Control of N-Heterocyclic Carbene Catalyzed Reactions of Enals: Asymmetric Synthesis of Oxindole-γ-Amino Acid Derivatives.

A strategy to control the switch between a non‐cycloaddition reaction and a cycloaddition reaction of enals, using N‐heterocyclic carbene (NHC) catalyisis, has been developed. The new scalable protocol leads to γ‐amino‐acid esters bearing a tetrasubstituted stereocenter in good yields and high stereoselectivities by homo‐Mannich reactions of enals and isatin‐derived ketimines. By simply changing the N‐ketimine substituent to an ortho‐hydroxy phenyl group, the corresponding spirocyclic oxindolo‐γ‐lactams are obtained. peerReviewed

N-Heterocyclic Carbene Catalyzed [3+2] Cycloaddition of Enals with Masked Cinnamates for the Asymmetric One-Pot Synthesis of Adipic Acid Derivatives.

A novel short entry to 3,4-disubstituted adipic acids has been developed by employing an asymmetric NHC-catalyzed [3+2] cycloaddition of enals with masked cinnammates in moderate to good yields and high stereoselectivities. The synthetic utility of the protocol was demonstrated by the basic conversion of the masked cyclopentanone intermediates to 3S,4S-disubstituted adipic acid precursors of pharmaceutically important gababutins.

N-Heterocyclic Carbene Catalyzed Quadruple Domino Reactions through α,β-Unsaturated Acyl Azolium Intermediates : Asymmetric Synthesis of Cyclopenta[c]chromenones

An N‐heterocyclic carbene catalyzed domino sequence via α,β‐unsaturated acyl azolium intermediates has been developed. This strategy provides a convenient enantioselective route to functionalized tricyclic coumarin derivatives and cyclopentanes. DFT studies and control experiments were performed to gain better insight into the reaction mechanism. peerReviewed

Asymmetric synthesis of functionalized tetrahydrofluorenones via an NHC-catalyzed homoenolate Michael addition

The first example of an N-heterocyclic carbene-catalyzed asymmetric desymmetrization of enal-tethered cyclohexadienones via an intramolecular homoenolate Michael addition/esterification reaction is described. This new protocol offers a direct entry to various functionalized tetrahydrofluorenones with three contiguous stereocenters in high yields, good diastereoselectivities and excellent enantioselectivities.

Highly Enantioselective Kinetic Resolution of Michael Adducts through N-Heterocyclic Carbene Catalysis: An Efficient Asymmetric Route to Cyclohexenes

Ahighly efficient strategy for the kinetic resolu-tion of Michael adductswas realized using achiral N-het-erocyclic carbene catalyst.The kinetic resolution providesanew convenientroute to single diastereomers of cyclo-hexenes and Michael adducts in good yields with highenantiomeric excesses (up to 99 % ee with aselectivityfactor of up to 458). This “two flies with one swat” con-cept allows the synthesis of these two synthetically valua-ble compound classes at the same time by asingle trans-formation. peerReviewed

N-Heterocyclic Carbene-Catalyzed Activation of α-Chloroaldehydes: Asymmetric Synthesis of 5-Cyano-Substituted Dihydropyranones

An N-heterocyclic carbene (NHC)-catalyzed asymmetric [4+2] annulation of (E)-2-benzoyl-3-phenylacrylonitriles with α-chloroaldehydes has been developed. The protocol leads to 5-cyano-substituted dihydropyranones in good to excellent yields with excellent diastereo- and enantioselectivities (up to 93% yield, >20:1 d.r. and 99% ee).

Cover Feature: Highly Enantioselective Kinetic Resolution of Michael Adducts through N-Heterocyclic Carbene Catalysis: An Efficient Asymmetric Route to Cyclohexenes (Chem. Eur. J. 39/2018)

Asymmetric Synthesis of Spirocyclic β-Lactams through Copper-Catalyzed Kinugasa/Michael Domino Reactions

The first copper-catalyzed highly chemo-, regio-, diastereo-, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne-tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β-lactams possessing four contiguous stereocenters, including one quaternary and one tetra-substituted stereocenter.

Asymmetric Synthesis of Spirocyclic β‐Lactams via Copper‐Catalyzed Kinugasa/Michael Domino Reactions

The first copper‐catalyzed highly chemo‐, regio‐, diastereo‐, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne‐tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β‐lactams possessing four contiguous stereocenters, including one quaternary and one tetra‐substituted stereocenter. peerReviewed

N‐Heterocyclic Carbene Catalyzed Asymmetric Synthesis of Pentacyclic Spirooxindoles via [3+3] Annulations of Isatin‐Derived Enals and Cyclic N‐Sulfonyl Ketimines

Asymmetric Synthesis of Spiro-oxindole-ε-lactones through N-Heterocyclic Carbene Catalysis

An unprecedented N-heterocyclic carbene-catalyzed annulation of isatin-derived enals and o-hydroxyphenyl-substituted p-quinone methides as bifunctional reagents has been discovered. The new protocol involves a 1,6-addition of the homoenolate equivalent intermediates to the hydroxy donor-1,6-Michael acceptors and leads to spirocyclic oxindole-ε-lactones in high yields and very good stereoselectivities.

N‐Heterocyclic Carbene Catalyzed Quadruple Domino Reactions: Asymmetric Synthesis of Cyclopenta[ c ]chromenones

An N-heterocyclic carbene catalyzed domino sequence via α,β-unsaturated acyl azolium intermediates has been developed. This strategy provides a convenient enantioselective route to functionalized tricyclic coumarin derivatives and cyclopentanes. DFT studies and control experiments were performed to gain better insight into the reaction mechanism.

Organocatalytic Asymmetric Synthesis of Trifluoromethylated Tetrahydrocarbazoles by a Vinylogous Michael/Aldol Formal [4+2] Annulation

N-Heterocyclic Carbene Catalyzed Asymmetric Synthesis of Dihydropyranothiazoles­ via Azolium Enolate Intermediates

A highly diastereo- and enantiostereoselective synthesis of bicyclic dihydropyranothiazoles combining a thiazole and δ-lactone skeleton via NHC-catalyzed [4+2] annulation of 5-alkenylthiazolones and α-chloroaldehydes has been developed. The heterocyclic products are formed via azolium enolate intermediates in good yields with high diastereo- and enantistereoselectivities.

N‐Heterocyclic Carbene Catalyzed [4+2] Annulation of Enals via a Double Vinylogous Michael Addition: Asymmetric Synthesis of 3,5‐Diaryl Cyclohexenones

A strategy for the N-heterocyclic carbene (NHC) catalyzed asymmetric synthesis of 3,5-diaryl substituted cyclohexenones has been developed via oxidative [4+2] annulation of enals and alkenylisoxazoles. It is the first example of using NHC organocatalysis in a double vinylogous Michael type reaction, a challenging but highly desirable topic. This unprecedented protocol affords good yields as well as high to excellent diastereo- and enantioselectivities.

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