Organocatalytic enantioselective tandem aldol-cyclization reaction of α-isothiocyanato imides and activated carbonyl compounds

The organocatalytic enantioselective tandem aldol-cyclization reactions of α-isothiocyanato imides and activated carbonyl compounds, such as isatins, an α-ketolactone and a 1,2-dione, have been studied with cinchona alkaloid-derived thiourea-catalysts. This methodology provided an easy way to access enantiomerically enriched spirobicyclic thiocarbamates with high yields and good to excellent stereoselectivity, which have been demonstrated to be useful precursors for the synthesis of biologically active molecules.

Figure optionsDownload as PowerPoint slide

(3R,4′S)-4′-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC16H15N3O5Sdr = 85:15 ee = 95%[α]D25=+89.0 (c 0.87, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(3R,4′S)-4-Chloro-4′-(4,4-dimethyl-2-oxooxazolidine-3-carbonyl)-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC16H14ClN3O5Sdr =78:22 ee = 98%[α]D25=+63.1 (c 1.04, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(3R,4′S)-4-Bromo-4′-(4,4-dimethyl-2-oxooxazolidine-3-carbonyl)-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC16H14BrN3O5Sdr =85:15 ee = 95%[α]D25=+73.7 (c 0.99, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(3R,4′S)-4′-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-5-fluoro-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC16H14FN3O5Sdr = 78:22 ee = 95%[α]D25=+95.2 (c 0.45, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(3R,4′S)-5-Bromo-4′-(4,4-dimethyl-2-oxooxazolidine-3-carbonyl)-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC16H14FN3O5Sdr = 81:19 ee = 88%[α]D25=+58.7 (c 0.78, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(3R,4′S)-4′-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-5-methoxy-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC17H17N3O6Sdr = 86:14 ee = 97%[α]D25=+95.8 (c 0.51, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(3R,4′S)-6-Bromo-4′-(4,4-dimethyl-2-oxooxazolidine-3-carbonyl)-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC16H14BrN3O5Sdr = 80:20 ee = 95%[α]D25=+117.4 (c 0.45, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(3R,4′S)-4,7-Dichloro-4′-(4,4-dimethyl-2-oxooxazolidine-3-carbonyl)-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC16H13Cl2N3O5Sdr = 85:15 ee = 96%[α]D25=+78.3 (c 0.54, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(3R,4′S)-1-Benzyl-4′-(4,4-dimethyl-2-oxooxazolidine-3-carbonyl)-2′-thioxospiro[indoline-3,5′-oxazolidin]-2-oneC23H21N3O5Sdr = 70:30 ee = 94%[α]D25=+87.0 (c 0.87, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4′S)

(4S,5R)-4-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-8,8-dimethyl-2-thioxo-1,7-dioxa-3-aza-spiro[4.4]nonan-6-oneC14H18N2O6Sdr = 92:8 ee = 94%[α]D25=+62.3 (c 0.90, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)

(4S,5R)-4-(4,4-Dimethyl-2-oxooxazolidine-3-carbonyl)-8,8-dimethyl-2-thioxo-1,7-dioxa-3-aza-spiro[4.4]nonan-6-oneC14H18N2O6Sdr = 65:35 ee = 90%[α]D25=+47.9 (c 1.04, THF)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5R)