Mechanisms of Catalytic Reactions. BIC. Novosibirsk 2009. Vol. II
New Catalytic Asymmestric Reactions - IASOCNew Catalytic Asymmestric Reactions Karl Anker Jørgensen...
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1 New Catalytic Asymmestric Reactions Karl Anker Jørgensen Danish National Reserach Foundation: Center for Catalysis Department of Chemistry, Aarhus University Denmark [email protected] 2 Goya: Mother showing her derformed child to two women Louvre, Paris When something goes wrong
Transcript of New Catalytic Asymmestric Reactions - IASOCNew Catalytic Asymmestric Reactions Karl Anker Jørgensen...
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New Catalytic Asymmestric Reactions Karl Anker Jørgensen
Danish National Reserach Foundation: Center for CatalysisDepartment of Chemistry, Aarhus University
2
Goya: Mother showing her derformed child to two womenLouvre, Paris
When something goes wrong
2
3
A failed reaction
O
HOEt
O OO
H
H
OH
+
O
N N
O
t-Bu t-Bu
MeMe
Cu(II)
O
HOEt
O
+Toluene
SnCl4Not formed
OHOEt
OMe
>90% yie ld
OHOEt
O
Chem. Commun. 1999, 1869
4
OOO
ClCl
NH
HN
HN
NH
O
OO
R
O
RO
OHOH
H
H
HN
O
HO2C
HO
R
X
NH
OR
Vancomycins
NO
S
CO2H
OAc
NH
O
NH2H
Cephaloglycin
ON
ONH
NO
CO2H
OH
OH
H
HO2CNH2
Nocardicin A
O
O2C
H3N
HN
O
O
O
Me
Me
MeH
Aspartame analogue
H
N
O
R1O
O
OR2+
Ar CO2R2
HNH
CO2R1
Chiral CatalystAr H
Catalytic asymmetric aza-Friedel-Crafts reactions
3
5Optically active aromatic α -amino acids
H
N P PhPh
O
H
PBnPh
O
OR2O
R1O N
O
R1O
O
OR2+
O
Ph
Bn
H
N
O
R1O
O
OR2+
Ar CO2R2
HNH
CO2R1
Chiral CatalystAr H
NH
CO2R2
R1O2C
Me2N
NH2
CO2R2
Me2N
R = Me: TMSI, 90% yield
R = E t : TMSI, 83% yield
R = Bn: H2, Pd(OAc)2, 98% yield
R = tBu: TFA, Quantitative yield
NH
CO2R2
MeO2C
H2N
PhIO then TMSN3 92% yield
NH
CO2R2
MeO2C
NOBF4 then H3PO2, Cu2O83% yield
H
Angew. Chem. Int. Ed. 2000, 39, 4114J. Org. Chem. 2002, 67, 4352
6
Scope and potential
N
COOEt
Pg
H+
(R)-Tol-BINAP-CuPF6Ar CO2Et
HN H
PgP
PCu(I)
Ar Ar
ArAr
Ar H
CO2Me
HN H
CO2Me
Me2N
80% yield98% ee
CO2Me
HN H
CO2Me
Me2N
MeO
81% yield96% ee
CO2Et
HN H
CO2Me
N
88% yield86% ee
CO2Me
HN H
CO2Me
NMe
79% yield98% ee
CO2Me
HN H
CO2Me
NMe
86% yield92% ee
CO2Me
HN H
CO2Me
Me2N
75% yield92% ee
O
HN
CO2MeMeOO
HN
CO2MeBnS
HN
CO2MeMeO
63% yield96% ee
40% yield95% ee
75% yield94% ee
H H
CO2Me CO2Me CO2Me
H
4
7Mechanistic Considerations
O CO2Me
NHMeO2C
Ph
H H
O CO2Me
NMeO2C
H H
Catalyst
Ph
H
HN
OMeO
OOEt H
NO
tBuO
OOEt
Low discriminationHigh Discr imination
ReactiveRe-face
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Catalytic asymmetric Friedel-Crafts alkylation reactions
OOMe
OPh
N
OO
NM
X Xt-Bu t-Bu
N
OO
N
TfO OTfPh Ph
Me MeMe Me
NH
NH
Ph HCOOMe
OCat .
