Bifunctional Thiourea-Catalyzed Diastereo- and Enantioselective
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Bifunctional Thiourea-Catalyzed Diastereo- and Enantioselective Aza-Henry Reaction Takemoto et. al. Chem. Eur. J. 2006, 12, 466-476. Kalyani Patil@ Wipf group 21 Jan 2006 Kalyani Patil @ Wipf Group 1 1/22/2006
Transcript of Bifunctional Thiourea-Catalyzed Diastereo- and Enantioselective
Bifunctional Thiourea-Catalyzed
Diastereo- and Enantioselective
Aza-Henry ReactionTakemoto et. al. Chem. Eur. J. 2006,
12, 466-476.
Kalyani Patil@ Wipf group 21 Jan 2006
Kalyani Patil @ Wipf Group 1 1/22/2006
Outline
• OrganocatalystsThiourea catalysts/Hydrogen Bonding
• Catalytic Asymmetric Aza-Henry Reaction
(Shibasaki, Jorgensen, Jacobsen, & Palomo Group)
• Title Paper
• Summary
Kalyani Patil @ Wipf Group 2 1/22/2006
Organocatalysts
NMe2
NN
S
HH
NH
CO2H
(L)-Proline
N
NH
O
Ph.TFA
Imidazolium catalyst MacMillan
CF3
F3C
Thiourea catalyst Takemoto
NN
N
O
O
Ph
Ph
ClO4
Triazolium catalyst Enders
N
OBocHN
N
N
H
O
NH
NH
O
Peptide based catalyst Miller
N N
O O
N N
OCH3
Ph
Ph
H3CO
NEt
H
NEt
H
Cinchona alkaloid catalyst Deng
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Organocatalysts: Double Hydrogen Bonding Activation
R1
R2
R1
R2
O O
HH
R
O
R
1 R1 = R2 = H Hine biphenylenediol catalyst
2 R1 = nPr, R2 = NO2 Kelly biphenylenediol catalyst
NH
NH
X
R1
R2
R1
R2
3a R1 = NO2, R2 = H, X = O Etter urea catalyst
3b R1 = CF3, R2 = CO2C8H17, X = O Curran's diarylurea
3c R1 = R2 = CF3, X = S Schreiner thiourea catalyst
NH
NH
Me2N
S
O
tBu
N
HO
tBu OCOtBu
5 Jacobsen thiourea catalyst
4 Takemoto thiourea catalyst
HN
HN
S
NMe2
F3C
CF3
Kalyani Patil @ Wipf Group 4 1/22/2006
Catalytic Asymmetric Aza-Henry Reaction
Promoted by Heterobimetallic complex
Ar NPPh2
O
+ CH3NO2
5 equiv.
Yb/K/binaphthol=1/1/320 mol%
toluene/THF (7/1), -40 °C Ar NH
PPh2
OO2N
Entry Ar Time (h) Yield (%) ee (%)
1. Ph 60 79 91
2. 4-Cl-C6H4 60 93 87
3. p-tolyl 168 85 89
4. 2-furyl 168 57 83
5. 2-thiophenyl 168 41 69
Shibasaki et al. Angew. Chem. Int. Ed. 1999, 38, 3504-3506.
O
O
OO
O
O
Yb
H H
K
* *
*OH OH
*
+
O
OO
O
Yb
K
* *
Yb
O
O
O
O
K
Yb
O
O
O
O
K
K
*
**
*
Kalyani Patil @ Wipf Group 5 1/22/2006
Catalytic Asymmetric Aza-Henry Reaction of
Nitronates with Imines
Jorgenson et al. J.Am.Chem.Soc. 2001, 123, 5843-5844.
N
Et
TMSO O+ N
CO2Et
PMP
O2NCO2Et
Et
HNPMP
THF, -100 °C
O
N N
O
PhPhCu
ClO4
90% yield, 3:1 dr, 90% ee
Kalyani Patil @ Wipf Group 6 1/22/2006
Catalytic Asymmetric Aza-Henry Reaction using
Thiourea Catalyst
Jacobsen et al. Angew. Chem. Int. Ed. 2005, 44, 466-468.
N
Ph H
1 (10 mol%), i-Pr2NEt
toluene, 4 °C, MS 4Å
Boc
+
R2
R1 NO2Ph
NO2
NHBoc
R1 R2
Me2NNH
NH
O
t-Bu S
NHAc
1
Entry Nitroalkane R1 R2 Yield (%) dr (syn:anti) ee (%)
1. 1-nitropropane Et H 99 7:1 95
2. nitromethane H H 87 - 92
3. 2-nitropropane Me Me 87 - 92
4. TBSOCH2CH2NO2 TBSOCH2 H 85 4:1 95
Kalyani Patil @ Wipf Group 7 1/22/2006
Catalytic Asymmetric Aza-Henry Reaction
Palomo et al. J. Am. Chem. Soc. 2005, 127, 17622-17623.
Palomo et al. Angew. Chem. Int. Ed. 2006, 45, 117-120.
