A Review of Contemporary Work Toward
Asymmetric Additions to Imines
Literature Presentation, December 9, 2003
Dave Ballweg
Utility of Amines
1. Amines are ubiquitous in organic/medicinal chemistry
2. Important precursers to imines, amides, sulfonamides
3. Main component in amino acid synthesis
4. Useful in library construction
5. Nitrogen containing ligands in organometallic chemistry
6. Nitrogen bases provide important pKa range (32-37)
7. Additive for breaking lithium aggregates (TMEDA)
Substrate Control vs. Catalyst Control
Catalyst Control
Substrate Contol
N
R1
R3
R2
Nucleophile
HN
R1
R3
N
Nuc
R2
R1 or R2 or R3 are stereogenic, and through
steric interactions or Felkin models the
stereochemistry of the product is controlled.
Pros
1. Diastereomers are seperable
2. Diastereomers potentially easier to analyze
3. Auxiliary recycle is possible
4. More straight forward analysis
Cons
1. Auxiliary waste/ removal difficulties
2. Stoichiometric chirality – cost
R1
R3
R2
catalyst
Nucleophile
HN
R1
R3
Nuc
R2
R1, R2, R3 are not stereogenic, the chirality
of the product is controlled by the catalyst.
Pros
1. Small amount of chirality goes far (cost effective).
2. No auxiliary waste/removal dificulties
3. Still emerging field, offers more opportunities
Cons
1. Cost – Effective catalyst system needed
2. Catalyst recovery
3. Catalyst turnover
4. Typically more complex mechanisms
5. Enantiomer seperation if not perfect selectivity
6. Potentially toxic metals
Substrate Control vs. Catalyst Control
Substrate control
1. Nitrogen substitution
Catalyst control
3. Mannich reaction
A. tert-butanesulfinyl
A. zirconium catalyst
B. carbon chelates
B. palladium catalyst
C. hydrazone addition
C. copper catalyst
2. α–imine chirality
4. Strecker reaction
A. Felkin-Ahn
A. aluminium catalyst
B. polar Felkin-Ahn
B. library approach
C. addition to ketoimine
5. Allylation via allyl tin/silicon
6. β–lactams
N–tert–butanesulfinyl Imine
O
Me
Me
S
Me
3
H
N
R1
R2MgBr
Et2O/CH2Cl2
–48 oC
R2
O
Me
Me
S
Me
N
H
R1
HCl
MeOH
R2
HCl H2N
5
R1
6
Rationale
RS
S
tBu
N
O
M
RL
R2
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995
N–tert–butanesulfinyl Imine
O
Me
Me
S
Me
3
O
R3
N
R2M
R1
Solvent
Me
Me
S
Me
R3
N
H
R2
R1
6
Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883-8904
N–tert–butanesulfinyl Imine
O
Me
Me
S
Me
R1
N
O
R2
1. Me3Al, toluene
2. R3Li, –78 oC
Me
Me
S
Me
R1
N
H
R3
R2
Rationale
R1
S
tBu
N
O
Li
AlMe3
R2
R3
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995
N–tert–butanesulfinyl Imine
O
Me
Me
S
Me
3
O
H
N
Ph
RMgBr, Toluene, –45
or RLi, THF, –78
oC,
oC,
4h
4h
Me
Me
S
Me
R
N
H
4
Ph
MeOH/4M HCl
25 oC, 30 min
NH2 HCl
Ph
R
(R) or (S)-5
Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303-310
N–tert–butanesulfinyl Imine
O
Me
Me
S
H
H
N
R2MgBr
R1
Me
R1
= 4-Cl-Ph
R2 = Ph
Me
S
Toluene
tBu
N
O
M
R1
S
Me
R2
Cl
R1
O
Me
N
H
R2
H
NH2
(S)
Chelating six-membered transition state model
Predicted and observed
absolute configurations
R2Li
THF
R1
H
R2Li
O
O
R1
N
H
Me
Me
Me
Me
H
R2
Cl
N
Me
Me
Non-chelating addition model
Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303-310
NH2
(R)
N–tert–butanesulfinyl Imine
O
N
R
S
H
4
O
t-Bu
Bu3SnLi
THF, –78 oC
HN
S
t-Bu
SnBu3
R
5
Rationale
(R)
H
S
t-Bu
O
Li
N
R
Sn
Bu3
O
t-Bu
Kells, K. W.; Chong, J. M. Org. Lett. 2003, 5(22), 4215-4218
S
SnBu3
N
H
R
(S)
Chiral Auxillary on Nitrogen
H
Me
OMe
R'
Me
OMe
R'–Li
R
N
Et2O, 0 oC, 5 h
R
N
H
Rationale
R
Ph
Me
Li O
N H
H
CH3
blocks
bottom face
Hashimoto, Yukihiko; Kobayashi, Natsuko; Kai, Akiyoshi; Saigo, Kazuhiko. Synlett 1995, 9, 961-2.
