Literature Presentation Febuary 9 th , 2010
54
N-Heterocyclic Carbene-Catalyzed Generation of Homoenolates: Historical Perspective and Contributions of Jeffrey W. Bode. Literature Presentation Febuary 9 th , 2010 Presented by Louis-Philippe Beaulieu
description
N-Heterocyclic Carbene-Catalyzed Generation of Homoenolates: Historical Perspective and Contributions of Jeffrey W. Bode. Literature Presentation Febuary 9 th , 2010. Presented by Louis-Philippe Beaulieu. Thiamine: a Naturally Occuring NHC Precursor. - PowerPoint PPT Presentation
Transcript of Literature Presentation Febuary 9 th , 2010
N-Heterocyclic Carbene-Catalyzed Generation of Homoenolates: Historical Perspective and Contributions of Jeffrey W. Bode.
Literature PresentationFebuary 9th, 2010
Presented byLouis-Philippe Beaulieu
Thiamine: a Naturally Occuring NHC Precursor
2
N
N
N
S
MeNH2
MeOR
1a: R = H1b: R =
PO
O
OOH
P
O
OHOH
HO H
R
OOH
+HO
R'
Ketose (n carbons)
Aldose(m carbons)
TransketolaseHO
R
Aldose(n - 2 carbons)
HO H
R'
OOH
Ketose (m + 2 carbons)
+
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
Thiamine: a Naturally Occuring NHC Precursor
3
N
N
N
S
MeNH2
MeOR
1a: R = H1b: R =
PO
O
OOH
P
O
OHOH
O
-O
Me
OPyruvatedecarboxylase
CO2
Me
H O
AcetaldehydePyruvate
NAD+NADH + H+
Me
H OHH
Ethanol
Alcoholdehydrogenase
H+
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
Thiamine: a Naturally Occuring NHC Precursor
4
N
N
N
S
MeNH2
MeOR
1a: R = H1b: R =
PO
O
OOH
P
O
OHOH
O
-O
Me
ODecarboxylation
CO2
Me O
Pyruvate
Oxidation
2 e-
Me O
Transferto CoA
CoA
OMe
SCoA
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
Mechanistic Insights
5Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.Krohnke, F. Angew. Chem. 1953, 65, 605-607
S
N+
Br-D D
(8 mol %)O
HO
O
O
OH
OKOH, EtOH/H2O
No D loss during reaction
N
R
R' H
O
N
ROH
R'
N
R
via
N
N
N
S
MeNH2
MeOR
Mechanistic Insights
6Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.Schenkel, H.; Schenkel-Rudin, M. Helv. Chim. Acta 1948, 31, 924-929.
N
S
HO
O
N
S
HO
O
HH+
CO2
N
S
N
S
HCO2
N
S
Favored
N
N
N
S
MeNH2
MeOR
Mechanistic Insights
7Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.Schenkel, H.; Schenkel-Rudin, M. Helv. Chim. Acta 1948, 31, 924-929.
N
S
HO
O
N
S
HCO2
N
S
S
NMe
Br
neutral D2O
rt, 24 hH S
NMe
BrD
1.2 atoms of Dincorporation
N
N
N
S
MeNH3
MeOH
H
Clneutral D2O
rt, 24 hN
N
N
S
MeND3
MeOD
D
Cl
5.2 atoms of Dincorporation
N
S
R+ H+
- HX
N
S
R
H
XN
S
R
N
N
N
S
MeNH2
MeOR
Mechanistic Insights
8Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.Lapworth, A. J. Chem. Soc., Trans., 1903, 83, 995-1005.
H
O
OH
CN
H
OH
CN
OH
CN
O
H
HCN
H+
H
O
H+
HOC N
O
OH
N
N
N
S
MeNH2
MeOR
Mechanistic Insights
9Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.Lapworth, A. J. Chem. Soc., Trans., 1903, 83, 995-1005.