N
Ph
Boc+
PhNO2
NHBoc
CH3NO2
Zn(OTf)2, i-Pr2NEt
(-)-NME, MS 4Å-20 °C, 15-20 h81%, 97% ee
NHBoc
R SO2Tol-p
N
OH
OMe
N
Ph
Cl
1
1 (12 mol%)CsOH.H2O (130 mol%)
toluene, -50 °C, 44h
CH3NO2
CH3CH2NO2
RNO2
NHBoc
RNO2
NHBoc
CH3
Entry R R1NO2 Yield (%) ee (%)
1. PhCH2CH2 CH3NO2 83 96
2. (CH3)2CH 81 95
3. 4-MeOC6H4 82 91
4. 4-F3CC6H4 80 82 (90)
5. 4-MeOC6H4 87 90 (95:5)
CH3NO2
CH3NO2
CH3NO2
CH3CH2NO2
Kalyani Patil @ Wipf Group 8 1/22/2006
Enantioselective Aza-Henry Reaction:(Title Paper)
NX
Ph H
CH3NO2, 1 (10 mol%)
CH2Cl2, rt PhNO2
XHN H
Entry (X) Time (h) Yield (%) ee (%)
1. Ts 4.5 99 4
2. P(O)Ph2 24 87 67 (S)
3. Ac 24 95 63
4. CO2Me 24 64 83
5. CO2Bn 24 68 85
6. Boc 24 76 90 (R)
7.a Boc 24 90 94 (R)
a Reaction was performed at -20 °C
NBoc
Ar H
CH3NO2, 1 (10 mol%)
CH2Cl2, -20 °C ArNO2
BocHN H
Entry Ar Time (h) Yield (%) ee (%)
1. p-CF3C6H4 24 80 98
2. p-MeC6H4 24 82 93
3. p-MeOC6H4 60 71 95
4. 1-naphthyl 24 85 95
5. 2-naphthyl 48 85 85
6. 2-furyl 60 81 91
7. 3-pyridyl 24 89 98
1
HN
HN
S
NMe2
F3C
CF3
Kalyani Patil @ Wipf Group 9 1/22/2006
Enantio/Diastereoselective Aza-Henry Reaction of
Nitropropane with organocatalysts
Both, thiourea and tertiary amine functionality is required
NBoc
Ph H
C3H7NO2, 1 (10 mol%)
CH2Cl2, -20 °CPh
NO2
Et
NHBoc
+Ph
NO2
Et
NHBoc
1a: 90%, 88/12 (95% ee)1b: 84%, 89/11 (92% ee)1c: 12%, 52/48 (7% ee)1d: 0%
Kalyani Patil @ Wipf Group 10 1/22/2006
Enantio- and Diastereoselective Aza-Henry Reaction
NBoc
Ar H
RCH2NO2, 1 (10 mol%)
CH2Cl2, -20 °CAr
NO2
Entry Ar Yield (%) dr
1. Ph 92 90/10
2. Ph 82 93/7
3. Ph CH2Ph 84 83/17
4. Ph 75 75/25
5. Ph CH2OBn 80 86/14
6. Ph (CH2)2OBn 86 93/7
7. Ph (CH2)3OBn 80 91/9
8. Ph 80 92/8
9. Ph (CH2)3OTf 78 93/7
10. p-CF3C6H4 CH2Ph 94 97/3
11. p-MeC6H4 CH2Ph 90 93/7
12. 3-pyridyl CH2Ph 93 83/17
R
R
NHBoc
ee (%)
93
99
97
90
95
94
92
89
90
95
92
93
CH3
C5H11
CH2OH
(CH2)3OH
1
HN
HN
S
NMe2
F3C
CF3
Kalyani Patil @ Wipf Group 11 1/22/2006
Proposed Model for the Thiourea-Catalyzed
Aza-Henry Reaction
Kalyani Patil @ Wipf Group 12 1/22/2006
Applications of Aza-Henry Reaction
NBoc
Ph H
NO2MsO
1, CH2Cl2, -20 °C80% (dr 86/14)
HNMsO
NO2
Ph
Boc
+HNMsO
NO2
Ph
Boc
96% ee 83% ee
1) TFA2) K2CO3
80% NH
NO2
Ph
(trans/cis = 9/1)
1) tBuOK, 0 °C2) AcOH, -78 °C
3) Zn, AcOH
NH
NH2
Ph
(cis/trans = 95/5)
o-MeOC6H4CHO
NaBH3CN, AcOH, MeOH, rt
75%NH
HN
PhOMe
(-) CP-99,994
Potent neurokinin-1 receptor antagonist
NBoc
Ph H 1, CH2Cl2, rt, 24h81% (dr 79/21)
NH
O2N CO2MeHN
CO2Me
Boc
Ph
NO2
syn 92% eeanti 72%ee
1) TFA
2) Et3N, THF70% (87% ee)
CO2MePh
O2N
Kalyani Patil @ Wipf Group 13 1/22/2006
Summary
• Catalytic Asymmetric Aza-Henry reaction: good diastereo-
and enantioselectivity
• Syn-!-nitroamines as major products
• Thiourea and tertiary amine functionality in the catalyst are
required
• Tolerance of aryl, alcohol, ether, and ester groups
• No additional reagents required
Kalyani Patil @ Wipf Group 14 1/22/2006
