Asymmetric epoxidation of cinnamic acid derivatives by in situ generated dioxiranes of chloroacetones: scope and limitations

Efficient epoxidation of chiral cinnamic acid derivatives has been achieved by in situ generated dioxiranes of chloroacetones with moderate to good diastereoselectivity (dr up to 90:10) in high yields. Reactivity of cinnamic acid derivatives containing different chiral auxiliaries versus chloroacetones–monochloroacetone 3 (MCA), 1,1-dichloroacetone 4 (DCA) and 1,1,1-trichloroacetone 5 (TCA) and Oxone™ loading was studied. Both Oxone™ loading and reaction time reduce with an increase of chlorine atoms in the acetone. The use of 1.1 equiv of TCA was found to be effective for the epoxidation of cinnamate substrates and enhances the reaction up to 4–10-fold compared to acetone and that also decreases the Oxone™ loading. This method provided methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (−)-2, a key intermediate for the synthesis of diltiazem hydrochloride, with >99% of enantiomeric purity.

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(2R,2′R,3′S)-N-[3′-{(4-Methoxyphenyl) oxyranyl}methaone]bornanesultamC20H25NO5SEe >99%[α]D29=-167.8 (c 0.5, CHCl3)Source of chirality: (2R)-bornanesultamAbsolute configuration: (2R,2′R,3′S)

Methyl (2R,3S)-3-(4-methoxyphenyl)glycidateC11H12O4Ee >99%[α]D29=-209.5 (c 1.0, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)