an unexpected organocatalytic asymmetric tandem michael ...ccc.chem.pitt.edu/wipf/current...
TRANSCRIPT
An Unexpected Organocatalytic Asymmetric TandemMichael/Morita-Baylis-Hillman Reaction
Silvia Cabrera, José Alemán, Patrick Bolze, SørenBertelsen, and Karl Anker Jørgensen
Angew. Chem. Int. Ed. 2007 Early ViewBryan Wakefield
Current Lit. 11/23/07
Bryan Wakefield @ Wipf Group 1 2/17/2008
Iminium Ion Activation of α,β UnsaturatedCarbonyls with 2° Amines: 1,4 Additions
R1 OOR3O
R2
NH
N
O
Bn tBu
20 mol%
DCM-H2OR1
OR2
O
O
D. MacMillan and co-workers, J. Am. Chem. Soc. 2003, 1192
6:1 to 31:1 syn:anti73-87% yield84-99% ee
R1
O
R2
NO2
NH
CO2H
20 mol%
R1
O
R2
O2N
5-100% yield34-86% ee
K. A. Jørgensen and coworkers J. Am. Chem. Soc. 2002, 8831also seeK. A. Jørgensen and coworkers Org. Lett. 2005, 3897
Bryan Wakefield @ Wipf Group 2 2/17/2008
Iminium Ion Activation of α,β UnsaturatedCarbonyls with 2° Amines: 1,4 Additions
NH
N
Bn CO2H
10 mol%
R1
O
R2
CO2Bn
CO2BnNeat, RT R1
O
R2
CO2BnBnO2C
2-99% yield59-99% ee
K. A. Jørgensen and coworkers Angew. Chem. Int. Ed. 2003, 661
O O
OH
R1
O
R2
NH
N
Ph CO2H
Ph
10 mol%
DCM O O
OH R1 R2
O
K. A. Jørgensen and coworkers Angew. Chem. Int. Ed. 2003, 4955
68-99% yield75-88% ee
Bryan Wakefield @ Wipf Group 3 2/17/2008
Mechanistic Insights for the Design ofTandem Processes
R1 O
NH
H2O
R1 N
Nu
R1 N
Nu
R1 N
Nu
H2O
R1 O
Nu
E
R1 N
Nu
E
H2O
R1 O
Nu
E
NH
Bryan Wakefield @ Wipf Group 4 2/17/2008
Examples of Iminium/Enamine TandemReactions
R1 OS
O
R2
NH
CO2H
20 mol%
R1
R2
OHC
6:1 to 72:1 d.r.63-85% yield89-96% ee
D. MacMillan and coworkers J. Am. Chem. Soc. 2005, 3240
R1 O Nu
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
R1
Nu
9:1 to 25:1 d.r.67-97% yield99% ee
D. MacMillan and coworkers J. Am. Chem. Soc. 2005, 15051
NH
NO
tBu
BnN
20 mol%
Bryan Wakefield @ Wipf Group 5 2/17/2008
Examples of Iminium/Enamine TandemReactions
NH
N
O
Bn tBu
20 mol%
O
O
R1
NH
EtO2C CO2Et
CHO
O
R
B. List and coworkers J. Am. Chem. Soc. 2005, 15036
15:1 to 50:1 d.r.86-98% yield86-96% ee
Bryan Wakefield @ Wipf Group 6 2/17/2008
Reaction Design: Trapping of the LatentEnamine
R1 N
O
CO2Et
R2
R1
EtO2C
O
N
R2
3
Bryan Wakefield @ Wipf Group 7 2/17/2008
Reaction Optimization
Bryan Wakefield @ Wipf Group 8 2/17/2008
Substrate Scope
Bryan Wakefield @ Wipf Group 9 2/17/2008
Mechanism
Bryan Wakefield @ Wipf Group 10 2/17/2008
Investigation of Morita-Baylis-HillmanReaction
Bryan Wakefield @ Wipf Group 11 2/17/2008
Functionalization of the Products
Bryan Wakefield @ Wipf Group 12 2/17/2008
Conclusion
• A new tandem organocatalytic reaction has beenreported.
• This is an unusual sequence involving the use of asecondary amine in a Morita-Baylis-Hillman reaction.
• This reaction generates highly functionalizedcyclohexanones that could be used as library buildingblocks or in natural products total synthesis.
Bryan Wakefield @ Wipf Group 13 2/17/2008