H
O
OH
H
OH
OHO
H
H+
H
O
N
S
R
S
N
R
S
N
R
S N R
HO
S
N
R
O
OH
N
N
N
S
MeNH2
MeOR
Mechanistic Insights
10Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
SN+
Me
Br-
H
O O
OHNaOH (2 mol %)MeOH, 34 C, 24 h
(5 mol %)
SN+
Me
Br-
H
O O
OHNaOH (2 mol %)MeOH, 34 C, 24 h
(5 mol %)
Me
N
N
N
S
MeNH2
MeOR
Mechanistic Insights
11Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
N
S
R
H+ M OH
X
N
S
R
N
N
N
S
MeNH2
MeOR
OH
NR
S M
M OH
Mechanistic Insights
12Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
O
Me
O
OH +O
Me H
N
S
Br
(50 mol %)
H2OpH adjusted to 8.4 with NaOH
34 C, 40 h
O
Me
OH
Me
Me Me
O
Me
O
OH +O
Me H
N
S
Br
(50 mol %)
H2OpH adjusted to 8.4 with NaOH
34 C, 40 h
O
Me
OH
Me30% yield compared to amount of acetoin generated withthiamine chloride hydrochloride
Ph Me
N
N
N
S
MeNH2
MeOR
Mechanistic Insights
13Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
Me
O
OH
Me
OH
Me
H
O
Me
OH
Me
CO2Me H
O
N
S
R
S
N
R
S
N
R
O
OM
O OS
N
R
O
Me
OH
Me
N
N
N
S
MeNH2
MeOR
Isolable NHCs: Contributions of Arduengo
14Arduengo, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361-363.Arduengo, A. J.; Dias, H. V. R.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1992, 114, 5530-5534.
N
NR4R1
R3
R2
H
Cl
NaH (1 equiv)KOt-Bu (5 mol %)
or
KOt-Bu (1 equiv)
THF, rt, 20 min 4 h N
NR4R1
R3
R2N
NR4R1
R3
R2
N
NH
H N
NH
H
Me
Me
Me
Me
Me
Me
N
NH
H
R
R
N
NMeMe
MeMe
y: 89%
y: 84%R = Me y: 45%R = Cl y: 43%
y: 96%
Asymmetric Benzoin Reaction
15Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743-1745.
Ar H
O
Ar
O
Ar
OH
O N
NNPh
tBu
BF4
(10 mol %)
KOtBu (10 mol %)
THF, 78, 0 or 18 C, 16 h
O N
NNPh
tBu
OH
Ar
O
ArHRe
Re
O NH
tBu
OMe3OBF4 (1.2 equiv)
CH2Cl2, rt, 15 hO N
tBu
OMe PhNHNH2 (1.0 equiv)Et3N (1.0 equiv)
THF, 80 C, 7d
O NH
tBu
NNHPh
i) HBF4 (1.0 equiv) CH2Cl2/Et2O, rt
ii) HC(OMe)3 (20.0 equiv) MeOH, 80 C, 12 h
O N
NNPh
tBu
BF4
quant. 77%
65%
Asymmetric Benzoin Reaction
16Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743-1745.
Ar H
O
Ar
O
Ar
OH
O N
NNPh
tBu
BF4
(10 mol %)
KOtBu (10 mol %)
THF, 78, 0 or 18 C, 16 h
O N
NNPh
tBu
OH
Ar
O
ArHRe
Re
Ph
O
Ph
OH
p-FC6H4
O
p-FC6H4
OH
p-ClC6H4
O
p-ClC6H4
OH
p-BrC6H4
O
p-BrC6H4
OH
y: 83%ee: 90%
y: 61%ee: 91%
y: 80%ee: 64%
y: 59%ee: 91%
p-MeC6H4
O
p-MeC6H4
OH
m-MeC6H4
O
m-MeC6H4
OH
p-MeOC6H4
O
p-MeOC6H4
OH
2-Fur
O
2-Fur
OH
y: 16%ee: 93%
y: 70%ee: 86%
y: 8%ee: 95%
y: 41%ee: 88%
Asymmetric Cross-Benzoin Reaction
17Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed. 2006, 45, 1463-1467.
