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Advancement of Direct Catalytic Mannich-type Reactions with Esters
or Ester-equivalents as Donors
Yong GuanOct. 17, 2007
Michigan State University
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
Background Information
Mannich, C. Arch. Pharm. 1917, 255, 261.http://www.dphg.de/images/dphg_ap_mannich.gif
O
CH3Ph
CH2O
NH4Cl
O
Ph N3
NN
O
Ph
CH3
antipyrine
CH2O
NH4Cl
NN
O
Ph
H3CCH3
CH3
N
3
Carl Mannich
Tollens and von Marle (1903)
Mannich (1917)
Mannich reaction
Tollens, B.; Marle, v. Ber. 1903, 36, 1351.Mannich, C. J. Chem. Soc., Abstracts 1917, 112, 634.
NHR
R O
HH R2
OR1
acid or baseR2
O
NR1
R
R
+ +
Reaction Mechanism
O
HH
RHN
R
H
HNR
R
OH H+
HNR
R
OH2
NR
R
Step 1. Formation of the Schiff base
Name Reactions – A Collection of Detailed Reaction Mechanisms. Jie Jack Li. Springer-Verlag, Berlin. 2002.
Step2. Amino alkylation of an acidic hydrogen containing compound
Basic conditions
Acidic conditions
R2
OR1
H
B:
enolateformation
R2
O-
R1
NR
R
R2
O
NR1
R
R
R2
OR1
H+
enolization R2
OR1
H
NR
R
R2
O
NR1
R
R
Background Information
• Indirect-type Mannich Reaction
• Direct-type Mannich Reaction
Indirect-type Mannich Reaction
EtO2C
NTs
R
OSiMe3+
CuClO4-tolBINAP (2-10 mol%)
THF, 0 oC EtO2C
NH
R
OTs
8 examples65-92% Yield89-98% ee
Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548.
Silyl enol ether
P(p-tolyl)2P(p-tolyl)2
tolBINAP
N
HO
OEt
TsCuP
P*
The First Direct Catalytic Asymmetric Mannich Reaction
Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett. 1999, 41, 307.
Direct-type Mannich Reaction
Ar
O MeOCH2NEt2ALB (30 mol%)
La(OTf)3 nH2O (30 mol%)toluene, 3 MS, 50 oC
Ar
O
NEt2
5 examples61-76% yield34-44% ee
.Å
OO
OO
Al
Li
(R)-ALB = AlLibis(binaphthoxide)
General Difficulties
• Many Lewis acids are deactivated or sometimes decomposed by the nitrogen atoms of starting materials or products ( t rapped by the n i t rogen atoms)
• Imine-chiral Lewis acid complexes are rather flexible and often have several stable conformers (including E/Z-isomers of imines). Multiple transition states would exist.
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
Background Information
O
HR
O
R2R1
Imines IminesMannichAdducts
O
OR2R1
?
Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348.Shibasaki, M.; Matsunaga, S. J. Organomet. Chem. 2006, 691, 2089Córdova, A. Acc. Chem. Res. 2004, 37, 102
O
CH3H3C
pKa 20
O
CH3t-BuO
pKa 24.5
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
NOR'
OAr
Ar
Glycine Schiff-bases
• Cu(I) Catalyst
• Phase-Transfer Catalyst
Glycine Schiff-bases
Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400.Ooi, T.; Takeuchi, M.; Kamede, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843.
NOR1
O
R2
R3
MeO2C CO2Me
MeO2C CO2Me
NH
CO2R1R2
R3
1,3-dipolar cycloaddition
NuSubstitution aldol reaction
Michealreaction
NOR1
O
R2
R3
CN
CH2=CHCN
OHCO2R1
NH2
OHCO2R1
NH2
CO2R1H2N
R4R5
Glycine Schiff-bases
• Challenges(1) “Force” the Lewis acid stabilized imino glycine alkyl ester to act
as a nucleophile rather than a 1,3-dipolar species
(2) Develop a chiral catalyst that can catalyze both a diastereo- and enantioselective addition of imino glycine alkyl ester to imines.
Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.
NOR1
O
R2
R3
MLn
NOR1
O
R2
R3
LnM
R3N
NOR1
O
R2
R3
LnM
NOR1
O
R2
R3
LnM
N
R
PG
NOR1
O
R2
R3
R NHPG
H2NOR1
O
R NHPG
Cu(I) Catalyst
Optimal conditionLigand -CuClO4 (10 mol%), Et3N (10 mol%), -20 oC, THF, 4 Å MS
Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.
NPh
PhOR1
O
Ph
NTs
+R3N
Lewis acidNPh
PhOR1
O
Ph NHTsLigand
PAr2PAr2
O
N N
O
t-Bu t-Bu
PAr2
O
N
PPh2
O
NPPh2
O
N PPh2
O
NR
Ar = 2,4,6-Me3-C6H2
Substrate Scope
R yield (%) syn/anti ee (%)
Ph 94 79:21 97
4-MeO-C6H4 90 82:18 97
2-Br-C6H4 99 61:39 96
2-furyl 88 54:46 90
iPr 73 >95:5 96
Cy 85 >95:5 92
nBu 61 >95:5 88
Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.
NPh
Ph
CO2Me
R
NTs Ligand-CuClO4 (10 mol%)
Et3N (10 mol%)
THF, 4 MS, -20 oCR
CO2MeNHTs
N
Ph
Ph+
Å
PAr2
O
N
Ar = 2,4,6-Me3-C6H4
Coordination Modes
PAr2
O
N
NPh
PhMeO
OCu
PAr2
O
N
NPh
PhMeO
OCu
PAr2
O
N
NPh
OMe
OCu
Ph
Semiempirical PM3 calculationBernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.
PAr2
O
N
NPh
OMe
OCu
Ph
Ar = PhΔHf
Ө = -10.9 kcal/mol14% ee
Ar = PhΔHf
Ө = -11.1 kcal/mol
Ar = 2,4,6-Me3-C6H2ΔHf
Ө = -39.2 kcal/mol97% ee
Ar = 2,4,6-Me3-C6H2ΔHf
Ө = -26.8 kcal/mol
Transition State
Approach of the imine (blue) to the Si face of the benzophenone imine glycine methyl ester anion
Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.
X-ray structure
Ph CO2EtNHTs
N
Ph
PhR
S
Phase-Transfer Catalyst
Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4564.
tartrate-derived diammonium salt (TaDiAS)
Crystal Structure (R = nPr)
O
O
N
N
C6H4-4-MeC6H4-4-MeC6H4-4-MeC6H4-4-Me
2BF4-R
R
Me
Me
Substrate Scope
NPh
Ph
CO2tBu+
N
R
Boc cat. (10 mol%)
Cs2CO3 (2 eq)PhF, -45 to -20 oC
19 to 72 h(1.1 eq)
HN
R
Boc
N
CO2tBu
Ph
Ph
O
O
N
N
C6H4-4-MeC6H4-4-MeC6H4-4-MeC6H4-4-Me
2BF4-
Me
Mep-F-C6H4
p-F-C6H4
R yield (%) dr (syn/anti) ee (%)
Ph 98 99:1 70
4-MeO-C6H4 95 95:5 82
4-Me-C6H4 98 98:2 80
2-Me-C6H4 99 97:3 68
4-Cl-C6H4 87 98:2 58
2-thiophenyl 98 98:2 80
(E)-PhCH=CH2 86 98:2 66
Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4564.
Kinetic Study
• Initial rate kinetic studies:1) First-order dependency for the glycine Schiff base and Cs2CO3
2) Zero-order dependency for the imine and the catalyst
Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4564.