Chiral Auxillary on Nitrogen
R
MeO
H
R
N
Ph
R'Li (5 eq.)
Ph
THF, –78 oC
~20–24 h
R
R'
R'
HN
OMe
HN
OMe
Ph
Ph
Ph
Ph
4b
4a
Entry
R
R'
1a
Ph
Me
2b
Ph
nBu
Yield / %
Rationale
4a:4bc
89
99:1
64
99:1
3
p-ClC6H4
Me
69
99:1
4
p-MeOC6H4
Me
60
94:6
5
PhCH=CH
Me
43
98:2
6
iPr
Ph
50
99:1
R'
R
H H
N Li OMe
H
Ph Ph
blocks
bottom face
aReaction
temperature: r.t. bReaction temperature: –78 oC~r.t.
cDetermined by GC.
Hashimoto, Y.; Takaoki, K. Sudo, A.; Ogasawara, T.; Saigo, K. Chem. Lett. 1995, 235.
Radical Addition to Aldehyde Hydrozones
O
N
R1
O
Lewis Acid, CH2Cl2/Ether
N
H
CH2Ph
O
Bu3SnH, O2, Alkyl-I, BEt3
–78 oC to room temp.
HN
R1
O
N
R2
CH2Ph
Using ZnCl2 as the Lewis Acid
Stereochemical Rational
H
O
O
N
LA
H
N
Ph
R1
Re Face Blocked
Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329-8330
Asymmetric Imine Addition Through Felkin Control
R = Pr, Me
R2 = Alkyl or aryl
R1 = SiR33, MOM, Bn
OR1
OR1
H
R2
NBn
H
R
SiMe3
R
R2
NHBn
ZnBr
7
SiMe3
8
Polar Felkin–Ahn Model
Nuc
HH
TBDMSO
N Ph
Bn
proposed intermediate
Me3Si
Pr
BrZn
H
H
BnN
c Gives four diastereoisomers
Ph
H
OTBDMS
Normant, J. F.; Poisson, J. J. Org. Chem. 2000, 65, 6553-6560
Substrate Control vs. Catalyst Control
Substrate control
1. Nitrogen substitution
Catalyst control
3. Mannich reaction
A. tert-butanesulfinyl
A. zirconium catalyst
B. carbon chelates
B. palladium catalyst
C. Hydrazone addition
C. copper catalyst
2. α–imine chirality
4. Strecker reaction
A. Felkin-Ahn
A. aluminium catalyst
B. polar Felkin-Ahn
B. library approach
C. addition to ketoimine
5. Allylation via allyl tin/silicon
6. β–lactams
Zr – Catalyzed Mannich Reaction
OH
HO
OSiMe3
Me
N
R1
H
OMe
Zr catalyst, CH2Cl2
N–methylimidazole
Me
NH
O
R1
OMe
Me
Me
2a
Zr(OtBu4)
Br
OH
N
OH
L
N
Br
Me
Br
Br
O L
O
Zr
O L
Br
O
Catalyst
Kobayashi, Shu.; Ueno, M.; Ishitani, H. J. Am. Chem. Soc. 2000, 122, 8180-8186.
