Toshihisa Ogawa

Stereochemistry of the 2-hydroxy-1,2,3,4-tetrahydropyridine intermediate of hantzsch cyclization

Abstract Hantzsch cyclization of cyanoethyl 3-aminocrotonate and (E,Z)-4-dialkoxymethyl-2-benzylidene-acetoacetates (5a,b) afforded 3,4-trans-2-hydr

Chemoenzymatic synthesis of optically active 1,4-dihydropyridine derivatives via enantioselective hydrolysis and transesterification

Abstract (4 R )-(−)-2-(Nicotinoylamino)ethyl 3-nitrooxypropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate ( 1 ), a new calcium antagonist, was synthesized via both enantioselective hydrolysis and transesterification of prochiral bis[2-(nicotinoylamino)ethyl]ester · 2HCl ( 5 ) by using enzymes. Hydrolysis of 5 by proteases originated from Aspergillus melleus and Bacillus licheniformis etc. in aqueous media afforded (4 R )-(−)-3-[2-(nicotinoylamino)-ethoxycarbonyl]-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid ( 6 ) in more than 99% e.e., which was converted to 1 by esterification with 3-nitrooxypropyl bromide. Enzymatic transesterification of 5 with 3-nitrooxypropanol gave 1 in more than 99.5% e.e. directly.

Synthesis and configurational assignment of methyl 3-nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

Enantiomeric (+)- and (–)-methy3-nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl) pyridine-3,5-dicarboxylate 1 were synthesized by esterification of the optically active monocarboxylic acids (+)-6 and (–)-6, which are available from racemate (±)-6 by optical resolution using cinchonidine and cinchonine. The absolute configuration of the key intermediates (S)-(+)-6 and (R)-(–)-6, was also unambiguously determined by the comparison with optical active (+)- and (–)-1 derived from (R)-(–)- and (S)-(+)-7 and (+)- and (–)-6, and X-ray crystallographic analysis of bromoethyl ester (R)-(–)-8 prepared from the acid (S)-(+)-7.

Chemistry of Hantzsch cyclization: stereochemistry of the 2-hydroxy-1,2,3,4-tetrahydropyridine intermediate of Hantzsch cyclization. X-Ray molecular structure of diastereoisomers of 5-(2-cyanoethyl) 3-methyl 2-dimethoxymethyl-2-hydroxy-6-methyl-4-(3-nitrophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylates

Hantzsch cyclization of cyanoethyl 3-aminocrotonate and (E,Z)-4,4-dialkoxy-2-benzylideneacetoacetates 12a–h afforded the corresponding 3,4-trans-2-hydroxy-1,2,3,4-tetrahydropyridines 14a–h with high stereoselectivity. 1H NMR and X-ray analyses of compound 14a established the configuration of 3-H and 4-H as trans and that of 3-H and 2-OH as trans also.