Angew. Chem. Int. Ed., 2001, 40, 234-236.
10 mol% catalyst
0 C, t-amyl alcohol
2-6 h
N
R2
R1
Ph
O
54-90% ee
Fe
Ph
Ph
Ph
Ph
catalyst
R2
X = OMe, OBn
R1 = Me, Et, Bn
R2 = Me, Ph, PMP
OBn
10 mol% catalyst
BnO
Me
O
N
0 C, t-amyl alcohol
2-6 h
OMe
91% ee
91% yield
BnO
10 mol% catalyst
0 C, t-amyl alcohol
2-6 h
Me
NH
Me
N
H
95% yield
dipeptide
OMe
OMe
OMe
O
R1
5 mol% catalyst
OR2
O
N
OR2
O
CH2Cl2, 35 C
72-95% yield
88-99% ee
X = NMe, O
R1 = alkyl, aryl
Ph
O
N
N
Ph
Fe
O
Ph
Ph O
Fe
Ph
Ph
R2 Ph
endo (cation-!)
Hills, I. D.; Fu, G. C. Angew. Chem. Int. Ed., 2003, 42, 3921-3924.
Ph
Ph
Ph
catalyst
Ph
N
Ph
Fe
Ph
catalyst
OTMS
O
Me
O
O
Me
5 mol% catalyst
R1
R1
Et2O, CH2Cl2, 23 C
R2
R1 = aryl
R2 = H, Me
R2
73-92% yield
80-99% ee
Me
R2
R2
cat.
cat.
OTMS
R1
O
O
R2
R1
R2
Me
NR3
Me
Me
NR3
O
R2
R2
TMSOAc
Ph
Ph
Ph
Ts
R1
Ph
N
R2
Ts
10 mol% cat.
O
N
PhMe, 78 C
Ph
R2
R1
45-65% yield
95-99% ee
8:1-15:1 dr
Ph
NR3
R1
zwitterion A
Fe
Ts
catalyst
N
CO2Et
EtO2C
NR3
R3N
cat.
R1
zwitterion B
Me
Me
Me
O
H
Me
Me
cat.
Ts
! Chiral amines have become functional nucleophilic catalysts, having been largly
overlooked until recently.
! Natural and synthetic alkaloids continue to have success across a variety of reaction types,
although definitive stereochemical rationale is not always possible
! Miller's combinatorial approach has successfully obtained catalysts that show high selectivity
! Fu has developed the first truly general synthetic DMAP analogue catalyst system.
Led the way in showing that nucleophilic catalysis is a general and useful concept.