Br
Proposed Catalytic Cycle
Br
OSiMe3
R3
HO
Br
N
R1
R4
Br
O
H
N
O
OH
H
Br
O
Zr
O
R1
R2
Br
Br
Br
Br
Br
Br
O
O
coordination change
of catalyst
O
O
Zr
R4
L L
O
R1
R3
R2
Br
Br
O
N
O
Zr
O
OH
Br
O
Me3Si
Br
SiMe3
OH
O
NH
O
R1
OMe
Me
Me
R4
R1
R3
R2
O
N
Br
O
Zr
O
OH
Br
O
Kobayashi, Shu.; Ueno, M.; Ishitani, H. J. Am. Chem. Soc. 2000, 122, 8180-8186.
Pd – Catalyzed Mannich Reactions
OSiMe3
R
PMP
H
PMP
O
r.t.
N
COOiPr
Cat.
R
Catalyst
HN
COOiPr
Ar
Ar Ar
P
P
O
Pd Pd
P
O
P
Ar Ar
Ar
Ar
Ar
2BF4–
Ar = C6H5, C6H4–4–Me
Possible Intermediate
R
P
P
N
COOR1
Pd
O
R2
Sodeoka, M.; Fujii, A.; Hagiwara, E. J. Am. Chem. Soc. 1998, 120, 2474-2475
Cu – Catalyzed Mannich Reaction
R3SiO
H
R
O
N
EtO
H
1b
Ts
2
2-10 mol% 3
THF or CH2Cl2
–78 oC to 0 oC
N
Ts
O
O
R
OEt
4a-4f
Catalyst
R'
P
P
R'
R'
MLn
R'
3
3a R' = C6H5, MLn = AgSbF6
3b R' = C6H5, MLn = Pd(ClO4)2
3c R' = C6H5, MLn = CuClO4
3d R' = 4-MeC6H4, MLn = CuClO4
Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.;
Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67-77
Strecker Reaction Catalyzed by Chiral
(Salen)Al(III) Complex
N
TMSCN
Ph
(1) Catalyst (5 mol%)
Toluene, 23 oC, 15h
(2) TFAA
H
N
M
t-Bu
O
t-Bu
O
t-Bu
t-Bu
F3C
N
Ph
M
N
O
CN
ee
% Conv.
1: M = H,H
No Reaction
2: M = Ti(IV)Cl2
24
19
3: M = Cr(III)Cl
0
83
4: M = Mn(III)Cl
20
80
5: M = Ru(III)(NO)Cl 6
93
6: M = Co(II)
0
43
7: M = Co(III)OAc
6
65
8: M = Al(III)Cl
45
100
Jacobsen, E. N.; Sigman, M. S. J. Am. Chem. Soc. 1998, 120, 5315-5316
Strecker Reaction Catalyzed by Chiral
(Salen)Al(III) Complex
(1) 1.2 Equiv HCN
Catalyst (5 mol%)
Toluene, –70 oC, 15h
N
Ph
Entry
a
b
c
d
e
f
g
h
i
Ph
p-CH3OC6H4
p-CH3C6H4
p-ClC6H4
p-BrC6H4
1-napthyl
2-napthyl
Cyclohexyl
t-butyl
91
93
99
92
93
95
93(55)c
77
69
F3C
(2) TFAA
H
%yielda
R
O
Ph
CN
Catalyst
%eeb
95
91
94
81
79
93
93(>99)c
57
37
N
N
N
Al
t-Bu
O
t-Bu
Cl
O
t-Bu
aIsolated
yield. bAll ee's were determined by
GC or HPLC chromatography using chiral
columns. cAfter recrystallization from hexanes.
