Post on 24-Aug-2020
Organocatalysis Enabled by N-Heterocyclic Carbenes
Jiaming Li2018/04/27
Acyl AnionsY
X N
Homoenolates
AcylazoliumAzolium enolate Base Catalysis
Stability of N-heterocyclic Carbenes
Bertrand, Chem. Rev. 2000, 100, 39
a1
b22s
2px,y,z
C
N
a1
b2
σ
pπ
a1
b2
2s
2px,y,z
C
N
a1
b2
σ
pπ
σ-electron-withdrawing substitutents σ-electron-donating substitutents
• σ-electron withdrawing substitutents favor the singlet state over the triplet state• σ-electron withdrawing substitutents inductively stablize the σ non-bonding orbital by increasing its s character and leaving thepπ orbital unchanged• σ-electron donating substitutents induce a smaller σ-pπ gap, favoring a triplet state
N
N σ-electronwithdrawal
π-electrondonation..
..
..
Stability of N-heterocyclic Carbenes
Bertrand, Chem. Rev. 2000, 100, 39
σ
pπ
b1
a2
σ
pπ
π-electron donation
• The energy of pπ orbital is increased by the interaction with the symmetric combination of the substitutent lone pairs.• Combined effect is to increase the σ−pπ gap and stablize the singlet-state carbene over the more reactive triplet-state carbene.
N
N σ-electronwithdrawal
π-electrondonation..
....
2N pz
C
Overview
Acyl Anions
R
OH
N
NR
R
O
R
YX N
OH
N
NR
R
O
Homoenolates
RR
• Benzoin condensation• Stetter reaction• Hydroacylation
• Annulation• Cyclopentene synthesis
O
N
NR
R
AcylazoliumAzolium enolate
• Claisen rearrangement• Cycloaddition
Base Catalysis• Transesterification• Michael addition
R2
O
N
NR1
RN
NR
R
HR
Benzoin condensation
Ph
O
H
Ph
O
H
Ph
OPh
OH
Ph
O
H
NaCN
• First reported benzoin condensation (Wohler, Liebig, 1832)
Ph
OPh
OH
CN–
Ph
HO H
N
OH
PhN
•
OH
H2O
Ph
HO CNHOPh
OH
• Ugai discovered thiazolium salts could catalyze benzoin condensation (1943)
Ph H
O
S N
HOMe
N
N Me
NH2Cl
NaOH, MeOHPh
PhO
OH
• Co-enzyme thiamine diphosphate is responsible for the generation of acyl anion
S N
OMe
N
N Me
NH2
PO
O
PHO
O
OO
thiamine diphosphate (TDP)RO
O
OR
O+ CO2
• Pyruvate decarboxylase• Pyruvate oxidase• Pyruvate dehydrogenase• Transketolase
Ugai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63, 296.
Benzoin condensation
Proposed Mechanism by Breslow
Breslow, R. J. Am. Chem. Soc.. 1958, 80, 3719
N
S
R1R2
R3 H
– H+N
S
R1R2
R3
N
S
R1R2
R3
N
S
R1R2
R3
N
S
R1R2
R3
Ph
O
H
Ph
O
N
S
R1R2
R3
Ph
OH
Breslowintermediate
Ph
O
H
N
S
R1R2
R3
OH
PhO Ph
Ph
OPh
OH
Enantioselective Benzoin Condensation
• First asymmetric benzoin condensation catalyzed by chiral thiazolium salts (Sheehan, 1966)
Ph H
O
S N
Me
Br
Et3N (10 mol%)MeOH
PhPh
O
OH
Sheehan, J. C.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666
O
Ph O
(10 mol%)
*
9% yield, 22% ee
Enantioselective Benzoin Condensation
• Improvement in the enantioselectivity of benzoin condensation
Ph H
OPh
PhO
OH
S N
Me
Br
cat. NHC
Me6% yield, 52% eeSheehan, 1974
NN N Ph
ClO4
66% yield, 75% eeEnders, 1996
O
O
Ph
MeMe