O
OR
O
OH
R
R = Me y: 93%, ee: 94% (S)R = Et y: 90%, ee: 95% (S)R = nBu y: 85%, ee: 98% (S)R = iBu y: 91%, ee: 98% (S)R = Bn y: 43%, ee: 93% (R)
(10 20 mol %)
KOt-Bu (9 19 mol %)
0.1 M THF, rt
N
NN
PhBF4
1
R
N
NN
O
H
HO
H
ReRe
O
OH
R
Asymmetric Cross-Benzoin Reaction
18
entry SM Product yield (%) ee (%) entry SM product yield
(%) ee (%)
1 44 96 5 47 90
2 70 96 6 74 85
3 69 60 7 91 98
4 73 39 8 73 99
Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew. Chem., Int. Ed. 2006, 45, 3492-3494.
Me
O
O
O
Me
O
O
Me
O
MeOO
EtOO
iPrOO
N O
PhOO
Me
OMe
Ph
N O
Me
OMe
OOH
O
iPrOH
OEt
OH
OMe
OH
O
MeOH
OOH
Me
OHO
Me
N O
OO
OO
N OOO
OHO
OO R
cat. 1 (20 mol %)DBU (20 mol %)
THF, rt, 0.5 24 hO OH
R* N
N
N
Ph
O
Cl
Exploration of Other Reactivity Modes of the Breslow Intermediate
19Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370-14371.
RN X
X
RN
R1
OH
d1
O
R1 R1
OH
O
HR1
a1
benzoin condensation
O
HR1
a1
H
O
R2
RN X X
RN
OH
d1
O
HR1
a1
-lactone synthesis
R2
X
RN
OH
R2
d3
d1d3
a1a3
O
O
R2 R1
Jeffrey W. Bode
20
Jeffrey studied chemistry and philosophy at Trinity University in San Antonio, Texas and worked in the research group of Prof. Michael P. Doyle.He began his graduate studies in organic chemistry at the California Institute of Technology in 1996. In 1998, he moved with his research advisor, Prof. Erick M. Carreira, to the Swiss Federal Institute of Technology (ETH)in Zürich, Switzerland, where he completed his Doc. Nat. Sci. in 2001. Following a two year Japan Society for the Promotion of Science PostdoctoralFellowship with Prof. Keisuke Suzuki at the Tokyo Institute of Technology in Tokyo, Japan, he joined the Department of Chemistry and Biochemistry atUC-Santa Barbara in 2003. In Fall 2007, he moved to the University ofPennsylvania as Associate Professor in the Department of Chemistry.
Synthesis of γ-Butyrolactones
21Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370-14371.
O
Ar
H +O
R1H
N
N
Mes
Mes
Cl
(8 mol %)
O
O
Ar
R1
DBU (7 mol %)10:1 THF/tert-BuOH
25 C, 3-15 h
O
O
R1R2
O
O
R2
R2
O
R1 R1
OH
O
OH
R2
R2
O
R1
OH
R2
O
R1
OH
R2
O
R1
R2 O
H
O
R2 O
HR2
Stetter-productscrossbenzoinproducts
homobenzoinproducts
Expected products from the organocatalyzed reaction of an ,-unsaturated aldehyde with another aldehyde
Synthesis of γ-Butyrolactones
22Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370-14371.
Ar
O
HAr
O
N
N
Mes
MesH
Ar
OH
N
N
Mes
Mes
Ar
OH
N
N
Mes
Mes
Ar
OH
N
N
Mes
MesOR1
O
R1H
Ar
O
N
N
Mes
MesOR1
O
O
Ar
R1
activated carboxylate
homoenolate
N
N
Mes
Mes
Synthesis of γ-Butyrolactones
23Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370-14371.
O
Ar
H +O
R1H
N
N
Mes
Mes
Cl
(8 mol %)
O
O
Ar
R1
DBU (7 mol %)10:1 THF/tert-BuOH
25 C, 3-15 h
O
O
Ph C6H4-p-Br
O
O
Ph C4H4-p-CO2Me
O
O
4-MeOC6H4 C6H4-p-Br
O
O
4-MeOC6H4 Ph
O
O
C4H4-p-CO2Me
TIPS
O
O
TIPS
TIPS
O
O
1-Naph
1-Naphy: 79%dr: 4:1
y: 87%dr: 5:1
y: 76%dr: 4:1
y: 65%dr: 4:1
y: 41%dr: 3:1
y: 83%dr: 5:1
y: 67%dr: 5:1
Synthesis of γ-Butyrolactones: Contribution of Glorius
24Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205-6208.
