Asymmetric Lewis Base Strategies for Heterocycle Synthesis · 2020. 6. 24. · Asymmetric Lewis...
Transcript of Asymmetric Lewis Base Strategies for Heterocycle Synthesis · 2020. 6. 24. · Asymmetric Lewis...
Asymmetric Lewis Base Strategiesfor Heterocycle Synthesis
Dr Andrew Smith
EaStCHEM, School of Chemistry, University of St Andrews
1st Scottish-Japanese Symposium of Organic Chemistry, University of Glasgow
Friday 9th September 2011
Thursday, 8 September 2011
N NN
PhTBSO Ph
N
N
S
N NPhPh
N NN
Ph
N
N
SPh
Ph
ADS group research
Organocatalysis
Organocatalysis
Probe new reactivity
N-heterocycliccarbenes
Isothioureas
Catalytic enolate chemistry
Catalystdevelopment
Thursday, 8 September 2011
R
ArO
NN
N PhPh Ph
TBSO
azolium enolate
O
N
N
SPh
ammonium enolate
Ar
ADS group research
Organocatalysis
Catalystdevelopment
Organocatalysis
Probe new reactivity
N-heterocycliccarbenes
Isothioureas
Catalytic enolate chemistry
N NN
PhTBSO Ph
N
N
S
N NPhPh
N NN
Ph
N
N
SPh
Ph
Thursday, 8 September 2011
O
ClR1
O
NR3Y/H
X
O
RO Cl
Ar R1
O
O O
FeN
NRO H
NN
R RR R
R
ormono-substitutedin-situ generated "ketene enolates"
di-substituted enolatesfrom isolable ketenes
For reviews 1. "ketene enolate" chemistry
Lectka et al. Tetrahedron, 2009, 65, 6771
2. For ammonium enolates Gaunt and Johansson,
Chem. Rev., 2007, 107, 5596
up to 94% eeFu et al.
Angew. Chem. Int. Ed.,2007, 46, 977
ON
O
ArR1
Ar
ammonium enolateR1
O
RO F
R1
OAr
R1
up to 96% eeFu et al.
Angew. Chem. Int. Ed.,2009, 48, 2391
NN
O
ArR1
CO2Me
CO2Me
up to 93% eeFu et al.
Angew. Chem. Int. Ed.,2008, 47, 7048
up to 99% eeLectka et al.
J. Am. Chem. Soc.,2008, 130, 17260
J. Org. Chem. 2010,75, 969
up to 99% eeLectka et al.
J. Am. Chem. Soc.,2006, 128, 1810
OO
Cl3C
99% eeWynberg et al.
J. Am. Chem. Soc.,1982, 104, 166
Lewis base catalysis: ammonium enolate chemistry
Thursday, 8 September 2011
N NN
PhTBSO PhN N
PhPh
N NN
Ph
Ph
R
ArO
NN
N PhPh Ph
TBSO
azolium enolate
ADS group research
Organocatalysis
Organocatalysis
Probe new reactivity
N-heterocycliccarbenes
Isothioureas
Catalytic enolate chemistry
Catalystdevelopment
Thursday, 8 September 2011
Typical organocatalytic NHC reactivity
• Generation of enolate equivalents
Organocatalytic NHC reactivity
Chem. Commun, 2011, 47, 373-375
H
O
N NR R
OH
N
NR
R
azolium enolate
Bode, Rovis (halide)Scheidt (aryloxy)
Cl
R1Cl
R1
O
N
NR
R
OAr
R1base - HCl
O
N
NR
RR1
Ar
azolium enolate
ADS / Ye
H
OO
R1
unstable
Ar O
OH
N
NR
R
O
R1
OAr
benchstable
O
N
NR
R
base
azolium enolate
ADS
asymmetriccatalysis
R1 R1
Thursday, 8 September 2011
Typical organocatalytic NHC reactivity
• Generation of enolate equivalents
Organocatalytic NHC reactivity