S N
TfO50% yield, 21% eeLeeper, 1997
OTBS
NN N
Cl
45% yield, 80% eeLeeper, 1998
O
PhPh
Enantioselective Benzoin Condensation
• Improvement in the enantioselectivity of benzoin condensation
Ph H
OPh
PhO
OH
S N
Me
Br
cat. NHC
Me6% yield, 52% eeSheehan, 1974
NN N Ph
ClO4
66% yield, 75% eeEnders, 1996
O
O
Ph
MeMe
S N
TfO50% yield, 21% eeLeeper, 1997
OTBS
NN N
Cl
45% yield, 80% eeLeeper, 1998
O
PhPh
NN N
X
R1
R2n
Tunable sterics
Tunable electronics• N-aryl-bicyclic triazolium structure
NN N
BF4
Ph
O
MeMeMe
83% yield, 90% eeEnders, 2002
Model
Enders, Chem. Rev. 2007, 107, 5606-5655
Enantioselective Benzoin Condensation
• Highly efficient system for the enantioselective benzoin reaction (Connon, 2009)
Ar H
OAr
ArO
OH
NN N
BF4
C6F5PhOHPh
4-8 mol% NHC4-8 mol% Rb2CO3THF, 20 h
17 - 100%
PhPh
O
OH
O
OHMeO
OMeO
OHCl
Cl
O
OH
O
OHOO
Cl
Cl
90% yield,>99% ee
91% yield,92% ee
92% yield,90% ee
17% yield,43% ee
26% yield,97% ee
Connon, S. J. J. Org. Chem. 2009, 74, 9214
Aldehyde-Ketone Cross-Benzoin Reaction
• Synthesis of Bicyclic Tertiary AlcoholsN
N N
ClMes
30 mol% cat.4-8 mol% Cs2CO3CH2Cl2, 40 ºC, 24 h
25 - 90%
67% yield,>99% ee
37% yield,94% ee
43% yield,95% ee
50% yield,78% ee
47% yield,86% ee
Sakai, Org. Lett. 2009, 11, 4866-4869
OO
O
RH
O O R
OOH
O
O
MeO
O O
Me
OHOH OH
O
O
Me
OH
O
32% yield,26% ee
OMe
OH O
O Me
OOH
Aldehyde-Imine Cross-Benzoin Reaction
• Cross Aza-Benzoin Reaction with N-Boc IminesN
N N
BF4
20 mol% cat.CsOAc (1 equiv)CH2Cl2, 4 Å MS, -20 ºC
33 - 93%
83% yield,96% ee
89% yield,96% ee
86% yield,84% ee
71% yield,92% ee
84% yield,96% ee
Rovis, Angew. Chem., Int. Ed. 2012, 51, 5904-5906
O
R H
O
33% yield,98% ee
+N
Ar H
Boc
RNHBoc
O
ArCl
Cl
Et NHBoc
Cl
O
Et NHBocO
Et NHBocO
OMe
MeNHBoc
Ph
O
NHBoc
Ph
O
Ph NHBoc
Ph
O
Me
Me
Acyl Anion Equivalent
Breslowintermediate
Ph H
O
Ph H
NS
R2R3
R1
Ph H
O
Ph
OPh
OH
benzoin condensation
Ph
O
Acyl Anion Equivalent
EWGR
Breslowintermediate
Ph H
O
Ph H
NS
R2R3
R1
Ph H
O
Ph
OPh
OH
Ph
O
EWG
EWG = COR, CO2R, CN SO2R, PO(OR)2
benzoin condensation
Stetter reaction
R
Ph
O
Seminal Works of Stetter Reaction
• First general intramolecular Stetter reaction catalyzed by NHC (Ciganek, 1995)
• First asymmetric intramolecular Stetter reaction (Enders, 1995)
Ciganek, Synthesis 1995, 1311-1314Enders, Angew. Chem., Int. Ed. 1995, 34, 1021-1023
H
O
O CO2Me
20 mol% cat.Et3N (1 equiv)
DMF, rt
88%
O
O
CO2Me
H
O
O CO2Me
20 mol% cat.K2CO3 (1 equiv)
THF, rt
73%, 60% ee
O
O
CO2Me
S N
HOMe
Bn
Cl
NN N Bn
ClO4O
O Ph
MeMe
Improved Asymmetric Intramolecular Stetter Reaction
• Highly enantioselective Stetter reaction (Rovis, 2002)
Rovis, J. Am. Chem. Soc. 2002, 124, 10298
H
O
O CO2Et
20 mol% cat.KHMDS (20 mol%)
xylene
94%, 94% ee
O
O
CO2Et NN N
BF4O
OMe
NN N
BF4
Bn
H
O
CO2Et
20 mol% cat.KHMDS (20 mol%)
xylene
81%, 95% ee
O CO2Et
Asymmetric Intermolecular Stetter Reaction
