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Organic Name reaction
JAYANTA SAHA
MSc
Asymmetric Michael Additions:
Advancements in Organocatalysis
Michael Additions
Arthur Michael
“the way how this combination (of malonate
ester with unsaturated acid ester) resulted wa...
Mechanism Of Micheal addition:
O
O
O
O
Na
O
O
Br
CO2Et
CO2Et
O
O
Br
Michael, A. J.Prakt.Chem. 1887, 35, 349;
“On the Addit...
1,2 - Addition
1,4 - Addition
O
Ph
Ph O
MgBr
MgBr
Ph OH
racemic
H
Nu
Me
Nu
Me
Nu
O
Me
O OR
R R
H
Me
Nu OH
R
R = H, alkyl
Classical Reaction Challenges
Nu
Me
Nu
Me
Nu
O
Me
O OR
R R
H
Me
Nu OH
R
Me
Nu O
R
E
E
(electrophile)
R = H, alkyl
• Scope ...
• Outline
• Enamine/Iminium Catalysts
• Michael Cascades
• Reductive Michael
• Hetero-Michael
Enamine / Iminium Catalysis
N
H
N
O Me
t-Bu
Ar
Imidazolidinone
= HNR2
·TFA
O
O
N
N
R
R
R
R
±H2O
±H2O
Enamine (En)
Iminium ...
I
• Imidazolidinone Catalyst
Me
N
H
NO
Me
t-Bu
Ph
N
N
O
N
H
NO
Me
Ph
Me
Me
H
H
H
HH
H
H
H
MeN
N
O H
H
H
HH
H
H
Me
N
R
MeN
...
Aromatic Nucleophiles
Me O
Ar (Nu)
(E)
O
Cl
Cl
Cl
Cl
Cl
Cl
Im En
20 mol% cat.
EtOAc
N
Bn
OTMSO
Me
71% yield, d.r. >25:1,
>...
Catalytic Cycle
N
H
N
O Me
t-Bu
Ar
N
N
O Me
t-Bu
Ar
N
N
O Me
t-Bu
Ar
R
X
RNu
+HX
N
N
O Me
t-Bu
Ar
RNu
+H2O
X
E
Me O
Nu
E
+...
Mukaiyama-Michael Reaction
O CO2MeO
t-BuO2C
O
O
CO2Me
O
CO2t-Bu20 mol%·TFA
THF-H2O, 4°C
N
N O
Me
t-Bu
Ph
90% yield, 89% ee...
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
Ph
CO2Bn
O N
H
H
N
CO2H
Bn
10 mol%
EtOH, 25°C
O
Ph
Ar
HO
CO2Bn
Ar = Ph
80% yield, 95% ee
97:3 d...
Michael Cascades
Ph
O
Ph
Ph
HO
CO2Bn
O
Ph
Ph
HO
CO2Bn
O
OPh
Ph
O
Ph
Ph
O
CO2Bn
CO2Bn
anti
syn
cis
equatorial
Ph
O
Ph
CO2Bn...
Chiral Cyclopentanes
O
H
R
CO2Et
CO2Me
MeO2C N
H
Ph
Ph
OTMS
N
R
Ph
Ph
OTMS
N
R
Ph
Ph
OTMS
MeO2C CO2Me
CO2Et
1st Michael 2n...
Triple Cascade
N
H
Ph
OTMS
Ph
O
Ph
NO2
O
Ph
(S)-1
A
B
C
3
4
5
2
(S)-1
Enamine catalysis
O
NO2
Ph
(S)-1
H2O
H2O
H2O
Iminium...
• Outline
• Enamine/Iminium Catalysts
• Michael Cascades
• Reductive Michael
• Hetero-Michael
Reductive Michael Additions
CHCl3, -30 50°C
O
R2
R1 O
R2N
H
MeMe
EtO2C CO2Et
N
N
H
Me
O
t-Bu
Ph O
Et
c-hex O
Et
t-Bu O
Me
...
Reductive Michael Cyclization
COPh
CHO
COPh
CHO
CHO
CHO
COPh
COPh
95% yield
72% ee, 24:1 d.r.
85% yield,
95% ee,12:1 d.r.
...
Reductive Michael Cascade
-H2O
N
H
MeMe
EtO2C CO2Et
N MeMe
EtO2C CO2Et
H
+H2O
N
H
NO
Me
Bn ·HCl
t-Bu
N
NO
Me
Bn Cl
t-Bu
O
...
Cyclic Reduction
MacMillan, D. et.al. J. Am. Chem. Soc. 2006, 128, 12662-12663.
O
R
O
R
N
H
N
Me
O
Ph
O
Me
N
H
Me
t-Bu t-B...
