Enamine Based Organocatalysis

1
Enamine Based Organocatalysis

• Anna Innitzer
• 21.06.05

2
Introduction
Hajos, J. Parrish, D. JOC, 1974, 39, 1615
3
Introduction
favourable O-H-O hydrogen bond
reaction is first order in proline
additional stability due to NC-H-O hydrogen bond
Houk, K. JACS 2002, 124, 7163
4
General Mechanism for Enamine-Catalytic-Cycle
5
Aldol Additions Ketones as Donors
List, B. JACS 2000, 122, 2395 List, B. JACS 2000,
122, 7386 List, B. Org. Lett. 2001, 3, 573
6
Use of Aldehydes as Donors Total Synthesis of
Prelactone B
MacMillan, D. JACS 2002, 124, 6798
7
Use of Aldehydes as Donors Total Synthesis of
Prelactone B
MacMillan, D. JACS 2002, 124, 6798
shortest reported synthesis most expensive
reagent is TBSOTf
Pihko, P. Tet. Lett. 2003, 44, 7607
8
Trimerisation of Propionaldehyde Carbohydrate
Syntheses
Barbas, C. Tet. Lett. 2002, 43, 9591
9
Aldol Addition to Activated Carbonyl Compounds -
An Access to ß-Hydroxynitrones
Jorgensen, K. Chem. Comm. 2002, 620 Jorgensen,
K. Synlett, 2003, 12, 1915
10
Mannich Reaction

• enamine addition to imine must be faster than
  addition to the aldehyde
• formation of the aldimine must be faster than
  the aldol addition

List, B. JACS, 2000, 122, 9336
11
Mannich Reaction

• enamine addition to imine must be faster than
  addition to the aldehyde
• formation of the aldimine must be faster than
  the aldol addition

• aliphatic aldehydes (incl. a-unbranched!)
• are good substrates, up to 93 ee and 90 yield
• aromatic aldehydes are even better,
• up to 99 ee and 95 yield

List, B. JACS, 2000, 122, 9336
12
Mannich Reaction- Diastereoselectivity
List, B. JACS, 2002, 124, 827
13
a-Iminoethylglyoxylate as Mannich Acceptor An
Access to a-Amino Acid Derivatives
for aldehydes as donors see
Barbas, C. JACS, 2002, 124, 1842
Barbas, C. JOC 2003, 68, 9624
14
Use of Products Synthesis of Oxazolindones,
b-Aminoalcohols and a-Amino Acid Derivatives
List, B. Synlett 2003, 1903
15
Use of Products Synthesis of Oxazolindones,
b-Aminoalcohols and a-Amino Acid Derivatives
List, B. Synlett 2003, 1903
Barbas, C. Tet. Lett 2003, 44, 1923
16
Anti Selective Mannich Reaction
Barbas, C. Tet. Lett. 2002, 43, 7749
17
a-Amination An Access to a-Amino Acids
List, B. JACS 2002, 124, 5656
18
a-Oxidation of Carbonyls with Nitrosobenzene
Yamamoto, H. Org. Lett. 2002, 4, 3579
R Me, n-Bu, i-Pr, allyl, Bn, Ph,
(CH2)3-OTIPS
product most isolated after reduction with NaBH4
yields 76 99 ee 97 - 99
McMillan, D. JACS 2003, 125, 10808
19
Michael Addition
Barbas, C. Org. Lett. 2001, 3, 3737
20
Michael Addition
Barbas, C. Org. Lett. 2001, 3, 3737
Jorgensen, K. Angew.Chem.Int.Ed. 2004, 43, 1272
21
SN2 Alkylations
List, B. JACS, 2003, 125, 450
List, B. PCT Int. Appl. 2005, WO2005037765
22
Enantioselective Inverse-Electron-Demand
Hetero-Diels-Alder Reaction
Jorgensen, K. Angew.Chem.Int.Ed. 2003, 42, 1498
23
Catalytic, Asymmetric 22 Cyclisation of
Ketenes/Zwitterionic Enolates and Imines
Lectka, T. Acc.Chem.Res. 2004, 37, 592 and
references therein.
24
Synthesis of b-Lactams and b-Substituted Aspartic
Acid Derivatives
25
Conclusion

• reactions are direct
• no need to modify (deprotonate, silylate) the
  donor

• catalysts are inexpensive, non-toxic,
  recoverable,
• commercially available or
• _at_ least easily accessible

• many reactions can be run _at_ room temperature,
• under aerobic atmosphere and in wet solvents

• various types of reactions can be catalysed

26
References

• mannich
• Barbas, C. Tet. Lett. 2002, 43, 7749
• Barbas, C. Tet. Lett 2003, 44, 1923
• List, B. Synlett 2003, 1903List, B. Synlett 2003,
  1903
• Barbas, C. JOC 2003, 68, 9624
• Barbas, C. JACS, 2002, 124, 1842
• List, B. JACS, 2002, 124, 827
• List, B. JACS, 2000, 122, 9336

• recent review
• Dalko, P. Angew. Chem. 2004, 116, 5248.
• special issue
• Asymmetric Organocatalysis Acc.Chem.Res. 2004,
  37, 8, 487.
• general stuff
• Hajos, J. Parrish, D. JOC, 1974, 39, 1615
• Houk, K. JACS 2002, 124, 7163
• aldol reactions
• List, B. JACS 2000, 122, 2395
• List, B. JACS 2000, 122, 7386
• List, B. Org. Lett. 2001, 3, 573
• MacMillan, D. JACS 2002, 124, 6798
• Pihko, P. Tet. Lett. 2003, 44, 7607
• Barbas, C. Tet. Lett. 2002, 43, 9591
• Jorgensen, K. Chem. Comm. 2002, 620
• Jorgensen, K. Synlett, 2003, 12, 1915

• SN2 alkylations
• List, B. PCT Int. Appl. 2005,
• WO2005037765
• List, B. JACS, 2003, 125, 450

• HAD
• Jorgensen, K. Angew.Chem.Int.Ed. 2003,
• 42, 1498

• 22
• Lectka, T. Acc.Chem.Res. 2004, 37, 592 and
  references therein.