Entry R1 1 Yield (%) cis/trans
1 4-ClC6H4 a 0 -
2 4-ClC6H4 a 53 80:20
3 4-ClC6H4 a 33 81:19
4 4-BrC6H4 b 49 80:20
5 4-MeO(CO)C6H4 c 70 79:21
6 4-F3CC6H4 d 44 77:23
7 3-FC6H4 e 52 78:22
8 3-ClC6H4 f 61 79:21
9 3-BrC6H4 g 60 79:21
10 2-ClC6H4 h 32 23:77
O
Ph
H +O
R1H
N
N
Mes
Mes
Cl
(5 mol %)
O
O
Ph
R1
KOt-Bu (10 mol %)THF, 25 C, 16 h
1
Synthesis of γ-Butyrolactones: Contribution of Glorius
25Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006, 2418-2439.
RN X
X
RN
R1
OH
d1
O
R1 R1
OH
O
HR1
a1
benzoin condensation
O
HR1
a1
OH
N
N
d1
shielded
OH
N
N
d1
shielded
Ph
d3
accessible
Formation and Esterification of Activated Carboxylates
26Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873-3876.
Ph H
ON
N
Mes
Mes
Cl
3 equiv EtOH1M THF, 40 C
(10 mol %)
w/ 15 mol % tBuOK
w/ 15 mol % DIPEA
O
O
Ph
OEt
O
Ph
H
Ph
Ph H
O+ EtOH
x mol % catalyst2x mol % DIPEA
1M THF, 40 C Ph OEt
O
N S
Me Me
Bn
Cl
N S
Me
Mes
ClO4
N NMes
Cl
Mes
1 2 3
NN
NAr
X
4 Ar = Ph, X = Cl: x = 10 mol %, trace conv.5 Ar = 4-MeOC6H4, X = Cl: x = 10 mol %, 98% conv.6a Ar = Mes, X = BF4: x = 10 mol %, 99% conv.6a Ar = Mes, X = Cl: x = 5 mol %, 99% conv.
x = 10 mol %15% conv.
x = 10 mol %trace conv.
x = 15 mol %80% conv.
Formation and Esterification of Activated Carboxylates
27Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873-3876.
Ph H
ON
N
Mes
Mes
Cl
3 equiv EtOH1M THF, 40 C
(10 mol %)
w/ 15 mol % tBuOK
w/ 15 mol % DIPEA
O
O
Ph
OEt
O
Ph
H
Ph
R1 H
O
+ R2OHOR2
O
R1
N
NN Mes
BF4
10 mol % DIPEA
1 M THF, 60 C
(5 mol %)
61-99%1 equiv 1-3 equiv
R1, R2 = alkyl and aryl
Formation and Esterification of Activated Carboxylates
28Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873-3876.
entry x (mol %) base pKa of conjugateacid in THF
relative yield (%)
1 5 NEt3 12.5 99
2 5 DIPEA ~13 99
3 5 DBU 16.8 15
4 5 KOt-Bu 29.4 ˃5
5 20 KOt-Bu 75
6 20 DIPEA 99
Ph H
O
+ EtOHOEt
O
Ph
x mol % of
N
NN Mes
Cl
10 mol % base
1 M THF, 60 C
Formation and Esterification of Activated Carboxylates
29Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873-3876.
DIPEA H+
DIPEA
Ph H
O
Ph
O
NN
N
MesH
Ph
OH
NN
N
Mes
Ph
OH
NN
N
MesH
Ph
O
NN
N
MesH
Ph
O
NN
N
Mes
OEt
- H++ H+
EtOH
Synthesis of β-Hydroxyesters from Epoxyaldehydes
30Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-8127.
