Chemoenzymatic preparation of optically active trans- and cis-cyclohex-4-ene-1,2-diamine and trans-6-aminocyclohex-3-enol derivatives

Lipase from Burkholderia cepacia (PSL-C) effectively catalyzed the kinetic resolution of both racemic trans-N,N-diallylcyclohex-4-ene-1,2-diamine (±)-6 and its precursor trans-6-(diallylamino)cyclohex-3-enol (±)-5. The resulting optically active vicinal diamine and β-amino alcohol were converted into a precursor of oseltamivir and a cis-cyclohex-4-ene-1,2-diamine derivative, respectively.     

A new eudesmane sesquiterpene glycoside from Parepigynum funingense

A new eudesmane sesquiterpene glycoside,1α,6β-dihydroxy-5,10-bis-epi-eudesm-4(15)-ene-6-O-β-D-glucopyranoside(2), together with a known analogue compound,1α,6β-dihydroxy-5,10-bis-epi-eudesm-3-ene-6-O-β-D-glucopyranoside(1),were isolated from the roots of Parepigynumfuningense.The structure of 2 was determined by 1D and 2D NMR spectroscopy.Compound 1 was isolated from this plant for the first time.     

Preparation of a chiral synthon for an HBV inhibitor: enzymatic asymmetric hydrolysis of (1α,2β,3α)-2-(benzyloxymethyl)cyclopent-4-ene-1,3-diol diacetate and enzymatic asymmetric acetylation of (1α,2β,3α)-2-(benzyloxymethyl)cyclopent-4-ene-1,3-diol

Enantioselective asymmetric hydrolysis of (1α,2β,3α)-2-(benzyloxymethyl)-cyclopent-4-ene-1,3-diol diacetate 1 to the corresponding (+)-monoacetate 2 was carried out using lipase PS-30 from Pseudomonas cepacia or pancreatin. A reaction yield of 85 M % with an enantiomeric excess (ee) of 98% was obtained. Using pancreatin, a reaction yield of 75 M % with an ee of 98.5% was obtained. Asymmetric acetylation of (1α,2β,3α)-2-(benzyloxymethyl)-cyclopent-4-ene-1,3-diol 3 to the corresponding (−)-monoacetate 4 was carried out using lipase PS-30 with isopropenyl acetate as the acylating agent. A reaction yield of 80 M % with an ee of 98% was obtained for (−)-monoacetate 4.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

Organometallic compound with Lewis base—IV : Dimerization of methyl crotonate by aluminum alkyl-tertiary amine complex

Aluminum alkyl-tertiary amine complex was found to induce the catalytic dimerization of methyl crotonate (MCr) to dimethyl 2-methylpent-4-ene-1,3-dicarboxylate (1) and dimethyl 2-methylpent-cis-3-ene-1,3-dicarboxylate (2). The of the γ-hydrogen of the MCr molecule. Dimer 2 is formed through the isomerization of dimer 1. The complex of AlR₃ with a bidentate ligand, sparteine, produces dimer 1, selectively. The complex of AlR₃ with monodentate ligand NEt₃, on the other hand, induces the isomerization of dimer 1 to the cis-form of dimer 2. The coordination number of aluminum alkyl-tertiary amine complex seems to control the dimerization mechanism of MCr.     

Asymmetric cyclization of meso-diepoxides using chiral (salen)Co(III)OAc catalyst forming optically active 1,4-anhydropentitols and 2,5-anhydrohexitols

The asymmetric hydrations of meso-diepoxides, 1,2:4,5-dianhydro-3-O-methylxylitol 2, 1,2:5,6-dianhydro-3,4-di-O-methylallitol 3 and 1,2:5,6-dianhydro-3,4-di-O-methylgalactitol 4, were carried out using (R,R)-1 and (S,S)-1. An optically active five-membered cyclic compound was selectively produced in good yield from 2, but a mixture of the five- and six-membered cyclic compounds was obtained in the cases of 3 and 4. The ees of all cyclic products exceeded 90%.     

