Organocatalysis: Chiral Amines in Asymmetric Synthesis

1
OrganocatalysisChiral Amines in Asymmetric
Synthesis

• Natalie Nguyen
• March 4, 2003

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Chiral Organocatalysts in Asymmetric Synthesis
Acylation of Alcohols and Amines Kinetic
Resolution
Baylis-Hillman Reaction
R OMe (Quinidine) R H (Cinchonine)
R OMe (Quinine) R H (Cinchonidine)
?-Lactone and ?-Lactam formation
Friedel-Crafts Alkylation Indole Alkylation
Diels-Alder Cycloadditon
Aldol Reaction Mannich Reaction Michael Additions
France, S. Guerin, D.J. Miller, S.J. Lectka,
T. Chem. Rev. 2003, 2985
3
Chiral Amines in Asymmetric Synthesis

• Proline Catalyzed
• Aldol Reaction
• Mannich Reaction
• Imidazolidinone Catalyzed
• Diels Alder Cycloaddition
• Total Synthesis of ()-Hapalindole Q

4
Proline Enzyme Mimic

• Inexpensive
• Available in both enantiomeric forms
• Chemzyme Mode of action very similar to enzymes

(S)-proline
(R)-proline
Bifunctional Acid and Base
Hydrogen-bond donor and acceptor
Iminium
Enamine
5
Proline in Asymmetric Synthesis

• The proline catalyzed Robinson annulation was one
  of the earliest examples of an enantioselective
  reaction
• Yamada, 1969

Yamada, S. Otani, G. Tetrahedron Lett. 1969, 4237
6
Proline in Asymmetric Synthesis
Hajos and Parrish, 1974
Synthesis of Taxol (Danishefsky, 1996)
Hajos, Z.G. Parrish, D.R. J. Org. Chem. 1974,
39, 1615 Danishefsky, S. et al. J. Am. Chem. Soc.
1996, 118, 2843
7
Intramolecular Aldol Reaction Solvents and
Catalyst

• Intramolecular aldol cyclization works best in
  aprotic polar solvents
• Protic solvents lower the enantioselectivity
  drastically
• Catalyst Screening
• Pyrrolidine ring, secondary nitrogen and
  carboxylic acid are important to catalysis

Hajos, Z.G. Parrish, D.R. J. Org. Chem. 1974,
39, 1615 Eder, U. Sauer, G. Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1976, 9, 412
8
Intramolecular Aldol Reaction Mechanism
Brown, K.L. Damm, L. Dunitz, J.D. Eschenmoser,
A. Hobi, R. Kratky, C. Helv. Chim. Acta. 1978,
61, 3108
9
Intramolecular Aldol Reaction Proposed
Transition State
Houk, 2001-2003
Agami, 1984-1986

• Attack occurs on the face opposite the carboxylic
  acid
• Transition state is controlled and stablized by
  N-H-----O hydrogen bonding

• Transition state is controlled and stablized by
  O-H-----O hydrogen bonding

Agami, C. Meynier, F. Puchot, C. Guilhem, J.
Pascard, C. Tetrahedron 1984, 40, 1031 Bahmanyar,
S Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911
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Intramolecular Aldol Reaction Proposed
Transition State
Houk, 2001-2003
Agami, 1984-1986

• Attack occurs on the face opposite the carboxylic
  acid
• Transition state is controlled and stablized by
  N-H-----O hydrogen bonding

• Transition state is controlled and stablized by
  O-H-----O hydrogen bonding
• Favorable electrostatic interactions ?NCH-----O?
  - (2.4 Å)

Agami, C. Meynier, F. Puchot, C. Guilhem, J.
Pascard, C. Tetrahedron 1984, 40, 1031 Bahmanyar,
S Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911
11
Intramolecular Aldol Reaction Proposed
Transition State
Houk, 2001-2003 List, 2003
Agami, 1984-1986

