michel addition
TRANSCRIPT
Organic Name reaction
JAYANTA SAHAMSc
Asymmetric Michael Additions: Advancements in Organocatalysis
Michael Additions
Arthur Michael
“the way how this combination (of malonateester with unsaturated acid ester) resulted was clearly knownby Mr. Claisen and correctly described. Mr. Michael contributed to make the reaction remarkably practical by the use ofsodium compounds of malonate and acetoacetate esters andto have substantially generalized.”- Ernst Von Meyer
Mechanism Of Micheal addition:
O
O
O
ONa
O
O
Br
CO2Et
CO2EtO
O
Br
Michael, A. J.Prakt.Chem. 1887, 35, 349;
“On the Addition of Sodioacetoacetic and Sodiomalonic Ester to Unsaturated Acid Esters,”
1,2 - Addition
1,4 - Addition
OPh
Ph OMgBr
MgBrPh OH
racemic
H
Nu Me
Nu
Me
NuO
Me
O OR
R RH
Me
Nu OH
R
R = H, alkyl
Classical Reaction Challenges
Nu Me
Nu
Me
NuO
Me
O OR
R RH
Me
Nu OH
R
Me
Nu O
RE
E
(electrophile)
R = H, alkyl
• Scope of Nucleophiles (formation of C–C, N, O, S, P Bonds)
• Alkene Substitution Patterns
• Scope of Electrophile
• Control Stereochemistry Catalytically
• Outline
• Enamine/Iminium Catalysts• Michael Cascades• Reductive Michael• Hetero-Michael
Enamine / Iminium Catalysis
NH
NO Me
t-BuAr
Imidazolidinone= HNR2
·TFA
O
O
N
N
R
R
R
R
±H2O
±H2O
Enamine (En)
Iminium (Im)
MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053
I
• Imidazolidinone Catalyst
Me
NH
NOMe
t-Bu
Ph
N
N
O
NH
NOMe
Ph
Me
Me
H
HHHH
H
H
H
MeN
N
O H
HHHH
H
H
MeNR
MeN
N
O Me
Me
Me
H
MeN
N
O Me
Me
Me
MeNR
HH
HH
MacMillan, D. and Austin, J. J. Am. Chem. Soc. 2002, 124, 1172-1173
Aromatic Nucleophiles
Me O
Ar (Nu)
(E)
OCl
Cl
ClCl
Cl
Cl
Im En
20 mol% cat.EtOAc
NBn
OTMSOMe
71% yield, d.r. >25:1, >99% ee
75% yield, d.r.=12:1, 99% ee
86% yield, d.r.=14:1, 99% ee
NBn
OMe OMe
NH
NOMe
t-BuBnN
catalyst
OCl
Me
OCl
Ar
Me
OCl
Me
OCl
Me
OO
Me
MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053.
Catalytic Cycle
NH
NO Me
t-BuAr
N
NO Me
t-BuAr
N
NO Me
t-BuAr
R
X
RNu
+HX
N
NO Me
t-BuAr
RNu
+H2O
X
E
Me O
Nu
E
+H2O
O
NuE
Cascade Product
Iminium (Im)
Enamine (En)
MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053.
Mukaiyama-Michael ReactionO CO2MeO
t-BuO2C
OO
CO2MeO
CO2t-Bu20 mol%·TFA
THF-H2O, 4°C
N
N O
Me
t-Bu
Ph
90% yield, 89% ee,11:1 syn :anti
TIPS
t-BuO2C O
H2ONH
NOt-Bu
Me
Ph
O CO2MeOTIPS
MacMillan, D. et.al. J. Am. Chem. Soc. 2003, 125, 1192-1194.
Chem. Soc. Rev., 2014, 43, 7430
Aza-Michael reaction
Catalytic Cycle
Chem. Soc. Rev., 2014, 43, 7430
Asymmetric Aza-Michaels
Chem. Soc. Rev., 2014, 43, 7430
Catalytic Cycle
Chem. Soc. Rev., 2014, 43, 7430
• Outline
• Enamine/Iminium Catalysts• Michael Cascades• Reductive Michael• Hetero-Michael
Michael-Aldol Cascade
Ar
O
PhCO2Bn
O NH
HN
CO2HBn
10 mol%
EtOH, 25°C
O
Ph ArHO
CO2Bn
Ar = Ph80% yield, 95% ee
97:3 d.r.
Ar yield (%) ee (%)4-Cl-Ph 60 97
2-NO2-Ph 56 962-furyl 40 85
2-thiophene 52 83
Jorgensen, K. et.al. Angew. Chem. Int. Ed. 2004, 43, 1272-1277
Michael Cascades
Ph
O
Ph PhHO
CO2Bn
O
Ph PhHO
CO2Bn
O
OPh
Ph
O
Ph
Ph
O
CO2Bn
CO2Bn
anti
syn
cis
equatorial
Ph
O
PhCO2Bn
O
NH
HN
CO2HBn
Iminium-catalyzedMichael
OPh
CO2BnPh
O
OPh
CO2Bn
O
Base-catalyzed Aldol
Jorgensen, K. et.al. Angew. Chem. Int. Ed. 2004, 43, 1272-1277
Chiral Cyclopentanes
O
H
R
CO2EtCO2Me
MeO2C NH
PhPh
OTMSN
R
PhPh
OTMS
N
R
PhPh
OTMS
MeO2C CO2Me
CO2Et
1st Michael 2nd Michael
H2O catalystR
CHO
MeO2C CO2Me
CO2Et
10 mol%
EtOH, 25°CMeO2C
CO2Me
CO2Et
Wang, W. et.al. Angew. Chem. Int. Ed. 2007, 46, 3732-3734.
