Chemo-enzymatic synthesis of new ferrocenyl-oxazolidinones and their application as chiral auxiliaries

A chemo-enzymatic synthesis of new chiral ferrocenyl-oxazolidinones has been developed. The key step was the addition of HCN to formylferrocene catalysed by the hydroxynitrile lyase from Hevea brasiliensis, which yielded an enantiomerically pure ferrocenyl-cyanohydrine in excellent yield and ee. The ferrocenyl-oxazolidinones obtained by this strategy were tested as chiral auxiliaries for asymmetric alkylations and aldol reactions and were shown to be effective in terms of yields, stereoselectivities and cleavage conditions.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(R)-(Cyanohydroxymethyl)ferroceneC12H11FeNOEe = 99%[α]D22=+150 (c 0.30, CH3CN)Source of chirality: biocatalysisAbsolute configuration: (R)

(R)-[Cyano(trimethylsilyloxy)methyl]ferroceneC15H19FeNOSiEe = 99%[α]D22=+153 (c 0.25, CH2Cl2)Source of chirality: biocatalysisAbsolute configuration: (R)

(4R,5R)-4-Benzyl-5-ferrocenyl-oxazolidin-2-oneC20H19FeNO2Ee = 99%[α]D22=-114 (c 1.0, CH2Cl2)Source of chirality: biocatalysisAbsolute configuration: (4R,5R)

(4S,5R)-4-Benzyl-5-ferrocenyl-oxazolidin-2-oneC20H19FeNO2Ee = 99%[α]D22=-37.8 (c 1.0, CH2Cl2)Source of chirality: biocatalysisAbsolute configuration: (4S,5R)

(4R,5R)-4-Benzyl-3-propionyl-5-ferrocenyl-oxazolidin-2-oneC23H23FeNO3Ee = 99%[α]D22=-116 (c 1.0, CH2Cl2)Source of chirality: biocatalysisAbsolute configuration: (4R,5R)

(4S,5R)-4-Benzyl-3-propionyl-5-ferrocenyl-oxazolidin-2-oneC23H23FeNO3Ee = 99%[α]D22=+42 (c 1.0, CH2Cl2)Source of chirality: biocatalysisAbsolute configuration: (4S,5R)

(4R,5R)-4-Benzyl-3-((2S)-2-methyl-3-phenylpropanoyl)-5-ferrocenyl-oxazolidin-2-oneC30H29FeNO3Ee = 99%[α]D22=-62 (c 1.0, CH2Cl2)Source of chirality: diastereoselective alkylationAbsolute configuration: (4R,5R,2S)

(4S,5R)-4-Benzyl-3-((2R)-2-methyl-3-phenylpropanoyl)-5-ferrocenyl-oxazolidin-2-oneC30H29FeNO3Ee = 99%[α]D22=+25 (c 1.0, CH2Cl2)Source of chirality: diastereoselective alkylationAbsolute configuration: (4S,5R,2R)

(4R,5R)-4-Benzyl-3-((2S)-2-methyl-pent-4-enoyl)-5-ferrocenyl-oxazolidin-2-oneC26H27FeNO3Ee = 99%[α]D22=-104 (c 1.0, CH2Cl2)Source of chirality: diastereoselective alkylationAbsolute configuration: (4R,5R,2S)

(4R,5R)-4-Benzyl-5-ferrocenyl-3-((2S,3R)-3-hydroxy-2-methyl-3-phenylpropanoyl)oxazolidin-2-oneC30H29FeNO4Ee = 95%[α]D22=-58 (c 1.0, CH2Cl2)Source of chirality: diastereoselective aldol reactionAbsolute configuration: (4R,5R,2S,3R)

(4S,5R)-4-Benzyl-5-ferrocenyl-3-((2R,3S)-3-hydroxy-2-methyl-3-phenylpropanoyl)oxazolidin-2-oneC30H29FeNO4Ee = 65%[α]D22=+53 (c 1.0, CH2Cl2)Source of chirality: diastereoselective aldol reactionAbsolute configuration: (4S,5R,2R,3S)

(S)-2-Methyl-3-phenylpropionic acidC10H12O2Ee = 95%[α]D22=+26.3 (c 1.0, CHCl3)Source of chirality: diastereoselective aldol reactionAbsolute configuration: (S)

(R)-2-Methyl-3-phenylpropionic acidC10H12O2Ee = 70%[α]D22=-18 (c 1.0, CHCl3)Source of chirality: diastereoselective aldol reactionAbsolute configuration: (R)

(S)-2-Methyl-pent-4-enoic acidC6H10O2Ee >95%[α]D22=+10.1 (c 1.0, CHCl3)Source of chirality: diastereoselective alkylationAbsolute configuration: (S)

(2S,3R)-3-Hydroxy-2-methyl-3-phenylpropionic acidC10H12O3Ee = 95%[α]D22=+38 (c 0.66, CHCl3)Source of chirality: diastereoselective adolreactionAbsolute configuration: (2S,3R)

(2R,3S)-3-Hydroxy-2-methyl-3-phenylpropionic acidC10H12O3Ee = 65%[α]D22=-26 (c 0.66, CHCl3)Source of chirality: diastereoselective adolreactionAbsolute configuration: (2R,3S)

(R)-2-Methyl-pent-4-enoic acidC6H10O2Ee = 75%[α]D22=-8.1 (c 1.0, CHCl3)Source of chirality: diastereoselective alkylationAbsolute configuration: (R)