Chem. Commun, 2011, 47, 373-375
H
O
N NR R
OH
N
NR
R
azolium enolate
Bode, Rovis (halide)Scheidt (aryloxy)
Cl
R1Cl
R1
O
N
NR
R
OAr
R1base - HCl
O
N
NR
RR1
Ar
azolium enolate
ADS / Ye
H
OO
R1
unstable
Ar O
OH
N
NR
R
O
R1
OAr
benchstable
O
N
NR
R
base
azolium enolate
ADS
asymmetriccatalysis
R1 R1
Thursday, 8 September 2011
Typical organocatalytic NHC reactivity
• Generation of enolate equivalents
Organocatalytic NHC reactivity
Chem. Commun, 2011, 47, 373-375
H
O
N NR R
OH
N
NR
R
azolium enolate
Bode, Rovis (halide)Scheidt (aryloxy)
Cl
R1Cl
R1
O
N
NR
R
OAr
R1base - HCl
O
N
NR
RR1
Ar
azolium enolate
ADS / Ye
H
OO
R1
unstable
Ar O
OH
N
NR
R
O
R1
OAr
benchstable
O
N
NR
R
base
azolium enolate
ADS
asymmetriccatalysis
R1 R1
Thursday, 8 September 2011
Typical organocatalytic NHC reactivity
• Generation of enolate equivalents
Organocatalytic NHC reactivity
Chem. Commun, 2011, 47, 373-375
H
O
N NR R
OH
N
NR
R
azolium enolate
Bode, Rovis (halide)Scheidt (aryloxy)
Cl
R1Cl
R1
O
N
NR
R
OAr
R1base - HCl
O
N
NR
RR1
Ar
azolium enolate
ADS / Ye
H
OO
R1
unstable
Ar O
OH
N
NR
R
O
R1
OAr
benchstable
O
N
NR
R
base
azolium enolate
ADS
asymmetriccatalysis
R1 R1
Thursday, 8 September 2011
Applications of NHC-generated enolates from ketenes
ArOH
OAr
OAr
RH
OC6Cl5
OAr
ClR
OCl
ClCl
Cl
ClCl
up to 60% eeEur. J. Org. Chem.,
2010, 5863
up to 84% eeAdv. Synth. Cat., 2009, 351, 3001
NN
O
ArR CO2Et
CO2Et
up to 91% eeYe et al, J. Org. Chem.,
2009, 74, 7585
NN
OO
COPh
Ph
RAr
up to 97% eeYe et al, Angew. Chem. Int. Ed,
2009, 48, 192
NNR'
R'
O
N
NR'
R'R
Ar
azolium enolate
NTs
Ar H
NTsO
Ph ArPh H
up to 90% eeOrg. Biomol. Chem.,
2008, 6, 1108
ONTsAr
O
NTsO
ArR
ArH
up to 95% eeYe et al, Angew. Chem. Int. Ed,
2010, 49, 8412
R' = CO2Et
R' = COPh
Generally - 2-aryl substitutedarylalkyl ketenes show
moderate reactivity
Thursday, 8 September 2011
ADS group research
Organocatalysis
Organocatalysis
Probe new reactivity
N-heterocycliccarbenes
Isothioureas
New Asymmetric Transformations
Catalystdevelopment
Catalytic generation of ammonium enolates from acids
One-pot domino Lewisbase catalysis
LB*
RO
OHR
O
N N
S
Ph
RO
N N
S
PhE
RO
EX
enolate
acyl donor
E-X
X
Thursday, 8 September 2011
O
OH
Me
NMe
BrOTf
+
Mukaiyamareagent (1.5 eq)
N
N
OAc
HOMe
Lewis base
aldoland
lactonisation
R = H or Me
CO2H
O
LB
O
R
R
O
Lewis base (LB)derived enolate
i-Pr2NEt,CH2Cl2, rt
N
N
PPY
O
OH
H
aldoland
lactonisation
48% yield>19:1 dr82% yield
>19:1 dr92% ee
Catalytic generation of enolates from acids: literature - Romo
J. Am. Chem. Soc., 2001,123, 7945.Org. Lett., 2006, 8, 4363.J. Am. Chem. Soc., 2008,130, 10478.Angew. Chem. Int. Ed., 2010, 49, 9479.