NPh
Ph
CO2tBu+
N
R
Boc cat. (10 mol%)
Cs2CO3 (2 eq)PhF, -45 to -20 oC
19 to 72 h(1.1 eq)
HN
R
Boc
N
CO2tBu
Ph
Ph
• Conclusions:1) The rate-determining step is deprotonation of the glycine Schiff base by
Cs2CO3
2) The catalyst is not involved in this step
Catalytic Cycle
Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4564.
N
R
Boc
N
CO2tBu
Ph
Ph
N
R
Boc
N
CO2tBu
Ph
Ph
NPh
Ph
CO2tBu
NPh
Ph
O
OtBu
Q Q+ +- Cs+
Cs2CO3
CsHCO3
NPh
Ph
O
OtBu
-Q Q+ +BF4-
CsBF4
-Cs+
N
R
Boc
TaDiAS
O
O
N
N
C6H4-4-MeC6H4-4-MeC6H4-4-MeC6H4-4-Me
2BF4-R
R
Me
Me
-Q Q+ +
BF4-
Interfacialdeprotonation
counteranionexchange
Control of Diastereoselectivity
The reaction may proceed via the nonchelate, acyclic transition-state model
Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794
NPh
Ph
CO2tBu+
NBoc
cat. (10 mol%)
Cs2CO3 (2 eq)PhF, 4 oC
HNBoc
N
CO2tBu
Ph
PhMeO MeO
1h, 77% ee, d.r. = 95:5without cat. , 24h, d.r. = 94:6
N
R
HN
OO
Ph
Ph
O
O
/ NR
NH
Ph
Ph
O
O
/
O OtBu tBu
anti syn
_ _
tBu tBu
H H
Control of Enantioselectivity
• The benzyl moieties around one ammonium cation covers the Si face of the Z enolate of the glycine Schiff base
• The electrophiles approach from the less-hindered face (Re face) to afford the products with S configuration
Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4564.Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794
NO
O
NMe
MeR'
R'
H HO ON
Ph PhtBu
NBoc
RH
Improvement
Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794
R yield (%) dr (syn/anti) ee (%)
Ph 66 99:1 79
4-MeO-C6H4 96 99:1 90
4-Me-C6H4 92 99:1 88
4-Cl-C6H4 88 98:2 70
nPr 95 >20:1 71
2-thiophenyl 89 98:2 83
(E)-PhCH=CH 89 >20:1 75
NPh
Ph
CO2tBu+
N
R
Boc cat. (10 mol%)
Cs2CO3 (2 eq)PhF/pentane (4:1)
-45 to -20 oC3 to 43 h
HNBoc
N
CO2tBu
Ph
PhR
O
O
N
N
C6H4-4-MeC6H4-4-MeC6H4-4-MeC6H4-4-Me
2BF4-
Me
Me
Ph
Ph
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
R1
O
OR2
O
R'O
O
OR'
O
β-Keto Esters or Malonates
• Cu(II) Catalysts
• Pd Catalysts
• Cinchona Alkaloid Catalysts
Cu(II) Catalysts
R yield (%) dr ee (%)
76 84:16 23
75 93:7 51
81 >95:5 53
43 >95:5 -66
33 >95:5 -88
Et
O
OR
O
Me
N
CO2Et
Ts Cu(OTf)2-(R)-Ph-BOX (10 mol%)
CH2Cl2, -20 oCEt
O HNTs
CO2EtMe CO2R
* *+
Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359.
O
N N
OMeMe
Ph Ph
(R)-Ph-BOX
Me
Ph
Ph
MeMe
Me
Et
O HNTs
CO2EtCO2CHPh2
(R,R)from X-ray structure
Me
Cu(II) Catalysts
R1
O
OtBu
O
Me
N
CO2Et
Ts+
Cu(OTf)2-(S)-tBu-BOX(10 mol%)
CH2Cl2R1
O HNTs
CO2EtMe CO2tBu
* *
R1 T (oC) t (h) yield (%) dr ee (%)
Me -20 40 55 97:3
84:16
93:7
84:16
95
iPr -20 40 15 92
Me RT 16 87 88
iPr RT 16 55 91
Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359.
