Organocatalytic Asymmetric Addition of Naphthols and Electron‐Rich Phenols to Isatin‐Derived Ketimines: Highly Enantioselective Construction of Tetrasubstituted Stereocenters

A quinine‐derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral 3‐amino‐2‐oxindoles with a quaternary stereocenter in high yields (up to 99 %) with excellent enantioselectivity (up to 99 % ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.     

Phosphine‐mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates

Phosphine‐catalyzed enantioselective annulation reactions involving ketimines are a daunting synthetic challenge owing to the intrinsic low reactivity of ketimine substrates. A highly enantioselective [3+2] cycloaddition reaction that makes use of isatin‐derived ketimines as reaction partners was developed. Notably, both simple and γ‐substituted allenoates could be utilized, and various 3,2′‐pyrrolidinyl spirooxindoles with a tetrasubstituted stereocenter were obtained in excellent yields and with nearly perfect enantioselectivity (>98 % ee in all cases).     

Organocatalytic Enantioselective Decarboxylative Reaction of Malonic Acid Half Thioesters with Cyclic N‐Sulfonyl Ketimines by Using N‐Heteroarenesulfonyl Cinchona Alkaloid Amides

The organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half thioesters (MAHTs) with cyclic N‐sulfonyl ketimines by using N‐heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation.     

Catalytic Enantioselective Aza‐Reformatsky Reaction with Cyclic Imines

A catalytic highly enantioselective aza‐Reformatsky reaction with cyclic aldimines and ketimines for the synthesis of chiral β‐amino esters with good yields and excellent enantioselectivities is reported. A readily available diaryl prolinol is used as a chiral ligand, ZnMe₂ as a zinc source and ethyl iodoacetate as reagent in the presence of air atmosphere. The reaction with cyclic ketimines generates a quaternary stereocenter with excellent levels of enantioselectivity. Furthermore, five‐membered N‐sulfonyl ketimines were used as electrophiles with good enantiomeric excesses, under the optimized reaction conditions. Moreover, several chemical transformations were performed with the chiral β‐amino esters.     

Copper-Catalyzed Highly Enantioselective Addition of a Silicon Nucleophile to 3-Substituted 2H-Azirines Using an Si−B Reagent

3-Substituted 2H-azirines can be considered strained cyclic ketimines, and highly enantioselective addition reactions of silicon nucleophiles to either acyclic or cyclic ketimines have been elusive so far. The present work closes this gap for those azirines by means of a copper-catalyzed silylation using a silyl boronic ester as a latent silicon nucleophile. The resulting C-silylated, unprotected (N−H) aziridines are obtained in high yields and with excellent enantioselectivities and can be further converted into valuable compounds with hardly any erosion of the enantiomeric excess.     

Enantioselective Friedel–Crafts Alkylation Reaction of Heteroarenes with N-Unprotected Trifluoromethyl Ketimines by Means of Chiral Phosphoric Acid

An enantioselective Friedel–Crafts alkylation reaction of pyrroles and indoles with N-unprotected trifluoromethyl ketimines by use of chiral phosphoric acid provided α-trifluoromethylated primary amines bearing chiral tetrasubstituted carbon centers in high yields and with high to excellent enantioselectivities. The present reaction is unique to N-unprotected trifluoromethyl ketimines. No reaction took place with N-p-methoxyphenyl (PMP)-substituted ketimine. Corresponding α-trifluoromethylated amines were transformed without loss of enantioselectivity.     

Enantioselective Rhodium‐Catalyzed Addition of Arylboroxines to N‐Unprotected Ketimines: Efficient Synthesis of Cipargamin

Highly enantioselective rhodium‐catalyzed addition of arylboroxines to N‐unprotected ketimines is realized for the first time by employing chiral BIBOP‐type ligands with a Rh loading as low as 1 mol %. A range of chiral α‐trifluoromethyl‐α,α‐diaryl α‐tertiary amines or 3‐amino‐3‐aryloxindoles were formed with excellent ee values and yields by employing either WingPhos or PFBO‐BIBOP as the ligand. The method has enabled an efficient enantioselective synthesis of cipargamin.     