Thursday, 8 September 2011
NEt
BrOTf
CO2H
Ph
O
O
Ph
OH
Hactivating agent (1.2 eq)
isothiourea
i-Pr2NEt (3.5 eq),CH2Cl2, rt
activating agent
N
N
S
N
N
SPh
isothiourea
1.0
0.2
yield
87%, dr 99:1
53%, dr 99:1
eq
0.5
0.2
73%, dr 99:1ee 97%
43%, dr 99:1ee 97%.HCl
O
Cl
N
N
SPh
.HCl
N
N
SPh
0.2
0.2
61%, dr 99:1ee 97%
72%, dr 80:20ee 70% (ent)
Catalytic generation of enolates from acids: Michael-lactonisation
J. Am. Chem. Soc., 2011,133, 2714
Thursday, 8 September 2011
NEt
BrOTf
CO2H
Ph
O
O
Ph
OH
Hactivating agent (1.2 eq)
isothiourea
i-Pr2NEt (3.5 eq),CH2Cl2, rt
activating agent
N
N
S
N
N
SPh
isothiourea
1.0
0.2
yield
87%, dr 99:1
53%, dr 99:1
eq
0.5
0.2
73%, dr 99:1ee 97%
43%, dr 99:1ee 97%.HCl
O
Cl
N
N
SPh
.HCl
N
N
SPh
0.2
0.2
61%, dr 99:1ee 97%
72%, dr 80:20ee 70% (ent)
Catalytic generation of enolates from acids: Michael-lactonisation
J. Am. Chem. Soc., 2011,133, 2714
Thursday, 8 September 2011
NEt
BrOTf
CO2H
Ph
O
O
Ph
OH
Hactivating agent (1.2 eq)
isothiourea
i-Pr2NEt (3.5 eq),CH2Cl2, rt
activating agent
N
N
S
N
N
SPh
isothiourea
1.0
0.2
yield
87%, dr 99:1
53%, dr 99:1
eq
0.5
0.2
73%, dr 99:1ee 97%
43%, dr 99:1ee 97%.HCl
O
Cl
N
N
SPh
.HCl
N
N
SPh
0.2
0.2
61%, dr 99:1ee 97%
72%, dr 80:20ee 70% (ent)
Catalytic generation of enolates from acids: Michael-lactonisation
J. Am. Chem. Soc., 2011,133, 2714
Thursday, 8 September 2011
NEt
BrOTf
CO2H
Ph
O
O
Ph
OH
Hactivating agent (1.2 eq)
isothiourea
i-Pr2NEt (3.5 eq),CH2Cl2, rt
activating agent
N
N
S
N
N
SPh
isothiourea
1.0
0.2
yield
87%, dr 99:1
53%, dr 99:1
eq
0.5
0.2
73%, dr 99:1ee 97%
43%, dr 99:1ee 97%.HCl
O
Cl
N
N
SPh
.HCl
N
N
SPh
0.2
0.2
61%, dr 99:1ee 97%
72%, dr 80:20ee 70% (ent)
Catalytic generation of enolates from acids: Michael-lactonisation
J. Am. Chem. Soc., 2011,133, 2714
Thursday, 8 September 2011
(i) pivaloyl chloride, NEt3
Michael addition
lactonisation mixed anhydride
ammonium enolate
N
N
SPh
O
Ph
OH
H
CO2COt-Bu
Ph
O
O
N
COPhHO Ph
H
O
NN
acyl ammonium
O
N N
COPh acyl ammonium
deprotonation
CO2H
Ph
O
N
S
Ph
S
Ph
S
Ph
O
N N
Ph
S
HH
O
R
Catalytic generation of enolates from acids: mechanism?
J. Am. Chem. Soc., 2011,133, 2714
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
(CH3)3CCOCl (1.2 eq)tetramisole.HCl
(20 mol%)
i-Pr2NEt (3.5eq),CH2Cl2, rt
1 hourCO2H
R2
O
O
R2
OH
H
N
N
SPh
.HClR1 R1
61%, dr 99:1ee 97%
O
Ph
OH
H
81%, dr 99:1ee 94%
O
Me
OH
H
94%, dr 99:1
ee 91%
O
Ph
OH
HO
Ph
OH
H
99%, dr 99:1
ee 99%
MeO
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