Jacobsen, E. N.; Sigman, M. S. J. Am. Chem. Soc. 1998, 120, 5315-5316
t-Bu
Schiff Base Catalyst for Asymmetric Strecker Reaction
Library Approach
Strecker Reaction
O
R1
H
NaCN
AcOH
NH2R2
HN
R1
R2
HN
H
R1
CN
R2
CO2H
Library 1
O
Library Size: 12 Compounds
N
H
R2
O
H
N
5
N
H
O
R2
N
H
N
TBSCN was used as the cyanide source
Metal (M)
HO
Benzaldimine was used as the imine
t-Bu
M
Ti Mn Fe Ru Co Cu Zn Gd Nd Yb Eu
ee (%)
19
4
5
10 13
0
9
1
2
conv. (%)
59
30 61 69 63
68
55
91 95
3
0
5
84 94 34
Jacobsen, E. N.; Sigman, M. S. J. Am. Chem. Soc. 1998, 120, 4901-4902
t-Bu
Schiff Base Catalyst for Asymmetric Strecker Reaction
Library Approach
Library 2
R1
O
H
N
5
N
H
Library Size: 48 Compounds
O
R2
O
N
H
R2
N
H
Diamines
N
H2N
Salicylaldehydes
Amino Acids
Leu
D-Leu
His
Phenyl-G
R3
CHO
HO
R3
R4
A
B
C
D
E
F
R4
tBu tBu
tBu
H
t
H
Bu
tBu OMe
Br
Br
tBu NO
2
HO
DP
H2N
R3
Ph
Ph
R4
H2N
CH
H2N
Amino acid has signifigant effect on enantioselectivity. L-leucine-derived catalyst provided best results
Diamine-derived catalyst effects the ee outcome
Substituents on the salicylaldehyde derivatives play critical role, A, B, D afford highest yields
Direct attachment of the amino acid group to the resin improved ee's
Replacement of the urea linker with thiourea improved ee's
Jacobsen, E. N.; Sigman, M. S. J. Am. Chem. Soc. 1998, 120, 4901-4902
Schiff Base Catalyst for Asymmetric Strecker Reaction
Library Approach
Library 3
R1
H
N
N
H
O
Library Size: 132 Compounds
Diamines
R2
S
H2N
R2
N
H
N
CP
N
H2N
OH
H2N
R3
R4
CH
H2N
L-Amino Acids
Salicylaldehydes
Leu
Nor (Nor-Leu)
Ile
Phenyl-Gly
Met
Cyclohex-Gly
Phe
t-Leu
Val
Tyr (OtBu)
Thr (OtBu)
CHO
HO
t-Bu
X
X = OMe
H
tBu
Br
H2N
Ph
DP
H2N
Ph
Amino acid components found to be crucial, with bulkiest derivatives found to give highest ee's
t-Leu proved best with CH, worst with CP – Highly beneficial to check all ligand possibilities
t-Leu, diamine CH, X=OMe found to be catalyst, it was independently synthesized and tested
Jacobsen, E. N.; Sigman, M. S. J. Am. Chem. Soc. 1998, 120, 4901-4902
Schiff Base Catalyst for Asymmetric Strecker Reaction
Library Approach
Catalyst
N
R
H
HCN
(1) 24h, toluene, –78
2 mol% cat.
(2) TFAA
oC
O
F3C
Ph
N
R
t-Bu
H
N
O
S
N
H
N
H
CN
N
HO
t-Bu
Jacobsen, E. N.; Sigman, M. S. J. Am. Chem. Soc. 1998, 120, 4901-4902
OMe
Strecker Reaction if Ketoimines
ScIII[(R)–BINOL]2 catalyst 10% mol.
R1
N
R2
Ph
1) HCN or TMSCN, toluene,–20
oC
NC
R1
H
N
Ph
R2
Vallee, Y.; Chavant, P. Y.; Byrne, J. J.; Chavarot M. Tetrahedron:Asymmetry 1998, 9, 1147-1150
Strecker Reaction if Ketoimines
R3
R1
R2
S
N
O
N
H
N
H
N
H
HO
t-Bu
NC
R3
N
R1
OCOtBu
R2
1 mol% catalyst, HCN, toluene, –78 oC
R3
Jacobsen, E. N.; Vachal, P. J. Am. Chem. Soc. 2002, 124, 10012-10014
N
H
R2
R1
Strecker Reaction if Ketoimines
O
N
R1
PPh2
R2
Gd(OiPr)3 (x mol%)
Ligand ( 2x mol%)
TMSCN (1.5 eq.)