O
N N
OMeMe
t-But-Bu
(S)-tBu-BOX
81% yield, 53% eedr = >95:5
33% yield, -68% eedr = >95:5
80% yield, 92% eedr = 98:2
Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359.
Transition States
Et
O
OR
O
Me
N
CO2R'
Ts Cu(OTf)2-ligand (10 mol%)
CH2Cl2, -20 oCEt
O NHTs
CO2R'Me CO2R
* *+
NO
NO
Ph
Ph
Cu
Me
Me
Ph2HCO
MeO
O Et
N
EtO2C
HTs
NO
NO
Ph
Ph
Cu
Me
MeEtO
O
OtBuMe
NTs
H CO2Et
NO
NO
Cu
Me
Me
t-Bu
tBu
Me
O Et
O
t-BuO
NTs
HEtO2C
Pd Catalysts
a: Ar = C6H5: (R)-BINAPb: Ar = 4-Me-C6H4: (R)-TOL-BINAP
c: Ar = C6H5: (R)-SEGPHOSd: Ar = 3,5-Me2-C6H3: (R)-DM-SEGPHOS
Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem.Int. Ed. 2005, 44, 1525.
PdP
POH2OH2
2TfO-2+
* O
R1
R2
O
OtBu
PdPP
*
+ TfO-
R1
O
R2OtBu
O
H2O, TfOH
PAr2PAr2
PAr2PAr2
O
O
O
O
Pd Catalysts
R1
OCO2tBu
R2
N
R3
PG
R1
O
R2 CO2tBuR3
NHPGPd cat.- a or c(x mol%)
THF, 1M+
(1.5 eq)
**PPh2PPh2
a: (R)-BINAP
PPh2PPh2
O
O
O
Oc: (R)-SEGPHOS
Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem.Int. Ed. 2005, 44, 1525.
O HNCO2Et
PMP
CO2tBu
OCO2Et
HN
CO2tBu
PMPO HN
Ph
Boc
CO2tBu
O HNBoc
CO2tBu
O
O HNTs
CO2tBu
ClHN
Boc
CO2tBuH3C
O
H3C
O HNTs
CO2tBu
Ph
c (5 mol%), 35 h63%, dr = 77:23, 99% ee
a (5 mol%), 42 h70%, dr = 74:26, 86% ee
c (2.5 mol%), 5 h93%, dr = 88:12, 99% ee
a (2.5 mol%), 2 h75%, dr >95:5, 86% ee
a (2.5 mol%), 3 h71%, dr = 82:18, 96% ee
c (5 mol%), 9 h99%, dr = 85:15, 97% ee
c (1 mol%), 24 h88%, dr = 90:10, 99% ee
O
One-Pot Reactions
O O
CO2EtH
OMe
NH2
THF, 1M, RT, 3 h
O
CO2tBu
HNCO2EtCO2tBu
PMP
+ + * *
O O
CO2EtH
NH2
Pd cat.- a(2.5 mol%)
THF, 1M, -20 oC, 72 h
O
CO2tBu
HNCO2EtCO2tBu + + * *
ClCl
61% yield, dr = 70:3096% ee (major), 96% ee (minor)
85% yield, dr = 95:598% ee (major), 88% ee (minor)
Pd cat.- a(2.5 mol%)
Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem.Int. Ed. 2005, 44, 1525.
PPh2PPh2
a: (R)-BINAP
Transition-State Model
Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem.Int. Ed. 2005, 44, 1525.
O
CO2tBu
HNPh
Boc
* *
1) LiAlH42) Ac2O
59% (2 steps)
O HNPh
Boc
PhOAc
R SCO2tBu
NMeAc
CO2tBu
P PdP
*
OO
O
R1 R2
NR3
H
H
PG
R1
O H NHR3
CO2tBuR2
PG
Re face
Cinchona Alkaloid Catalysts
Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256.