(CH3)3CCOCl (1.2 eq)tetramisole.HCl
(5-20 mol%)
O CO2H
R
O
O
O
R
OH
H
i-Pr2NEt (3.5 eq),CH2Cl2, rt
15 minutes
98%, dr 99:1
ee 94%87%, dr 96:4
ee 95%Ar = 4-MeC6H495%, dr 96:4
ee 94%
Ar = 4-ClC6H463%, dr 97:3
ee 84%
OCO2MeO
R
H
HMeOH
OCO2MeO
Ph
H
H
OCO2MeO
Me
H
H
OCO2MeO
Ar
H
H
OCO2MeO
Ar
H
H
1 hourR' R' R'
73%, dr 99:1
ee 92%62%, dr 99:1
ee 94%79%, dr 96:4
ee 96%75%, dr 98:2
ee 95%
OCO2MeO
Me
H
H
OCO2MeO
Me
H
H
OCO2MeO
Me
H
H
OCO2MeO
Me
H
HO2N Me
MeMe
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
(CH3)3CCOCl (1.2 eq)tetramisole.HCl
(5-20 mol%)
O CO2H
R
O
O
O
R
OH
H
i-Pr2NEt (3.5 eq),CH2Cl2, rt
15 minutes
98%, dr 99:1
ee 94%87%, dr 96:4
ee 95%Ar = 4-MeC6H495%, dr 96:4
ee 94%
Ar = 4-ClC6H463%, dr 97:3
ee 84%
OCO2MeO
R
H
HMeOH
OCO2MeO
Ph
H
H
OCO2MeO
Me
H
H
OCO2MeO
Ar
H
H
OCO2MeO
Ar
H
H
1 hourR' R' R'
73%, dr 99:1
ee 92%62%, dr 99:1
ee 94%79%, dr 96:4
ee 96%75%, dr 98:2
ee 95%
OCO2MeO
Me
H
H
OCO2MeO
Me
H
H
OCO2MeO
Me
H
H
OCO2MeO
Me
H
HO2N Me
MeMe
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
(CH3)3CCOCl (1.2 eq)tetramisole.HCl
(5-20 mol%)
O CO2H
R
O
O
O
R
OH
H
i-Pr2NEt (3.5 eq),CH2Cl2, rt
15 minutes
98%, dr 99:1
ee 94%87%, dr 96:4
ee 95%Ar = 4-MeC6H495%, dr 96:4
ee 94%
Ar = 4-ClC6H463%, dr 97:3
ee 84%
OCO2MeO
R
H
HMeOH
OCO2MeO
Ph
H
H
OCO2MeO
Me
H
H
OCO2MeO
Ar
H
H
OCO2MeO
Ar
H
H
1 hourR' R' R'
73%, dr 99:1
ee 92%62%, dr 99:1
ee 94%79%, dr 96:4
ee 96%75%, dr 98:2
ee 95%
OCO2MeO
Me
H
H
OCO2MeO
Me
H
H
OCO2MeO
Me
H
H
OCO2MeO
Me
H
HO2N Me
MeMe
Thursday, 8 September 2011
Catalytic generation of enolates from acids: intermolecular reaction
J. Am. Chem. Soc., 2011,133, 2714
Ph OH
O isothioureapivaloyl chloride (1.2 eq)
i-Pr2NEt (3.5 eq),CH2Cl2
Ph CO2Me
OOPh
Ph
O
CO2Me
N
N
SPh
.HClN
N
SPh
20 mol%, rt 61%, dr 95:5ee 82% (ent)
20 mol%, rt 68%, dr 95:5
ee 91%
5 mol%, -30˚C
67%, dr 95:5ee 96%
+
Thursday, 8 September 2011
Catalytic generation of enolates from acids: intermolecular reaction
J. Am. Chem. Soc., 2011,133, 2714
Ph OH
O isothioureapivaloyl chloride (1.2 eq)
i-Pr2NEt (3.5 eq),CH2Cl2
Ph CO2Me
OOPh
Ph
O
CO2Me
N
N
SPh
.HClN
N
SPh
20 mol%, rt 61%, dr 95:5ee 82% (ent)
20 mol%, rt 68%, dr 95:5
ee 91%
5 mol%, -30˚C
67%, dr 95:5ee 96%
+
Thursday, 8 September 2011
Catalytic generation of enolates from acids: intermolecular reaction
J. Am. Chem. Soc., 2011,133, 2714
Ph OH
O isothioureapivaloyl chloride (1.2 eq)
i-Pr2NEt (3.5 eq),CH2Cl2
Ph CO2Me
OOPh
Ph
O
CO2Me
N
N
SPh
.HClN