• Intermolecular Stetter reaction with Chalcones (Enders, 2008)
Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066
Ar1 H
O
10 mol% cat.Cs2CO3 (10 mol%)
THF
49-98%, 58-78% ee
NN N Bn
BF4
NN N C6F5
BF4
Bn
20 mol% cat.iPr2NEt (1 equiv)
MgSO4
CCl4
+ Ar3
O
Ar2
Ar1
OAr3
OAr2 OTBDPS
ON
OH
O
• Intermolecular Stetter reaction with highly activated alkylidene dicarbonyls (Rovis, 2008)
CO2t-Bu
CO2t-Bu
Et
Et
O Me
O
NMe2
NCO2t-Bu
O
O O
Et
CO2t-Bu
N
O
O O
Et
O Me
O
NMe2
84%, 90% ee
90%, 92% ee, 5:1 dr
Asymmetric Intermolecular Stetter Reaction
• Intermolecular Stetter reaction with nitroalkenes
H
O 10 mol% cat.iPr2NEt (1 equiv)
CCl4, -10 ºC, 12 h
NN N C6F5
BF4
NN N Mes
Cl
O
NO2
Cy
• Stetter reaction of Methyl 2-Acetamidoacrylate
NNO2
Cy
N
MeMe
90% yield, 88% ee
NN N C6F5
BF4
MeMe
95% yield, 95% ee
F+
R H
O 20 mol% cat.16 mol% KO-tBu
PhMe, rt, 24 h38-98%
93-99% ee
R
O
CO2Me+
NHAc
CO2MeO
Bn
NHAc
Selected Examples:
O
CO2Me
NHAc
Br
O
CO2Me
NHAc
Fe
O
CO2Me
NHAcMe
8
98%, 96% ee 56%, 99% ee
52%, 97% ee
Rovis, J. Am. Chem. Soc. 2011, 133, 10402-10405.Glorius, Angew. Chem., Int. Ed. 2011, 50, 1410-1414
One-Pot Synthesis of Pyrrols and Furans
R1 SiMe3
O+
R2 Ph
O OOR1
PhR2 R2
OR1 Ph
R2Br +Ph
OH
R2
NR1 Ph
20 mol% 2DBU, iPrOH
1. Pd(PPh3)2Cl2, CuI, Et3N2. R1CHO, 20 mol% 1
HOAc
R3NH2TsOH
N
S
Me Me
HOI N
S
Me Et
HOBr
1 2
R3
Muller et al.
Scheidt et al.
Müller, T. J. J. Org. Lett. 2001, 3, 3297Scheidt, K. A. Org. Lett. 2004, 6, 2465
Acyl Anion Equivalent
EWGR
Breslowintermediate
Ph H
O
Ph H
NS
R2R3
R1
Ph H
O
Ph
OPh
OH
Ph
O
EWG
EWG = COR, CO2R, CN SO2R, PO(OR)2
benzoin condensation
Stetter reaction
R
Ph
O
Hydroacylation
EWGR
Breslowintermediate
Ph H
O
Ph H
NS
R2R3
R1
Ph H
O
Ph
OPh
OH
Ph
O
EWG
EWG = COR, CO2R, CN SO2R, PO(OR)2
benzoin condensation
Stetter reaction
R
Ph
O
unactivatedalkenes
R
Ph
O
RHydroacylation
Hydroacylation
• First hydroacylation precedent (She, 2008)
H
O
O
ROTs
25 mol% cat.70 mol% DBUxylene, 4 h
O
O
O
O
MePh
R = H
R = Ph
72%
82%
S N Me
HOMe
I
Hydroacylation
• First hydroacylation precedent (She, 2008)
H
O
O
ROTs
25 mol% cat.70 mol% DBUxylene, 4 h
O
O
O
O
MePh
R = H
R = Ph
72%
82%
S N Me
HOMe
I
H
O
O
Ph
hydroacylation
Hydroacylation
• First hydroacylation precedent (She, 2008)
H
O
O
ROTs
25 mol% cat.70 mol% DBUxylene, 4 h
O
O
O
O
MePh
R = H
R = Ph
72%
82%
S N Me
HOMe
I
• Asymmetric intramolecular hydroacylation (Glorius, 2011)
H
O
OAr
10 mol% cat.10 mol% DBUdioxane, 80 ºC
28-99%, 96-99% ee
O
O
MeAr
NN N Mes
ClO
Bn
Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983She, X. Tetrahedron 2008, 64, 8797
Hydroacylation Mechanism
Glorius, F. J. Am. Chem. Soc. 2009, 131, 14190.Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983
•Concerted but highly asynchronous transition state (Glorius, Grimme)
O
O
H
NN
NR Mes
OH
NN
NR Mes
O
O
NN
NR
Mes
MeO
H
O
O
NN
NR Mes
O
MeO
OH
≠
or
δ+
δ−O
NR2
H≠δ+
Conia-ene Reverse-Copeelimination
vs.
