Search

The enzymatic esterification or hydrolysis of 1-hydroxy-((±)-1), 1-acetoxy-((±)-2) and 1-butyryloxy-5-methyl-3-vinylcyclohex-2-ene ((±)-3) was carried out using lipid-lipase aggregates. The esterification of (±)-1 provided (1S,5S)-1 with >99% ee using lipid-lipase Amano P with vinyl butyrate as the acylating reagent.

Chiral inductions of meso triacetate (4) and meso diol (15) were carried out on the basis of enzymatic reaction using lipase to give chiral synthons having three consecutive chiral centers with high enantiomeric excess.

Silica gel promotes the lactonization and the concomitant aryl rearrangement of 4-aryl-5-tosyloxy pentanoates ( 3c-j ) to give γ-lactones along with complete inversion in high yields.

Enantioselective hydrolysis of water-insoluble α-acyloxy esters, (±)-5 and (±)-6, was carried out using lipases immobilized with Celite or a synthetic prepolymer (ENTP-4000 or ENT-4000) in a water-saturated organic solvent to produce chiral intermediates, (2S, 3S)-5 and (2S, 3R)-4, for the synthesis of diltiazem hydrochloride 1 and (-)-indolmycin 2, respectively. Furthermore, enantioselective hydrolysis of (±)-6 using lipid-lipase aggregates in water-saturated organic solvent was also found to give (2S, 3R)-4.

When the beta-acyloxy esters (+/-)-10 and (+/-)-11 were exposed to the lipase OF-360 from Candida rugosa or immobilized lipase OF-360 in a water-saturated organic solvent, the hydrolyzed product (8aS)-6 was obtained in high chemical (40%) and optical (> 99% ee) yields. The absolute structure of (8aS)-6 was confirmed by the fact that (8aS)-6 was converted into an authentic sample gamma-keto nitrile (8aS)-17. Treatment of the diol (+/-)-12 with isopropenyl acetate in the presence of the lipase Godo E-4 from Pseudomonas sp. provided the unchanged (8aR)-12 (89% ee) in 42% yield.

Bis(oxazoline)-palladium(II) catalyzed carbonylation of homopropargyl alcohols afforded acyclic methoxyacrylate 2 and 6-membered lactone 3a, 3b, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k in good combined yield. In the case of propargyl alcohols, 5-membered lactones 3p, 3q, 16 were obtained in moderate yields. The one-pot synthesis of kawa lactones 3a, 3r, 3s and formal synthesis of dihydroxycystothiazole A and dihydroxycystothiazole C are presented. To elucidate the stereochemistry of (+)-annularin G and (−)-annularin H, the first asymmetric syntheses of these natural products were achieved.

Neutral amphiphiles of a new type corresponding to 1, 2-dialkylated mannitol ethers (6-10) were synthesized. Amephiphile-lipase aggregates were found to function as an immobilized enzyme system for enantioselective acetylation or enantioselective hydrolysis of α-hydroxy esters or α-acetoxy esters, respectively, in organic solvents.

A short path synthesis of the ethyl (methyl 2, 3-O-isopropylidene-β-D-allofuranosid)uronate (5) and ethyl(methyl 2, 3-O-isopropylidene-α-L-talofuranosid)uronate (6) from methyl 2, 3-O-isopropylidene-β-D-ribopentodialdo-1, 4-furanoside (3) using (1-ethoxyvinyl)lithium and its application to the total synthesis of the pyrimidine nucleosides, thymine polyoxin C (1) and uracil polyoxin C (2), are described.

Enantioselective acetylation of (±)-4-(1-hydroxyethyl)benzenesulfonamide 6 with `Acylase I' (No. A 2156) from Aspergillus melleus in the presence of vinyl acetate gave ( R )-4-(1-acetoxyethyl)benzenesulfonamide 7 (98% ee) and ( S )- 6 (98% ee). Both ( S )- 6 and ( R )- 7 were individually converted to the ( S )-hydroxyhexamide 2 (>99% ee) and ( R )-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (−)-hydroxyhexamide 2 from acetohexamide 1 was found to be S based on unequivocal chemical methods including X-ray analysis.