Triple Cascade
NH
PhOTMS
Ph
O
PhNO2
O
Ph
(S)-1
A B
C
3
4
5
2
(S)-1
Enamine catalysis
O
NO2
Ph
(S)-1
H2O
H2O
H2O
Iminium catalysis
CASCADECYCLEN
NO2
Ph Ph
PhOTMS
Ph
O N
NO2
Ph Ph
PhOTMS
Ph
O
O
PhPhNO2
TBSO
TBSO
TBSO
TBSO
TBSO
Enders, D. et.al. Nature 2006, 441, 861-863
• Outline
• Enamine/Iminium Catalysts• Michael Cascades• Reductive Michael• Hetero-Michael
Reductive Michael Additions
CHCl3, -30 50°C
O
R2
R1 O
R2NH
MeMe
EtO2C CO2EtN
NH
MeO
t-Bu
Ph O
Et
c-hex O
Et
t-Bu O
Me
MeO2C O
Me
20 mol% ·TFAR1
74% yield, 94% ee 95% yield, 97% ee83% yield, 91% ee 95% yield, 91% ee
MacMillan, D. et.al. J. Am. Chem. Soc. 2004, 127, 32-33
Reductive Michael Cyclization
COPh
CHO
COPh
CHO
CHO
CHO
COPh
COPh
95% yield72% ee, 24:1 d.r.
85% yield,95% ee,12:1 d.r.
NH
MeMe
EtO2C CO2EtNH
NOMe
Bn ·HCl
dioxane25°C
COR
CHOCHO
CORt-Bu
20 mol%
R = Ph, 98% yield, 96% ee, 15:1 d.r.
R = Me, 91% yield, 91% ee, 50:1 d.r.
List, B. et.al. J. Am. Chem. Soc. 2005, 127, 15036-15037
Reductive Michael Cascade
-H2ONH
MeMe
EtO2C CO2Et
N MeMe
EtO2C CO2Et
H
+H2O
NH
NOMe
Bn ·HCl
t-Bu
N
NOMe
Bn Clt-Bu
OO
O
N
NOMe
Bn
Cl
t-BuO
Cl
N
NOMe
Bnt-Bu
HO
O
O
List, B. et.al. J. Am. Chem. Soc. 2005, 127, 15036-15037.
Cyclic Reduction
MacMillan, D. et.al. J. Am. Chem. Soc. 2006, 128, 12662-12663.
O
R
O
RNH
NMe
O
Ph
O Me
NH
Me
t-Bu t-Bu
Me
20mol%
O
R
O
REt2O, 0°C
O O O
n-Bu MeO
82% yield90% ee
71% yield88% ee
81% yield96% ee
78% yield91% ee
O
c -hex
• Outline
• Enamine/Iminium Catalysts• Michael Cascades• Reductive Michael• Hetero-Michael
Asymmetric Hetero-MichaelO
XX O
X = S, O, N, P
Michael
retro-Michael
Sulfa-Michael
Ph O t-Bu SH
NH
OTMS
ArAr
10 mol%Ar=3,5-(CF3)2C6H3
PhCO2H (10 mol%)toluene, -24°C
Ph O
St-Bu
Ph OH
St-Bu
NaBH4
80% yield, 90% ee
Me OH
SBn
80% yield, 89% ee
Jørgensen, K. et.al. J. Am. Chem. Soc. 2005, 127, 15710-15711.
Tetrahydrothiophenes
Jørgensen, K. et.al. J. Am. Chem. Soc. 2006, 128, 14986-14991.
PhSH
R
O
O
NH
ArAr
OTMS
10 mol%, PhCO2H
R
N
R S
PhO
N
S
Ph
R
HO
Michael
Aldol
Hydrolysis
CHO
S
Ph
R
HO
tetrahydrothiophenes
N
ArAr
OTMS
ArAr
OTMS
ArAr
OTMS
R = alkyl44-74% yield90-95% ee
Oxa-Michael
O
OHX
NH
PhPh
OTMS
20 mol% cat.20 mol% o-NO2PhCO2H
O
CHO
X
O
Rtoluene, 25°C
O Ph
CHO
O
CHO
O CO2Et
CHO
O
CHO
O CO2Et
CHO
O CO2Et
CHO
81% yield, 88% ee
57% yield, 87% eeNO2
95% yield, 90% ee
92% yield, 93% ee
MeO
F
Me
65% yield, 97% ee
72% yield, 98% ee
R
Chromenes = privileged structure
Cordova, A. et.al. Chem. Eur. J. 2007, 13, 574-581; Nicolaou, K.C. et.al. J. Am. Chem. Soc. 2000, 122, 9968.
Oxa-Michael
RSC Adv., 2015, 5, 88133,L.-Y. Cui,ab Y.-H. Wang,ab S.-R. Chen,ab Y.-M. Wangab and Z.-H. Zhou
PROPOSED TRANSITION STATE
RSC Adv., 2015, 5, 88133,L.-Y. Cui,ab Y.-H. Wang,ab S.-R. Chen,ab Y.-M. Wangab and Z.-H. Zhou