O
NN
N
Mes
R
H
R
1st2nd
≠
concerted butasynchronous mechanism
(Computation)
concerted mechanisms
Intermolecular Hydroacylation
Glorius, Angew. Chem., Int. Ed. 2010, 49, 9761-9764. Glorius, Angew. Chem., Int. Ed. 2011, 50, 12626-12630.Glorius, Angew. Chem., Int. Ed. 2013, 52, 2585-2589.
• Intermolecular hydroacylation of cyclopropenes
Ar1 H
O5 mol% cat.K2CO3 (1 equiv)THF, 40 ºC, 24 h
44 - 97%1.6:1 to 20:1 dr
NN N Mes
Cl
• Asymmetric intramolecular hydroacylation
NN N
BF4O
Bn
+R Ar2 R Ar2
Ar1
O
H
O20 mol% cat.K3PO4 (1.5 equiv)THF, 40 ºC, 24 h
91%, 92% ee+
Me PhMe Ph
O
ClCl
(R,R)
Ar H
O5 mol% cat.K2CO3 (1.5 equiv)DMSO, 40 ºC, 16 h
16 - 78%+
• Intermolecular hydroacylation of styrenes
R RAr
O
MeR
OAr
Linear
Branched
Ar
O
CN49% yieldL:B = > 20:1
39% yieldL:B = < 1:20
O
F3CMe
tBu
+
MeMe
MeO
MeO
NN N
Cl
MeO
MeO
Increased reactivity with OMe
Umpolung of Michael Acceptor
Fu, J. Am. Chem. Soc., 2006, 128,1472–1473
• Heck-type cyclization (Fu, 2006):
EWG
Br
n
10 mol% cat.K3PO4 (2.5 equiv)glyme, 80 ºC
48-94%
EWG
n
NN N
Ph
MeO OMe
EWG = CO2Et, CO2allyl, CO2N(Me)OMe, CNn = 1,2
ClO4
Br
O
OEt
O
EtO
BrN N
NPh
Ph
Ph
O
EtO
N N
NPh
Ph
Ph
CO2EtN
NN
Ph
Ph Ph
O
EtO
BrN N
NPh
Ph
Ph
tautomerization
Overview
Acyl Anions
R
OH
N
NR
R
O
R
YX N
OH
N
NR
R
O
Homoenolates
RR
• Benzoin condensation• Stetter reaction• Hydroacylation
• Annulation• Cyclopentene synthesis
O
N
NR
R
AcylazoliumAzolium enolate
• Claisen rearrangement• Cycloaddition
Base Catalysis• Transesterification• Michael addition
R2
O
N
NR1
RN
NR
R
HR
Generation of Homoenolate
R1 H
OR1
O
N
NMes
Mes
R1
OH
N
NMes
Mes
R1
OH
N
NMes
Meshomoenolate
NNMes Mes
R
O
Annulation Reactions
R1
OH
N
NMes
Mes
R1
O
Ar H
O
O
O
R1 Ar
R3
O
R2O
O
R3R2
R1
R3
N
R2N
O
R3R2
R1
SO2Ar
SO2Ar
Ph
O
R2
Ph
N
R2
SO2Ar
R2
OH
Me Me
O
OO
HMe
OHMe
R2
R1
NO
H Ph
R2
R1
SO2Ar
R2
R1
Ph
Cyclopentene Synthesis
Nair, J. Am. Chem. Soc. 2006, 128, 8736-8737.
