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.

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(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)