Chemoenzymatic synthesis of optically active 1,2-disubstituted ferrocenes with planar chirality

A new pathway for the synthesis of 2-substituted ferrocenyl compounds with planar chirality using a chemoenzymatic resolution as the key step is described. The kinetic resolution of racemic 2-hydroxymethyl phenylthioferrocene 4 has been optimised and carried out on a multi-gram scale using CAL-B lipase, giving the resulting acetate and remaining alcohols in ee’s >99%. The enantiomerically enriched sulfides have been transformed via a two-step sequence, in a new family of 2-substituted ferrocenyl alcohol by using a sulfoxide–lithium exchange/electrophilic trapping sequence; this gives straightforward access to non-racemic ferrocenyl alcohols with planar chirality.

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(RFc)-2-Acetoxymethyl-1-phenylthioferroceneC19H18FeO2SChiral HPLC analysis (Chiralpak AD column) (hexane/EtOH: 99/1; 1 mL/min): rt1 = 9.5 min, rt2 = 12.8 min.Ee = 95%[α]D=+95.7[α]D=+95.7 (c1.45, CH2Cl2)Absolute configuration: (RFc)

(SFc)-2-Hydroxymethyl-1-phenylthioferroceneC17H16FeOSEe = 99%[α]D=-56.2[α]D=-56.2 (c 1, CH2Cl2)Absolute configuration: (SFc)

2-Hydroxymethyl-1-phenylsulfinyl ferroceneC17H16FeO2S[α]D=+381.5[α]D=+381.5 (c 1, CH2Cl2)Absolute configuration: (SFc,Rs)

(SFc)-2-Hydroxymethyl-1-trimethylsilyl ferroceneC14H20FeOSi[α]D=-10.4[α]D=-10.4 (c 1, CH2Cl2)Absolute configuration: (SFc)

(SFC)-2-Hydroxymethyl-1-tributylstannyl ferroceneC23H38FeOSn[α]D=-1.6[α]D=-1.6 (c 1, CH2Cl2)Absolute configuration: (SFc)

(SFC)-2-Hydroxymethyl-1-iodoferroceneC11H11FeIO[α]D=+21.3[α]D=+21.3 (c 1, CH2Cl2)Absolute configuration: (SFc)

(RFC)-2-Hydroxymethyl-1-ferrocenylcyclohexanolC17H22FeO2[α]D=-5[α]D=-5 (c 1.5; CH2Cl2)Absolute configuration: (RFc)