10 mol%
M = Cu(II), X = OTf (CH2Cl2): 100% conversion, 88% eeM = Cu(II), X = OTf (Et2O): 100% conversion, 97% eeM = Zn(II), X = OTf (CH2Cl2): 100% conversion, 87% ee
+
100% conversion, 42% ee
Cu
Angew. Chem. Int. Ed. 2001, 41, 160
5
9
OOR
OR4
N N
R4 HCOOR
OR3
R2
R1R2
R3
R1
O
OR
OR
4
R4 HCOOR
OO
OOR
OR4
R4 HCOOR
O
MeO
OMe
MeO
MeO
OOR
OR4
N N
R4 HCOOR
OR3
R2
R1R2
R3
R1
O
OR
OR
4
OR1
OOR
OR4
R4 HCOOR
O
MeO
OMe
MeO
MeO
Cat.2-10 mol%
+
R1 = H, alkylR2 = H, Cl, COOR
R3 = H, OMeR4 = Ar, alkyl, CH2OBn
70-96% yield80->99.5% ee
Cat.2-10 mol%
+
R4 = Ar, alkyl, CH2OBn
>90% yield>79% ee
Cat.2-10 mol%
+
R4 = Ar, alkyl
65-68% yield60-89% ee
+
+
+
O
R1
10
Catalytic enantioselective Friedel-Crafts reactionsa simple approach to optically active α-aromatic α-hydroxy carboxylic acids
NMe2
OO
OEt
HN
HO
O
OEt
R
TBS
a, b, c R = Me: 92% yieldR = H: 95% yield
a) PHIO, TMSN3
b) sat. NaHCO3 (aq)c) 10% HCl/EtOH
O
COOEtH
NMe2 NMe2
HOOEt
O
CH2Cl2: 85% yield, 70% eeTHF: 82% yield, 94% eeEt2O: 92% yield, 90% ee
N
OO
N
t-Bu t-BuCu(II)
MeMe
Cat10 mol%
+
J. Am. Chem. Soc. 2000, 122, 12517J. Org. Chem. 2001, 66, 1009
6
11
Scope and potential
O
COOEtH
NMe2 NMe2
HOO Et
O
>80 yield , >85% ee
X X
O
COOEtH
n = 1: 54% yield, 85% ee
N(CH2)n
Me
N(CH2)n
Me
OH
EtO
O
n = 2: 56% yield, 93% ee
Cat10 mol%
+
Cat10 mol%
+
NR
OEtO
ONR
O
EtO
OOxidation
Pg Pg
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Catalytic asymmetric tandem reactions – formation of optically active dihydro-benzopyrans
O
CO 2MeAr
XH
+
X Ar
HO CO2Me
RO ROMgX2-BOX
X = OH, NMe
N
O
N
O
Me Me
R R
(R)-4a: R = t-Bu(S)-4b: R = Ph(S)-4c: R = 1-Np
high yield, one diastereomeree up to 85%
O
CO2MeR1
XH
+O
CO2MeR1
X
O
CO 2MeR1
XX R
1
HO CO 2Me
R2
R2
R2
R2
Submitted 2002
7
13
N N
OO
t -But-BuCu(OTf)2
Discovery of a direct aldol reaction
O
O
OEtMe
HOO
OEtChiral LA
5 eqv.
