No abstract

Two syntheses of some optically active 2‐benzyl‐2,3‐dihydro‐4H‐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‐4H‐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. (4R,S)‐Benzamido‐2‐benzyl‐2,3‐dihydro‐6‐(methoxycarbonyl)‐4H‐1‐benzopyran‐4‐carboxylic acid 16 was prepared from 11 by amidoalkylation with α‐hydroxyhippuric acid in methanesulfonic acid solution followed by spiroalkylation to (4R,S)‐2‐benzyl‐2,3‐dihydro‐6‐(methoxycarbonyl)spiro[4H‐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‐4H‐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‐4H‐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 2R‐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 2R‐benzyl‐2,3‐dihydro‐4H‐benzopyran (R)‐30. Formylation of (R)‐30 provided 2R‐benzyl‐6‐(formyl)‐2,3‐dihydro‐4H‐benzopyran (R)‐25 identical with that from the first synthesis. These optically active intermediates are used in the preparation of the hypoglycemic agent englitazone.

studied the diazotization/halogenation of 6-aminopenicillanic acid (II) in aqueous media. Accordingly, Clayton was able to generate 6,6-dibromopenicillanic acid (Ilia), a most useful ¡3-lactam intermediate,7 in approximately 34% yield and was able to convert this product via a reduction to penicillanic acid (Illb). While this diazotization/halogenation procedure conceptually provided a solution to our problem, the low yield for this transformation was unacceptable for our purposes and similarly has plagued those who have used Ilia in ¡8-lactam syntheses.This diazotization reaction, in our hands, generated varying amounts of -bromopenicillanic acid (IIIc) in addition to the desired 6,6-dibromopenicillanic acid (Ilia).8 The inefficiency of this transformation, we thought, could be attributed to the presence of hydrogen bromide in the reaction media, which was intercepting the diazo intermediate to form IIIc, and also to the prolonged exposure of the desired dihalogenated product Ilia to strongly acidic conditions. We therefore reasoned that a high-yield conversion of 6-APA ( ) to 6,6-dibromopenicillanic acid (Ilia)

A new synthesis of the aldose reductase inhibitors sorbinil(1) and its 2(R)-methyl homologue 2 is presented. The amidoalkylation of 2-(4'-fluorophenoxy)ethyl halides 6 with N-benzoyl-a-hydroxyglycine yielded Nbenzoyl-5-fluoro-2-(2-haloethoxy)phenylglycines 10. The N-benzoyl amino acid group was dehydrated to oxazolidin-5-one 11 and underwent subsequent intramolecular spiroalkylation to 2,3-dihydro-6-fluorospiro[4H-lbenzopyran-4,4'-2-phenyloxazolidin]-5-one (12) in high yield upon treatment with acetic anhydride and either triethylamine or potassium carbonate. Acidic hydrolysis of oxazolidin-5-one 12 provided the desired racemic spiro amino acid ruc-5, completing a three-step insertion of a glycine moiety. The methyl ester of rac-5 was resolved by stereospecific hydrolysis with a-chymotrypsin and converted to (S)-1 with potassium cyanate in acetic acid. The method was extended to (2R,4S)-2 by utilizing (S)-ethyl lactate as the source of chirality at C-2.A new strategy for regiospecific imidazole alkylation of suitably protected histidines is described wherein a phenacyl group serves as a protecting group of the distal imidazole nitrogen atom. Alkylation of N-BOC-1phenacyl-L-histidine methyl ester at N(3), followed by reductive removal of the phenacyl group from N(1) of the resulting imidazolium intermediate with zinc and acetic acid offers an efficient and flexible route to 3-substituted L-histidines.

Controlled action of acid on pterocarpin (I; R = H) or homopterocarpin (11, R = H) produces the isoflavenes (V; R = H) or (VI; R = H), respectively. Hydrogenation of (V; R = Me) gives the flavan (IV; R = Me) with the properties reported for the synthetic compound, thus further supporting formula (I ; R = H) for pterocarpin. Oxidation of the isoflavenes (V; R = Ac) and (VI; R = Ac) with osmium tetroxide, followed by the action of alkali, leads to ( rt: )-pisatin ( I ; R = OH) and the analogue (11; R = OH). Reaction of pterocarpin and homopterocarpin with potassamide in liquid ammonia leads to benzofuran derivatives of type (X). 1 I.