• Reaction is second order in proline
• A negative non-linear effect was observed
• Two prolines are involved

• Reaction is first order in proline
• A linear effect was observed
• One proline involved

Agami, C. Puchot, C. Sevestre, H. Tetrahedron
Lett. 1986, 27, 1501 Hoang, L. Bahmanyar, S.
Houk, K.N. List, B. J. Am. Chem. Soc. 2003, 125,
16
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Intramolecular Aldol Reaction Proposed
Transition State
si-face attack
re-face attack

• The hydrogen bonding allows the iminium double
  bond to be almost planer
• Favorable electrostatic interactions ?NCH-----O?
  - (2.4 Å)

• The hydrogen bonding forces the iminium double
  bond out of planarity
• Small electrostatic interaction
• ?NCH-----O? - (3.4 Å)
• Transition state is 3.4 kcal/mol higher in energy
  

Bahmanyar, S. Houk, K.N. J. Am. Chem. Soc. 2001,
123, 12911
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Intermolecular Aldol Reaction

• Evans Oxazolidinone Chiral auxillary

First Proline Catalyzed Direct Aldol Reaction
(List, 2000)
List, B. Lerner, R.A. Barbas III, C.F. J. Am.
Chem. Soc. 2000, 122, 2395
14
Intermolecular Aldol Reaction Mechanism

• Previously proposed Zimmerman-Traxler transition
  state is unlikely because N-H bonding does not
  occur

List, B. Tetrahedron, 2002, 58, 5573 Bahmanyar,
S. Houk, K.N. J. Am. Chem. Soc. 2001, 123, 11273
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Intermolecular Aldol Reaction Amino Acid
Catalysts
Catalyst Yield ee
68 76
(L)-His, (L)-Val (L)-Tyr, (L)-Phe lt10 -
55 40
lt10 -
Catalyst Yield ee
lt10 -
67 73
66 86
lt10 -
List, B. Lerner, R.A. Barbas III, C.F. J. Am.
Chem. Soc. 2000, 122, 2395 Sakthivel, K. Notz,
W. Bui, T. Barbas III, C.F. J. Am. Chem. Soc.
2001, 123, 5260
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Intermolecular Aldol Reaction Amino Acid
Catalysts
Catalyst Yield ee
68 76
(L)-His, (L)-Val (L)-Tyr, (L)-Phe lt10 -
55 40
lt10 -
Catalyst Yield ee
lt10 -
67 73
66 86
lt10 -
List, B. Lerner, R.A. Barbas III, C.F. J. Am.
Chem. Soc. 2000, 122, 2395 Sakthivel, K. Notz,
W. Bui, T. Barbas III, C.F. J. Am. Chem. Soc.
2001, 123, 5260
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Intermolecular Aldol Reaction Substrate Scope
Product Yield ee
1 2 68 60 76 86
1 85 99
1 34 72
1 2 0 0 -
1
2

• Reaction works best with large excess of ketone
• Reaction is general to
• aromatic aldehydes
• ?-substituted aldehydes
• ?-Unsubstituted aldehydes
• Aldol condensation product was the major product

List, B. Lerner, R.A. Barbas III, C.F. J. Am.
Chem. Soc. 2000, 122, 2395 Sakthivel, K. Notz,
W. Bui, T. Barbas III, C.F. J. Am. Chem. Soc.
2001, 123, 5260
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Intermolecular Aldol Reaction Anti-Aldol Products
Product Yield anti/syn ee
1 2 60 45 201 201 99 95
1 85 11 (anti) 85 (syn) 76
1 68 201 97
1
2

• Thiaproline (2)
• Not as general as proline

Notz, W. List, B. J. Am. Chem. Soc. 2000, 122,
7386 Sakthivel, K. Notz, W. Bui, T. Barbas
III, C.F. J. Am. Chem. Soc. 2001, 123, 5260 List,
B. Pojarliev, P. Castello, C. Org. Lett. 2001,
3, 573
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Cross Aldol Reaction
Transition State
Product Yield anti/syn ee
88 31 97
81 31 95
80 241 95
82 241 99
Northrup, A.B. MacMillan, D.W.C. J. Am. Chem.
Soc. 2002, 124, 6798
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Mannich Reaction