O
R1
R2
O
H+ R3OH
R1 OR3
O
R2
OH
S
NMe
Me
BnCl
8 mol % DIPEA
30 C, 3 15 h
(10 mol %)
R1
OH
R2
O
S
NMe
Me
Bn
activated carboxylate
Synthesis of β-Hydroxyesters from Epoxyaldehydes
31
Ph
OH
Me
OBn
O
Ph
OH
Me
OiPr
O
y: 89%dr: 10:1
y: 79%dr: 10:1
Ph
OH
MeOCD3
O
(H)D
y: 81%dr: 9:1
Ph
OH
OEt
O
Cy
OH
Me
OMe
O
y: 84% y: 82%dr: 7:1
OH
OEt
O
y: 85%
Me
Me
Me
O
R1
R2
O
H+ R3OH
R1 OR3
O
R2
OH
S
NMe
Me
BnCl
8 mol % DIPEA
30 C, 3 15 h
(10 mol %)
Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-8127.
Synthesis of β-Hydroxyesters from Epoxyaldehydes
32
O
R1
R2
O
H+ R3OH
R1 OR3
O
R2
OH
S
NMe
Me
BnCl
8 mol % DIPEA
30 C, 3 15 h
(10 mol %)
Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-8127.
N
Ph
O
H+ EtOH
Ph OEt
OTsNH
S
NMe
Me
BnCl
8 mol % DIPEA
30 C,15 h
(10 mol %)Ts
y: 53%
Synthesis of β-Hydroxyesters from Epoxyaldehydes
33
S
N
Bn
Me
Me
O
R1
R2
O
H
O
R1
R2
O
S
NMe
Me
BnH
O
R1
R2
OH
S
NMe
Me
Bn
O
R1
R2
OH
S
NMe
Me
BnH
or
O
R1
R2
O
S
NMe
Me
Bn
OH
R1
R2
O
S
NMe
Me
Bn
H
OH
R1
R2
O
S
NMe
Me
Bn
R3OH
R3O
+
OH
R1
R2
O
OR3
S
N
Bn
Me
Me
DIPEA
HCl
Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-8127.
NHC-Mediated Opening of Chiral Formylcyclopropanes
34Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021-6024.
EWG
R1
H
O
Nu H+
N
NN Mes
Cl(5 mol %)
DBU (20 mol %)THF, 23 40 C
EWG
R1 O
Nu
Ph
O Ph
OMe
O
Ph
O nPr
OMe
O
Ph
O Me
OMe
O
Ph
O
OMe
O
Me
tBu
O nPr
OMe
O
Ph
O Ph
SC12H25
O
Ph
O Ph
OH
O
y: 90%ee SM: 89%ee Pd: 89%
y: 87%ee SM: 93%ee Pd: 90%
y: 84%ee SM: 83%ee Pd: 77%
y: 96%ee SM: 83%ee Pd: 81%
y: 95%ee SM: 93%
y: 99%ee SM: 88%ee Pd: 88%
y: 92%ee SM: 88%ee Pd: 87%
NHC-Mediated Opening of Chiral Formylcyclopropanes
35Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021-6024.
Ph
H(D)
O
+
N
NN Mes
Cl(5 mol %)
DBU (20 mol %)THF, 23 40 C
O
Ph CD3OD
100% D incorporation
Ph
OO
Ph
NN
N
MesH
Ph
OHO
Ph
NN
N
Mes
Ph
OHO
Ph
NN
N
Mes
Ph
OHO
Ph
NN
N
Mes
CD3O DD
R3N+ D(H)
activated carboxylate
O
Ph
Ph O
D D(H) NN
N
Mes
O
Ph
Ph
OCD3
O
D D(H)
Breslow intermediate
NHC-Mediated Opening of Chiral Formylcyclopropanes
36Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021-6024.