MeMe2NMe2N
Not formed
CO2Et
OHO Me
EtO2C
Chiral LA
14
O
O
OEtMe
Chiral LA CO2Et
OHO Me
EtO2C NEt3/TBSClOO
TBSOCO2Et
Me
49% yield from EPV
N N
OO
t-But-BuCu(SbF6)2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Solvent
(+)-77CyNMe2/10
(+)-75PhNBn2 /10
(+)-63PhNMe2/10
(–)-50-
Ee [%]Amine [mol%]
A catalytic asymmetric homo-aldol reaction
Chem. Commun. 2000 , 2211
(–)-67Et( iPr)2N/10
(–)-93PhNBn2 /10
(–)-96PhNMe2/5
(–)-79PhNMe2/10
(–)-65-
Ee [%]Amine [mol%]
N N
OO
t-But-BuCu(OTf)2
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15
The concept
O
O
EtO
N N
OO
PhPh Cu
2
N N
OO
PhPh CuO O
OEtRH
2
Electrophilic carbon
N N
OO
PhPh CuHO O
OEtR
2
Nucleophilic carbon
R
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O
EtO2CN
CO2Et
PgChiral LA
O
EtO2C CO2Et
HNPg
RR
Imine candidates
N
CO2Et
N
CO2Et
S N
CO2Et
MeO
O
O
MeO
RO
Catalytic asymmetric direct Mannich reactions
Angew. Chem. Int. Ed. 2001, 40, 2995
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17
N+
Me
CatalystO
EtO2C CO2Et
TsHN
CO2EtEtO2C
OTs
N N
OO
PhPh
N N
OO
t-But-BuCu(OTf)2
Cu(OTf)2
N N
OO
PhPhCu(OTf)2
PhPh
CH2Cl276% yield-33% ee
THF16% yield33% ee
CH2Cl270% yield
89% ee
CH2Cl244% yield
12% ee
THF45% yield76% ee
Optimisation of the direct Mannich reaction
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N+
O
EtO2C
Ts HN
CO2EtEtO2C
O
RCO2Et
Ts
R
N N
OO
PhPhCu(OTf)2
CH2Cl2
HN
CO2EtEtO2C
O
Me
TsHN
CO2EtEtO2C
OTs
HN
CO2EtEtO2C
O
Bn
TsHN
CO2EtEtO2C
O
Br
Ts
70% yield89% ee
89% yield>10:1 dr>98% ee
94% yield>10:1 dr97% ee
79% yield3:1 dr
78% ee
Scope of the direct Mannich reaction
10
19
HN
CO2EtEtO2C
O
R
TsL-Selectride
THF -78 °C, 90min
HN
CO2EtEtO2C
OH
R
Ts
PTSA
PhMe 70°C4h
HN
CO2Et
O
R
Ts O
R = Me: 92% yieldone diastereomer
R = Bn 70% yieldone diastereomer
Reduction of the Mannich product
20
N
CO2EtMe
O
OBocHN
CO2EtMe
O
OBoc2O / DMAP
MeCN, r.t.98%
Ts Ts
N
CO2EtMe
O
OBoc
HN
CO2MeMe
O
O
Mg/MeOH/THF=3:1
Sonication 60 min71%
Boc
Ts
Detosylation
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Proposed Mechanism
O
CuN
O
NO
Me
Me
Ph
Ph
O
H
OEt
R
H
O
Cu N
ON
O
NO
Me
Me
Ph
PhTs
O
H
OEt
R
H
OEt
O
CuN
O
NO
Me
Me
Ph
Ph
O OEt
R
22
O
EtO OEt
O N+
Ts HN