• The rate of the Mannich reaction must be faster
  than the rate of aldol reaction

First Proline Catalyzed Direct Mannich Reaction
(List, 2000)
List, B. J. Am. Chem. Soc. 2000, 122, 9336 List,
B. Pojarliev, P. Biller, W.T. Martin, H.J. J.
Am. Chem. Soc. 2002, 124, 827
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Mannich Reaction Transition State
(E)-enamine
(E)-enamine
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
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Mannich Reaction Transition State
(E)-imine
(E)-enamine
(E)-enamine
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
23
Mannich Reaction Transition State
Nonbonding interactions
(E)-imine
(E)-enamine
(E)-enamine
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
24
Mannich Reaction Amino Acid Catalysts
Catalyst Yield ee
90 93
56 76
22 15
60 16
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
25
Mannich Reaction Amino Acid Catalysts
Catalyst Yield ee
90 93
56 76
22 15
60 16
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
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Mannich Reaction Variation in Aldehydes
Aldehyde Yield ee
50 94
90 93
35 96
56 70
Transition State
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
27
Mannich Reaction Variation in Ketones
Product Yield ee
96 2.51 99
94
93 98
Transition State
List, B. Pojarliev, P. Biller, W.T. Martin,
H.J. J. Am. Chem. Soc. 2002, 124, 827
28
Aldol and Mannich Reaction

• Direct Aldol
• Deprotonation or silylation is not required
• Direct Mannich
• Imine electrophile can be generated in situ
• Proline proved to the optimal catalyst
• Nontoxic
• Inexpensive
• Both enantiomers available
• Can be used in wet solvents and open to air
• Can be removed from reaction mixture by aqueous
  workup

(S)-proline
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Organocatalyzed Diels-Alder Cycloaddition

• Asymmetric Diels-Alder Reaction by Chiral Bases
  (Kagan, 1989)
• 
  

Transition State
Riant, O. Kagan, H.B. Tetrahedron, 1989, 30,
7403
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Diels-Alder Cycloaddition

• Exo vs Endo

exo
endo
Enantioselectivity in Diels Alder Reaction
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Diels-Alder Cycloaddition Lewis Acids and
Iminiums

• Lewis Acids and Iminiums
• lowers the energy of the LUMO

Energy
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Organocatalytic Diels-Alder Cycloaddition

• MacMillans Catalyst Design
• Lowers the energy of LUMO of the dienophile
• Kinetically labile ligand for catalytic turnover
• Chiral molecule would induce stereoselectivity

Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Am. Chem. Soc. 2000, 122, 4243
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Diels-Alder Cycloaddition Catalyst Screening
Catalyst Yield endoexo exo ee
81 12.7 48
92 12.6 57
82 13.6 74
99 11.3 93
Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Am. Chem. Soc. 2000, 122, 4243
34
Diels-Alder Cycloaddition Catalyst Screening
Catalyst Yield endoexo exo ee
81 12.7 48
92 12.6 57
82 13.6 74
99 11.3 93
Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Am. Chem. Soc. 2000, 122, 4243
35
Diels-Alder Cycloaddition Variation in
Dienophiles
R Yield endoexo exo ee endo ee
75 11 86 90
81 11 84 93
99 11.3 93 93
20 17 - -
Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Am. Chem. Soc. 2000, 122, 4243
36
Diels-Alder Cycloaddition Variation in Dienes
Diene Yield endoexo endo ee
82 141 94
90 - 83
75 51 90
72 111 85
Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Am. Chem. Soc. 2000, 122, 4243
37
Diels-Alder Cycloaddition Transition State

