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Organocatalysis: Chiral Amines in Asymmetric Synthesis. Natalie Nguyen March 4, 2003. Chiral Organocatalysts in Asymmetric Synthesis. Acylation of Alcohols and Amines Kinetic Resolution. Baylis-Hillman Reaction. R = OMe (Quinine) R = H (Cinchonidine). R = OMe (Quinidine)

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Organocatalysis: Chiral Amines in Asymmetric Synthesis

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Organocatalysis chiral amines in asymmetric synthesis l.jpg

Organocatalysis:Chiral Amines in Asymmetric Synthesis

Natalie Nguyen

March 4, 2003


Chiral organocatalysts in asymmetric synthesis l.jpg

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

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


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Chiral Amines in Asymmetric Synthesis

Proline Catalyzed:

  • Aldol Reaction

  • Mannich Reaction

    Imidazolidinone Catalyzed:

  • Diels – Alder Cycloaddition

    Total Synthesis of (+)-Hapalindole Q


Proline enzyme mimic l.jpg

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


Proline in asymmetric synthesis l.jpg

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


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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


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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


Intramolecular aldol reaction mechanism l.jpg

Intramolecular Aldol Reaction:Mechanism

Brown, K.L.; Damm, L.; Dunitz, J.D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta. 1978, 61, 3108


Intramolecular aldol reaction proposed transition state l.jpg

Attack occurs on the face opposite the carboxylic acid

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

Intramolecular Aldol Reaction:Proposed Transition State

Houk, 2001-2003

Agami, 1984-1986

  • 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


Intramolecular aldol reaction proposed transition state10 l.jpg

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)

Intramolecular Aldol Reaction:Proposed Transition State

Houk, 2001-2003

Agami, 1984-1986

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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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

Intramolecular Aldol Reaction:Proposed Transition State

Houk, 2001-2003

List, 2003

Agami, 1984-1986

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


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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

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

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

  • 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

1

2

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

  • Thiaproline (2):

    • Not as general as proline

1

2

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

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


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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


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Mannich Reaction:Amino Acid Catalysts

List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827


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Mannich Reaction:Amino Acid Catalysts

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

Transition State

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 Ketones

Transition State

List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827


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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

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


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Diels-Alder Cycloaddition:Catalyst Screening

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

Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243


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Diels-Alder Cycloaddition:Variation in Dienophiles

Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243


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Diels-Alder Cycloaddition:Variation in Dienes

Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243


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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


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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


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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


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Diels-Alder Cycloaddition:Catalyst Screening

Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243


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Diels-Alder Cycloaddition:Variation in Dienophiles

Transition State

Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243


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Diels-Alder Cycloaddition:Variation in Dienes

Transition State

Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243


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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-AlderReaction

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


Hapalindole q synthesis l.jpg

(+)- 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 MacMillan’s 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


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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


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