N
SPh
20 mol%, rt 61%, dr 95:5ee 82% (ent)
20 mol%, rt 68%, dr 95:5
ee 91%
5 mol%, -30˚C
67%, dr 95:5ee 96%
+
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
N
N
SPh
Ar OH
O(CH3)3CCOCl (1.2 eq)isothiourea (10 mol%)
i-Pr2NEt (3.5 eq),CH2Cl2, -30˚CPh CO2Me
OOAr
Ph
O
CO2Me
+
O
Ph
O
CO2Me67%, dr 95:5
ee 97%81%, dr 95:5
ee 99%67%, dr 95:5
ee 97%66%, dr 95:5
ee 87%
O
Ph
O
CO2Me
Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me62%, dr 90:10
ee 93%76%, dr 95:5
ee 98%72%, dr 96:4
ee 86%73%, dr 93:7
ee 97%
O
Ph
O
CO2Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me
Br MeO
Me
Me
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
N
N
SPh
Ar OH
O(CH3)3CCOCl (1.2 eq)isothiourea (10 mol%)
i-Pr2NEt (3.5 eq),CH2Cl2, -30˚CPh CO2Me
OOAr
Ph
O
CO2Me
+
O
Ph
O
CO2Me67%, dr 95:5
ee 97%81%, dr 95:5
ee 99%67%, dr 95:5
ee 97%66%, dr 95:5
ee 87%
O
Ph
O
CO2Me
Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me62%, dr 90:10
ee 93%76%, dr 95:5
ee 98%72%, dr 96:4
ee 86%73%, dr 93:7
ee 97%
O
Ph
O
CO2Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me
Br MeO
Me
Me
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
N
N
SPh
Ar OH
O(CH3)3CCOCl (1.2 eq)isothiourea (10 mol%)
i-Pr2NEt (3.5 eq),CH2Cl2, -30˚CPh CO2Me
OOAr
Ph
O
CO2Me
+
O
Ph
O
CO2Me67%, dr 95:5
ee 97%81%, dr 95:5
ee 99%67%, dr 95:5
ee 97%66%, dr 95:5
ee 87%
O
Ph
O
CO2Me
Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me62%, dr 90:10
ee 93%76%, dr 95:5
ee 98%72%, dr 96:4
ee 86%73%, dr 93:7
ee 97%
O
Ph
O
CO2Me
O
Ph
O
CO2Me
O
Ph
O
CO2Me
Br MeO
Me
Me
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
N
N
SPh
Ph OH
O(CH3)3CCOCl (1.2 eq)isothiourea (10 mol%)
i-Pr2NEt (3.5 eq),CH2Cl2, -30˚CR1 CO2R2
OOPh
R1
O
CO2R2
+
OPh
Ph
O
CO2Me
67%, dr 95:5
ee 97%67%, dr 87:13
ee 99%87%, dr 94:6
ee 97%82%, dr 95:5
ee 99%
OPh
Ph
O
CO2i-Pr
OPhO
CO2Me
OPhO
CO2Me
OPhO
CO2Me
71%, dr 96:4
ee 98%66%, dr 92:8
ee 99%82%, dr 95:5
ee 99%80%, dr 88:12
ee 96%
OPhO
CO2Me
OPhO
CO2Me
OPh
Me
O
CO2Me
Br Me
O
N
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
N
N
SPh
Ph OH
O(CH3)3CCOCl (1.2 eq)isothiourea (10 mol%)
i-Pr2NEt (3.5 eq),CH2Cl2, -30˚CR1 CO2R2
OOPh
R1
O
CO2R2
+
OPh
Ph
O
CO2Me
67%, dr 95:5
ee 97%67%, dr 87:13
ee 99%87%, dr 94:6
ee 97%82%, dr 95:5
ee 99%
OPh
Ph
O
CO2i-Pr
OPhO
CO2Me
OPhO
CO2Me
OPhO
CO2Me
71%, dr 96:4
ee 98%66%, dr 92:8
ee 99%82%, dr 95:5
ee 99%80%, dr 88:12
ee 96%
OPhO
CO2Me
OPhO
CO2Me
OPh
Me
O
CO2Me
Br Me
O
N
Thursday, 8 September 2011