CO2EtEtO2C
CO2Et
Ts
CO2EtRR
(10 mol%)
CH2Cl2
Yields: >80%; >85% eeR = Me, n-Bu, i-Bu, Bn
N NOO
t-But-BuCu(OTf)2
Malonic esters and β -keto esters as nucleophiles in direct Mannich reactions
O
R1 Ot-Bu
O
R2
N+
Ts HN
CO2EtR1
O
R2CO2Et
TsN NOO
t-But-BuCu(OTf)2
t-BuO2CCH2Cl2
R1 = R2 = Me: 87%, 93:7 dr, 88% eeR1 = Et, R2 = Me: 80%, 98:2 dr, 92% eeR1 = i-Pr, R2 = Me: 55%, 84:16 dr , 91% eeR1 = Bn, R2 = Me: 83%, 96:4 dr, 93% eeR1 = Me, R2 = allyl: 69%, 92:8 dr, 87% eeR1 = R2 = (CH2)4: 89%, 99:1 dr, 86% ee
Submitted for publication
12
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N
N+
O
EtO2CN
HN
CO2R2EtO2C
O
R1
CO2R2
R1
N N
OO
PhPhCu(OTf)2
CH2Cl2
O
O
OR2R2O
Catalytic asymmetric direct α -amination
R1
CO2Et
OR1
CO2Et
O
NN
R2O2C
CO2R2 NNH
CO2R2R2O2C
R1
CO2Et
OH
NNH
CO2R2R2O2CN O
O
CO2MeR1
HN
R2O2C
Catalyst
L-Selectr ide-78 °C
1) 0.5 N NaOH
2) TMSCHN2
J. Am. Chem. Soc. 2002, 124, 2420
24
N N
OO
PhPhCu(OTf)2
N N
OO
PhPhCu(OTf)2
PhPh
THF57% yield89% ee
CH2Cl250% yield70% ee
CH2Cl255% yield77% ee
THF58% yield88% ee
N N
OO
PhPhCu(OTf)2
CH2Cl239% yield90% ee
THF60% yield82% ee
Ph Ph
CO2Et
O
NN
BnO2C
CO2Bn
N O
O
CO2Me
HN
BnO2CCatalyst
PhPh
Optimisation of the direct α -amination reaction
13
25
N N
OO
PhPhCu(OTf)2
PhPhN N
OO
PhPhCu(OTf)2
N O
O
CO2Me
HN
Cbz N O
O
CO2MeMe
HN
Cbz N O
O
CO2MeC5H11
HN
Cbz N O
O
CO2Me
HN
Cbz
N O
O
CO2Me
HN
Cbz N O
O
CO2Me
HN
Cbz N O
O
CO2Me
HN
Cbz N O
O
CO2Me
HN
Cbz
CH2Cl239% yield
90%ee
CH2Cl245% yield
90%ee
THF72% yield
96%ee
CH2Cl278% yield
95%ee
CH2Cl253% yield
96%ee
CH2Cl252% yield
92%ee
THF57% yield
89%ee
CH2Cl278% yield
92%ee
CH2Cl248% yield
97%ee
CH2Cl262% yield
93%ee
Ph
Scope of the direct α -amination reaction
26
N O
O
CO2Me
HN
BnO2CHN O
O
CO2Me
1) Pd/C H2 MeOH
2) Zn acetone HOAcPhPh
88% yield
N O
O
CO2Me
HN
BnO2CHN O
O
CO2Me
1) Pd/C H2 MeOH
2) Zn acetone HOAc
89% yield
Synthesis of oxazolidinones
14
27
Synthesis of syn-α -hydroxy-β -amino acids
CO2Et
O
CO2Et
O
NN
Cbz
Cbz NNH
CbzCbz
CO2Et
OH
NNH
CbzCbz
Catalyst
L-Selectr ide-78 °C
1) Ra-Ni H2 MeOH
2) Boc2O DMAP3) MeONa MeOH
Ph Ph
PhCO2Me
OH
HNBoc
Ph
33% yield
28
N
HN
NH
CO2 i-Pr
OH
R
O
OO
O
N NH
R = i-Pr; KRI-1230R = c-hexyl; KRI-1314
Va l-Val-Asp-OH