EWG
R1
H
O
Nu H+
N
NN Mes
Cl(5 mol %)
DBU (20 mol %)THF, 23 40 C
EWG
R1 O
Nu
entry RCHO NuH product yield (%)
1 C12H25SH 81
2 MeOH 95
3 MeOH 98
4 MeOH 90
O
CHO
H
O
EtO
O
H
O
N
O
Me
MeO
O2NH
O
O
SC12H25
O
O
EtO
O
OMe
O
N
O
OMeMeO
Me
O2N
O
OMe
NHC-Mediated Opening of Chiral Formylcyclopropanes
37
EWG
R1
H
O
+
N
NN Mes
Cl(5 mol %)
DBU (20 mol %)Imidazole (1.1 equiv) 0.5 M THF, 40 C, 15 h
EWG
R1 O
NR3
R2
HNR2
R3
1.5 equiv 1.0 equiv
Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798-13799.
EtO
O
NHBn
O
EtO
O
NH
O
EtO
O
NHCy
O
EtO
O
NH
O
EtO
O
NHPh
O
EtO
O
NHOBn
O
y: 90% y: 65% y: 74%
y: 99% y: 70% y: 53%
n-C8H17
Ph
O Ph
NHBn
O
y: 81%
Ph
O Me
NHBn
O
y: 83%
O2NNHBn
O
y: 54%
Ot-Bu
O
Ph
NHC-Mediated Opening of Chiral Formylcyclopropanes
38Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798-13799.
EtO2C
O
H
H2N Ph
EtO2C
N
H
Phfast and apparently irreversible in the absence of catalyst and imidazole
EtO2C
OH
N N
not observed eitherwith or without DBU
THF, rt
+N
HN
f ast
N
NN Mes
Cl(5 mol %)
DBU (20 mol %)
O
EtO N
O
N
H2N PhO
EtO NH
O
Ph
Catalytic Redox Amidations of Enals
39Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798-13799.
entry RCHO product yield (%)
1 63
2 68
3 63
4 56
5 78
6 52
Ph
Cl
H
O
Ph H
O
H
O
MeO
H
O
O
Me
H
O
AllylO
AllylO
AllylO
H
O
O
EtO
Ph NHBn
O
Ph NHBn
O
NHBn
O
MeO
NHBn
O
O
Me
NHBn
O
AllylO
AllylO
AllylO
NHBn
O
O
EtO
Enantioselective Azadiene Diels-Alder Reactions
40He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418-8420.
O
HR1
O
+N
H R2
ArO2S(10 mol %)
DIPEA (10 mol %)
10:1 Tol/THF, rt
O
N N
NMes
Cl
N
R2
O
ArO2S
R1O
Ar = p-MeOC6H4
dr: 50:1
N
Ph
O
ArO2S
OEtO
N
C6H4-p-OMe
O
ArO2S
OEtO
N
C6H4-p-(CO)Me
O
ArO2S
OEtO
N
2-fur
O
ArO2S
OEtO
y: 90%ee: 99%
y: 90%ee: 99%
y: 81%ee: 99%
y: 71%ee: 99
N
Ph
O
ArO2S
Ot-BuO
y: 70%ee: 97%
N
n-Pr
O
ArO2S
MeO
y: 71%ee: 98%
N
C6H4-p-OMe
O
ArO2S
PhO
y: 52%ee: 99%
N
n-Pr
O
ArO2S
OEtO
y: 58%ee: 99
Enantioselective Azadiene Diels-Alder Reactions
41He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418-8420.
EtO2C H
O
EtO2C
O
NN
N
MesH
EtO2C
OH
NN
N
Mes
EtO2C
O
NN
N
Mes
NN
N
Mes
H
EtO2C
O
NN
N
MesH
Ph
N
H
SO2Ar
N
OSO2Ar
EtO2C
Ph
N
NNMes
NSO2Ar
EtO2C
Ph
O
Enantioselective Azadiene Diels-Alder Reactions
42He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418-8420.
O
HR1
O
+N
H R2
ArO2S(10 mol %)
DIPEA (10 mol %)
10:1 Tol/THF, rt
O
N N
NMes
Cl
N
R2
O
ArO2S
R1O
Ar = p-MeOC6H4
dr: 50:1
R2H
O
NN
NO
Ar
NS
OO
MeOC6H4 R1
Enantioselective Oxodiene Diels-Alder Reactions
43He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088-15089.