R1
O
OR2O
N
H Ar
O
R3O+catalyst
R1
O
OR2O
Ar
HN
O
OR3
N
N
HOH
H
cinchonine
N
H
H
OH
N
cinchonidine
quinine
N
N
HOH
H
O
quinidine
activate electrophile
activate nucleophile
N
H
H
OH
N
O
Cinchona Alkaloid Catalysts
H3C
O
OO
N
H Ar
O
H3CO
1) cinchonine (10 mol%)CH2Cl2, 0.5 M, -35 oC, 16 h
2) 5 mol% Pd(II)methyl acetoacetate
+ H3C
O HN
Ar
OCH3
O
N
N
HOH
H
cinchonine
H3C
O HN
Ar
OCH3
O
OO
Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256.
Ar yield (%) ee (%)
Ph 79 92
4-F-C6H4 95 93
3-CH3-C6H4 78 96
3,4-(OCH2O)C6H3 77 80
2-furyl 78 93
2-thienyl 69 92
2-naphthyl 80 95
H3C
O
OO
N
H Ar
O
H3CO
1) cinchonine (10 mol%)CH2Cl2, 0.5 M, -35 oC, 16 h
2) 5 mol% Pd(II)methyl acetoacetate
+ H3C
O HN
Ar
OCH3
O
N
N
HOH
H
cinchonine
Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256.
Substrate Scope
Transition-State Model
N
OH
HN
O
O
OMe
HH
N
HO
MeO
Cinchonine/methyl 2-oxocyclopentanecarboxylate enol tautomer complex (MMFF) approaching the Re face of methyl benzylidenecarbamate
Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003.
O O
OMe
H
N
Ph
O
MeO
cinchonine (5 mol%)CH2Cl2, 0.5 M, -55 oC
O
Ph
HN
O
OMe
OMeO
RS+
98% yield, 98% de, 90% ee
Cinchona Alkaloid Derivatives
McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.
NN
N
NS
H
H
F3C CF3
*
OMeThiourea moiety-activate electrophiles-two coplanar protons for H-bond donation-rigid
Thiourea N-aryl group-relatively unhindered-substitution variable-CF3 gruops serve as non Lewis basic EWG
Cinchona Alkaloid Derivatives
R
NBoc
HCH2(COOMe)2 R
NHBoccat. (20 mol%)COOMe
COOMe
+
(1.5 eq)acetone, -60 oC, 36 h
R yield (%) ee (%)
2-Me-C6H4 98 99
4-Me-C6H4 92 97
4-Cl-C6H4 98 99
4-MeO-C6H4 98 97
2-furyl 99 97
2-thienyl 95 97
Et 63 89
nBu 64 92
N
MeO
HN
HN
SAr
N
H
Ar = 3,5-bisCF3-C6H3
Song, J.; Wang, Y.; Deng, L. J. Am.Chem. Soc. 2006, 128, 6048.