O
OH
Amastatin
NH2HO2C
HN
Ph
OH
NH2O
Bestatin
NH
HN
N
HN CO2H
NH2
OH
MeO
O
O
OMe
OH
OHMicroginin
HO2CHN
OH
NH2O
Valinoctin A
O
OBoc HN
OH
OH
OBz OAcH
HO OH
O
HO
ABT-271
15
29
Proposed mechanism
O
CuN
O
NO
Me
Me
Ph
Ph
O
H
OEt
R
H
NO
Cu N
ON
O
NO
Me
Me
Ph
PhCbz
O
H
OEt
R
H
OBn
O
CuN
O
NO
Me
Me
Ph
Ph
O OEt
R
30
N
N+
O
EtO EtO
O
R1
N N
OO
PhPhCu(OTf)2
CH2Cl2
O
R2
Cbz
Cbz R2
O
R1NCbz
CbzHN
EtO
O
R2
O
R1NCbz
CbzHN
EtO
O
R2
O
R1H2N
EtO
O
R2
OH
R1H2N
Catalytic asymmetric direct α -amination of β -keto esters – optically active β -keto-
and β -hydroxy-α -amino acids
Submitted for publication
16
31
O
Me OEt
O
MeNCbzHN
CBz
81% yield, 98% ee
O
Et OEt
O
MeNCbzHN
CBz
94% yield, 98% ee
O
Ph OEt
O
MeNCbzHN
CBz
88% yield, 98% ee
n(H2C)
O
OEt
O
N CBz
CbzHN
n = 1: 99% yield, 99% een = 2: 94% yield, 98.5% een = 2: 92% yield, 98% ee
Scope
32
Metal CatalysedAldol Reaction:Type II Aldolase
Organo CatalyticAldol Reaction:Type I Aldolase
17
33
O
MeNN
+
EtO2CN
HN
CO2Et
O
MeCO2Et
CO2EtNH
CO2H
NO
O
MeN
N
O
EtOO
OEtH
NO
O
Me
H
L-Proline catalysed asymmetric α -amination of aldehydes
Solvent L-Proline (mol%)
Reaction time [min]
Yield [%]
ee [%]
C H2Cl 2 50 45 93 92
C H2Cl 2 5 105 87 91
C H2Cl 2 2 300 92 84
MeCN 50 30 70 91
EtOAc 50 300 77 81
PhMe 50 450 81 86
Angew. Chem. Int. Ed. 2002, 41, 1790 (rec. 01.03.02)List, J. Am. Chem. Soc. 2002, 124, 5656 (rec. 07.03.02)
34
O
R1NN
+
R2O2CN
HN
CO2R2
O
R1CO2R2
CO2R2
L-ProlineN
HN
CO2R2
OH
R1
CO2R2
O N
R1
OHN
CO2R2NaBH4 NaOH
O N
Me
OHN
CO2Et O N
Et
OHN
CO2Et O N
i-Pr
OHN
CO2Et
O N
t-Bu
OHN
CO2Et O N
OHN
CO2Et O N
Bn
OHN
CO2Et O N
i-Pr
OHN
CO2Bn
Yield 67%ee 93%
Yield 77%ee 95%
Yield 83%ee 93%
Yield 70%ee 91%
Yield 68%ee 89%
Yield 92%ee 93%
Yield 57%ee 91%
Scope of the L-proline catalysedasymmetric α -amination of aldehydes
18
35
NO
O
NHCbz
iPr
NHO
O
iPr
1) H2 /Pd-C MeOH2) Zn/acetone-HOAc
O
H
iPr
NHN
MeO
iPr
NHBocO
Boc
Boc
1) KMnO4 oxidation2) TMSCHN23) TFA4) H2/Ra-Ni5) (Boc)2O/DMAP
Product modification / Determination of absolute configuration
36
O
R2NN
+
EtO2C
NHN
CO2Et
O
R2CO2Et
CO2EtNH
CO2H
R1R1(10 mol%)
ON
CO2Et
HNCO2Et
for R1 = Me
R2MeCN
L-proline catalysed asymmetric α -amination of ketones