Enzymatic glycosidation of the various kinds of primary alcohols 5, 7, 9, 11, 13 and 15 and 4-nitrophenyl-β- d -glucopyranoside 4 using β-glucosidase from almonds gave stereoselectively β- d -glucosides 6, 8, 10, 12, 14 and 16 including the naturally occurring β-glucosides in moderate yield. Among them, the β-glucosides 6, 8 and 10 were converted to the cyanoglycosides, rhodiocyanoside A 20a, osmaronin 24a and sutherlandin 29, respectively.

The enantioselective hydrolysis of (±)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)-benzenesulfonamides 3 with lipase Amano P from Pseudomonas sp. in a water-saturated solvent gave (R)-4-(1-hydroxyethyl)-N-(cyclohyxylcarbamoyl)benzenesulfonamide 2 (39%, >99% ee) and unchanged (S)-3 (50%, 62% ee). On the other hand, enantioselective esterification of (±)-2 with lipase Amino P in the presence of vinyl acetate provided (R)-3 (41%, >99% ee) and unchanged (S)-2 (46%, 78% ee).

The stereoselective conversion of (4R)-5-hydroxy-4-(4′-methoxyphenyl)-2(E)-pentenoate 5 into the (4S)-4-hydroxy-5-(4′-methoxyphenyl)-2(E)-pentenoate 6 using an AgNO3/MS 4A/MeNO2 system was accomplished along with complete inversion at the exposition, and the synthesis of the intermediate (4S)-7 for the chiral synthesis of (−)-anisomycin 8 from (4S)-6 based on osmium tetroxide-catalyzed stereoselective dihydroxylation was achieved.

Stereoselective synthesis of 4'-α-alkylcarbovir derivatives 4 was described based on asymmetric synthesis or a chemoenzymatic procedure. The asymmetric alkylation of chiral acetal 7 gave the alkylated enol ethers 9a-c possessing a chiral quaternary carbon. The key carbocyclic intermediates 14a-c were synthesized from 9a-c via eleven-steps. Coupling of 14a-c with 2-amino-6-chloropurine followed by desilylation and subsequent hydrolysis afforded the target compounds 4a-c in moderate yield. The optically active cyclopentene intermediates 5a-c and 6a-c were also prepared by enzymatic resolution of (±)-5a-c and (±)-6a-c, respectively.

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.

The oxidative cyclization–methoxycarbonylation of cyclic- and acyclic-4-yn-1-ols 1 in the presence of Pd(II)/ p- benzoquinone in methanol at 0°C under a carbon monoxide atmosphere (balloon) afforded ( E )-cyclic-β-alkoxyacrylates 2 in good to excellent yields. The present reaction is applicable to the above-mentioned substrates bearing the additional functional groups such as acetate, hydroxyl, ketone, ester, terminal acetylene and the acid-sensitive protecting groups (TBDPS, TBDMS, MOM and THP). A new synthesis of the left part of the cystothiazoles is presented.

A highly enantioselective synthesis of versatile chiral synthons possessing one stereogenic center, ( S )- and ( R )-4-aryl-5-hydroxy-(2 E )-pentenoate 3 was achieved based on the enzymatic reaction of (±)- 4 with commercially available lipase ‘OF-360’ from Candida rugosa . An application of ( S )- 3 and ( R )- 3 to the total syntheses of ( S )-elvirol 1 and ( R )-elvirol 1 , respectively, is described.

The first example of asymmetric cyclization–carbonylation of cyclic-2-methyl-2-propargyl-1,3-diols 1 catalyzed by palladium(II) with chiral bisoxazolines was investigated. The reaction of 1 in the presence of palladium(II)-chiral ligands/p-benzoquinone in methanol at 0 to −45°C under carbon monoxide atmosphere (balloon) afforded (E)-bicyclic-β-alkoxyacrylates 2 in excellent yields with moderate enantioselectivities.

Treatment of arylpropyl vinyloxiranes linked to ester with BF3 was found to produce seven-membered ring products in excellent yields. This reaction proceeded in an inversion fashion.

A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (+/-)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of(S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.