Organocatalytic Enantioselective Mukaiyama–Mannich Reaction of Isatin-Derived Ketimines for the Synthesis of Oxindolyl-β3, 3-Amino Acid Esters

Mukaiyama–Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama–Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-β^{3, 3}-amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.     

Direct Enantioselective Vinylogous Mannich Reaction of Ketimines with γ‐Butenolide by Using Cinchona Alkaloid Amide/Zinc(II) Catalysts

A direct enantioselective vinylogous Mannich reaction of ketimines with γ‐butenolide has been developed. Good yields and enantioselectivities were observed for the reaction of various ketimines by using a cinchona alkaloid amide/Zn(OTf)₂ catalyst and Et₃N. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts.     

Direct Asymmetric Mannich‐Type Reaction of α‐Isocyanoacetates with Ketimines using Cinchona Alkaloid/Copper(II) Catalysts

The enantioselective direct Mannich‐type reaction of ketimines with α‐isocyanoacetates has been developed. Excellent yields and enantioselectivity were observed for the reaction of various ketimines and α‐isocyanoacetates using cinchona alkaloid/Cu(OTf)₂ and a base. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. This process offers an efficient route for the synthesis of α,β‐diamino acids.     

Highly enantioselective aza-henry reaction of ketimines catalyzed by a chiral bifunctional thiourea-tertiary amine derived from quinine

We have developed a highly enantioselective aza-Henry reaction of aryl α-ketoester-derived N-Ts ketimines with a wide range of substrate scope by a simpler bifunctional thiourea-tertiary amine catalyst derived from quinine. A variety of ketimines were investigated and corresponding products were obtained in excellent yields (up to 99% yield) with excellent enatioselectivities (up to 99% ee).     

Enantioselective hydrosilylation of ketimines catalyzed by Lewis basic C2-symmetric chiral tetraamide

l-Proline derived C₂-symmetric chiral tetraamide 5b was found to behave as an effective Lewis basic catalyst in the enantioselective hydrosilylation of ketimines, affording high isolated yields (up to 95%) and moderate to high enantioselectivities (up to 86% ee) for a broad range of ketimines. A clear synergistic effect of the two identical diamide units of 5b was observed for asymmetric induction.     

Development of highly enantioselective new Lewis basic N-formamide organocatalysts for hydrosilylation of imines with an unprecedented substrate profile

l-Pipecolinic acid derived N-formamides have been developed as new Lewis basic organocatalysts that promote the asymmetric reduction of N-aryl ketimines using trichlorosilane as the reducing agent. The substituent on N4 of the piperazinyl backbone and the 2-carboxamide group both proved to have profound effects on the efficacy of the catalyst. The reductions of both N-aryl acyclic methyl ketimines and non-methyl ketimines were catalyzed to afford the desired amines in good to high yield and enantioselectivity. In particular, catalyst 6e enabled the reduction of the difficult bulky ketimines to be highly efficient and enantioselective, affording up to 99% yield and 97% ee. This catalyst proved to prefer the relatively bulkier non-methyl acyclic ketimines to the methyl ketimines as substrate, which is so far unprecedented in catalytic asymmetric reduction of imines.     

Enantioselective Synthesis of AG‐041R by using N‐Heteroarenesulfonyl Cinchona Alkaloid Amides as Organocatalysts

The organocatalytic enantioselective decarboxylative addition of malonic acid half thioesters to ketimines derived from isatins by using N‐heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity. The products could be converted into optically active AG‐041R. X‐ray crystallographic analysis revealed that the hydrogen bonding between the sulfonimide proton and the 8‐quinolyl nitrogen atom plays an important role in exerting the enantioselectivity of the reaction.     