N
NH
N
H
NS
CF3
CF3
HH
O
OOMe
OMe
H
NBocR
O
H
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
O
CCl3R'
Trichloromethylketones
• -CCl3 is a good leaving group
• Strong inductive effect of -CCl3
Morimoto, H.; Wiedemann, S. H.; Yamaguchi, A.; Harada, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 3146
CCl3
O
R
CCl3
OR E
RCCl3
O
Nu
O
RR Cl
Cl
O
M+base
a
b
c
d
Nu-
E+
enolate
haloformC-C cleavage
intermolecularreaction with E+
Favorskirearrangement
Substrate Scope
R
NPPh2
O
CCl3
O
MeR
NH
Me
O
CCl3
Ph2PO
p-MeO-C6H4OLi(10 mol%)
THF/CH2Cl2 = 1:1-40 oC, 3 MSÅ
+
syn (rac)(2 eq)
R t (h) yield (%) syn/anti
Ph 3 96 >20:1
4-Cl-C6H4 4 93 >20:1
4-MeO-C6H4 5 68 >20:1
2-furyl 1 88 6:1
2-thienyl 2 89 8:1
(E)-PhCH=CH 1 81 7:1
Cy 2 78 >20:1
iPr 3 71 >20:1
nBu 3 73 >20:1
Morimoto, H.; Wiedemann, S. H.; Yamaguchi, A.; Harada, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 3146
Catalytic Cycle
Morimoto, H.; Wiedemann, S. H.; Yamaguchi, A.; Harada, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 3146
OR' Cl
ClCl
ArOH
ArOLi
OR' Cl
ClClH
Li
R
N
R'
O
CCl3
Ph2PO
Li
R
NH
R'
O
CCl3
Ph2PO
ArOH
+
O
Cl
ClClHR
N
PPh Ph
OLi
R'
H
R
NPPh2
O
Asymmetric Variant
R
N
H
S OO CCl3
O
CH3
+
La(OAr)3 (10 mol%)(S,S)-iPr-pybox (10 mol%)
LiOAr (5mol%)
THF/toluene (1:1, 1.0M)3 MS, -40 oC
( Ar= 4-MeO-C6H4-)
CCl3
O
CH3
R
NHSO
O
S S
(2.0 eq) Å
NO
N N
O
(S,S)-iPr-pybox
R t (h) yield (%) dr (syn/anti) ee (%)
Ph 9 96 21:1 96
4-Cl-C6H4 20 97 20:1 96
4-MeO-C6H4 21 96 22:1 95
2-furyl 4 98 8:1 96
2-thienyl 19 98 20:1 95
(E)-PhCH=CH 19 75 21:1 96
Cy 22 85 >30:1 96
iBu 25 72 30:1 98
Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc., 2007, 129, 9588
NO
N N
O
La(OAr)3
+LiOAr
Mechanism Study
• La-OAr moiety functions as a Brønsted base to form La-enolate
• Preliminary kinetic studies on the concentration of trichloromethyl ketone suggested that the enolateformation is the RDS in the absence of LiOAr.
• Two possibilities for the role of LiOAr: (a) Complexation with La(OAr)3/pybox to form more basic ate complex(b) LiOAr deprotonates trichloromethyl ketone to form Li-enolate, followed by rapid transmetallation to generate La-enolate.
NO
N N
O
La(OAr)3
+LiOAr
Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc., 2007, 129, 9588
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
O
NOH
N-acylpyrroles
Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,Int. Ed. 2005, 44, 4365
OHOH
O
HOHO
a: X= H: (S, S)-linked-binolb: X= TMS: (S, S)-6,6',6'',6'''-TMS-linked-binol
X X
X X
+ In(OiPr)3
O
OH
O
NOH
Y
aromaticketone
N-acylpyrrole
aromaticity of pyrrolesame coordination mode as ketoneactivated carboxylic acid derivative
Substrate Scope
R yield (%) dr (syn/anti) ee (%) (syn, anti)
(E)-PhCH=CH 94 91:9 96, 83
Ph 98 61:39 91, 81
