A straightforward approach to the enantioselective synthesis of chiral 5,6-dihydrophenanthridines was developed. A series of chiral 6-aryl-5,6-dihydrophenanthridines were obtained through an organocatalytically modified Pictet–Spengler reaction of biphenyl-2-amines and aromatic aldehydes. In the reaction, H8-BINOL-derived chiral imidodiphosphoric acid exhibited strong stereocontrolling and catalytic activities to afford the desired 6-aryl-5,6-dihydrophenanthridines in high yields (up to 98 %) with high enantioselectivities (up to 99 % ee).

AbstractA highly enantioselective Friedel–Crafts arylation of indoles with isatins catalyzed by H8-1,1’-bi-2-naphthol (BINOL) imidodiphosphoric acids is reported here. This reaction proceeds smoothly under mild conditions and afford a range of 3-hydroxy-3-indolyloxindoles with high yields (<92 %) and excellent enantioselectivities (<99 % ee). To the best of our knowledge, this is the first example in which the highly enantioselective arylation of indoles with isatins has been catalyzed by a Brønsted acid.

The first enantioselective aza-Friedel–Crafts reaction between pyrroles and enamides has been achieved by using a novel H8-BINOL-type imidodiphosphoric acid catalyst. This methodology was also applied to the highly enantioselective aza-Friedel–Crafts reaction between pyrroles and imines. The catalyst loadings in these two reactions are low (0.3–2 mol%). Both processes are amenable to gram scales.

Penta-substituted 1,4-dihydropyridines were synthesized via catalytic enantioselective cyclization reactions of β,γ-unsaturated α-ketoesters, arylamines and acetylacetone for the first time. H8-BINOL-type chiral imidodiphosphoric acid 4c was a suitable catalyst and exhibited high catalytic and stereocontrolling abilities in these enone-type reactions. Under the optimized conditions, these 1,4-dihydropyridines were obtained with excellent enantioselectivities (up to 97% ee). In addition, the typical product 8ba was converted into the corresponding substituted piperidine with high yield (87%) and excellent enantioselectivity (95% ee) in a single-step reduction.The H8-BINOL chiral imidodiphosphoric acids catalyzed enantioselective cyclization reaction of β,γ-unsaturated α-ketoesters, arylamines and acetylacetone was developed. Five-substituted 4-aryl-1,4-dihydropyridines were obtained with up to 61% yields and up to 97% ee.(R)-Methyl-5-acetyl-1-(3-methoxyphenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC23H22N2O688% ee[α]D20 = +143.4 (c 0.456, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Ethyl-5-acetyl-1-(3-methoxyphenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC24H24N2O685% ee[α]D25 = +145.2 (c 0.566, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(3-methoxyphenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC25H26N2O690% ee[α]D25 = +238.0 (c 0.484, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Benzyl-5-acetyl-1-(3-methoxyphenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC29H26N2O689% ee[α]D25 = +179.8 (c 0.502, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(3-chlorophenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC24H23ClN2O591% ee[α]D25 = +226.7 (c 0.486, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(4-chlorophenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC24H23ClN2O589% ee[α]D25 = +226.5 (c 0.476, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(3-bromophenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC24H23BrN2O588% ee[α]D25 = +240.6 (c 0.271, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(3-fluorophenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC24H23FN2O594% ee[α]D25 = +248.0 (c 0.508, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(4-fluorophenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC24H23FN2O587% ee[α]D25 = +303.4 (c 0.470, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-6-methyl-4-(3-nitrophenyl)-1-(m-tolyl)-1,4-dihydropyridine-2-carboxylateC25H26N2O583% ee[α]D25 = +117.4 (c 0.301, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-6-methyl-4-(3-nitrophenyl)-1-(p-tolyl)-1,4-dihydropyridine-2-carboxylateC25H26N2O575% ee[α]D25 = +102.2 (c 0.256, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Benzyl-5-acetyl-1-(3-chlorophenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC28H23ClN2O594% ee[α]D25 = +189.2 (c 0.446, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Benzyl-5-acetyl-1-(3-bromophenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC28H23BrN2O594% ee[α]D25 = +193.5 (c 0.307, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-4-(4-bromophenyl)-1-(3-chlorophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC24H23BrClNO392% ee[α]D25 = +417.2 (c 0.494, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(3-bromophenyl)-4-(4-bromophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC24H23Br2NO391% ee[α]D25 = +160.9 (c 0.307, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Methyl-5-acetyl-4-(3-bromophenyl)-1-(3-chlorophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC22H19BrClNO393% ee[α]D25 = +217 (c 0.203, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(3-chlorophenyl)-4-(4-cyanophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC25H23ClN2O395% ee[α]D25 = +704 (c 0.486, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-4-(4-cyanophenyl)-1-(3-fluorophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC25H23FN2O394% ee[α]D25 = +249.9 (c 0.214, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Ethyl-5-acetyl-1-(3-bromophenyl)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC23H21BrFNO391% ee[α]D25 = +213.1 (c 0.502, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Ethyl-5-acetyl-1-(3-chlorophenyl)-6-methyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyridine-2-carboxylateC24H21ClF3NO391% ee[α]D25 = +205.7 (c 0.244, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Methyl-5-acetyl-1-(3-chlorophenyl)-4-(3,4-dichlorophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC22H18Cl3NO395% ee[α]D25 = +240.0 (c 0.490, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(3-chlorophenyl)-4-(3,4-dichlorophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC24H22Cl3NO393% ee[α]D25 = +191.6 (c 0.262, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Methyl-5-acetyl-1-(3-bromophenyl)-4-(3,4-dichlorophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC22H18BrCl2NO394% ee[α]D25 = +201.5 (c 0.271, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Ethyl-5-acetyl-1-(3-bromophenyl)-4-(3,4-dichlorophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylateC23H20BrCl2NO392% ee[α]D25 = +179.5 (c 0.507, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Isopropyl-5-acetyl-1-(3-bromophenyl)-6-methyl-4-(p-tolyl)-1,4-dihydropyridine-2-carboxylateC25H26BrNO390% ee[α]D25 = +195.6 (c 0.226, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Methyl-5-acetyl-1-(3-bromophenyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC22H19BrN2O594% ee[α]D25 = +273.4 (c 0.237, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-Benzyl-5-acetyl-1-(3-fluorophenyl)-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylateC28H23FN2O597% ee[α]D25 = +251.5 (c 0.334, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

