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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

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)

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


Chiral Amines in Asymmetric Synthesis

Proline Catalyzed:

  • Aldol Reaction

  • Mannich Reaction

    Imidazolidinone Catalyzed:

  • Diels – Alder Cycloaddition

    Total Synthesis of (+)-Hapalindole Q


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

  • 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


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


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

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


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


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


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


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


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


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


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


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


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


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


Cross Aldol Reaction

Transition State

Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2002, 124, 6798


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


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


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


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


Mannich Reaction:Amino Acid Catalysts

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


Mannich Reaction:Amino Acid Catalysts

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


Mannich Reaction:Variation in Aldehydes

Transition State

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


Mannich Reaction:Variation in Ketones

Transition State

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


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


Organocatalyzed Diels-Alder Cycloaddition

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

Transition State

Riant, O.; Kagan, H.B.; Tetrahedron, 1989, 30, 7403


Diels-Alder Cycloaddition

Exo vs Endo

exo

endo

Enantioselectivity in Diels Alder Reaction


Diels-Alder Cycloaddition : Lewis Acids and Iminiums

Lewis Acids and Iminiums

  • lowers the energy of the LUMO

Energy


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


Diels-Alder Cycloaddition:Catalyst Screening

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


Diels-Alder Cycloaddition:Catalyst Screening

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


Diels-Alder Cycloaddition:Variation in Dienophiles

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


Diels-Alder Cycloaddition:Variation in Dienes

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


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


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


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


Diels-Alder Cycloaddition:Catalyst Screening

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


Diels-Alder Cycloaddition:Variation in Dienophiles

Transition State

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


Diels-Alder Cycloaddition:Variation in Dienes

Transition State

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


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


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


(+)-Hapalindole Q: Retrosynthesis


(+)- Hapalindole Q: Synthesis


(+)- Hapalindole Q: Synthesis


(+)- Hapalindole Q: Synthesis


(+)- Hapalindole Q:Synthesis


(+)- Hapalindole Q: Synthesis


(+)- 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


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


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


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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