Search

By using lipase ‘PL-266’ from Alcaligenes sp. enantioselective acetylation of (±)-albicanol 4 with isopropenyl acetate gave the enantiomerically pure (+)-albicanyl acetate 3 and (+)-albicanol 4. Deprotection of (+)-3 afforded the natural (+)-albicanol 4 which was converted to the natural products (−)-albicanyl 3,4-dihydroxycinnamate 7, (−)-drimenol 8, (−)-drimenin 9 and (−)-ambrox 10.

Syntheses of (S)-chroman-2-carboxaldehyde congener 1 and (S)-chiral isoprene unit 3 were achieved based on the enzymatic acetylation of (±)-chroman-2-methanol 6 and (±)-(2, 3)-anti-2-methyl-3-(p-methoxyphenyl)-1, 3-propane diol 12, respectively. Synthesis of the side-chain part corresponding to (3R, 7R)-3, 7, 11-trimethyldodecan-1-ol 27 was achieved by the couping reaction of (S)-3 and (R)-3, 7-dimethyloctyl iodide 4. The Witting reaction of (3R, 7R)-phosphonium salt 2 derived from (3R, 7R)-27 and (S)-1 gave the olefin 28 which was subjected to cat-alytic hydrogenation to afford (2R, 4' R, 8' R)-α-tocopherol.

Stereoselective syntheses of (−)-ambrox 2 and (+)-zonarol 3 were achieved based on the enzymatic syntheses of (8a S )- and (8a R )-decalin-type 1,3-diols 1 , respectively. Non-racemic intermediates such as (8a S )- 1 and (8a R )- 1 were obtained based on the enantioselective hydrolyses of the phenolic acetal derivative (±)- 7 by acylase I.

The structural requirements of acetohexamide reductases purified from rabbit liver, kidney, and heart for substrates and inhibitors were examined. Acetohexamide, an oral antidiabetic drug with a ketone group, and analogs of it with various alkyl groups instead of the cyclohexyl group were used as substrates for these three enzymes. The results obtained as to substrate specificity suggested that the nature of the substrate-binding region of the heart enzyme is markedly different from those of the substrate-binding regions of the liver and kidney enzymes. Tolbutamide, which has no ketone group within its chemical structure, strongly inhibited the heart enzyme, whereas it had little ability to inhibit the liver or kidney enzyme. The inhibition of the heart enzyme by tolbutamide was competitive with respect to acetohexamide and uncompetitive with respect to NADPH. Furthermore, tolbutamide analogs with n-pentyl and n-hexyl groups instead of the n-butyl group exhibited very pronounced inhibition of only the heart enzyme. Therefore, it is reasonable to postulate that the heart enzyme, unlike the liver and kidney ones, has a cleft of a strongly hydrophobic nature near its substrate-binding region, and that this hydrophobic cleft plays a critical role in the interaction of the heart enzyme with the cyclohexyl group of acetohexamide.

An enzyme catalyzing the metabolic reduction of acetohexamide [4-acetyl-N-(cyclohexyl-carbamoyl)benzenesulfonamide], an oral antidiabetic drug, was purified to homogeneity from the cytosolic fraction of rabbit heart. The molecular mass of the purified enzyme was estimated to be 110 kDa by gel filtration and nondenaturing PAGE and 28 kDa by SDS-PAGE, suggesting that the enzyme is composed of four identical-size subunits. 4-Benzoyl-pyridine and p-nitroacetophenone, typical substrates of carbonyl reductase [EC 1.1.1.184], were not reduced by the enzyme. Of drugs with a ketone group tested, only acetohexamide was a good substrate of the enzyme. the enzyme effectively reduced analogs substituted with various alkyl groups instead of the cyclohexyl group in acetohexamide, although it had little or no ability to reduce analogs substituted with various alkyl groups instead of the methyl group in acetohexamide. The enzyme was inhibited not only by quercetin, a well-known inhibitor of carbonyl reductase, but also by phenobarbital, a potent inhibitor of aldehyde reductase [EC 1.1.1.2]. These results indicate that the enzyme purified from rabbit heart is a novel enzyme responsible for the reduction of acetohexamide and its analogs.

Three kinds of oudemansin X, (-)-1, (+)-1 and (±)-1, were totally synthesized. The key point in the present chiral synthesis was the enantioselective acetylation of the racemic alcohols, (±)-5 and (±)-8, using lipase in an organic solvent. The synthetic (-)-1 was found to exhibit strong antifungal activity against several molds and yeasts.

By applying the Hantzsch thiazole procedure, the synthesis of bithiazole derivatives (2 and (±)-3) corresponding to degradation products of myxothiazol was achieved. Optically active (S)-3 (87-88% ee) and its analog (S)-16(91% ee) were obtained through enantioselective hydrolysis of the corresponding acetates ((±)-18, (±)-20 and (±)-21) using lipase in water-saturated organic solvent.

(−)-Oudemansin X ( 1 ) was synthesized based on enzymatic resolution of (±)-diol 5 using immobilized lipase.

Syntheses of (S)-chroman-2-carboxaldehyde congener 1 and (S)-chiral isoprene unit 3 were achieved based on the enzymatic acetylation of (±)-chroman-2-methanol 6 and (±)-(2, 3)-anti-2-methyl-3-(p-methoxyphenyl)-1, 3-propane diol 12, respectively. Synthesis of the side-chain part corresponding to (3R, 7R)-3, 7, 11-trimethyldodecan-1-ol 27 was achieved by the couping reaction of (S)-3 and (R)-3, 7-dimethyloctyl iodide 4. The Witting reaction of (3R, 7R)-phosphonium salt 2 derived from (3R, 7R)-27 and (S)-1 gave the olefin 28 which was subjected to cat-alytic hydrogenation to afford (2R, 4' R, 8' R)-α-tocopherol.

Enzymatic monobenzoylation of (+/-)-2-hydroxy-decahydro-5,5,8a-trimethyl-1-naphthalenemethano l derivatives (1-4) using vinyl benzoate in organic solvent gave the optically active diols (1-4) and monobenzoates (16-19). The enantiomeric excess (ee) of the enzymatic reaction products were found to be in the range of 11% to 49%. On the other hand, enzymatic hydrolysis of the acetoxybenzylidene acetal (+/-)-25d, e was found to give more than 90% ee of (10aS)-25d, e in moderate yield. Finally, the 90% ee of (10aS)-25e was converted to the 90% ee of the desired (8aS)-1.