1. Organocatalysis: Chiral Amines in Asymmetric Synthesis
Natalie Nguyen
March 4, 2003

2. Chiral Organocatalysts in Asymmetric Synthesis
Acylation of Alcohols and
Amines
Kinetic Resolution
Baylis-Hillman Reaction
R = OMe (Quinine)
R = H (Cinchonidine)
R = OMe (Quinidine)
R = H (Cinchonine)
-Lactone and -Lactam formation
An increasing number of reactions are being catalyzed by chiral nucleophiles. A major contributor to this new area is the use of chiral amines. As in the natural products Quinine and it’s analogues, quinidine, cinchonidine and cinchonin. other nucleophiles and Lewis bases are also being used
Nuclephilic Chiral Amines as Catalysts in Asymmetric Synthesis….Chem. Rev , 2985
Aldol Reaction
Mannich Reaction
Michael Additions
Friedel-Crafts Alkylation
Indole Alkylation
Diels-Alder Cycloadditon
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
S-proline produced the s configuration
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
Agami,
Houk,
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

10. Intramolecular Aldol Reaction: Proposed Transition State
Agami,
Houk,
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
Agami,
Houk,
List, 2003
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

12. 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
Observed first order kinetics and a linear effect
Suggesting only one proline involved
Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911

13. 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
Based on calculated transition states, the N-H hydrogen bond does not lower the relative energy of the transition state
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

15. Intermolecular Aldol Reaction: Amino Acid Catalysts
Yield ee
68%
76%
(L)-His, (L)-Val
(L)-Tyr, (L)-Phe
<10% -
55%
40%
Catalyst
Yield ee
<10% -
67%
73%
66%
86%
Direct Catalytic asymmetric aldo reactions of Aldehydes…Jorgenson Chem. Commun. 2002, 620
Proline Catalyzed Direct Aldol..List, JACS, 2000, 122, 2395
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

16. Intermolecular Aldol Reaction: Amino Acid Catalysts
Yield ee
68%
76%
(L)-His, (L)-Val
(L)-Tyr, (L)-Phe
<10% -
55%
40%
Catalyst
Yield ee
<10% -
67%
73%
66%
86%
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

17. Intermolecular Aldol Reaction: Substrate Scope
Product
Yield ee 1 2
68%
60%
76%
86%
85%
99%
34%
72% 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

18. Intermolecular Aldol Reaction: Anti-Aldol Products
Yield
anti/syn ee 1 2
60%
45%
20:1
99%
95%
85%
1:1
(anti) 85%
(syn) 76%
68%
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

19. Cross Aldol Reaction Product Yield ee Transition State anti/syn 88%
3:1
97%
81%
95%
80%
24:1
82%
99%
Transition State
Aldehydes polymerize under metal catalyzed conditions
Tendency for homodimerization
Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2002, 124, 6798

20. 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)
Alpha-Amination of aldehydes…Jorgenson, Angew. Chem. 2002, 41, 1790
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

21. 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

22. 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
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
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

26. Mannich Reaction: Variation in Aldehydes
Yield ee
50%
94%
90%
93%
35%
96%
56%
70%
Transition State
Despite competition with the Aldol reaction, high yields and enantioselectivites were observed
Products have opposite stereochemistry of aldol products
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%
2.5:1
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

29. Organocatalyzed Diels-Alder Cycloaddition
Asymmetric Diels-Alder Reaction by Chiral Bases (Kagan, 1989)
Transition State
Riant, O.; Kagan, H.B.; Tetrahedron, 1989, 30, 7403

30. Diels-Alder Cycloaddition
Exo vs Endo
exo
endo
Enantioselectivity in Diels Alder Reaction

31. Diels-Alder Cycloaddition : Lewis Acids and Iminiums
lowers the energy of the LUMO
Energy

32. Organocatalytic Diels-Alder Cycloaddition
MacMillan’s 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

33. Diels-Alder Cycloaddition: Catalyst Screening
Yield
endo:exo
exo ee
81%
1:2.7
48%
92%
1:2.6
57%
82%
1:3.6
74%
99%
1:1.3
93%
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

34. Diels-Alder Cycloaddition: Catalyst Screening
Yield
endo:exo
exo ee
81%
1:2.7
48%
92%
1:2.6
57%
82%
1:3.6
74%
99%
1:1.3
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
Yield
endo:exo
exo ee
endo ee
75%
1:1
86%
90%
81%
84%
93%
99%
1:1.3
20%
1:7 -
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

36. Diels-Alder Cycloaddition: Variation in Dienes
Yield
endo:exo
endo ee
82%
14:1
94%
90% -
83%
75%
5:1
72%
11:1
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
Yield
endo:exo ee
20%
7:1 -
89%
25:1
90%
Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

41. Diels-Alder Cycloaddition: Variation in Dienophiles
Yield
endo:exo ee
89%
24:1
90%
78%
6:1
24%
8:1
Transition State
Bulky R2 groups give poor enantioselectivities
Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

42. Diels-Alder Cycloaddition: Variation in Dienes
Yield
endo:exo
endo ee
88%
200:1
94%
91%
100:1
89%
92%
83%
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

44. Aaron C. Kinsman and Michael Kerr
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

45. (+)-Hapalindole Q: Retrosynthesis

46. (+)- Hapalindole Q: Synthesis

47. (+)- Hapalindole Q: Synthesis

48. (+)- Hapalindole Q: Synthesis

49. (+)- Hapalindole Q: Synthesis

50. (+)- Hapalindole Q: Synthesis

51. (+)- Hapalindole Q: Conclusion
The first total synthesis utilizing an organomediated Diels-Alder reaction
It was the most structurally complex molecule used with MacMillan’s catalyst
(+)-Hapalindole Q was synthesized in 12 steps in 1.7% overall yield

52. 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

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