• 1,3,4-trisubstituted Cyclopropene Synthesis by NHC (Nair, 2006)
N N Mes
ClR1 H
O
R2 R3
O+
6 mol% cat.12 mol% DBUTHF, RT, 8 h
R3
R1 R2
Mes
S
Cl
MeOMe S
Cl
Me
ClMeO
88% yield> 20:1 dr
73% yield> 20:1 dr
55% yield> 20:1 dr
Mechanism
N N MesMesR1 H
O
O
R1
NN MesMes
OH
R1
NN MesMes
R3 R2
OH
R1
NN MesMes
R3
OR2
OH
R1
NN MesMes
R3
OR2
O
NN MesMes
R1R2
OR3
OO
R3
R1 R2 R1 R2
R3
- CO2
O
Cyclopentene Synthesis
• Enantioselective Synthesis Cyclopropene by NHC (Bode, 2007)
NN N Mes
BF4R1 H
O
MeO2C R2
O+
6 mol% cat.12 mol% DBUTHF, RT, 8 h
R2
R1
Ph
Ph Ph
78% yield11:1 dr99% ee
O
CO2Me
O
CO2Me Ph
Br
CO2Me
Ph
nPr CO2Me
93% yield>20:1 dr98% ee
50% yield11:1 dr99% ee
25% yield14:1 dr96% ee
Bode, J. Am. Chem. Soc. 2007, 129, 3520-3521
CO2Me
Mechanism
NN N Mes
R1 H
OO
NN N Mes
R
R
OR1
NN N Mes
R
R
OHR1
MeO2C R2
O
NN N Mes
O
R1CO2Me
HOO
R2
NN N Mes
O
R1CO2Me
HOO
R2
NN N Mes
R
R
O
R1MeO2C
HOR2
R1MeO2C
R2O O
-CO2
R1MeO2C
R2
Mechanism
• Origin of cis/trans stereoselectivity
N NN
O
Me
Me
Me
O
Ph
OMe
O
Ph
OH
s-cis
N NN
O
Me
Me
Me
O
Ph
H
s-trans
O Ph
Ph
PhCO2Me
Cat.Ph
OOH
≠
Boat oxy-Cope TS
Ph PhPh
OHO
Cat.
H
≠
Ph
Ph CO2Me
Ph
Ph Ph
Chair oxy-Cope TS
O
PhPh +H Ph
O10 mol% cat.15 mol% DBU
ClCH2CH2Cl0-23 ºC, 40 h45% yield
Ph
Ph
PhH
> 20:1 dr (72% ee)
s-cis
β-lactam Formation
Bode, J. Am. Chem. Soc. 2008, 130, 418-419
• Scope of β-lactam formation
R H
O+
Ar1 Ar2
NSO2Ar
10 mol% cat.15 mol% DBU
EtOAc, 23 ºC, 1 h
45-94%N
O SO2Ar
Ar2H
Ar1
R
NN N Mes
Cl
94% yield>20:1 dr99% ee
O
45% yield>20:1 dr98% ee
76% yield5:1 dr99% ee
72% yield>20:1 dr88% ee
NO SO2Ar
PhH
Ph
Me
NO SO2Ar
PhH
Ph
NO SO2Ar
PhH
Ph
NO SO2Ar
PhH
Ph
Me
F3C
Aza-Benzoin-Oxy-Cope Rearrangement Mechanism
NN N Mes
Me H
OO
NN N Mes
R
R
OMe
NN N Mes
R
R
OHR1N
N N Mes
O
MePh
OPh
NN N Mes
O
MePh
OPh
SO2ArON
ent-1
ArO2SN Ph
PhHNSO2Ar
HNSO2Ar
NN N Mes
O
MePh
OPh
NSO2Ar
tautomerization/Mannich
PhH
Me
Ph
Overview
Acyl Anions
R
OH
N
NR
R
O
R
YX N
OH
N
NR
R
O
Homoenolates
RR
• Benzoin condensation• Stetter reaction• Hydroacylation
• Annulation• Cyclopentene synthesis
O
N
NR
R
AcylazoliumAzolium enolate
• Claisen rearrangement• Cycloaddition
Base Catalysis• Transesterification• Michael addition
R2
O
N
NR1
RN
NR
R
HR
Biomimetic Origin of Acylazolium Reactivity
• Clavulanic acid biosynthesis through acylazolium intermediate