Catalytic generation of enolates from acids: Generality
J. Am. Chem. Soc., 2011,133, 2714
N
N
SPh
Ph OH
O(CH3)3CCOCl (1.2 eq)isothiourea (10 mol%)
i-Pr2NEt (3.5 eq),CH2Cl2, -30˚CR1 CO2R2
OOPh
R1
O
CO2R2
+
OPh
Ph
O
CO2Me
67%, dr 95:5
ee 97%67%, dr 87:13
ee 99%87%, dr 94:6
ee 97%82%, dr 95:5
ee 99%
OPh
Ph
O
CO2i-Pr
OPhO
CO2Me
OPhO
CO2Me
OPhO
CO2Me
71%, dr 96:4
ee 98%66%, dr 92:8
ee 99%82%, dr 95:5
ee 99%80%, dr 88:12
ee 96%
OPhO
CO2Me
OPhO
CO2Me
OPh
Me
O
CO2Me
Br Me
O
N
Thursday, 8 September 2011
ADS group research
Catalytic generation of ammonium enolates from acids
Intramolecularand
Intermolecular
One-pot domino Lewisbase catalysis
LB*
Catalystvariation
Electrophilevariation
Product derivatisationand mechanistic
studies
RO
OHR
O
N N
S
Ph
RO
N N
S
PhE
RO
EX
enolate
acyl donor
E-X
X
"activation"
catalyst
Thursday, 8 September 2011
Ar
R O
NH
O
Ar R
then NH4Cl (aq)
N O
NOH
Boc
O
NOH
Boc
+
ADS group research
Organocatalysis
Organocatalysis
Probe new reactivity
N-heterocycliccarbenes
Isothioureas
New asymmetric transformations
Catalystdevelopment
Thursday, 8 September 2011
Ph
N OPh
H Ph Et
O
NH
O
Ph Et
83% yield
THF, 30 minsthen
0.1M HCl (aq)
Serendipity
Ph
N OPh
H Ph Et
O N NN
Ph ON OPh
Ph Et Ph[3+2]
Thursday, 8 September 2011
Ph
N OPh
H Ph Et
O
NH
O
Ph Et
83% yield
THF, 30 minsthen
0.1M HCl (aq)
Serendipity
• Anticipated [3+2]-cycloaddition gave consistent by-product
•Reaction occurs in the absence of NHC “catalyst”
Ph
N OPh
H Ph Et
O N NN
Ph ON OPh
Ph Et Ph[3+2]
Thursday, 8 September 2011
NO
OPh
Ph [3,3]
sigmatropicrearrangement
N
OPh
O
HPh
Ph
Ph ON ON
O
Ph Ph
N
OHPh
O
Ph Ph
Ph O
PhO
O
Ph
Ph"2:1 adduct""1:1 adduct"
HH
1 eq 1 eq
Literature precedent
Staudinger and Miescher, Helv. Chim Acta., 1919, 2, 554Hafiz and Taylor., J. Chem. Soc., Perkin Trans. 1, 1980, 8, 1700
No examples of asymmetric reactions
Thursday, 8 September 2011
Ar
R ON O
NH
O
Ar R
+
asymmetric induction?
then NH4Cl (aq)R1
R2R2
O
HR1
chiral auxiliary
cleaved and regenerated on
work-up
N O
NO
Boc
H
O
NO
Boc
H
(R,Z)
NH
OH
MgSO4
CH2Cl287%
H
Asymmetric Hetero-Claisen Reactions
Org. Lett., 2009, 11, 3858
Thursday, 8 September 2011
Ar
R ON O
NH
O
Ar R
+
asymmetric induction?
then NH4Cl (aq)R1
R2R2
O
HR1
chiral auxiliary
cleaved and regenerated on
work-up
N O
NO
Boc
H
O
NO
Boc
H
(R,Z)
NH
OH
MgSO4
CH2Cl287%
H
Asymmetric Hetero-Claisen Reactions
Org. Lett., 2009, 11, 3858
Thursday, 8 September 2011
Ar
R ON O
NH
O
Ar R
+
asymmetric induction?
