Methyl 2-(cis-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate → methyl 2-((1R,3S)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate

Participants

Reaction Steps

490 g of the crude, racemic methyl cis-2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate (see Example 1) were dissolved in 3.1 l of methylene chloride and 850 ml of vinyl acetate, admixed with 18 g of Novozym 435 and stirred at 21–24° C. After 28 h, a further 2 g of Novozym 435 were added. After a total of 44 h, the reaction was ended by filtering off the enzyme and the filtrate was concentrated by evaporation under reduced pressure to obtain 540 g. Chromatography of the residue on approx. 6 kg of silica gel (1:1 ethyl acetate/n-heptane) gave 184 g of methyl (1R,3S)-2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate; >98% ee (HPLC on Chiralpak AD-H 250×4.6; 1 ml/min, heptane/EtOH/CH3CN 25:1:0.5+0.1% TFA); 1H NMR (CDCl3), δ =1.27 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.74 (m, 1H), 1.83 (m, 1H), 2.05 (m, 1H), 2.34 (s, 3H), 3.47 (m, 1H), 3.72 (m, 1H), 3.91 (s, 3H), 4.58 (dd, 2H), 7.15 (d, 1H), 7.20 (d, 2H), 7.27 (m, 1H) and 239 g of the (1S,3R)-acetate (93% ee, HPLC on Chiralcel OD/20 250×4.6, 1 ml/min, 100:1:0.5 heptane/EtOH/CH3CN).

Provenance & Evidence