4-Cl-C6H4 97 59:41 96, 94
Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,Int. Ed. 2005, 44, 4365
R yield (%) dr (anti/syn) ee (%) (anti, syn)
2-naphthyl 87 77:23 94, 89
2-MeO-C6H4 74 77:23 92, 86
Cyclopropyl 86 75:25 98, 90
NO
NOH
In(OiPr)3 (20 mol%)Ligand a (10 mol%)
5 MS, THF, RT89-111 h
Å
O
NOH
NH
R
o-Ts
SR
O
NOH
NH
R
o-Ts
SS+
syn anti(2 eq)
+R
o-Ts
O
NOH
In(OiPr)3 (20 mol%)Ligand a or b (10 mol%)
5 MS, THF, RT65-99 h
Å
O
NOH
NH
R
o-Ts
SR
O
NOH
NH
R
o-Ts
SS +
synanti(2 eq)
+N
R
o-Ts
Transition-State Model
RH
NO H
o-Ts
O N
In RH
NH O
o-Ts
N OIn
O
NOH
NH
R
o-Ts
SR
syn
TS-1 TS-2
R = alkenyl,less hindered Ar
O
NOH
NH
R
o-Ts
SS
anti
R = cyclopropyl,o-substituted Ar
Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,Int. Ed. 2005, 44, 4365
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
O
NR
OMe
Boc
N-Boc-anilides
R yield (%)
Ph 91
4-MeO-C6H4 63
4-Cl-C6H4 81
1-naphthyl 95
2-furyl 78
2-thienyl 83
(E)-PhCH=CH 76
N
HR
PPh2 O
N
OMe
Boc
O
NH
OMeN
R
BocPh2PBa(Ot-Bu)2 (5 mol%)
p-MeOC6H4OH (11 mol%)
RT, DMSO, 0.2 M5 MS, 30 min
(1.2 eq)
+
O O
Å
Saito, S.; Tsubogo, T.; Kobayashi, S. Chem. Commun. 2007, 1236.
N-Boc-anilides
N
HR
PPh2 O
N
OMe
Boc
O
NH
OMeN
R
BocPh2PBa(Ot-Bu)2 (5 mol%)Ligand (11 mol%)
RT, DMSO, 0.2 M5 MS, 30 min
(1.2 eq)
+
O O
Å
R yield (%) syn/anti
Ph 86 14:86
1-naphthyl 76 8:92
2-furyl 81 9:91
2-thienyl 81 15:85
OMeOH
Saito, S.; Tsubogo, T.; Kobayashi, S. Chem. Commun. 2007, 1236.
Catalytic Cycle
Saito, S.; Tsubogo, T.; Kobayashi, S. Chem. Commun. 2007, 1236.
N
O
OtBu
O
PMP
N
O
OtBu
O
PMP
BaOAr
N
HR
PPh2
O
O
NH
PMPN
R
BocPh2PO
R O
N N PMP
t-BuO
Ph2PArOBa O
O
O
NPMP
N
R
BocPh2P
Ba(OAr)2
ArOH
BaOAr
O
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
N2
CO2tBu
Tert-Butyl Diazoacetate
CO2HCO2H
t-Bu
t-Bu
Ar t (h) yield (%) ee (%)
Ph 24 80 95
2-Me-C6H4 72 53 90
4-Me-C6H4 18 79 95
4-Cl-C6H4 26 89 96
4-MeO-C6H4 20 72 95
2-naphthyl 17 77 94
2-furyl 5 84 85
Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc., 2007, 129, 10054
N
Ar N2
CO2tBu
N2
CO2tBuAr
NHBoccat. (5 mol%)
CH2Cl2, 4 MS, 0 oCÅ+
Boc
Outline
• Background Information
• Esters or Ester-equivalents- Glycine Schiff-bases- β-Keto Esters or Malonates- Trichloromethylketones- N-acylpyrroles- N-Boc-anilides- Diazoacetates
• Conclusions
Conclusions
• Future challenges1) Expansion on esters or ester-equivalents2) Development of catalytic versions of the racemic reactions3) Improvement on the unsatisfactory reactions (new ligands, new
metal sources, etc.)4) One-pot cascades reactions
N OR'
OAr
Ar
R1
O
OR2
O
R'O
O
OR'
O
or
O
CCl3R'
N
O
OH
O
NR'
OMe
Boc
N2
CO2tBu
R
NH
R1R2
OPG
Acknowledgement
Dr. WulffDr. Walker, Dr. Staples
Li, Zhenjie, Aman, Munmun, Zhensheng, Anil, Nilanjana, Dima, Victor, Alex, Kostas
All those attended the seminar