Practical syntheses of optically active carbagalactose and their potential application to the carbocyclic analogues of KRN7000

Carba-α- and β-d-galactose derivatives were efficiently prepared from a cyclohex-3-ene-1,2-diol derivative 1. Regioselective inversion of 2-OH, and stereoselective dihydroxylation of 1 were accomplished to provide a carba-β-d-galactose derivative 6 in a good yield and with a high stereoselectivity. Stereo-inversion of 1-OH of 6 via oxidation/reduction gave carba-α-d-galactose derivative 12 with a high stereoselectivity. An efficient coupling of carba-α-galactose 12 with an aziridine derivative of sphingosine has been demonstrated to give 1-O-carba-α-galactosyl sphingosine derivative 14.     

Protecting group effect on the 1,2-dehydrogenation of 19-hydroxysteroids: a highly efficient protocol for the synthesis of estrogens

19-O-Acylation was found to be indispensable for 1,2-dehydrogenation of 19-hydroxyandrost-4-ene-3,17-dione 1a with DDQ as an oxidant after exploring a variety of C-19 substituents. 1,2-Dehydrogenation in combination with subsequent A-ring aromatization via retro-aldol reaction provided a flexible and efficient protocol for the synthesis of estrogens. To demonstrate the utility of the protocol, pharmaceutically attractive estrogens were synthesized from easily available 19-hydroxy-4-ene-3-keto steroids.     

Preparation of novel bicyclic piperazines by reduction of bicyclo[4.2.2]diketopiperazines: rearrangement involving 1,2-bond migration

Reduction of (1R,6R)-7,9-diazabicyclo[4.2.2]dec-3-ene-8,10-dione (5) with lithium aluminum hydride gave a mixture of the expected (1R,6R)-7,9-diazabicyclo[4.2.2]dec-3-ene (2) as well as 7,9-diazabicyclo[4.3.1]dec-3-ene (3), resulting from 1,2-σ (C-C) migration of the pendant cis-2-butenyl ring. More of the rearranged product was observed in polar solvents and upon the addition of HMPA. The relief of ring strain imparted by the olefin may promote this rearrangement, as it was not observed when the olefin was reduced prior to the reduction.     

Studies on organophosphorus compounds—XXXVI: Simple new routes to phosphorins from 2-hydroxy-, 2-mercapto-, and 2-aminobenzoic acids and their derivatives

2-Hydroxybenzoic acid heated with 2,4 - bis(4 - methoxyphenyl) - 1,3,2,4 - dithiadiphosphetane - 2,4 -disulfide, 1, gave 2 - (p - methoxyphenyl) - 4$\text{H}$ - 1,3,2 - benzoxathiaphosphorin - 4 - one 2 - sulfide, 3, and its thio-analogue, 4, while its ethyl or phenyl esters gave 4 as the sole product. 2 - Mercaptobenzoic acid and its ethyl ester when heated with 1 produced 3$\text{H}$ - 1,2 - benzodithiole - 3 - one, 8, 3$\text{H}$ -1,2 - benzodithiole - 3 - thione, 9, and 2- (p - methoxyphenyl) - 4$\text{H}$ - 1,3,2 - benzodithia - phosphorin - 4 - one 2 - sulfide, 10. The reaction of 2 -aminobenzoic acid with 1 gave 1,2 - dihydro - 2 - (p - methoxyphenyl) - 4$\text{H}$ - 3,1,2 - benzoxaphosphorin - 4 - one 2 - sulfide, 12. Reactions of 1 with methyl 2 - aminobenzoate and 2 - aminobenzamides are described. Mechanistic considerations for the formation of the heterocyclic phosphorus compounds are presented.     

Officinatrione: an unusual (17S)-17,18-seco-lupane skeleton,and four novel lupane-type triterpenoids from the roots of Taraxacum officinale

Novel 5 lupane-type of triterpenois, i.e., 3β-acetoxy-18α,19α-epoxylupan-21β-ol (1), 18α,19α-epoxy-21β-hydroxylupan-3-one (2), lup-18-ene-3,21-dione (3), lupa-18,21-dien-3β-yl acetate (4), and (17S)-17,18-seco-lup-19(21)-ene-3,18,22-trione (5), named officinatrione, as well as 16 known compounds from the roots of Taraxacum officinale collected in Takatsuki city, Osaka, Japan. Of the above compounds, 5 was the first lupane-type triterpene, of which the D-ring was open to form a nine-membered ring. Compounds 2 and 5 exhibited moderate cytotoxic activities against L1210 cell line (IC₅₀ 10.5 and 10.1 μM).     