H
OOH
OPO3
PP-O
H2N
N
N
N
STDP
R2
R1N
S
OH
OPO3H OHG3P R2
R1N
SOPO3
HH
O
R2
R1N
S O
L-Arg
R2
R1N
SO
acylazolium
HNNH
NH2
NH
COOHN
O
COOH
OH
O
H
Clavulanic acid
Townsend, J. Am. Chem. Soc. 1999, 121, 9223-9224
Generation of Acylazolium • Genertion of acylazolium intermediate by MnO2 oxidation (Scheidt, 2007)
Ph OHNHC cat., DBU
MnO2, MeOH Ph OMe
O
Scheidt, Org. Lett., 2007, 9, 371-374
Generation of Acylazolium
R1 H
OR1
O
N
NMes
Mes
R1
OH
N
NMes
Mes
R1
OH
N
NMes
Meshomoenolate
NNMes Mes
• Genertion of acylazolium intermediate by MnO2 oxidation (Scheidt, 2007)
Ph OHNHC cat., DBU
MnO2, MeOH Ph OMe
O
slow
fast
R1
O
N
NMes
Mes
MnO2
MeOH
acylazolium
MnO2
Scheidt, Org. Lett., 2007, 9, 371-374
Generation of Acylazolium
Ar1
O
N
NAr2
Racylazolium
Ar1
O
H
O
H
Ar1
O
HBr
Ar1
O
RR = F, OR
Ar1or
[O]
• comparison of homoenolate/acylazolium reactivity
R
OH
N
NAr
Ar
R
O
N
NAr
Ar
YR1 O
Y = O, NR
electrondonor
MichaelAcceptor
Y
R
R1
O O
OR
R1 R1
Dihydropyranone Synthesis Through Acylazolium
• Intramolecular Rearrangement
R4 R3
10 mol% cat.20 mol% KOtButoluene, Δ, 16 h N N Mes
O
O
R2
R1
O
R2
R1
R3 R4O
MesCl
• Intermolecular Reaction
Ar
OTMS
R2
R1
O
F+
20 mol% cat.40 mol% KOtButoluene, Δ, 16 h O
R2
R1
Ar O
N N DIPPDIPPCl
Lupton, J. Am. Chem. Soc. 2009, 131, 14176-14177
Mechanism
R4 R3
O
O
R2R1
O
R2R1
R3 R4O
N
N
R
R
O
R2R1
O
R3
R4
N
N
R
R
+
O
R3
N
N
R
R
R2
OR1R4
O
R3
N
N
R
R
R2
OR1R4
addition
Conjugate additionproton transfer
acylation
Enantioselective Coates-Claisen Rearrangement
• Catalytic, Enantioselective Couplings with Kojic Acids (Bode, 2010)
H
O+
1. 10 mol% cat.PhMe, 40 ºC
2. MeOH, 23 ºC
78-98%92-99% ee
NN N Mes
Cl
80% yield97% ee
O
R1O
O
R2
HO
O
O
R2
HO
MeO2CR1
O
OHO
MeO2CPh
OTBS
95% yield95% ee
O
OHO
MeO2COTBS
Me87% yield99% ee
O
OHO
MeO2COTBS
90% yield99% ee
O
O
Me
HO
MeO2CPh
98% yield97% ee
O
OHO
MeO2COTBS
78% yield99% ee
O
OHO
MeO2COTBS
Me
Cl
Bode, J. Am. Chem. Soc. 2010, 132, 8810-8812
Mechanism
NN N MesR
H
O
O
NN
N MesR
R1
R1
R
R
Breslowintermediate
O
NN
N MesR
R
R1
protonation
O
HOO
R2
NNN
Mes
R
R
R1
O
HOOH
NN
N MesR
R
O
OO
R2
R1
O
NN
N MesR
R
O
OHO
R2
R1
O
O
R2
1,2-addition
MeOHO
HOO
R2MeO2CR1
ClaisenRearrangement
Mechanistic Dichotomy
Mayr, Angew. Chem., Int. Ed. 2012, 51, 5234-5238 Schoenebeck, Chem. Sci. 2012, 3, 2346-2350.
