Stereoselective synthesis of spirooxindole derivatives using an organocatalyzed tandem Michael–Michael reaction

Abstract

A highly efficient stereoselective method for the synthesis of functionalized spirooxindole derivatives with three stereogenic centers was realized through an organocatalytic tandem Michael-Michael reaction. By employing (S)-α,α-diphenylprolinol trimethylsilyl ether as the catalyst and N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea as the cocatalyst, the reaction between N-tritylisatylidenemalononitriles and (E)-7-alkyl-7-oxohept-5-enals yields the desired spirooxindole products in good yields (76-95%) and with excellent diastereoselectivities (up to 97 : 3 dr) and enantioselectivities (up to 98% ee), which can be stereoselectively converted into the spiro[indoline-3,8'-isoquinoline] derivative through an intramolecular reductive amination reaction.

Asymmetric Michael Reaction of Aldehydes and Dicyanoalkenes Catalyzed by Diphenylprolinol Silyl Ether

“…Dicyanoalkenes are useful Michael acceptors, [9] and are also used in asymmetric Michael reactions catalyzed by organocatalysts. Zhao and co-workers used enals and tritylisatylidenemalononitriles via a tandem Michael-Michael reaction catalyzed by 1 to synthesize highly functionalized spirooxindole derivatives, [10] whereas Wennemers reported the Michael reaction of acetophenones and dicyanoalkenes catalyzed by tripeptide. [11] However, as far as we are aware, there are no reports on the asymmetric catalytic Michael reaction of aldehydes and dicyanoalkenes, which we will describe here.…”

“…Organocatalysts have been successfully applied to the Michael reaction, which represents one of the most powerful methods for forming carbon-carbon bonds in organic synthesis. Zhao and co-workers used enals and tritylisatylidenemalononitriles via a tandem Michael-Michael reaction catalyzed by 1 to synthesize highly functionalized spirooxindole derivatives, [10] whereas Wennemers reported the Michael reaction of acetophenones and dicyanoalkenes catalyzed by tripeptide. This catalyst has been applied to many Michael reactions of aldehydes as the Michael donors, and a variety of Michael acceptors, such as nitroalkenes, [3] vinyl sulfones, [6] methyl vinyl ketones, [3,7] -substituted α-nitroacrylates, [8] etc.…”

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[293] Using the secondary amine (S)-45 as the catalyst and the achiral thiourea 745 as the co-catalyst, the reaction between N-tritylisatylidenemalononitriles 615 and (E)-7-alkyl-7-oxohept-5-enals 541 produced the desired spirooxindoles 744 in good to excellent yields and high diastereoselectivities and enantioselectivities. Thea ddition of the achiral thiourea 745 to the catalytic system not only improvedt he stereoselectivities of this reaction, but also dramatically improvedt he product yields.…”

“…Thea ddition of the achiral thiourea 745 to the catalytic system not only improvedt he stereoselectivities of this reaction, but also dramatically improvedt he product yields. [293] Thes ynergetic effects between (S)-45 and 745 were explained in terms of the proposed transitions tate 746,i nw hich 745 activates the substrate 615 through hydrogen bonding and also makes the attack of the enamine onto the Si-face of 615 more favorable (Scheme200). [293] Scheme 197.…”

“…[293] Thes ynergetic effects between (S)-45 and 745 were explained in terms of the proposed transitions tate 746,i nw hich 745 activates the substrate 615 through hydrogen bonding and also makes the attack of the enamine onto the Si-face of 615 more favorable (Scheme200). [293] Scheme 197. Applicationo ft he in-situ-generated chiral fluoride anion in the asymmetric domino sulfa-Michael/aldol condensationreaction.…”