Enantioselective Construction of Vicinal Tetrasubstituted Stereocenters by the Mannich Reaction of Silyl Ketene Imines with Isatin‐Derived Ketimines

A highly enantioselective Mannich reaction of silyl ketene imines with isatin‐derived ketimines has been realized by using a chiral N,N′‐dioxide/Zn^II catalyst. A variety of β‐amino nitriles containing congested vicinal tetrasubstituted stereocenters were obtained with excellent outcomes (up to 98 % yield, >19:1 d.r. and 99 % ee). Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.     

Organocatalytic Enantioselective Aza‐Friedel–Crafts Reaction of Cyclic Ketimines with Pyrroles using Imidazolinephosphoric Acid Catalysts

Organocatalytic enantioselective aza‐Friedel–Crafts reactions of cyclic ketimines with pyrroles or indoles were catalyzed by imidazoline/phosphoric acid catalysts. The reaction was applied to various 3H‐indol‐3‐ones to afford products in excellent yields and enantioselectivities. The chiral catalysts can be recovered by a single separation step using column chromatography and are reusable without further purification. Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.     

An Organocatalytic Mannich/Denitration Reaction for the Asymmetric Synthesis of 3‐Ethylacetate‐Substitued 3‐Amino‐2‐Oxindoles: Formal Synthesis of AG‐041R

The highly enantioselective organocatalytic addition of ethyl nitroacetate to isatin‐derived N‐Boc ketimines (Boc=tert‐butoxycarbonyl), followed by the removal of the nitro group, is described. The scalable reaction sequence leads to the title compounds as important intermediates of pyrroloindoline alkaloids and related drugs in excellent yields and enantioselectivities. The synthesis of the hexahydrofurano[2,3‐b]indole skeleton, the spirocarbamate oxindole unit, and the formal synthesis of AG‐041R have been carried out to demonstrate the synthetic utility of this protocol.     

Synthesis and application of axially chiral biscarbolines with functional N-O and sulfone for 1,2-transfer hydrogenations of ketimines

A series of axially chiral biscarboline-based sulfones were synthesized from l-tryptophane and applied for enantioselective 1,2-transfer hydrogenations of ketimines using trichlorosilane. The catalyst 4e, which had a tertiary butyl group, exhibited a good conversion and high enantioselectivities up to 96%ee in the series of reactions.     

Synthesis of chiral quaternary fluorinated cyclic sulfamidates via palladium-catalyzed arylation with arylboronic acids

An enantioselective palladium-catalyzed arylation of fluorinated cyclic N-sulfonyl ketimines with arylboronic acids is described. This methodology provides an efficient and convenient route to chiral quaternary fluorinated cyclic sulfamidates in high yields with up to 99% ee.     

Regio‐ and Enantioselective Synthesis of Trifluoromethyl‐Substituted Homoallylic α‐Tertiary NH2‐Amines by Reactions Facilitated by a Threonine‐Based Boron‐Containing Catalyst

A method for catalytic regio‐ and enantioselective synthesis of trifluoromethyl‐substituted and aryl‐, heteroaryl‐, alkenyl‐, and alkynyl‐substituted homoallylic α‐tertiary NH₂‐amines is introduced. Easy‐to‐synthesize and robust N‐silyl ketimines are converted to NH‐ketimines in situ, which then react with a Z‐allyl boronate. Transformations are promoted by a readily accessible l ‐threonine‐derived aminophenol‐based boryl catalyst, affording the desired products in up to 91 % yield, >98:2 α:γ selectivity, >98:2 Z:E selectivity, and >99:1 enantiomeric ratio. A commercially available aminophenol may be used, and allyl boronates, which may contain an alkyl‐, a chloro‐, or a bromo‐substituted Z‐alkene, can either be purchased or prepared by catalytic stereoretentive cross‐metathesis. What is more, Z‐trisubstituted allyl boronates may be used. Various chemo‐, regio‐, and diastereoselective transformations of the α‐tertiary homoallylic NH₂‐amine products highlight the utility of the approach; this includes diastereo‐ and regioselective epoxide formation/trichloroacetic acid cleavage to generate differentiated diol derivatives.