The first enantioselective synthesis of 5,6-dihydroindolo[1,2-a]quinoxalines is achieved by using a newly developed H8-BINOL-type imidodiphosphoric acid catalyst with low catalyst loading through efficient Pictet–Spengler-type reactions of indolyl anilines with ketones. This methodology also generates phenyl-4,5-dihydropyrrolo[1,2-a]quinoxalines with high yields and excellent enantioselectivities. Moreover, this method was utilized to synthesize an HIV-1 inhibitor with high yield and good enantioselectivity through a one-step procedure.

The first enantioselective synthesis of pyrrolyl-substituted triarylmethanes has been accomplished using a novel imidodiphosphoric acid catalyst, which is derived from two (R)-BINOL frameworks with different 3,3′-substituents. This strategy was also expanded to the synthesis of bis(indolyl)-substituted triarylmethanes with high enantioselectivities, which could only be obtained with moderate ee values in previous reports. These two efficient Friedel–Crafts alkylation processes feature low catalyst loading, broad functional group compatibilities, and the potential to provide practical pathways for the synthesis of enantioenriched bioactive triarylmethanes.

A double axially chiral bisphosphorylimide has been demonstrated to be an efficient and highly sterically hindered Brønsted acid in asymmetric three-component Mannich reactions. Optically active syn-β-amino ketones were obtained in high yields (up to 99%) with excellent diastereoselectivity (99:1) and enantioselectivity (up to 99% ee). A gram-scale reaction was also performed to prove the synthetic application value of this reaction.(11b′R)-4,4′-Azanediylbis(dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide)C40H25NO6P2[α]D20=-99.6 (c 1, THF)Source of chirality: (R)-(+)-1,1′-bi-2-naphtholAbsolute configuration: (R,R)(11b′R)-4,4′-Azanediylbis(2,6-diphenyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide)C64H41NO6P2[α]D20=-175.6 (c 1, THF)Source of chirality: (R)-(+)-1,1′-bi-2-naphtholAbsolute configuration: (R,R)4-(((11bR)-2,6-Di(naphthalen-1-yl)-4-oxidodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-yl)amino)-2,6-diphenyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxideC72H45NO6P2[α]D20=-204.6 (c 1, THF)Source of chirality: (R)-(+)-1,1′-bi-2-naphtholAbsolute configuration: (R,R)(11b′R)-4,4′-Azanediylbis(2,6-di(naphthalen-1-yl)dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide)C80H49NO6P2[α]D20=-94.2 (c 1, THF)Source of chirality: (R)-(+)-1,1′-bi-2-naphtholAbsolute configuration: (R,R)4-(((11bR)-2,6-Bis(3,5-bis(trifluoromethyl)phenyl)-4-oxidodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-yl)amino)-2,6-diphenyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxideC68H37F12NO6P2[α]D20=-307.0 (c 1, THF)Source of chirality: (R)-(+)-1,1′-bi-2-naphtholAbsolute configuration: (R,R)4-(((11bR)-2,6-Bis(3,5-dimethylphenyl)-4-oxidodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-yl)amino)-2,6-diphenyldinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxideC68H49NO6P2[α]D20=-258.0 (c 1, THF)Source of chirality: (R)-(+)-1,1′-bi-2-naphtholAbsolute configuration: (R,R)

A novel and efficient microwave-assisted one-step reaction was developed to synthesize chiral N-sulfonylaziridines by the reaction of different chiral amino alcohols and sulfonic chlorides. The newly developed microwave synthetic method has the advantage of reducing the reaction time from 24 to 0.5 h with improved yields (84–93%) and minimizing by-products.A novel and efficient microwave-assisted one-step reaction was developed to synthesize N-sulfonylaziridines in 0.5 h with improved yields (84–93%) and minimized by-products.

Simple N-proline-based dipeptides with two N–H groups in combination with 2,4-dinitrophenol (DNP) catalyze the direct asymmetric aldol reactions of aldehydes with a broad range of ketones to furnish the corresponding aldol products in high yields (up to 99%) and with high enantioselectivities (up to 97%) and diastereoselectivities (up to >99:1, anti/syn) at room temperature and in brine.(S)-2-Amino-N-(4-(piperidin-1-yl)pyridin-3-yl)propanamideC13H20N4O[α]D25=+16.5 (c 0.2, CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (S)(S)-2-Amino-N-(4-(piperidin-1-yl)pyridin-2-yl)propanamideC13H20N4O[α]D25=-15.3 (c 0.2, CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (S)(S)-N-((S)-1-Oxo-1-((4-(piperidin-1-yl)pyridin-3-yl)amino)propan-2-yl)pyrrolidine-2-carboxamideC18H27N5O2[α]D25=-230.2 (c 0.2, CHCl3)Source of chirality: (S)-alanine and (S)-prolineAbsolute configuration: (S,S)(S)-N-((S)-1-Oxo-1-((4-(piperidin-1-yl)pyridin-2-yl)amino)propan-2-yl)pyrrolidine-2-carboxamideC18H27N5O2[α]D25=-94.9 (c 0.2, CHCl3)Source of chirality: (S)-alanine and (S)-prolineAbsolute configuration: (S,S)

The first organocatalytic asymmetric nucleophilic addition of arylpyrazoles to 2H-azirines and kinetic resolution of racemic 2H-azirines have been realized. Chiral aziridines were obtained with up to 98% yields and up to 99.9% ee. Meanwhile, simply changing the ratio of reactants, optically active 2H-azirines were recovered in good yields with excellent enantioselectivities.

The first enantioselective aza-Friedel–Crafts reaction between pyrroles and enamides has been achieved by using a novel H8-BINOL-type imidodiphosphoric acid catalyst. This methodology was also applied to the highly enantioselective aza-Friedel–Crafts reaction between pyrroles and imines. The catalyst loadings in these two reactions are low (0.3–2 mol%). Both processes are amenable to gram scales.