(±)-2-Hydroxy-3-(1H-4′-iodoindol-3′-yl)butanoate 6 was stereoselectively converted into the (±)-(2,3)-syn-2-thioacetoxy ester 13 with retention of C2-stereochemistry in (±)-6. Palladium-catalyzed cyclization of indolyl iodide and the internal C2 thiol group of the substrate (±)-14 gave the (±)-cis methyl ester 2 of natural chuangxinmycin (1). Stereoselective total syntheses of (−)-(4S,5R)- and (+)-(4R,5S)-chuangxinmycins 1 were achieved based on the enzymatic syntheses of (2R,3S)- and (2S,3R)-epoxy butanoates 9, respectively. Chiral intermediates such as (2R,3S)- and (2S,3R)-2-hydroxy-3-(1H-4′-iodoindol-3′-yl)butanoate 6 for the chiral synthesis of (−)- and (+)-1 were also obtained by the enantioselective hydrolysis of the corresponding acetate (±)-16 by lipase.

seco-Macrosphelide E has been isolated from a strain of Periconia byssoides originally separated from the sea hare Aplysia kurodai. Its absolute stereostructure, with the same configuration as that of macrosphelide E, have been elucidated on the basis of spectroscopic analyses and unambiguous synthesis.

The oxidative cyclization–carbonylation of 4-yn-1-ones 6 in the presence of (CH 3 CN) 2 PdCl 2 / p -benzoquinone in methanol under a carbon monoxide atmosphere (balloon) afforded cyclic-ketals 7 in good to moderate yields. The product 7 were easily converted into 2-cyclopentenone carboxylates 11 and 12 .

Three kinds of seco-macrosphelide A congeners, (4R,5S,10R,11S,15S)-6, (4R,5S,9S,14R,15S)-7 and (3S,8R,9S,14R,15S)-8 were chemically synthesized, and they were exposed to the lipase OF-360 from Candida rugosa to give three hydroxy carboxylic acids, respectively. Macrolactonization of the hydroxy acid (4R,5S,10R,11S)-18 derived from (4R,5S,10R,11S,15S)-6 gave 12-membered lactone (19) in 47% overall yield from 6, while that of the seco-acid (4) derived from (4R,5S,9S,14R,15S)-7 afforded (−)-dibenzyl macrosphelide A (25) in 27% overall yield from 7. Macrolactonization of the hydrolysis product, seco-acid (5) derived from (3S,8R,9S,14R,15S)-8, provided (−)-dibenzyl macrosphelide A (25) (5% overall yield from 8) and 12-membered lactone (19) (20% overall yield from 8) concurrently.

The oxidative cyclization–methoxycarbonylation of propargylic acetates 1 in the presence of (CH 3 CN) 2 PdCl 2 / p -benzoquinone in methanol under carbon monoxide atmosphere (balloon) afforded ( E )-cyclic-orthoesters 5 in moderate yields.

For the purpose of carrying out smoothly enzymatic reaction of water-insoluble substrates in organic solvents, a new type of immobilized enzyme, a lipid-lipase aggregate, was developed. In order to prepare various kinds of lipid-lipase aggregates, 27 kinds of dialkyl ether-type phospholipid analogues were newly synthesized and used for the preparation of aggregates with lipase. Thus obtained lipid-lipase aggregates were found to catalyze the enantioselective hydrolysis of the (±)-α-acyloxy ester 2 much more efficiently than lipase immobilized with synthetic prepolymer (ENTP-4000) in water-saturated isopropyl ether. Namely. the reaction time became much shorter (2 to 3d for completion as compared with 21 d) and the chemical and optical yields of the reaction products were found to be high.

Palladium(II) catalyzed carbonylation of 1,2-allenyl ketones 1 in the presence of p-benzoquinone (1 equiv) under a CO atmosphere (balloon) afforded difuranylketones 4 in moderate to good yields. Mechanistically, the electron-withdrawing nature of the acyl group should enhance the electrophilicity of the acylpalladium species B, and thus promote the oxypalladation of an additional molecule of 1, leading to the difuranyl ketone 4.

