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Enantioselective annulations for dihydroquinolones by in situ generation of azolium enolates.

Lee A, Younai A, Price CK, Izquierdo J, Mishra RK, Scheidt KA - J. Am. Chem. Soc. (2014)

Bottom Line: A convergent, catalytic asymmetric formal [4 + 2] annulation for the synthesis of dihydroquinolones has been developed.Carboxylic acids can be employed as precursors to NHC enolates through an in situ activation strategy.Simultaneous generation of a reactive aza-o-quinone methide under the basic conditions employed for NHC generation leads to a dual activation approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University , Silverman Hall, Evanston, Illinois 60208, United States.

ABSTRACT
A convergent, catalytic asymmetric formal [4 + 2] annulation for the synthesis of dihydroquinolones has been developed. Carboxylic acids can be employed as precursors to NHC enolates through an in situ activation strategy. Simultaneous generation of a reactive aza-o-quinone methide under the basic conditions employed for NHC generation leads to a dual activation approach.

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Dual activationstrategy.
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fig1: Dual activationstrategy.

Mentions: Organocatalysis has emerged as a powerful strategy to constructvarious hetero- and carbocyclic systems. N-Heterocycliccarbenes (NHCs) in particular demonstrate great versatility and selectivityto facilitate many transformations, including enolate processes andnontraditional umpolung reactivity.9 Wehave been engaged in enhancing NHC reactivity and selectivity throughthe integration of this Lewis base catalysis mode with other strategies,including Lewis acids,10,11 Lewis bases such as fluoride,12 and Brønsted acids.13,14 On the basis of this cooperative catalysis/activation concept, weenvisioned that a “dual activation” approach could leadto the formation of dihydroquinolone derivatives. The dual activationclassification would apply if a compatible Brønsted base couldbe leveraged to both provide NHC formation from the azolium salt precatalysts and promote in situ creation of an aza-o-quinone methide (aza-o-QM).15 This species could behave as an electrophile with an NHC-enolateto provide the desired dihydroquinolone in a convergent process (Figure 1A). However, given the potential high reactivityof the aza-o-QM, it was also entirely possible atthe onset of these investigations that a nucleophilic NHC and/or basewould simply undergo an unproductive addition reaction.


Enantioselective annulations for dihydroquinolones by in situ generation of azolium enolates.

Lee A, Younai A, Price CK, Izquierdo J, Mishra RK, Scheidt KA - J. Am. Chem. Soc. (2014)

Dual activationstrategy.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120988&req=5

fig1: Dual activationstrategy.
Mentions: Organocatalysis has emerged as a powerful strategy to constructvarious hetero- and carbocyclic systems. N-Heterocycliccarbenes (NHCs) in particular demonstrate great versatility and selectivityto facilitate many transformations, including enolate processes andnontraditional umpolung reactivity.9 Wehave been engaged in enhancing NHC reactivity and selectivity throughthe integration of this Lewis base catalysis mode with other strategies,including Lewis acids,10,11 Lewis bases such as fluoride,12 and Brønsted acids.13,14 On the basis of this cooperative catalysis/activation concept, weenvisioned that a “dual activation” approach could leadto the formation of dihydroquinolone derivatives. The dual activationclassification would apply if a compatible Brønsted base couldbe leveraged to both provide NHC formation from the azolium salt precatalysts and promote in situ creation of an aza-o-quinone methide (aza-o-QM).15 This species could behave as an electrophile with an NHC-enolateto provide the desired dihydroquinolone in a convergent process (Figure 1A). However, given the potential high reactivityof the aza-o-QM, it was also entirely possible atthe onset of these investigations that a nucleophilic NHC and/or basewould simply undergo an unproductive addition reaction.

Bottom Line: A convergent, catalytic asymmetric formal [4 + 2] annulation for the synthesis of dihydroquinolones has been developed.Carboxylic acids can be employed as precursors to NHC enolates through an in situ activation strategy.Simultaneous generation of a reactive aza-o-quinone methide under the basic conditions employed for NHC generation leads to a dual activation approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University , Silverman Hall, Evanston, Illinois 60208, United States.

ABSTRACT
A convergent, catalytic asymmetric formal [4 + 2] annulation for the synthesis of dihydroquinolones has been developed. Carboxylic acids can be employed as precursors to NHC enolates through an in situ activation strategy. Simultaneous generation of a reactive aza-o-quinone methide under the basic conditions employed for NHC generation leads to a dual activation approach.

Show MeSH
Related in: MedlinePlus