Production mechanism of proepitheaflagallin, a precursor of benzotropolone-type black tea pigment, derived from epigallocatechin via a bicyclo[3.2.1]octane-type intermediate

An unstable intermediate proepitheaflagallin B (2), a precursor of proepitheaflagallin (3), was isolated as an enzymatic oxidation product of (−)-epigallocatechin (1), and the structure of 2 was determined based on spectroscopic data. The structure and its decomposition revealed that the detailed production mechanism of proepitheaflagallin (3) via a bicyclo[3.2.1]octane-type intermediate was related to that of major black tea pigments, theaflavins.     

Laccase-catalyzed conversion of green tea catechins in the presence of gallic acid to epitheaflagallin and epitheaflagallin 3-O-gallate

Green tea extract containing catechin mixtures was treated with gallic acid using laccase (EC 1.10.3.2) to improve its function as a food material. After enzymatic oxidation, two new products were detected on an HPLC chromatogram. These products were purified by extraction with ethyl acetate, sequential column chromatographies, and crystallization. On the basis of ¹H/¹³C NMR, MALDI-TOF/high resolution MS, and UV-visible absorption spectral analyses, they were confirmed to be epitheaflagallin (5) and epitheaflagallin 3-O-gallate (6). This enzymatic process allows us to preferentially convert catechin derivatives in a crude mixture of green tea into different compounds.     

Synthesis of bicyclo[3.2.1]octanones via ketyl radical promoted rearrangements under reductive PET conditions

Photoinduced electron transfer (PET) reactions from triethylamine (TEA) to ketones have been utilized for a clean and efficient route to bicyclo[3.2.1]octanones. A one-pot conversion of bicyclo[2.2.2]octenones to such molecules has been described. MeOH as well as acetonitrile/LiClO₄ combinations have been found to be the most effective solvents for these reactions.     

Synthesis of 8-substituted bicyclo[3.2.1]octane-6-carboxylic acids and anti-convulsant properties of the corresponding amides

Novel 8-substituted bicyclo[3.2.1]octane-6-carboxylic acids have been made via [3+2]cycloaddition to alkyne 2. A number of the corresponding amides are anti-convulsant in mice.     

Mild and efficient Sonogashira couplings of 8-oxa- and 8-thiabicyclo[3.2.1]octanone derived alkenyl nonaflates

We demonstrate in this report that bicyclic alkenyl nonaflates (nonafluorobutanesulfonates) generated from 8-heterobicyclo[3.2.1]octan-3-one derivatives are excellent substrates for Sonogashira couplings with alkynes. Employing CuI, Pd(OAc)₂, PPh₃ in DMF/i-Pr₂NH as standard reagents structurally diverse bicyclic nonaflates were coupled with phenyl acetylene in generally high yields. Particularly efficient are transformations of precursors 16, 18, and 20 bearing methyl groups at the bridgehead carbons, which furnished the expected enynes 17, 19, and 21 in approximately 90% yield. With respect to the alkyne component the scope of this palladium-catalyzed reaction seems also to be fairly broad. Thus, trimethylsilyl acetylene and propargyl alcohol could also be used, affording coupling products 22, 23, and 25 with high efficacy. The protocol of Grieco was applied to induce a domino coupling of tricyclic alkenyl nonaflate 14 with trimethylsilyl acetylene affording product 26 in moderate yield and as 1:1 mixture of the expected two diastereomers.     

Simple NMR method for assigning relative stereochemistry of bridged bicyclo[3.n.1]-2-enes and tricyclo[7.n.1.0]-2-enes

The stereochemistry of syn and anti-forms of bridged bicyclo[3.n.1]-2-ene, tricyclo[7.n.1.0]-2-ene (n=1-3) and bicyclo[4.3.1]dec-7-ene derivatives can be assigned from the ¹³C chemical shift difference of the double bond. Both syn-9-R-bicyclo[3.3.1]non-2-enes and syn-13-R-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes have a large shielding difference between sp² carbons, while the corresponding anti-forms have a smaller one. In contrast, 8-R-bicyclo[3.2.1]oct-2-enes and 12-R-tricyclo[7.2.1.0^2,7]dodec-2(7)-enes have an inverse correlation. The reason of this specificity is the influence of the γ-gauche effect on the chemical shift of C(2) atom. The GIAO theory has been applied to investigate the ¹³C chemical shifts. The conformational equilibrium in the formamide group of 13-formylamino-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes has been studied.     

Allylsilane-interrupted homo-Nazarov cyclization and synthesis of bicyclo[3.2.1]octan-8-ones

The combination of homo-Nazarov cyclization of 2-(tert-butyldiphenylsilylmethyl)cyclopropyl vinyl ketone leading to oxyallyl cation and its subsequent [3+2] capture by allylsilane has been demonstrated as an useful strategy for the construction of functionalized bicyclo[3.2.1]octan-8-ones. The [3+2] capture proceeds exclusively in the exo mode to make the overall reaction diastereoselective. The less substituted end of the oxyallyl cation was found to react nearly two times faster than the more substituted end.     