Stereospecific enzymatic hydrolysis of racemic epoxide: a process for making chiral epoxide

Among various microbial cultures evaluated, Rhodotorula glutinis SC 16293 and Aspergillus niger SC 16311 catalyzed the stereospecific hydrolysis of the racemic epoxide, RS-1-{2′,3′-dihydrobenzo[b]furan-4′-yl}-1,2-oxirane, 1 to the corresponding R-diol, R-1-{2′,3′-dihydrobenzo[b]furan-4′-yl}-ethane-1,2-diol, 3. The S-epoxide, S-1-{2′,3′-dihydrobenzo[b]furan-4′-yl}-1,2-oxirane, 2 remained unreacted in the reaction mixture. A reaction yield of 45–50% (theoretical maximum yield is 50%) and an enantiomeric excess (ee) of >95% were obtained for unreacted S-epoxide 2 using each culture. Addition of 10% methyl tert-butyl ether to an aqueous reaction mixture during hydrolysis by R. glutinis improved the ee of the unreacted S-epoxide 2 to >99% (yield 48%) and that of the R-diol 3 to 79%. Unlike R. glutinis, hydrolysis of racemic epoxide 1 in the presence of 10% methyl tert-butyl ether by A. niger showed an adverse effect and gave S-epoxide 2 in 54% yield and 49% ee.     

Reactions of (1R,2S)-1,2-di(2-furyl)-1,2-di(3-guaiazulenyl)ethane and (1R,2S)-1,2-di(3-guaiazulenyl)-1,2-di(2-thienyl)ethane with tetracyanoethylene (TCNE) in benzene: comparative studies on the products and their spectroscopic properties

Reactions of the title meso forms, (1R,2S)-1,2-di(2-furyl)-1,2-di(3-guaiazulenyl)ethane (1) and (1R,2S)-1,2-di(3-guaiazulenyl)-1,2-di(2-thienyl)ethane (2), with a two molar amount of TCNE in benzene at 25 °C for 5 h (for 1) and 48 h (for 2) under oxygen give new compounds, 2,2,3,3-tetracyano-4-(2-furyl)-8-isopropyl-6-methyl-1,4-dihydrocyclohepta[c,d]azulene (3) and 2,2,3,3-tetracyano-8-isopropyl-6-methyl-4-(2-thienyl)-1,4-dihydrocyclohepta[c,d]azulene (4), respectively, in 74 and 21% isolated yields. Comparative studies on the above reactions as well as the spectroscopic properties of the unique products 3 and 4, possessing interesting molecular structures, are reported and, further, a plausible reaction pathway for the formation of these products is described.     

Optical response of phenantroimidazole-dyes covalently linked to a polynorbornene-backbone to acid and base

Two norbornene derivatives bearing phenantroimidazole dyes, namely endo/exo-11-(4-(1H-phenanthro[9,10-d]imidazol-2-yl)phenoxy) undecylbicyclo[2.2.1] hept-5-ene-2-carboxylat (5) and 11-(4-(1-Methyl-1H-phenanthro[9,10-d]imidazol-2-yl)phenoxy) undecylbicyclo[2.2.1]hept-5-ene-2-carboxylate (6) were synthesized. 5 and 6 were used to prepare statistical copolymers with endo,exo-bicyclo[2.2.1.]hept-2-ene-5,6-dicarboxylic acid dimethylester (7) via ring opening metathesis polymerization. The photophysical properties of the monomers and polymers and to what extent polymerization and substitution patterns influence the photophysical properties were investigated. Furthermore, the optical response upon addition of acid was investigated. The emission of monomer 5 shows a small bathochromic shift of 13 nm upon protonation while the emission of the resultant polymer poly5/7 exhibits a large red shift of 62 nm. In contrast, the according methylated monomer 6 and the resulting polymer poly6/7 gave similar absorption and emission characteristics. The differences were attributed to an increased tendency of the non-methylated dyes to interact when brought in close proximity in the polymer.     

