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A catalytic asymmetric aldol reaction directly employing amides as latent enolates has remained elusive because of the resistance of amides to enolization. A direct aldol reaction of α-alkylamides without any electron-withdrawing group harnessed by specific activation of 7-azaindoline amides under soft Lewis acid/Brønsted base cooperative catalysis is reported. Diastereo- and enantioselective coupling with ynals and aromatic aldehydes as well as divergent functional group interconversion of the amide provided expeditious access to a variety of aliphatic and aromatic chiral building blocks.

Mixing of acryloylchloride, dienone 2, N,N-diisopropylethylamine with chiral organocatalyst 5a, which could simultaneously act as Brønsted and Lewis base catalysts, led to a one-pot amidation/Rauhut-Currier sequence, affording α-methylidene-γ-lactams 4. Catalyst 5a could be recovered and reused by acid/base extraction without any loss of catalytic activity in the stepwise protocol.

Direct enolate formation coupled with subsequent enantioselective C-C bond formation remains a topic of intense interest in asymmetric catalysis. This methodology is achieved even with low acidic amides without an electron-withdrawing group at the α-position in the context of a Mannich-type reaction. Acetate-, propionate-, and butyrate-type 7-azaindoline amides served as enolate precursors to afford the desired Mannich adducts with high stereoselectivity, and ligand-enabled diastereo-divergency provided access to both anti/syn diastereomers. The facile transformation of the amide moiety ensures the synthetic utility of the Mannich adducts.

The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, α- and β-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Brønsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chemistry.

Enantioselective organocatalytic synthesis of tetrahydropyridines bearing a chiral tetrasubstituted carbon stereogenic center has been achieved. The spiro-type monoaryl phosphine catalyst, (R)-SITCP, was found to promote the formal [4+2] cycloaddition of saccharin-derived ketimines and α-methyl allenoate to afford the corresponding six-membered N-heterocycles in high yields and excellent regioselectivities with up to 93% ee.

The introduction of a 1,3-propanediamine unit at the 3-position of ( S )-BINOL using a methylene spacer led to the formation of a chiral bifunctional organocatalyst for the aza-Morita–Baylis–Hillman (aza-MBH) reaction. The organocatalyst 1k mediated aza-MBH transformations with high chemical yields and with up to 82% ee.

An enantioselective organocatalyzed aza-MBH-type reaction of ketimines and allenoates has been developed. The present formal [2 + 2] cycloaddition produces highly functionalized azetidines with a chiral tetrasubstituted carbon stereogenic center in good to excellent yields and high enantioselectivities.

The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C–C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, α- and β-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions...

An enantio-, diastereo-, regio-, and chemoselective phosphine-catalyzed β,γ-umpolung domino reaction of allenic esters with dienones has been developed for the first time. The designed sequence, involving oxy-Michael and Rauhut–Currier reactions, produced highly functionalized tetrahydrobenzofuranones, bearing a chiral tetrasubstituted stereogenic center, in up to 96 % ee.

Starting from easily accessible Baylis—Hillman adducts the synthesis of alkenes having four different C-substituents including a challenging -CH2F is presented.

Enantioselective organocatalytic synthesis of tetrahydropyridines bearing a chiral tetrasubstituted carbon stereogenic center has been achieved. The spiro-type monoaryl phosphine catalyst, (R)-SITCP, was found to promote the formal [4+2] cycloaddition of saccharin-derived ketimines and α-methyl allenoate to afford the corresponding six-membered N-heterocycles in high yields and excellent regioselectivities with up to 93% ee.

Highly E-selective all-carbon tetrasubstituted alkenes with a C(sp(3))-F unit have been synthesized through a dehydroxyfluorination of Morita-Baylis-Hillman (MBH) adducts which can be readily prepared from α,β-unsaturated carbonyl compounds and α-keto esters. A variety of subsequent transformations afforded monofluoromethyl substituted heterocycles in high yields.

The introduction of a 1,3-propanediamine unit at the 3-position of ( S )-BINOL using a methylene spacer led to the formation of a chiral bifunctional organocatalyst for the aza-Morita–Baylis–Hillman (aza-MBH) reaction. The organocatalyst 1k mediated aza-MBH transformations with high chemical yields and with up to 82% ee.

The title reaction is highly E-selective and provides azetidines in good yields with high enantioselectivities.

Vanadium-mediated enantioselective Friedel-Crafts (FC)-type reactions were established using the dinuclear vanadium complex (R(a),S,S)-1a. The vanadium complex promoted the FC-type reaction of imines with 2-naphthols or indoles to give corresponding adducts with high enantioselectivities.