then NH4Cl (aq)R1
R2R2
O
HR1
chiral auxiliary
cleaved and regenerated on
work-up
N O
NO
Boc
H
O
NO
Boc
H
(R,Z)
NH
OH
MgSO4
CH2Cl287%
H
Asymmetric Hetero-Claisen Reactions
Org. Lett., 2009, 11, 3858
Thursday, 8 September 2011
Asymmetric Hetero-Claisen Reactions: Generality
Org. Lett., 2009, 11, 3858
R2
O
NH
O
R2R1
R1
NH
O
Me
NH
ONH
O
NH
O
Me
NH
O
F
NH
O
Me
85%, 87% ee 80%, 81% ee 82%, 78% ee
78%, 80% ee 91%, 86% ee 84%, 87% ee
NH
O
Me
91%, 90% ee
MeO
N
HN
O
Boc
O
THF, -78˚C 3 hours thenNH4Cl (aq)
HN
O
Boc
O
+
78-91% yield
Me
NH
O
88%, 90% ee
MeO
Thursday, 8 September 2011
Asymmetric Hetero-Claisen Reactions: Generality
Org. Lett., 2009, 11, 3858
R2
O
NH
O
R2R1
R1
NH
O
Me
NH
ONH
O
NH
O
Me
NH
O
F
NH
O
Me
85%, 87% ee 80%, 81% ee 82%, 78% ee
78%, 80% ee 91%, 86% ee 84%, 87% ee
NH
O
Me
91%, 90% ee
MeO
N
HN
O
Boc
O
THF, -78˚C 3 hours thenNH4Cl (aq)
HN
O
Boc
O
+
78-91% yield
Me
NH
O
88%, 90% ee
MeO
Thursday, 8 September 2011
Asymmetric Hetero-Claisen Reactions: Generality
Org. Lett., 2009, 11, 3858
R2
O
NH
O
R2R1
R1
NH
O
Me
NH
ONH
O
NH
O
Me
NH
O
F
NH
O
Me
85%, 87% ee 80%, 81% ee 82%, 78% ee
78%, 80% ee 91%, 86% ee 84%, 87% ee
NH
O
Me
91%, 90% ee
MeO
N
HN
O
Boc
O
THF, -78˚C 3 hours thenNH4Cl (aq)
HN
O
Boc
O
+
78-91% yield
Me
NH
O
88%, 90% ee
MeO
Thursday, 8 September 2011
Ar
R O
N O
NO
R
NH
O
RAr
N O
NO
R
OAr
R
[3,3]-sigmatropic
rearrangement
nucleophilicaddition
hydrolysisand
cyclizationN
O
HCO2
Ar R
N
NO
R
CO2H
Ar R
imino acidN
O
R
H
O+
R
N
HH
H
H
Asymmetric Hetero-Claisen Reactions: mechanism?
How doeschiral auxiliary
imposeenantioselectivity?
Thursday, 8 September 2011
StA to SF
Thursday, 8 September 2011
StA to SF
Thursday, 8 September 2011
StA to SF
Thursday, 8 September 2011
StA to SF
Thursday, 8 September 2011
StA to SF
Thursday, 8 September 2011
StA to SF
Thursday, 8 September 2011
Reaction modelling
• March
unpublished results
Thursday, 8 September 2011
Reaction modelling
Your project is an excellent one for us to study computationally, and we will be happy to do so! .....!We look forward to collaborating with you and should have the answers to your questions, soon! !Ken Houk
• March
unpublished results
Thursday, 8 September 2011
Reaction modelling
Your project is an excellent one for us to study computationally, and we will be happy to do so! .....!We look forward to collaborating with you and should have the answers to your questions, soon! !Ken Houk
• March
• 6 months later....
unpublished results
Thursday, 8 September 2011
Your [3,3]-sigmatropic rearrangement is rather more challenging than we expected.
Reaction modelling
Your project is an excellent one for us to study computationally, and we will be happy to do so! .....!We look forward to collaborating with you and should have the answers to your questions, soon! !Ken Houk
• March
• 6 months later....
unpublished results
Thursday, 8 September 2011
Your [3,3]-sigmatropic rearrangement is rather more challenging than we expected.
To put a long story short, we could locate a TS for the rearranged product, but its geometry does not resemble a [3,3]-sigmatropic rearrangement transition structure at all - that's something we don't understand, as yet. Colin Lam
Reaction modelling
Your project is an excellent one for us to study computationally, and we will be happy to do so! .....!We look forward to collaborating with you and should have the answers to your questions, soon! !Ken Houk
• March
• 6 months later....
