Enantioselective Stetter Reactions Catalyzed by Bis(amino)cyclopropenylidenes: Important Role for Water as an Additive

Abstract

The first highly enantioselective intermolecular Stetter reaction using simple enones is reported. A series of novel chiral BAC structures were designed and prepared. They were tested in the Stetter reaction with simple aldehydes and enones. The products were generated in excellent yields and enantioselectivities (up to 94% ee). Surprisingly, a substoichiometric amount of water was crucial to obtain high enantioselectivities. Chiral BACs were also shown to catalyze 1,6-conjugate addition reactions with paraquinone methides enantioselectively.

Enantioselective direct Michael addition of cyanohydrin ether derivatives to enones catalyzed by chiral bis(guanidino)iminophosphorane organosuperbase

“…1b , right bottom), our primary aim was to convert the cyano group into another functionality as an alternative to the conventional catalytic Stetter reactions. 10 Towards this goal, the hydrolysis of the cyano group of Michael product 4ba was conducted by taking advantage of the characteristics of the multifunctionalized product formed in the present reaction. Enantioenriched Michael product 4ba (92% ee) was treated with platinum catalyst 5 at 80 °C in an ethanol/water mixture.…”

“…For instance, the retro cyanohydrin formation reaction affords a ketone derivative, and the cyano group is hydrolyzed into an amide derivative or transformed into an amine functionality through the reduction or addition of organometallic reagents. In particular, the enantioselective Michael addition of cyanohydrin ether derivatives as the pronucleophile to enones provides multifunctionalized products, and further elaboration of the products gives not only 1,4-diketones 10 but also densely functionalized derivatives having a tetrasubstituted stereogenic center in an enantioenriched form ( Fig. 1b ).…”

Synthesis of Novel 1,4-Diketone Derivatives and Their Further Cyclization

“…Cyanide ion, , thiazolium salt, , bis­(amino)­cyclopropenylidenes, chiral bicyclic thiazolium salt, ThDP-linked enzymes like lyases, MenD, and PigD, , and NHCs ,,,− have been utilized as catalysts in the Stetter reaction. The first isolation of free carbenes was carried out independently by Bertrand et al and Arduengo et al, and this discovery led to the emergence of suitable approaches for obtaining medically and biologically important compounds. , Recently, NHCs have performed effective reactions with homoenolates, enolates, vinyl enolates, acyl azoles, and acyl anion reagents to provide products that are not readily available by other means, and their interest in the field of catalytic synthesis is increasing .…”

“…Cyanide ion, 18 , 21 thiazolium salt, 21 , 22 bis(amino)cyclopropenylidenes, 23 chiral bicyclic thiazolium salt, 20 ThDP-linked enzymes like lyases, MenD, and PigD, 24 , 25 and NHCs 9 , 13 , 16 , 26 − 32 have been utilized as catalysts in the Stetter reaction. The first isolation of free carbenes was carried out independently by Bertrand et al 33 and Arduengo et al, 34 and this discovery led to the emergence of suitable approaches for obtaining medically and biologically important compounds.…”

α-Trifluoromethyl Carbanion-catalyzed Intermolecular Stetter Reaction of Aromatic Aldehydes with 2-Bromo-3,3,3-trifluoropropene: Synthesis of β-Alkoxyl-β-trifluoromethylated Ketones

“…Umpolung reactions create new activities by reversing the intrinsic polarity of carbonyls to render the carbonyl carbon nucleophilic and subsequently allow the development of new C–C bond formation reactions under transition-metal free and mild conditions. , This umpolung protocol has notably been utilized in the Stetter reactions, the addition of aldehydes to Michael acceptors to construct ketones. Extensive efforts in this area culminated in elegant works on both intra- , and intermolecular , variants of this reaction with diverse alkene Michael acceptors under the catalysis of N -heterocyclic carbenes (NHCs), ,, toxic cyanide anion, or enzymes (Scheme a). However, these Stetter reactions limited to the generation and transformation of stabilized carbanion intermediates.…”