Synthesis of optically active 2‐benzyldihydrobenzopyrans for the hypoglycemic agent englitazone

Two syntheses of some optically active 2‐benzyl‐2,3‐dihydro‐4 H ‐benzopyrans and benzopyran‐4‐ones are presented. An asymmetric synthesis starting from D‐ and L‐phenylalanine was used to provide both enantiomers of 2‐benzyl‐6‐(methoxycarbonyl)‐2,3‐dihydro‐4 H ‐benzopyran‐4‐one 19. Phenylalanine was diazotized in aqueous sulfuric acid to 2‐hydroxy‐3‐phenylpropionic acid 6 which was converted in four steps to 1‐bromo‐2‐(4‐methoxycarbonylphenoxy)‐3‐phenylpropane 11. (4 R,S )‐Benzamido‐2‐benzyl‐2,3‐dihydro‐6‐(methoxycarbonyl)‐4 H ‐1‐benzopyran‐4‐carboxylic acid 16 was prepared from 11 by amidoalkylation with α‐hydroxyhippuric acid in methanesulfonic acid solution followed by spiroalkylation to (4 R,S )‐2‐benzyl‐2,3‐dihydro‐6‐(methoxycarbonyl)spiro[4 H ‐benzopyran‐4,4′‐2′‐phenyloxazolidin]‐5′‐one 15. After the phenyloxazolidin‐5‐one 15 was hydrolyzed to the spirobenzamido carboxylic acid 16 , oxidative decarboxylation with sodium hypochlorite yielded optically active 2‐benzyl‐6‐(methoxycarbonyl)‐2,3‐dihydro‐4 H ‐benzopyran‐4‐one 19. The ketone in 19 was reduced by hydrogenation over palladium on carbon to a methylene group and the ester was converted to the aldehyde to give both isomers of the desired intermediate 2‐benzyl‐6‐(formyl)‐2,3‐dihydro‐4 H ‐benzopyran 25. The second synthesis relied on an enzymatic hydrolysis of ethyl 2,3‐dihydrobenzopyran‐2‐carboxylate 27 with the lipase from P. fluorescens to provide the desired 2 R ‐ester. The ester group in ( R )‐ 27 was converted to the triflate ( R )‐ 29. Displacement of the triflate group with phenylmagnesium bromide and cuprous bromide as catalyst gave 2 R ‐benzyl‐2,3‐dihydro‐4 H ‐benzopyran ( R )‐ 30. Formylation of ( R )‐ 30 provided 2 R ‐benzyl‐6‐(formyl)‐2,3‐dihydro‐4 H ‐benzopyran ( R )‐ 25 identical with that from the first synthesis. These optically active intermediates are used in the preparation of the hypoglycemic agent englitazone.