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Functionalized 2H-chromenes are widely distributed in biologically important natural products and pharmaceutical agents.1 While a variety of synthetic methods for chromene derivatives has become well developed, asymmetric synthetic methods for optically active chromene derivatives remain limited.2 We describe in this paper our approach for the asymmetric preparation of 2,3-disubstituted chromene deriva­ tives using the kinetic resolution of p-chromenyl-p-hydroxy esters. For the preparation of enantioenriched chromene deriva­ tive 2, we initially examined an asymmetric Reformatsky reaction of 2H-chromene 3-carbaldehyde (1) with chiral ligand 3. Treatment of 1 with BrZnCHzCOzt-Bu in the presence of chiral ligand 3 (30 mol%) for 1 h at room tem­ perature provided p-chromenyl-p-hydroxy ester 2 with no detectable enantioselectivity. We recently reported that enantioenriched p-hydroxy esters can alternatively be prepared from asymmetric dehydration.3 Based on our previous inve­ stigation, we carried out the reaction of racemic p-hydroxy ester 2 with chiral ligand 3 (5 mol%) and BrZnCHzCOzt-Bu (8 equiv) for 4 h in refluxing THF. As shown in Scheme 1, the dehydration of 2 gave the eliminated product and enantioenriched (R)-2 with 87% ee in 53% conversion (s = 22).4 The efficiency of the catalyst drastically decreased with less than 8 equiv of BrZnCHzCOzt-Bu. When 4 equiv of BrZnCHzCOzt-Bu was used, (R)-2 was obtained with 45% ee in 44% conversion (s = 6). To develop a more efficient ligand for the kinetic resolution, p-fluoro substituted chiral ligand 4 has been tested for asymmetric dehydration of various p-hydroxy esters as shown in Table 1. When p-chromenyl-p-hydroxy ester 2 was treated with chiral ligand 4, the reaction provided a higher selectivity compared to the reaction with chiral ligand 3 (Entry 1). However, dehydrations of p-aryl-p-hydroxy esters 5-7 and pstyryl-p-hydroxy esters 8-10 with p-fluoro substituted chiral

Kinetic Resolution of β-Chromenyl-β-Hydroxy Esters for Asymmetric Preparation of Flavene Derivatives