O
O
Me CO2Me
Ph
y: 88%dr: 20:1ee: 99%
O
O
Ph CO2Me
Ph
y: 91%dr: 8:1ee: 99%
O
O
p-BrC6H4 CO2Me
Ph
y: 80%dr: 6:1ee: 99%
O
O
Cy CO2Me
Ph
y: 76%dr: 20:1ee: 86%
O
O
2-fur CO2Me
Ph
y: 94%dr: 8:1ee: 99%
O
O
Me CO2Me
n-C9H19
y: 71%dr: 20:1ee: 99%
O
O
Ph CO2Me
n-C9H19
y: 90%dr: 20:1ee: 99%
O
O
Ph CO2Me
OTBS
y: 80%dr: 3:1ee: 97%
H
O
R1
Cl
+R2
O
R3
(5 mol %)
Et3N (1.5 equiv)
0.2 M EtOAc, rt
O
O
R2 R3
R1
O
N N
NMes
Cl
Enantioselective Oxodiene Diels-Alder Reactions
44He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088-15089.
H
O
R1
Cl
+R2
O
R3
(5 mol %)
Et3N (1.5 equiv)
0.2 M EtOAc, rt
O
O
R2 R3
R1
O
N N
NMes
Cl
O
O
EtO2C p-Tol
Ph
y: 71%dr: 20:1ee: 99%
O
O
EtO2C n-Pr
Ph
y: 71%dr: 20:1ee: 99%
O
O
EtO2C Cy
Ph
y: 71%dr: 20:1ee: 99%
O
O
EtO2C p-Tol
OTBS
y: 83%dr: 20:1ee: 95%
Cyclopentene Formation Through Benzoin-Oxy-Cope Reactions
45Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520-3521.
R1 H
O
MeO2C R2
O
+
(10 mol %)
R2
R1
MeO2C
O
N N
NMes
Cl
15 mol % DBUClCH2CH2Cl, 0 23 C, 40 h
Ph
Ph
MeO2C
y: 78%dr: 11:1ee: 99%
p-MeOC6H4
Ph
MeO2C
y: 58%dr: 5:1ee: 99%
p-BrC6H4
Ph
MeO2C
y: 50%dr: 11:1ee: 98%
2-fur
Ph
MeO2C
y: 93%dr: 20:1ee: 98%
Ph
p-BrC6H4
MeO2C
y: 78%dr: 11:1ee: 99%
Ph
p-CF3C6H4
MeO2C
y: 68%dr: 4:1ee: 98%
Ph
2-fur
MeO2C
y: 53%dr: 5:1ee: 99%
Ph
n-Pr
MeO2C
y: 25%dr: 14:1ee: 96%
Cyclopentene Formation Through Benzoin-Oxy-Cope Reactions
46Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520-3521.
Ph H
O
Ph
O
NN
N
MesH
Ph
OH
NN
N
Mes
MeO2C Ph
O
d1
OHO
N N
N
Mes
PhMeO2C Ph
OO
N N
N
Mes
PhMeO2C Ph
OO
N N
N
Mes
PhMeO2C Ph
a1
Ph
Ph
MeO2C
N N
NMes
O
Cyclopentene Formation Through Benzoin-Oxy-Cope Reactions
47Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520-3521.
R1 H
O
MeO2C R2
O
+
(10 mol %)
R2
R1
MeO2C
O
N N
NMes
Cl
15 mol % DBUClCH2CH2Cl, 0 23 C, 40 h
N
N
N
O
PhO
OMe
Ph
O
HO
Me
MeMe
N
N
N
O
PhO
OMe
Ph
O
HO
Me
MeMePh
Ph
CO2Me
NHC-Mediated Bicyclo-β-Lactam Formation
48He, M.; Bode, J. W. J. Am. Chem. Soc. 2007, 130, 418-419.