O
N N
N
Mes
R
RAr +
Y = O, NR
YR2R1
path Apath B
Y
N N
N
Mes
R
RArO
R1
R2[3,3]
Coates-Claisen
O
N N
N
Mes
R
R
Ar
R2
R1
Y
Schoenebeck, Bode(loose ion pair)
Mayr, Studer(contact ion pair)
Enantioselective Hetero-Diels-Alder Reaction
Bode, J. Am. Chem. Soc. 2006, 128, 8418-8420
H
N
10 mol% cat.DIPEA (1 equiv)PhMe/THF 10:1
52-90%
NN N Mes
BF4
O
H
O N
90% yield99% ee
R1
SO2ArR2
O
OSO2Ar
R1
O
R2
+
N OSO2Ar
Ph
O
OEt
71% yield99% ee
N OSO2Ar
O
OEt
58% yield99% ee
N OSO2Ar
n-Pr
O
OEt
71% yield99% ee
N OSO2Ar
n-Pr
O
OMeO
Enantioselective Hetero-Diels-Alder Reaction
HR2O
NNN
OAr
N RSO
O
MeO
H
N
NN N Mes
O
H
ON
R
SO2Ar
EtO
O
OSO2Ar
R
O
OEt
proton transfer
NN N Mes
R
R
HO
CO2Et
NN N Mes
R
R
O
CO2Etazolium enolate
N SO2Ar
R
O
EtO
O
NN N Mes
R
R
Transition State of Azadiene Diels-Alder Reaction:
NN N Mes
R
R
HO
CO2Et
Ketene Cycloaddition
NN N Ph
Ar1 R
NN N Ph
R
R
OAr1 azolium enolate
PhTBSO
Ph
•O
R
Ar2 H
NBoc
NN N Ph
R
R
O
NBoc
Ar1
Ar2
R
H
NO Boc
Ar2RAr1
Ar1 R
•O
Ar2 H
NBoc
NO Boc
Ar2RAr1
10 mol% cat.10 mol% Cs2CO3
THF+
53-98% yield91-99% ee2.5-99:1 dr
Ye, S.; Org. Lett. 2008, 10, 277.
Ketene Cycloaddition
NN N Ph
NN N Mes
R
R
OAr
azolium enolate
PhTBSO
Ph
R
Ar R
•O
[2+2]
[3+2]
[4+2]
N
O
O
O
R1
ArR
NN
O CO2Et
CO2Et
Ye, S. Synlett 2013, 1614
ArR
ON
O Ar1
RAr
ClNTs
O
NTs
O
O
ArR
Cl
BzNN
Bz NN
OO Ph
Bz
ArR
PhHN
OMeO
O
Ph Et
80% yield, 99% ee
1. K2CO3, MeOH/acetone
2. SmI2, HF-MeOH
KOH HO COOH
Ph Et
75% yield, 90% ee
Overview
Acyl Anions
R
OH
N
NR
R
O
R
YX N
OH
N
NR
R
O
Homoenolates
RR
• Benzoin condensation• Stetter reaction• Hydroacylation
• Annulation• Cyclopentene synthesis
O
N
NR
R
AcylazoliumAzolium enolate
• Claisen rearrangement• Cycloaddition
Base Catalysis• Transesterification• Michael addition
R2
O
N
NR1
RN
NR
R
HR
Transesterification
N N R
R1 OR2
5 mol% cat.THF, 23 ºC
+O R3OH
R
R = Mes or Cy
R1 OR3
+O R2OH
MeMe
Me
O
99% yield
Me
O
MeO
OMeOBn
O
95% yield
OBn
O
96% yieldO2N
OR
O
R = Et, 85% yield i-Pr, 72% yield t-Bu, < 1% yield
R1 OR2
O
R1
O
N
NMe
Me
O
R1OR2
OR3
H
N
NMe
Me
O
R1OR2
OR3
N
NMe
Me
H
favored disfavored
R1 OR3
+O R2OH
Nolan, Org. Lett. 2002, 4, 3583-3586Hedrick, Org. Lett. 2002, 4, 3587-3590
Kinetic Resolution of Secondary Alcohols
N N
3 mol% cat.3 mol% KOtBu
THF, 23 ºC+
R1 R2
+OAc
R3R3
Me Me R3 = Ph, 1-naphthyl
OAc
4-52% yield9-58% ee
R1 R2
OH
R1 R2
OH
36-85% yield1-23% ee
Suzuki (2004):
N N
3 mol% cat.3 mol% KOtBu
THF, 23 ºC+
R1 R2+O
R3R3
Me Me R3 = Ph, 1-naphthyl
O
27-39% yield84-96% ee
R1 R2
OH
R1 R2
OH
36-85% yield1-23% ee
OPh
Ph
O
CHPh2
Me
O
O
CHPh2
32% yield96% ees = 80
Me
O
O
CHPh2
29% yield94% ees = 47
Me
O
O
CHPh2
Ph
27% yield84% ees = 16
Maruoka (2005):
Suzuki, Chem. Commun. 2004, 2770-2771 Maruoka, Org. Lett. 2005, 7, 1347-1349
