Amino alcohol ligand and its use in preparation of chiral proparglic tertiary alkohols and tertiary amines via enantioselective addition reaction
AssigneeShanghai Institute of Organic Chemistry, Chinese Academy of Sciences
InventorsBiao Jiang, Yugui Si
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Abstract
The invention disclosed a new process of asymmetric alkynylation of ketone or ketimine, involving the chiral ligand-mediated asymmetric addition of zinc or copper acetylide to a trifluoromethyl ketone or ketimine intermediate to give a chiral tertiary proparglic alcohols or amines. The adduct compounds include the key precursors to the potent HIV reverse transcriptase inhibitor Efavirenz (DMP 266), DPC 961 and DPC 083. The invention also disclosed a novel chiral amino alcohol ligand.
Claims21
A process for the asymmetric synthesis of the chiral compound of the structure
- where Y is H, mono or multisubsubstituted electronwithdrawing group or electron-donating group, wherein Y can be located at m-, o-, or p-positon of the benzene ring;
- P is hydgogen or an amino protecting group,
- Rf is fluoro-containing alkyl,
- R is trialkylsilyl, alkyl, cycloalkyl or aryl group,
- R6 is hydrogen when R5 is hydroxy, also R5and R6 can be —HNCO— of the structure or its enantiomer
- where Y, P, R, Rf is the same as above;
- Comprising the steps of:
- (a) providing a mixture of chiral ligand (1R, 2R)-2-N,N-substituted-1-(substituted-phenyl)-2-R3-substituted-2-aminoethanol or its enantiomer, of the structure
- wherein R1, R2 is amino protecting group, and R3 is alkyl;
- alkyl substituted with alkyloxy or silyoxy, carboxylic group, carbalkoxy group, hydroxyl methyl, cycloalkyl, aryl or CH2OR4,
- wherein R4 is an oxygen protecting group,
- Z is H, mono or multisubsubstituted electronwithdrawing group or electron-donating group,
- wherein Z can be located at m-, o-, or p-positon of the benzene ring;
- with a terminal alkyne and a Zn(II), Cu(II) or Cu(I) salts in the presence of an organic base in aprotic solvent, wherein the terminal alkyne is
- is the same as above,
- (b) mixing with the mixture of step (a) of reactant of the structure
- or of the structure
- wherein P is hydrogen or an amino protecting group, Rf is fluoro-containing alkyl, Y is the same as above;
- obtains the target addition product after normal isolation.
The compound of the structure or its enantiomer
- wherein R1, R2 is amino protecting group, and R4 is oxygen protecting group;
- Z is mono or multisubstituted electronwithdrawing group or electron-donating group;
- and when Z is NO2 at 4-postion of the phenyl, R1 is N═O, R2 is COCH3, R4 is only alkyl, substituted alkyl, benzyl substituted benzyl, or trialkylsilyl;
- and when Z is NO2 at 4-postion of the phenyl, R1, R2 is CH3, the ligand is only (1R, 2R)-2-N,N-dimethylamino-1-(4-nitrophenyl)-3-O—R4-1-propanol;
- and when Z is OCH3 at 4-postion of the phenyl, R1, R2 is CH3, R4 is only alkyl, substituted alkyl, benzyl substituted benzyl;
- said substituted group is phenyl, naphthyl, halogen, NO2, hydroxyl, C1˜C3 hydroxyalkyl, C1˜C4 alkyl, C1˜C3 alkoxy or CN;
Dependencies are inferred from the claim text.