CH3CH2CN, –40 oC
NC
R1
H
N
R2
O
P
Ph2
Ligand
Ph
Ph P
O
O
HO
O
F
HO
F
Shibasaki, M.; Kanai, M.; Suzuki, M.; Usuda, H.;
Masumoto, S. J. Am. Chem. Soc. 2003, 125,
5634-5635
Allylation Via Chiral Bis-π-allylpalladium Complexes
R1
H
SnBu3
N
1
R2
5 mol% cat.
solvent, 0 oC
R1
HN
R2
2
a; R1 = Ph, R2 = Bn
b; R1 = Ph, R2 = p –MeOC6H4CH2
c; R1 = Ph, R2 = Ph
d; R1 = Ph, R2 = Pr
e; R1 = p –MeOC6H4, R2 = Bn
f; R1 = 2–naphtyl, R2 = Bn
g; R1 = PhCH=CH, R2 = Bn
h; R1 = c–Hex, R2 = Bn
Catalyst 3e
Me
Cl
Pd
Pd
Cl
Me
Yamamoto, Y.; Nakamura, K.; Nakamura, H. J. Am. Chem. Soc. 1998, 120, 4242-4243
Allylation Via Chiral Bis-π-allylpalladium Complexes
Other Attempted Catalysts
R
PPh2
R
Me
PdCl2
Pd
Pd
Pd
Me
Pd
Me
Pd
Me
Cl
R
R
R=H
R = Me
Very low ee's
39% yield
0% ee
Me
Cl
Pd
Cl
Cl
PPh2
Me
Cl
Cl
Not effective
R = H 63% yield
50% ee's
Probable Transition-State Models
Me
Pd
HN
N
Ph
R
(R)
R
H
Bn
Me
R
Pd
N
(S)
Ph
R
HN
Bn
H
Yamamoto, Y.; Nakamura, K.; Nakamura, H. J. Am. Chem. Soc. 1998, 120, 4242-4243
Allylation Via Chiral Bis-π-allylpalladium Complexes
Proposed Catalytic Cycle
3e
SnBu3
Bu3SnCl
1
2
Pd
R1
Me
N
SnBu3 R2
CH2
R1
Pd
N
Me
R2
H
SnBu3
R1
Pd
N
R2
Me
Yamamoto, Y.; Nakamura, K.; Nakamura, H. J. Am. Chem. Soc. 1998, 120, 4242-4243
Allylation Via Chiral Bis-π-allylpalladium Complexes
R1
H
N
R2
SiBu3
5 mol% cat.
solvent, r.t.
R1
HN
50 mol% TBAF
1
a; R1 = Ph, R2 = Bn
b; R1 = Ph, R2 = Ph
c; R1 = Ph, R2 = p –MeOC6H4
d; R1 = Ph, R2 = n–Pr
R2
2
e; R1 = p –MeOC6H4, R2 = Bn
f; R1 = (E)-PhCH=CH, R2 = Bn
g; R1 = Ph, R2 = p –MeOC6H4CH2
h; R1 = 2–Naphthyl, R2 = Bn
Catalyst
Me
Cl
Pd
Pd
Cl
Me
Yamamoto, Y.; Nakamura, K.; Nakamura, H. J. Am. Chem. Soc. 1998, 120, 4242-4243
β−Lactams
OMe
NMe2 NMe2
O
Cl
O
BQ
N
BQ HCl
R
H
N
R
O
H
Me2N
Ts
NMe2Cl
O
N
Ts
O
O
N
BQ
H
H
COOEt
R
EtOOC
R
benzoylquinine
[BQ]
One pot synthesis for generation of β-lactams
Ketene generated in situ
BQ found to be excellent "shuttle base" when added to acetyl chloride
Strong base "proton sponge" found to liberate BQ
BQ then acts as nucleophilic catalyst
Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832
β−Lactams
Transition state
OMe
N
N
O
H
O
Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832
O
Ph
Summary
1. Substitution on the nitrogen controls stereochemistry through steric models.
2. Substitution on the α position controls stereochemistry through Felkin models.
3. Effective catalysts for asymmetric Mannich reactions have been developed.
4. High yields were obtained using metal catalysts for the Strecker reactions.
5. Non–metal catalyzed Strecker reactions developed using a library approach.
6. Useful allyl amines were synthesized from palladium catalysts.
7. β–lactams were synthesized using organic catalysts in high ee's.
Possible Future Directions
1. The development of tethered reactions to form cyclic and bicyclic molecules.
2. The addition of silicon anions could prove synthetically useful through coupling
reactions or conversion to alcohols.
3. The development of new chiral organic catalysts could replace toxic metal catalysts.
4. The formation of hemi–aminals from imines may novel synthetic route.