Die direkte Umwandlung einer terminalen Alkinfunktion in einen β-Methoxyacrylat-Rest gelingt mithilfe eines Bisoxazolin(box)-Liganden. Acetyl- und Ketal-Schutzgruppen werden unter den Reaktionsbedingungen ebenso wenig angegriffen wie freie Hydroxygruppen und saureempfindliche glycosidische Bindungen. (±)-Dihydrokawain wurde aus dem Homopropargylalkohol in einem Eintopfverfahren synthetisiert. tfa=Trifluoracetat.

Methylophiopogonanone B, a constituent of Ophiopogonis tuber, found to be a potent inhibitor of hypoxia induced factor-1α (HIF-1α) activity, was synthesized from 2,4,6-trihydroxy-3,5-dimethylacetophenone in 57% yield. The synthetic methylophiopogonanone B inhibited the reporter activity at 3 to 10 μg/mL.

First convergent synthesis of (+)-myxothiazol A ( 1 ) was achieved based on modified (one-pot) Julia olefination between (3,5 R )-dimethoxy-(4 R )-methyl 6-oxo-(2 E )-hexenamide ( 2 ), corresponding to left-side of the final molecule, and E -4-2′-(1 S ,6-dimethylheptadiene)-(2,4′-bis-thiazole)-4-methybenzothiazole sulfone ( 4 ) corresponding to right-side.

Die direkte Umwandlung einer terminalen Alkinfunktion in einen β-Methoxyacrylat-Rest gelingt mithilfe eines Bisoxazolin(box)-Liganden. Acetyl- und Ketal-Schutzgruppen werden unter den Reaktionsbedingungen ebenso wenig angegriffen wie freie Hydroxygruppen und saureempfindliche glycosidische Bindungen. (±)-Dihydrokawain wurde aus dem Homopropargylalkohol in einem Eintopfverfahren synthetisiert. tfa=Trifluoracetat.

Optically active 2-methyl-3-hydroxy propionic acid derivatives which are expected to be useful building blocks for the synthesis of polyoxo-macrolide antibiotics or the related bioactive compounds have been synthesized based on the asymmetric hydrolysis using various industrialized lipases. As an example of synthetic studies using these synthons, a total synthesis of the aglycone of venturicidins A and B is described.Hydrolysis of water-insoluble substrates with lipases immobilized with celite or prepolymer (ENTP-4000) proceeds even in organic solvent. However improvement of efficiency is required. Thus a new immobilization method was developed. Namely, an aggregate of lipases with various phospholipid analogue whose hydrophobic aliphatic chains are linked by ether bonding was found to catalyze an asymmetric hydrolysis much more effectively than the previous immobilization methods.

Microbiological enantioselective transformation of 4, 9-dimethyl-3, 5-dioxo-Δ4(10)-octalin, (±)-1 was accomplished with various yeasts, e.g. Rhodotorula rubra. With properly selected microorganisms, (+)-4, 9S-dimethyl-5S-hydroxy-(2a) and (-)-4, 9R-dimethyl-5S-hydroxy-3-oxo-Δ4(10)-octalin (3b), (-)-4, 9R-dimethyl-3S-hydroxy- (6b) and (+)-4, 9S-dimethyl-3S-hydroxy-5-oxo-Δ4(10)-octalin (7a) were obtained with high optical purity.These compounds have now become available for the total syntheses of sesquiterpenoids such as tuberiferine and temisin.

The enantioselective hydrolysis of (+/-)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)-benzenesulfona mides 3 with lipase Amano P from Pseudomonas sp. in a water-saturated solvent gave (R)-4-(1-hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2 (39%,99% ee) and unchanged (S)-3 (50%, 62% ee). On the other hand, enantioselective esterification of (+/-)-2 with lipase Amano P in the presence of vinyl acetate provided (R)-3 (41%,99% ee) and unchanged (S)-2 (46%, 78% ee).

Palladium(II) catalyzed carbonylation of 1-ethynyl-1-propargyl acetate 1 is described; in the absence of the bisoxazoline (box) ligand, the second triple bond did not react, affording cyclic orthoesters 3 and 4. The use of meso-Phbox-Pd(II) strikingly changed the course of the reaction, yielding bicyclic lactone 2 by tandem carbonylative cyclization as a result of insertion of the second triple bond.