Synthetic approaches to 9-arylated Cinchona alkaloids: stereoselective addition of Grignard reagents to cinchonanones and hydroxylation of 9-phenylcinchonanes

All 8,9-isomers of the 9-phenyl Cinchona alkaloids were obtained by autoxidation of 9-deoxy-9-phenyl-alkaloids and by the addition of Grignard reagents to the respective ketones. The diastereoselective addition of phenyl-, methyl-, and vinylmagnesium reagents to quinidinone and cinchoninone gave the corresponding (8R,9S)-products with acceptable yields and starting material recovery. The configurations of the compounds obtained were established by chemical correlations, NMR experiments, and were supported by DFT calculations and X-ray structures. Stereochemical models for both reactions were also devised and discussed.

Figure optionsDownload as PowerPoint slide

(8R,9S)-6′-Methoxy-9-phenyl-9-cinchonanolC26H28N2O2De >95% (by 1H NMR)[α]D26=+127 (c 0.7, 96% EtOH) 100% eeSource of chirality: natural productAbsolute configuration: (1S,3R,4S,8R,9S) (by chemical correlation and X-ray structure)

(8R,9R)-6′-Methoxy-9-phenyl-9-cinchonanolC26H28N2O2De >95% (by 1H NMR)[α]D24=+110 (c 0.3, 96% EtOH) 100% eeSource of chirality: natural productAbsolute configuration: (1S,3R,4S,8R,9R) (by chemical correlation and 13C NMR chemical shifts)

(8S,9R)-6′-Methoxy-9-phenyl-9-cinchonanolC26H28N2O2De >95% (by 1H NMR)[α]D26=-27 (c 0.4, 96% EtOH) 100% ee[α]D20=-9.1 (c 1, CH2Cl2) 100% eeSource of chirality: natural productAbsolute configuration: (1S,3R,4S,8S,9R) (by chemical correlation and 13C NMR chemical shifts)

(8S,9S)-6′-Methoxy-9-phenyl-9-cinchonanolC26H28N2O2[α]D20=+13 (c 0.2, 96% EtOH) de 90% by 1H NMRSource of chirality: natural productAbsolute configuration: (1S,3R,4S,8S,9S) (by chemical correlation and 13C NMR chemical shifts)

(8R,9S)-6′-Methoxy-9-vinyl-9-cinchonanolC22H26N2O2De >95% (by 1H NMR)[α]D21=+97 (c 0.92, 96% EtOH) 100% eeSource of chirality: natural productAbsolute configuration: (1S,3R,4S,8R,9S) (by chemical correlation)

(8R,9S)-6′-Methoxy-9-(3-aminophenyl)-9-cinchonanolC26H29N3O2De >95% (by 1H NMR)[α]D23=+104 (c 0.8, 96% EtOH) 100% eeSource of chirality: natural productAbsolute configuration: (1S,3R,4S,8R,9S) (by chemical correlation)

(8R,9S)-9-Phenyl-9-cinchonanolC25H26N2ODe >95% (by 1H NMR)[α]D23=+11 (c 0.45, 96% EtOH) 100% eeSource of chirality: natural productAbsolute configuration: (1S,3R,4S,8R,9S) (by chemical correlation)