• Formation of (E)-imine to avoid nonbonding
  interactions between the geminal methyls
• Benzyl group shields the top face leaving the
  si-face exposed

Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Am. Chem. Soc. 2000, 122, 4243
38
Diels-Alder Cycloaddition Transition State

• Formation of (E)-imine to avoid nonbonding
  interactions between the geminal methyls
• Benzyl group shields the top face leaving the
  si-face exposed

Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Am. Chem. Soc. 2000, 122, 4243
39
Diels-Alder Cycloaddition Transition State

• Formation of (E)-imine to avoid nonbonding
  interactions between the geminal methyls
• Benzyl group shields the top face leaving the
  si-face exposed

Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Am. Chem. Soc. 2000, 122, 4243
40
Diels-Alder Cycloaddition Catalyst Screening
Catalyst Yield endoexo ee
20 71 -
89 251 90
Northrup, A.B. MacMillan, D.W.C. J. Am. Chem.
Soc. 2000, 122, 4243
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Diels-Alder Cycloaddition Variation in
Dienophiles
Dienophile Yield endoexo ee
89 241 90
78 61 90
24 81 0
Transition State
Northrup, A.B. MacMillan, D.W.C. J. Am. Chem.
Soc. 2000, 122, 4243
42
Diels-Alder Cycloaddition Variation in Dienes
Diene Yield endoexo endo ee
88 2001 94
91 1001 89
92 2001 83
90 2001 90
Transition State
Northrup, A.B. MacMillan, D.W.C. J. Am. Chem.
Soc. 2000, 122, 4243
43
Diels-Alder Cycloadditon Conclusions

• Organocatalyzed Diels-Alder Cycloadditions
• Highly enantioselective
• Applicable to a variety of substrates
• Chiral Amines
• Nontoxic
• Can be used in wet solvents and open to air
• Can be removed from reaction mixture by aqueous
  workup

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The Total Synthesis of ()-Hapalindole Q by an
Organomediated Diels-Alder Reaction
Aaron C. Kinsman and Michael Kerr J. Am. Chem.
Soc. 2003, 125, 14120

• Isolated from the terrestrial blue-green algae
  Hapalosiphon fontinalis
• Cyanobacterium indigenous to the Marshall Islands
• Isolated in 1984 by Moore and co-workers
• Exhibits antimycotic activity through its ability
  to directly inhibit RNA polymerase
• Has been synthesized by 5 groups

Hapalindoles R1 NC, NCS R2 H, Cl, OH
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()-Hapalindole Q Retrosynthesis
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()- Hapalindole Q Synthesis
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()- Hapalindole Q Synthesis
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()- Hapalindole Q Synthesis
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()- Hapalindole Q Synthesis
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()- Hapalindole Q Synthesis
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()- Hapalindole Q Conclusion
()-Hapalindole Q

• The first total synthesis utilizing an
  organomediated Diels-Alder reaction
• It was the most structurally complex molecule
  used with MacMillans catalyst
• ()-Hapalindole Q was synthesized in 12 steps in
  1.7 overall yield

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Conclusions

• The First Proline Catalyzed
• Direct Aldol reaction
• Direct Mannich reaction
• Organocatalyzed Diels-Alder Cycloadditions
• Highly enantioselective
• Applicable to a variety of substrates
• Key step in the synthesis of ()-Hapalindole Q

(S)-proline
53
Acknowledgements

• Dr. Alex Fallis
• The Fallis Group
• Megan ApSimon
• Dr. Christophe Benard
• Matt Clay
• Aaron Dumas
• Dr. Nancy Lamb
• Dr. Sara Palmier
• Jeremy Praetorius
• Thiva Thurugam
• Kelly VanCrey

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Diels-Alder Reaction Synthesis of Catalyst
Ahrendt, K.A. Borths, C.J. MacMillan, D.W.C. J.
Amer. Chem. Soc. 2000, 122, 4243