A novel synthesis of bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones through [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with ring expansion

Treatment of [chloro(p-tolylsulfinyl)methylidene]cyclobutanes, which were synthesized from cyclobutanones and chloromethyl p-tolyl sulfoxide in three steps in high overall yields, with excess cyanomethyllithium gave enaminonitriles in high yields. Heating of these enaminonitriles with H₃PO₄ in acetic acid gave 2-cyanobicyclo[3.3.0]oct-1-en-3-ones in good yield. On the other hand, treatment of the [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with cyanomethyllithium followed by lithium carbanion of the homologues of acetonitrile afforded enaminonitriles having a substituent at the 3-position. Heating of the enaminonitriles with H₃PO₄ in acetic acid gave 2-substituted bicyclo[3.3.0]oct-1-en-3-ones in good to high yields. This method offers a novel and versatile procedure for synthesis of 2-substituted bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones in good overall yields.     

Synthesis,characterization, and properties of colorless rigid-rod poly(benzobisthiazole) derived from bicyclo[2.2.2]octane

Polycondensation in polyphosphoric acid of 2,5-diamino-1,4-benzene dithiol dihydrochloride with bicyclo[2.2.2]octane-1,4-dicarboxylic acid, as well as the corresponding dimethyl ester or diacid chloride, led to rigid-rod benzobisthiazole polymers. Colorless and soluble polymers with intrinsic viscosities as high as 30.6 dL/g (methanesulfonic acid, 30°C) were obtained. The ultraviolet-visible spectrum of a polymer film cast from methanesulfonic acid under reduced pressure displayed no absorptions in the visible range (400–900 °m). The polymer was thermooxidatively stable up to 420°C in air as determined by thermogravimetric analysis. Fibers spun from a lyotropic polyphosphoric acid solution exhibited a tensile strength of 300–450 Ksi, a modulus of 26 Msi, and a compressive strength of 53 Ksi. Wide-angle X-ray scattering patterns of polymer fibers indicated a 3-dimensional crystal structure rather than a nematic liquid crystal structure. © 1994 John Wiley & Sons, Inc.     

ASYMMETRIC SYNTHESIS OF THE DERIVATIVES OF (+)-1R,3R(3S), 5S-2,4,3-DIAZAPHOSPHABICYCLO [3.2.1] OCTANE

A new series of dextrorotatory derivatives of 1R,3RS,5S-1,8,8-trimethyl-2,4,3-diazaphosphabicyclo [3.2.1] octane with a newly formed chiral phosphorus atom has been prepared by an asymmetric reaction of (+)-cis-1R,3S-1,2,2-trimethyl-1,3-cyclopentadiamine with some thiophosphoryl dichlorides. The optically active products consisted of two unequal amounts of diastereomers,(1R, 3R, 5S) isomers and(1R, 3S, 5S) isomers. Two regioselective reactions took place when phenoxy thiophosphoryl dichloride and N,N-dialkylamino thiophosphoryl dichlorides were chosen as the reagents for the reaction. The content of (1R, 3R, 5S) isomers in the product was over 90% for the former and there were only (1R, 3S, 5S) isomers obtained for the latter.     

Studies on alkylation of bicyclo[2.2.2]octenones and 3,3-sigmatropic shift: synthesis of advanced cis-decalins

A stereoselective method for alkylation of bicyclo[2.2.2]octenones and their 3,3-sigmatropic shift leading to cis-decalins containing various types of appendages is described. A simple and convenient method for the introduction of a butenyl chain onto the bicyclooctenones employing 1,4-dibromobutane as an equivalent of 4-bromobutene, was developed.     

3-Cyanochromones in [3+2] cycloadditions with an azomethine ylide derived from sarcosine and formaldehyde. A short synthesis of 1-benzopyrano[2,3-c:3,4-c′]dipyrrolidines

Reactions of 3-cyanochromones with sarcosine and paraformaldehyde proceed diastereoselectively to give 1-benzopyrano[2,3-c]pyrrolidines and tetrahydro-1H-spiro[chromeno[2,3-c]pyrrol-9,5′-oxazolidine]-9a-carbonitriles, depending on the reactant ratio, as a result of a 1,3-dipolar cycloaddition of the intermediate nonstabilized azomethine ylide at the double bond and carbonyl group of the chromone system. The latter undergoes demethylenation and recyclization into a novel hexahydrochromeno[2,3-c:3,4-c′]dipyrrole tetracyclic system on heating with hydrochloric acid.     

A simple and efficient synthesis of 8-methyl-3,8-diazabicyclo[3.2.1]octane (azatropane) and 3-substituted azatropanes therefrom using pyroglutamic acid

8-Methyl-3,8-diazabicyclo[3.2.1]octane (3-azatropane) is synthesized efficiently from pyroglutamic acid making use of amide activation. The key step of the synthesis involves reduction and cyclization of a nitroenamine intermediate. Several 3-substituted analogues of this azatropane were also synthesized via this methodology and evaluated for their affinity at D₂ and 5-HT_2A receptors.     

