Asymmetric synthesis approach of enantiomerically pure spiro-indenoquinoxaline pyrrolidines and spiro-indenoquinoxaline pyrrolizidines

An efficient, one-pot, four-component procedure for the synthesis of a small library of novel chiral spiro-indenoquinoxaline pyrrolidines and chiral spiro-indenoquinoxaline pyrrolizidines with high regio-, diastereo- (up to 96 dr), and enantioselectivity (up to 99% ee), through a 1,3-dipolar cycloaddition reaction of azomethine ylides and an optically active cinnamoyl–crotonoyl oxazolidinone is described. This methodology was very simple and was utilized to construct complex products from simple starting materials. The process was carried out in aqueous ethanol as an eco-friendly solvent and in the absence of any Lewis acids catalysts. The oxazolidinone chiral auxiliary was removed through a non-destructive protocol. The reaction mechanism is discussed on the basis of the assignment of the absolute configuration of the cycloadducts and using quantum mechanical calculations. The regio- and stereoselectivity were described on the basis of transition states’ stabilities and global and local reactivity indices of the reactants. The results of the theoretical calculations are in agreement with the experimental outcomes.

Figure optionsDownload as PowerPoint slide

(S)-4-Benzyl-3-((1′R,2′S,3′R,7a′R)-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-ylcarbonyl)oxazolidin-2-oneC38H32N4O3[α]D25 = +165.3 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(1′R,2′S,3′R,7a′R)

(S)-4-Benzyl-3-((1′S,2′S,3′R,7a′R)-1′-methyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-ylcarbonyl)oxazolidin-2-oneC33H30N4O3[α]D25 = +134.7 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(1′S,2′S,3′R,7a′R)

(S)-4-Benzyl-3-((1′R,2′S,3′R,7a′R)-7,8-dimethyl-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-ylcarbonyl)oxazolidin-2-oneC40H36N4O3[α]D25 = +164 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(1′R,2′S,3′R,7a′R)

(S)-4-Benzyl-3-((1′S,2′S,3′R,7a′R)-1′,7,8-trimethyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-ylcarbonyl)oxazolidin-2-oneC35H34N4O3[α]D25 = +136.7 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(1′S,2′S,3′R,7a′R)

(S)-4-Benzyl-3-((1′R,2′S,3′R,6′R,7a′R)-6′-hydroxy-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-ylcarbonyl)oxazolidin-2-oneC38H32N4O4[α]D25 = +112 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(1′R,2′S,3′R,6′R,7a′R)

(S)-4-Benzyl-3-((1′R,2′S,3′R,6′R,7a′R)-6′-hydroxy-7,8-dimethyl-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-ylcarbonyl)oxazolidin-2-oneC40H36N4O4[α]D25 = +111.2 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(1′R,2′S,3′R,6′R,7a′R)

(S)-4-Benzyl-3-((1′S,2′S,3′R,6′R,7a′R)-6′-hydroxy-1′-methyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-ylcarbonyl)oxazolidin-2-oneC35H34N4O4[α]D25 = +128 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(1′S,2′S,3′R,6′R,7a′R)

(S)-4-Benzyl-3-((2′R,3′S,4′R)-1′-methyl-4′-phenylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-ylcarbonyl)oxazolidin-2-oneC36H30N4O3[α]D25 = +270.7 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(2′R,3′S,4′R)

(S)-4-Benzyl-3-((2′R,3′S,4′S)-1′,4′-dimethylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-ylcarbonyl)oxazolidin-2-oneC31H28N4O3[α]D25 = +283.1 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: 4-(S), 3-(2′R,3′S,4′S)

Methyl(1′R,2′S,7a′R,11R)-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-carboxylateC29H25N3O2[α]D25 = −18 (c 0.02, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (1′R,2′S,7a′R,11R)

Methyl(1′S,2′S,7a′R,11R)-1′-methyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-carboxylateC24H23N3O2[α]D25 = −17 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (1′S,2′S,7a′R,11R)

Methyl(1′R,2′S,7a′R,11R)-7,8-dimethyl-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-carboxylateC31H29N3O2[α]D25 = −23.4 (c 0.02, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (1′R,2′S,7a′R,11R)

Methyl(1′S,2′S,7a′R,11R)-1′,7,8-trimethyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-carboxylateC26H27N3O2[α]D25 = −20.2 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (1′S,2′S,7a′R,11R)

Methyl(1′R,2′S,6′R,7a′R,11R)-6′-hydroxy-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-carboxylateC29H25N3O3[α]D25 = −14 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (1′R,2′S,6′R,7a′R,11R)

Methyl(1′R,2′S,6′R,7a′R,11R)-6′-hydroxy-7,8-dimethyl-1′-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-carboxylateC31H29N3O3[α]D25 = −18 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (1′R,2′S,6′R,7a′R,11R)

Methyl(1′S,2′S,6′R,7a′R,11R)-6′-hydroxy-1′-methyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indeno[1,2-b]quinoxaline-11,3′-pyrrolizine]-2′-carboxylateC24H23N3O3[α]D25 = −16.4 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (1′S,2′S,6′R,7a′R,11R)

Methyl (3′S,4′R,11R)-1′-methyl-4′-phenylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-carboxylateC27H23N3O2[α]D25 = −34 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (3′S,4′R,11R)

Methyl(3′S,4′S,11R)-1′,4′-dimethylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-carboxylateC22H21N3O2[α]D25 = −33 (c 0.03, CH2Cl2)Source of chirality: the chiral auxiliaryAbsolute configuration: (3′S,4′S,11R)