unpublished results
Thursday, 8 September 2011
......we could not find the intermediate that results from the nucleophilic addition of the nitrone onto the ketene......Colin Lam
Reaction modelling
unpublished results
Thursday, 8 September 2011
......we could not find the intermediate that results from the nucleophilic addition of the nitrone onto the ketene......Colin Lam
Ar
R O
N
R
O N
R
O
OAr
Rnucleophilicaddition
H H
Reaction modelling
unpublished results
Thursday, 8 September 2011
In fact, we located two 3+2 TSs (one of them has the nitrone adding across the C=C bond of ketene, the other across the C=O bond of ketene), which have much lower enthalpies of activationColin Lam
Reaction modelling
Angew. Chem., accepted
Thursday, 8 September 2011
In fact, we located two 3+2 TSs (one of them has the nitrone adding across the C=C bond of ketene, the other across the C=O bond of ketene), which have much lower enthalpies of activationColin Lam
Reaction modelling
Angew. Chem., accepted
N
RH
O
Et Ph
O ON O
Et PhR
[3+2]C=C
Thursday, 8 September 2011
In fact, we located two 3+2 TSs (one of them has the nitrone adding across the C=C bond of ketene, the other across the C=O bond of ketene), which have much lower enthalpies of activationColin Lam
Reaction modelling
Angew. Chem., accepted
N
RH
O
O
[3+2]C=O
Et Ph
O
ON
R
Et
Ph
N
RH
O
Et Ph
O ON O
Et PhR
[3+2]C=C
Thursday, 8 September 2011
In fact, we located two 3+2 TSs (one of them has the nitrone adding across the C=C bond of ketene, the other across the C=O bond of ketene), which have much lower enthalpies of activationColin Lam
N
R
O
OPh
Et [3,3]-sigmatropicrearrangement
H
ringopening
Reaction modelling
Angew. Chem., accepted
N
RH
O
O
[3+2]C=O
Et Ph
O
ON
R
Et
Ph
N
RH
O
Et Ph
O ON O
Et PhR
[3+2]C=C
Thursday, 8 September 2011
2 weeks later: I have some exciting results about the pathway of the hetero-Claisen reaction!
We now find a low-energy TS involving N-O bond cleavage.! This results in a seven-membered ring that is a formal [3,3]-sigmatropic transformation.Colin Lam
Reaction modelling: a pericyclic cascade
Angew. Chem., accepted
Thursday, 8 September 2011
2 weeks later: I have some exciting results about the pathway of the hetero-Claisen reaction!
We now find a low-energy TS involving N-O bond cleavage.! This results in a seven-membered ring that is a formal [3,3]-sigmatropic transformation.Colin Lam
Reaction modelling: a pericyclic cascade
Angew. Chem., accepted
NH
O
EtPh
hydrolysisand
cyclization
RH
O+
tautomerisationand
ring-opening
N
R
CO2H
Ph Et
H
N
RH
O
O
[3+2]C=O
Et Ph
OON
R
EtPh
[3,3]
NO
R
OPh EtH
Thursday, 8 September 2011
2 weeks later: I have some exciting results about the pathway of the hetero-Claisen reaction!
We now find a low-energy TS involving N-O bond cleavage.! This results in a seven-membered ring that is a formal [3,3]-sigmatropic transformation.Colin Lam
Reaction modelling: a pericyclic cascade
Angew. Chem., accepted
asymmetric step
NH
O
EtPh
hydrolysisand
cyclization
RH
O+
tautomerisationand
ring-opening
N
R
CO2H
Ph Et
H
N
RH
O
O
[3+2]C=O
Et Ph
OON
R
EtPh
[3,3]
NO
R
OPh EtH
Thursday, 8 September 2011
Reaction modelling: Asymmetric oxindole synthesis
Angew. Chem., accepted
Stereoselectivity a consequence of:• allylic strain controls facial selectivity of nitrone• addition of nitrone anti to Ph substituent of ketene
NOPh H
N OH
PG
O
Me
Ph
NOPh H
N OH
PG
O
Ph
Me
Ph Me
O O
N RH
Si face
Re faceMe Ph
O O
N RH
*
*
NO
R
OMe PhH
NH
O
Me Ph
NO
R
OPh MeH
NH
O
Ph Me
observed
C-Nanti/Rinside
*
*
anti to Ph
favoured
Thursday, 8 September 2011
N NN
PhTBSO Ph
N
N
SPhPh
R
ArO
NN
N PhPh Ph
TBSO
azolium enolate
O
N
N
SPh
ammonium enolate
Ar
Conclusions
• NHCs and isothioureas are efficient Lewis base catalysts
• Future: further catalytic asymmetric applications of azolium and ammonium enolates
• One-pot synthesis of oxindoles from acids and the development of a catalytic variant?
Thursday, 8 September 2011
Acknowledgements
The Carnegie TrustFor the Universities of Scotland
Dorine Belmessieri
Craig Campbell
Phil Woods
Caroline Joannesse
James Douglas
Kenneth Ling
Edward Richmond
Chris Collett
Eoin Gould
Siobhan Smith
Prof. Alex Slawin (X-ray)Dr David Fox (Warwick)Dr. AnnMarie OʼDonoghue (Durham)Prof. Douglas Philp
Stuart Leckie
Pei-Pei Ye
Carmen Simal
Louis Morrill
Craig Johnston
Thursday, 8 September 2011