J. Am. Chem. Soc. 2002, 124, 6254
NHN
CO2Et
O
Me
CO2Et
MeN
HN
CO2Et
O
Et
CO2Et
MeN
HN
CO2Et
O
Bn
CO2Et
Me
NHN
CO2Et
O
i-Pr
CO2Et
MeN
HN
CO2Et
O
Me
CO2Et
EtN
HN
CO2Et
OCO2Et
Regioselectivity: 91:9Yield: 80%ee: 95%
Regioselectivity: 81:19Yield: 77%ee: 98%
Regioselectivity: 82:18Yield: 92%ee: 95%
Regioselectivity: 76:24Yield: 69%ee: 99%
Yield: 79%ee: 94%
Yield: 67%ee: 84%
19
37
Stereoselective formation of optically active oxazolidinones
O
Bn
NCO2Et
HNCO2Et
O N
BnMe
O
NH O NH
BnMe
O
O N
BnMe
O
NHCO2Et
1) NaBH4
2) 0.5 N NaOH
1) TMSI2) Acetone3) Zn/HOAc
1) TiCl4/Et3SiH2) 0.5 N NaOH
Me
CO2Et
38
N R
R
O
R
NH
R
Enamine intermediate
OR'
R
Nucleophile
Electron-richalkene
NH
R
O
R
N R
R
O EWG
R2
N R
RO
EWGR2
O
R2R
HO EWG
The first organo-catalytic inverse-electron demand hetero-Diels-Alder reaction – direct
evidence for enamine intermediate
Submitted for publication
20
39
Further into the mechanism
NH
R
O
R
N R
R
O EWG
R2
N R
RO
EW GR2
O
R2R
EW GN
R
O
R2R
EWGSilica
HO
O
R
R2
EWG
O
O
R2R
EWGO
40
Screening of catalysts
O CO2Me
Ph
O
Phi-Pr
CO2MeHO O
R2R
EWGOO
i-Pr+
Cat.10 mol%
Silica
PCC
NH
CO 2H NH
N
NH
HN
O
CO2H
NH
HN
O
CO2H
NH
HN
O
CO2H
NH
HN
O
CO2H
Me i-Pr Bn
NH
NH OH
NH2
ONH
NH
Me
Me
MeMe
NH
NPh
CO 2H
Me
NH
HN
Ph
Ph
CO 2HNH
HN
Ph
PhPh
NH
PhPh
low yield low yield low yield 5% yield64% ee
15% yield47% ee
9% yield20% ee
9% yield22% ee
25% yield8% ee
69% yield51% ee
54% yield56% ee
28% yield75% ee low yield
69% yield92% ee
46% yield88% ee
21
41
Potential of the reaction
O CO2R3
R2
O
R2R1
CO2R3HOO
R1+
Silica
NH
Me
Me
MeMe
10 mol%
One diastereomer
R1
R2
R3 Yield
[%] ee [%]
Et Ph Me 50 88
i-Pr Ph Me 93 89
Bn Ph Me 70 81
Et 4-ClPh Me 79 85
i-Pr 4-ClPh Me 70 90
i-Pr Me Et 75 94
42
Catalytic asymmetric Henry reactionsa simple approach to optically active β-nitro and β-amino α-hydroxy
carboxylic acids
O
O
OEtMe
Chiral LA CO2Et
OHO Me
EtO2C
Not formed
OH
O
OEtMe
O2N
High yieldand enantioselectivity
MeNO2
22
43Catalytic Enantioselective Henry Reaction of 2-Keto Esters
O
O
OEtMe
N N
OO
t-But-BuCu(OTf)2
MeNO2
OH
CO2EtMeNO2
NEt3
OH
CO2EtMeNO2
Yield: 95%ee: 92%
OH
CO2EtEtNO2
Yield: 73%ee: 87%
OH
CO2EtNO2
Yield: 47%ee: 77%
OH
CO2EtC6H13
NO2