Synthesis and structure of a chiral areno-bridged [2.4]metacyclophane

The reductive coupling reaction of 1,4-bis(3-acetyl-5-tert-butyl-2-methoxyphenyl)butane 3 was carried out using TiCl₄-Zn in pyridine followed by a McMurry coupling reaction to afford the compounds anti and syn 1,2-dimethyl[2.4]MCP-1-ene 4. Bromination of 4 with BTMA-Br₃ in dry CH₂Cl₂ afforded the interesting compound 1,2-bis-(bromomethyl)-5,15-di-tert-butyl-8,18-dimethoxy[2.4]MCP-1-ene 6 and consecutive debromination with Zn and AcOH in CH₂Cl₂ solution afforded the stable solid 5,15-di-tert-butyl-8,18-dimethoxy-1,2-dimethylene[2.4]MCP 7 in 89% yield. Compound 7 was conveniently employed in a Diels–Alder reaction with dimethyl acetylenedicarboxylate (DMAD) to provide 2-(3′,6′-dihydrobenzo)-5,15-di-tert-butyl-8,18-dimethoxy[2.4]MCP-4′,5′-dimethylcarboxylate 8 in good yield. Diels–Alder adduct 8 was converted into a novel and inherently chiral areno-bridged compound [2.4]MCP 9 by aromatization. The chirality of the two conformers was characterized by circular dichroism (CD) spectra of the separated enantiomer which are perfect mirror images of each other.     

Reaction of azulene with 1,2-bis[4-(dimethylamino)phenyl]-1,2-ethanediol in a mixed solvent of methanol and acetonitrile in the presence of hydrochloric acid: a facile one-pot synthesis and properties of new triarylethylenes possessing an azulen-1-yl group

Reaction of azulene (1) with 1,2-bis[4-(dimethylamino)phenyl]-1,2-ethanediol (2) in a mixed solvent of methanol and acetonitrile in the presence of 36% hydrochloric acid at 60 °C for 3 h gives 2-(azulen-1-yl)-1,1-bis[4-(dimethylamino)phenyl]ethylene (3) (8% yield), 1-(azulen-1-yl)-(E)-1,2-bis[4-(dimethylamino)phenyl]ethylene (4) (28% yield), and 1,3-bis{2,2-bis[4-(dimethylamino)phenyl]ethenyl}azulene (5) (9% yield). Besides the above products, this reaction affords 1,1-di(azulen-1-yl)-2,2-bis[4-(dimethylamino)phenyl]ethane (6) (15% yield), a meso form (1R,2S)-1,2-di(azulen-1-yl)-1,2-bis[4-(dimethylamino)phenyl]ethane (7) (6% yield), and the two enantiomeric forms (1R,2R)- and (1S,2S)-1,2-di(azulen-1-yl)-1,2-bis[4-(dimethylamino)phenyl]ethanes (8) (6% yield). Furthermore, addition reaction of 3 with 1 under the same reaction conditions as the above provides 6, in 46% yield, which upon oxidation with DDQ (=2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in dichloromethane at 25 °C for 24 h yields 1,1-di(azulen-1-yl)-2,2-bis[4-(dimethylamino)phenyl]ethylene (9) in 48% yield. Interestingly, reaction of 1,1-bis[4-(dimethylamino)phenyl]-2-(3-guaiazulenyl)ethylene (11) with 1 in a mixed solvent of methanol and acetonitrile in the presence of 36% hydrochloric acid at 60 °C for 3 h gives guaiazulene (10) and 3, owing to the replacement of a guaiazulen-3-yl group by an azulen-1-yl group, in 91 and 46% yields together with 5 (19% yield) and 6 (13% yield). Similarly, reactions of 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene (12) and 1,1-bis{4-[2-(dimethylamino)ethoxy]phenyl}-2-(3-guaiazulenyl)ethylene (13) with 1 under the same reaction conditions as the above provide 10, 2-(azulen-1-yl)-1,1-bis(4-methoxyphenyl)ethylene (16), and 1,3-bis[2,2-bis(4-methoxyphenyl)ethenyl]azulene (17) (93, 34, and 19% yields) from 12 and 10 and 2-(azulen-1-yl)-1,1-bis{4-[2-(dimethylamino)ethoxy]phenyl}ethylene (18) (97 and 58% yields) from 13.     