• NHC as non-covalent chiral templates (Huang, 2014)
Huang, Nat. Commun. 2014, 5, 3437
Me
20 mol% cat.16 mol% LHMDS
20 mol% HFIP
4Å MS, MTBE- 40 ºC, 48 h
NN N Mes
BF4O
Me
O O+
PhNO2
PhNO2
MeMe
O O
92% yield, 99% ee
NNNMes
O
OH
O
Me Me
PhNO2
N NN
Mes
O
HO
Me O
Me
Ph
NO2
negative non-linear effects:
Asymmetric Conjugate Addition of 1,3-Dicarbonyls
Overview
Acyl Anions
R
OH
N
NR
R
O
R
YX N
OH
N
NR
R
O
Homoenolates
RR
• Benzoin condensation• Stetter reaction• Hydroacylation
• Annulation• Cyclopentene synthesis
O
N
NR
R
AcylazoliumAzolium enolate
• Claisen rearrangement• Cycloaddition
Base Catalysis• Transesterification• Michael addition
R2
O
N
NR1
RN
NR
R
HR
Application in Total Synthesis
•Synthesis of (+)-sappanone B
reaction type:N
N N
Cl
7.5 mol% cat.Et3N
toluene, 23 ºC, 12 h
92%, 99% ee
Suzuki, Org. Lett. 2007, 9, 2713-2716
O
CF3
CF3
CHO
O
OMeOMe
OMeO
OMeO
OOH
XX
(X = OMe)
(+)-sappanone B (X = OH)
Application in Total Synthesis
•Synthesis of atorvastatin (Lipitor)
reaction type:
S N
BrEt
Roth, Tetrahedron Lett. 1992, 33, 2283-2284
F
CHO+ NHPh
Me
MeO
Ph O
NHPhMe
MeO
Ph O
O
F
HO
Me
20 mol% cat.
Et3N, 70 ºC
80%
H2N OtBu
O O O
Me Me1.
2. HCl, MeOH, then NaOH3. Ca(OAc)2Ph
N
OPhHN
Me
Me
COO
F
HO
HO Ca2+
2
atorvastatin (Lipitor)
1:1 E/Z
Paal-Knorr Reaction
Application in Total Synthesis
•Synthesis of maremycin Breaction type:
NN N
BF4
Mes
Scheidt, Angew. Chem. Int. Ed. 2012, 51, 4963-4967
5 mol% cat.
DBU, THF, 23 ºC
76%, 5:1 dr78% ee
99% ee after 1 recrystalization
NMe
O
O
MeCHO
+
O
Ph
Ph
NMe
O
O
OMe
5 steps
NMe
O
NH
HNO
OHOMe
SMe
maremycin B
Application in Total Synthesis
•Synthesis of (–)-7-deoxyloganinreaction type:
N N
Candish, Lupton, Org. Lett. 2010, 12, 4836-4839.
20 mol% cat.
THF, -78ºC-23 ºC
63%, 3.4:1 dr, 97% ee
O
4 steps
Me O
CO2Me
Me Me
Me
Me
Me
Me
O
Me O
CO2Me
H
H
O
Me
CO2Me
H
H
O OHOOH
OHOH
(–)-7-deoxyloganin
Application in Total Synthesis
•Synthesis of (+)-Dactylolidereaction type:
NN N Me
Hong, Angew. Chem. Int. Ed. 2012, 51, 5735-5738.
Me
O
O
O Me
O
Me
H
O
(+)-dactylolide
H H
I O
O
O Me
CN
Me
TBDPSO
H H
S S
OTBSOH
O
O Me
CN
Me
TBDPSO
H H
S S
OTBS(30 mol%)
OO
tButBu
tBu tBuDBU, DMAP, 4Å MSCH2Cl2, 25 ºC, 20 h
65%11 steps
4 steps
S S
HO
Reviews
1. N-Heterocyclic Carbenes as Organocatalysts Nolan, Angew. Chem. Int. Ed. 2007, 46, 2988 – 3000
2. Organocatalysis by N-Heterocyclic Carbenes Enders, Chem. Rev. 2007, 107, 5606-5655
3. A Continuum of Progress: Applications of N-Hetereocyclic Carbene Catalysis in Total Synthesis Sheidt, Angew. Chem. Int. Ed. 2012, 51, 11686 – 11698
4. Organocatalytic Reactions Enabled by N‐Heterocyclic Carbenes Rovis, Chem. Rev. 2015, 115, 9307−9387