R1 H
O
+N
Ar1 Ar2
ArO2S(10 mol %)
DBU (15 mol %)
0.1 M EtOAc, rt, 15 h
O
N N
NMes
Cl
Ar = p-MeOC6H4
N
H Ar1
R1
Ar2
O SO2Ar
N
N
N
O
Me
Ph
N
HO
Me
MeMe
N
N
N
O
MePh
Ph
N
HO
Me
MeMe
Ph
Me
Ph
ArO2SPh ArO2S
ArO2SN
O H
NHC-Mediated Bicyclo-β-Lactam Formation
49
N
H Ph
Me
Ph
O SO2ArN
H Ph
n-Pr
Ph
O SO2ArN
H Ph
Ph
O SO2ArN
H Ph
Ph
O SO2Ar
Me
Me
N
H Ph
Ph
O SO2Ar
Me
N
H p-BrC6H4
n-Pr
p-BrC6H4
O SO2ArN
H Ph
Me
p-MeOC6H4
O SO2ArN
H Ph
Me
p-BrC6H4
O SO2Ar
y: 94%dr: 10:1ee: 99%
y: 81%dr: 10:1ee: 99%
y: 45%dr: 10:1ee: 99%
y: 50%dr: 10:1ee: 87%
y: 76%dr: 5:1ee: 99%
y: 75%dr: 10:1ee: 99%
y: 63%dr: 10:1ee: 99%
y: 77%dr: 10:1ee: 99%
He, M.; Bode, J. W. J. Am. Chem. Soc. 2007, 130, 418-419.
NHC-Mediated γ-Lactam Formation
50
Entry R1 R2 R3 yield (%) cis/trans
1 Ph Ph H 89 3:1
2 Ph thiophen-2-yl H 90 4:1
3 Ph p-CNC6H4 H 83 1:1
4 Ph Ph Me 96 4:1
5 Ph Me H 72 9:1
6 p-MeOC6H4 Ph H 95 4:1
7 1-propenyl Ph H 75 6:1
8 1-propyl Ph H 96 5:1
9 Me Ph H 78 3:1
10 H PH H 80 -
R1 H
O+ N S
R2
O O
R3
N N
N
MesCl
(0.5 5 mol %)
DBU (20 mol %)
0.2 M CH2Cl2, 25 C
N S
R2
O O
R3
O
R1
Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 17266-17267.
NHC-Mediated γ-Lactam Formation
51
R1 H
O+ N S
R2
O O
R3
N N
N
MesCl
(0.5 5 mol %)
DBU (20 mol %)
0.2 M CH2Cl2, 25 C
N S
R2
O O
R3
O
R1
Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 17266-17267.
Me
NS
O O
Ph
O
Sodium Naphthalide
DME, 23 C90 seconds
(61%) Me
HN
Ph
O
NHC-Mediated γ-Lactam Formation
52Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 17266-17267.
S
N
Me
OO
Ph
O
H+
N N
N
Mes
OH
Ph
N N
N
Mes
H
Cl
PhH
N
NNMes
Cl
OH
S
N
Me
OO
PhN
NNMes
Cl
OH
H
OPh
NN
N
MesClMe
NHS
O O
OH
Ph
N N
N
Mes
OH
Ph
N N
N
Mes
H
Cl
Ene-like homoenolate
α’-Hydroxyenones as Suitable Substrates
53Chiang, P.-C.; Rommel, M.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 8714-8718.
Ar
O
H
N N
N
Mes
Ar
O
N N
N
Mes
H
Ar
O
Ar
O
NN
NMes
OH
Me
Me
Ar
OH
N N
N
Mes
Breslow intermediate/homoenolate equivalent
retro-benzoin
Me
O
Me
tautomerization
OH
Me Me
One-step synthesis
Chemically stable
Broad substrate scope
No competing dimerization
Ar
O
H+
Me
O
OH
Me Me
Multistep synthesis
Unstable to storage
Competing dimerization
Conclusion
54Chiang, P.-C.; Rommel, M.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 8714-8718.
R1
O
H
Ph
N
Ph
SO2ArN
O
SO2ArPh
R1
Ph
NN
N
Mes
O
Cl
MeO2C
O
Ar
O
ArR1
O
O
H Ar
N NMes Mes
Cl
NN
NMes
N S
R2
O O
Cl
NS
R2
O OO
R1
Ar
R1
MeO2C
d1d3