Novel stereoselective syntheses of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-N1,N5-dimethyl-N1,N5-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine

We report two different synthetic approaches for the stereoselective synthesis of (2E,4E)-4-(4,4-dimethylpent-2-ynylidene)-N¹,N⁵-dimethyl-N¹,N⁵-bis(naphthalen-1-ylmethyl)pent-2-ene-1,5-diamine 1, an important impurity-reference standard for the chemical characterization of terbinafine. The diamine 1 was obtained in only six steps with a good overall yield starting from commercially available glutaconic acid.     

Synthesis of 4-unsubstituted dihydropyrimidines having acyl and alkoxycarbonyl groups at 5- and 6-positions by cyclization–elimination reactions using 1,3-diaza-1,3-butadienes

A synthetic method for novel 4-unsubstituted 2-phenyldihydropyrimidines having acyl and alkoxycarbonyl groups at the 5- and 6-positions was developed. The cyclization of 4-dimethylamino-1,3-diaza-1,3-butadiene having N-protecting groups (Boc, Cbz) with 1,2-disubstituted ethylenes, such as diethyl maleate, diethyl fumarate, (Z)-hex-3-ene-2,5-dione, (E)-1,4-diphenylbut-2-ene-1,4-dione, and unsymmetrical (E)-ethyl 4-oxo-4-phenylbut-2-enoate, following the elimination of a dimethylamino group proceeded smoothly, producing the corresponding dihydropyrimidines in good overall yield. The N-protecting group (Boc) could be easily removed to obtain N-unsubstituted dihydropyrimidines as a mixture of tautomers, and their tautomeric behavior was analyzed by ¹H NMR spectroscopy.     

A new cycloartane triterpenoid from the leaves and stems of Fritillaria hupehensis

A new triterpenoid has been isolated from the leaves and stems of Fritillaria hupehensis Hsiao et K.C.Hsia.Its structure wasestablished as(23Z)-9,19-cycloart-23-ene-3α,25-diol 1 through chemical and spectroscopic studies including 2D NMR.Anotherknown triterpenoid 9,19-cycloart-25-ene-3β,24ξ-diol 2 was also isolated.     

Transformations of S-substituted 5,7-dimethyl-4а,5а-diphenyl-3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-2-ones under treatment of 1,2-benzoquinones and photochemical properties of reaction products

For the first time 5,7-di-tert-butyl-1,3-dimethyl-3a,9a-diphenyl-3,3a-dihydro-1H-benzo[5,6][1,4]dioxino[2,3-d]imidazol-2(9aH)-one 13 and complex 9 of 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol with 1,3-dimethyl-4,5-diphenyl-1H-imidazol-2(3H)-one 10a were prepared by the reactions of 3-alkylthio-5,7-dimethyl-4a,7a-diphenyl-4a,5,7,7a-tetrahydro-1H-imidazo[4,5-e]-1,2,4-triazin-6(4H)-ones with 3,5-di-tert-butyl-1,2-benzoquinone 1 and 4,6-di-tert-butyl-3-nitro-1,2-benzoquinone 2, respectively. Photochemical transformations of compounds 9 and 10a as well as products of its photooxygenation involving singlet oxygen under UV irradiation: urea 16, isomeric 1,3-dimethyl-4,5-diphenylimidazolidin-2-ones 17 and 17′, and compound 18 were studied by the spectral-kinetic method. Data on the absorption and fluorescence properties of synthesized compounds and their photoproducts were obtained.