• Outline
• Enamine/Iminium Catalysts
• Michael Cascades
• Reductive Michael
• Hetero-Michael
Asymmetric Hetero-Michael
O
X
X O
X = S, O, N, P
Michael
retro-Michael
Sulfa-Michael
Ph O t-Bu SH
N
H
OTMS
Ar
Ar
10 mol%
A...
Tetrahydrothiophenes
Jørgensen, K. et.al. J. Am. Chem. Soc. 2006, 128, 14986-14991.
Ph
SH
R
O
O
N
H
Ar
Ar
OTMS
10 mol%, Ph...
Oxa-Michael
O
OH
X
N
H
Ph
Ph
OTMS
20 mol% cat.
20 mol% o-NO2PhCO2H
O
CHO
X
O
R
toluene, 25°C
O Ph
CHO
O
CHO
O CO2Et
CHO
O
...
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
Michel Addition
Michel Addition
Michel Addition
Michel Addition
Michel Addition
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Michel Addition

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Michel Addition & recent advancement

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Michel Addition

  1. 1. Organic Name reaction JAYANTA SAHA MSc Asymmetric Michael Additions: Advancements in Organocatalysis
  2. 2. Michael Additions Arthur Michael “the way how this combination (of malonate ester with unsaturated acid ester) resulted was clearly known by Mr. Claisen and correctly described. Mr. Michael contributed to make the reaction remarkably practical by the use of sodium compounds of malonate and acetoacetate esters and to have substantially generalized.”- Ernst Von Meyer
  3. 3. Mechanism Of Micheal addition: O O O O Na O O Br CO2Et CO2Et O O Br Michael, A. J.Prakt.Chem. 1887, 35, 349; “On the Addition of Sodioacetoacetic and Sodiomalonic Ester to Unsaturated Acid Esters,”
  4. 4. 1,2 - Addition 1,4 - Addition O Ph Ph O MgBr MgBr Ph OH racemic H Nu Me Nu Me Nu O Me O OR R R H Me Nu OH R R = H, alkyl
  5. 5. Classical Reaction Challenges Nu Me Nu Me Nu O Me O OR R R H Me Nu OH R Me Nu O R E 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
  6. 6. • Outline • Enamine/Iminium Catalysts • Michael Cascades • Reductive Michael • Hetero-Michael
  7. 7. Enamine / Iminium Catalysis N H N O Me t-Bu Ar 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
  8. 8. I • Imidazolidinone Catalyst Me N H NO Me t-Bu Ph N N O N H NO Me Ph Me Me H H H HH H H H MeN N O H H H HH H H Me N R MeN N O Me Me Me H MeN N O Me Me Me Me N R HH HH MacMillan, D. and Austin, J. J. Am. Chem. Soc. 2002, 124, 1172- 1173
  9. 9. Aromatic Nucleophiles Me O Ar (Nu) (E) O Cl Cl Cl Cl Cl Cl Im En 20 mol% cat. EtOAc N Bn OTMSO Me 71% yield, d.r. >25:1, >99% ee 75% yield, d.r.=12:1, 99% ee 86% yield, d.r.=14:1, 99% ee N Bn O Me OMe N H NO Me t-BuBnN catalyst O Cl Me O Cl Ar Me O Cl Me O Cl Me O O Me MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053.
  10. 10. Catalytic Cycle N H N O Me t-Bu Ar N N O Me t-Bu Ar N N O Me t-Bu Ar R X RNu +HX N N O Me t-Bu Ar RNu +H2O X E Me O Nu E +H2O O Nu E Cascade Product Iminium (Im) Enamine (En) MacMillan, D. et.al. J. Am. Chem. Soc. 2005, 127, 15051-15053.
  11. 11. Mukaiyama-Michael Reaction O CO2MeO t-BuO2C O O CO2Me O 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 H2O N H NO t-Bu Me Ph O CO2MeOTIPS MacMillan, D. et.al. J. Am. Chem. Soc. 2003, 125, 1192-1194.