Yield: 91%ee: 93%
OH
CO2EtNO2
Yield: 97%ee: 94%
OH
CO2EtNO2
Yield: 90%ee: 94%
OH
CO2Eti-BuNO2
Yield: 99%ee: 92%
OH
CO2EtPhNO2
Yield: 81%ee: 86%
OH
CO2EtNO2
Yield: 91%ee: 88%
OH
CO2EtNO2
Yield: 99%ee: 93%
Ph
OH
CO2EtNO2
Yield: 92%ee: 94%
OH
CO2EtNO2
Yield: 68%ee: 57%
Cl O2N MeO
Chem. Commun. 2001 , 2222J. Org. Chem. 2002, 67, 4875
44
OH
CO2EtMe
NO2
Ra-Ni / H2 (atm)OH
CO2EtMe
NH2
OH
CO2EtMe
NHBoc
Boc2O, cat. DMAP
OH
CO2EtNO2
Ra-Ni / H2 (atm)OH
CO2 EtNH2
EtO2CNHO
O
Cl
Cl Cl
COCl2
Reduction of nitro functionality
23
45
O
C O2EtR Et3NH OTf
OH
C O2EtR
NO2
Et3N
M e
NOO
NO
NO
CuOO
OR
OEt
NO
t-Bu
t-Bu
NO
NO
C uOO
OR
OEt
NOMe
t-Bu
t-Bu
-2 O Tf
NO
NO
C uOO
OR
EtO
NO
t-Bu
t-Bu
NO
NO
C uTfO OTf
t -B u
t-Bu
+
Et3 N +
O
CO2EtR Me
NOO
+
Proposed mechanism
46
The catalytic enantioselective aza-Henry reactiona simple approach to optically active β-nitro and β-amino α-amino carboxylic acids
94% yield25:1 dr95% ee
67% yield5:1 dr
>98% ee
87% yield39:1 dr83% ee
93% yield32: 1 dr88% ee
N +
CO2Et
N N
OO
PhPhCu(OTf)2
20 mol%/- 100 C
MeO
N
R
TMSO O HN
CO2Et
PMP
O2N
R
HN
CO2Et
PMP
O2N
Et
HN
CO2Et
PMP
O2N
Me
HN
CO2Et
PMP
O2N
C5H11
HN
CO2Et
PMP
O2N
Bn
HN
CO2Et
PMP
O2N
Et
H2/Ra-Ni HN
CO2Et
PMP
H2N
Et
J. Am. Chem. Soc. 2001, 123, 5843
24
47The catalytic asymmetric nitro-Mannich reaction
N
CO2Et
CO2EtR
O2N
NO2
R
PMP
HNPMP
+
R = H: 38% yield, 97% eeR = Me: 61% yield, 7: 3 dr, 99% eeR = Et: 81% yield, 95: 5 dr, 97% eeR = Pentyl: 52% yield, 93:7 dr, 97% eeR = Bn: 80% yield, 95:5 dr, 95% eeR = Ph: 59% yield, 55:45 dr, 74% ee
Et3N (20%)room t emp
ambient conditions
CH2RN
O
Cu N
OOEt
ON
O
NO
Me
Me
Ph
PhPg
CuN
O
NO
Me
Me
Ph
Ph
OTf
OTf
CuN
OOEt
N
O
NO
Me
Me
Ph
Ph Pg
NO
CuN
OOEt
R
H
NO
NO
Me
Me
Ph
Ph Pg
O
O
OEt
NPg
NO2EtO
R
HNPg
O
- 2 TfO
RCH2NO2
Et3N
Cat .
Angew. Chem. Int. Ed. 2001, 40, 2992
48
Acknowledgements
Sorin Aburel Pay Bayon
Anders Bøgevig Christina Christensen
Xiangming Fang Nicholas Gathergood
Kurt V. Gothelf Rita G. Hazell
Anne K. Jensen Kim B. Jensen
Karsten Juhl Kristian R. Knudsen
Nagaswamy Kumaragurubaran Hester V. Lingen
Mauro Marigo Nagatoshi Nishiwaki
Tine Risgaard Mark Roberson
Steen Saaby Wei Zheng
Danish National Research Foundation
