Synthesis, characterization and enantioselective free radical reductions of (1 R,2 S,5 R)-menthyldiphenylgermane and its enantiomer

Abstract

(1 R,2 S,5 R)-Menthyldiphenylgermane and its enantiomer have been prepared in a few steps from germanium tetrachloride. The initial step in this sequence, namely the reaction between germanium tetrachloride and menthylmagnesium chloride, produces menthylgermanium trichloride, which is the exclusive product of this Grignard reaction, presumably due to the bulk of the menthyl group. When used at a low temperature (−78 °C) and in conjunction with Lewis acids, such as magnesium salts, these chiral germanes are capable of reducing ester functionalized radicals in high enantioselectivity, but in low-moderate yield. For example, ( R)-naproxen ethyl ester was obtained in 15% yield and 99% ee by reaction in toluene of 2-bromonaproxen ethyl ester with (1 R,2 S,5 R)-menthyldiphenylgermane in toluene at −78 °C in the presence of magnesium bromide. At 80 °C, (1 R,2 S,5 R)-menthyldiphenylgermane reacted with primary alkyl radicals with a rate constant of 1.02 × 10 6 M −1 s −1. Kinetic studies reveal the Arrhenius expression for this reaction to be: log(k/M −1 s −1) = (11.1 ± 0.4) − (34.6 ± 3.1)/ θ where θ=2.3 RT kJ mol −1.