  12. 12. Chem. Soc. Rev., 2014, 43, 7430 Aza-Michael reaction
  13. 13. Catalytic Cycle Chem. Soc. Rev., 2014, 43, 7430
  14. 14. Asymmetric Aza-Michaels Chem. Soc. Rev., 2014, 43, 7430
  15. 15. Catalytic Cycle Chem. Soc. Rev., 2014, 43, 7430
  16. 16. • Outline • Enamine/Iminium Catalysts • Michael Cascades • Reductive Michael • Hetero-Michael
  17. 17. Michael-Aldol Cascade Ar O Ph CO2Bn O N H H N CO2H Bn 10 mol% EtOH, 25°C O Ph Ar HO CO2Bn Ar = Ph 80% yield, 95% ee 97:3 d.r. Ar yield (%) ee (%) 4-Cl-Ph 60 97 2-NO2-Ph 56 96 2-furyl 40 85 2-thiophene 52 83 Jorgensen, K. et.al. Angew. Chem. Int. Ed. 2004, 43, 1272-1277
  18. 18. Michael Cascades Ph O Ph Ph HO CO2Bn O Ph Ph HO CO2Bn O OPh Ph O Ph Ph O CO2Bn CO2Bn anti syn cis equatorial Ph O Ph CO2Bn O N H H N CO2H Bn Iminium-catalyzed Michael O Ph CO2Bn Ph O O Ph CO2Bn O Base-catalyzed Aldol Jorgensen, K. et.al. Angew. Chem. Int. Ed. 2004, 43, 1272-1277
  19. 19. Chiral Cyclopentanes O H R CO2Et CO2Me MeO2C N H Ph Ph OTMS N R Ph Ph OTMS N R Ph Ph OTMS MeO2C CO2Me CO2Et 1st Michael 2nd Michael H2O catalyst R CHO MeO2C CO2Me CO2Et 10 mol% EtOH, 25°C MeO2C CO2Me CO2Et Wang, W. et.al. Angew. Chem. Int. Ed. 2007, 46, 3732-3734.
  20. 20. Triple Cascade N H Ph OTMS Ph O Ph NO2 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 CASCADE CYCLEN NO2 Ph Ph Ph OTMS Ph O N NO2 Ph Ph Ph OTMS Ph O O PhPh NO2 TBSO TBSO TBSO TBSO TBSO Enders, D. et.al. Nature 2006, 441, 861-863
  21. 21. • Outline • Enamine/Iminium Catalysts • Michael Cascades • Reductive Michael • Hetero-Michael
  22. 22. Reductive Michael Additions CHCl3, -30 50°C O R2 R1 O R2N H MeMe EtO2C CO2Et N N H Me O t-Bu Ph O Et c-hex O Et t-Bu O Me MeO2C O Me 20 mol% ·TFA R1 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
  23. 23. Reductive Michael Cyclization COPh CHO COPh CHO CHO CHO COPh COPh 95% yield 72% ee, 24:1 d.r. 85% yield, 95% ee,12:1 d.r. N H MeMe EtO2C CO2Et N H NO Me Bn ·HCl dioxane 25°C COR CHO CHO COR t-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
  24. 24. Reductive Michael Cascade -H2O N H MeMe EtO2C CO2Et N MeMe EtO2C CO2Et H +H2O N H NO Me Bn ·HCl t-Bu N NO Me Bn Cl t-Bu O O O N NO Me Bn Cl t-BuO Cl N NO Me Bn t-Bu HO O O List, B. et.al. J. Am. Chem. Soc. 2005, 127, 15036-15037.
  25. 25. Cyclic Reduction MacMillan, D. et.al. J. Am. Chem. Soc. 2006, 128, 12662-12663. O R O R N H N Me O Ph O Me N H Me t-Bu t-Bu Me 20mol% O R O REt2O, 0°C O O O n-Bu Me O 82% yield 90% ee 71% yield 88% ee 81% yield 96% ee 78% yield 91% ee O c -hex
  26. 26. • Outline • Enamine/Iminium Catalysts • Michael Cascades • Reductive Michael • Hetero-Michael
  27. 27. Asymmetric Hetero-Michael O X X O X = S, O, N, P Michael retro-Michael Sulfa-Michael Ph O t-Bu SH N H OTMS Ar Ar 10 mol% Ar=3,5-(CF3)2C6H3 PhCO2H (10 mol%) toluene, -24°C Ph O S t-Bu Ph OH S t-Bu NaBH4 80% yield, 90% ee Me OH S Bn 80% yield, 89% ee Jørgensen, K. et.al. J. Am. Chem. Soc. 2005, 127, 15710-15711.
  28. 28. Tetrahydrothiophenes Jørgensen, K. et.al. J. Am. Chem. Soc. 2006, 128, 14986-14991. Ph SH R O O N H Ar Ar OTMS 10 mol%, PhCO2H R N R S Ph O N S Ph R HO Michael Aldol Hydrolysis CHO S Ph R HO tetrahydrothiophenes N Ar Ar OTMS Ar Ar OTMS Ar Ar OTMS R = alkyl 44-74% yield 90-95% ee
  29. 29. Oxa-Michael O OH X N H Ph Ph OTMS 20 mol% cat. 20 mol% o-NO2PhCO2H O CHO X O R toluene, 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% ee NO2 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.
  30. 30. 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
  31. 31. 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

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