A versatile synthesis, including asymmetric synthesis, of bicyclo[n.1.0]alkanes from cyclic ketones via the magnesium carbenoid 1,3-CH insertion as a key reaction

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from various cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps, in high yields, with lithium enolate of tert-butyl acetate or its homologues gave the adducts in quantitative yields. The adducts were treated with isopropylmagnesium chloride in ether in dry toluene as the reaction solvent to afford bicyclo[n.1.0]alkanes in high to quantitative yields via magnesium carbenoid 1,3-CH insertion. When this method was carried out starting from unsymmetrical cyclic ketones and (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of bicyclo[n.1.0]alkane was realized.     

Electrochemical carboxylation of bicyclo[n.1.0]alkylidene derivatives

Electrochemical carboxylation of bicyclo[n.1.0]alkylidene derivatives (ring-fused alkylidenecyclopropanes) in a suitable aprotic solvent using a one-compartment electrochemical cell equipped with a platinum plate cathode and a zinc plate anode under an atmospheric pressure of carbon dioxide afforded either mono- or dicarboxylic acid in moderate to good yields.     

Galanthamine analogs: 6H-benzofuro[3a,3,2,-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine

The known cholinesterase inhibitory capability of the Amarylidaceae alkaloid galanthamine prompted preparation of analogs in which the position of the nitrogen within the azepine ring is altered. The analogs 6H-benzofuro[3a,3,2-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine were prepared in 19 and 2.5%, respectively, following Kametani and Shimizu approaches, respectively. The aniline derivative 6H-benzofuro[3a,3,2-e,f][1]benzazepine failed to undergo most of the reactions typical for galanthamine. Thus, it neither oxidized to the analogous narwedine, nor epimerized to the analogous epigalanthamine, nor reduced to the lycoramine analog, under the conditions used for galanthamine.     

Studies on uracils: a facile one-pot synthesis of oxazino[4,5-d]-, pyrano[2,3-d]-, pyrido[2,3-d]- and pyrimido[4,5-d]pyrimidines using microwave irradiation in the solid state

N,N-Dimethyl-5-formylbarbituric acid 1 reacts with maleimide 2 and phenyl isocyanate/phenyl isothiocyanate 4 under microwave-assisted conditions in the solid phase to afford pyrano[2,3-d]pyrimidines 3 and oxazino[4,5-d]pyrimidines 5 in excellent yields. Under identical conditions, N,N-dimethyl-6-amino-5-formyluracil 6 reacts with 2 and 4 to give pyrido[2,3-d]pyrimidine derivative 7 and pyrimido[4,5-d]pyrimidines 8 in high yields.     

Expeditious synthesis of imidazo[1,2-c]pyrimidines via a [4+1]-cycloaddition

A new and versatile synthesis of imidazo[1,2-c]pyrimidines via a [4+1]-cycloaddition is described. The reported novel synthetic approach leads to pharmacologically interesting scaffolds containing three points of potential diversity, which previously were not accessible under conventional conditions. In addition, this novel synthetic procedure is amenable to the assembly of libraries with this interesting core structure.     

A synthesis of bicyclo[n.1.0]alkanes having tert-butyl carboxylate or acetamide moiety via the intramolecular 1,3-CH insertion of magnesium carbenoids

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from various cyclic ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters or N,N-dimethylacetamide gave adducts in high yields. The adducts were treated with ether solution of isopropylmagnesium chloride in dry toluene to give bicyclo[n.1.0]alkane derivatives having tert-butyl carboxylate or acetamide moiety on the bridgehead carbon in high to quantitative yields via magnesium carbenoid 1,3-CH insertion reaction. The 1,3-CH insertion reaction proved to be regioselective and stereospecific. The reaction mechanism and origin of the selectivity and specificity are discussed.     

One-pot synthesis of carbohydrate exo-cyclic enones and hemiketals with 6,8-dioxabicyclo-[3.2.1]octane moieties. Serendipitous formation of a spironolactone when 2-pyridinecarboxaldehyde is used as the reactant. Part II

A library of exo-cyclic carbohydrate enones 2–13 were prepared via a base-catalyzed, highly stereoselective aldol condensation of dihydrolevoglucosenone 1 (cyrene) with various aromatic aldehydes. In the case of 4-chlorobenzaldehyde as a reactant, under conditions of the aldol condensation, exo-cyclic enone 9 and a secondary product 9A was isolated. When 2-pyridinecarboxaldehyde was used as a reactant, an unexpected spironolactone 19 was exclusively observed. ¹H NMR, ¹³C NMR, MS analyses and single-crystal x-ray diffraction of the representative enone 9, the secondary product 9A, hemiketal 18, and spironolactone 19 unequivocally confirms the structural assignments. Mechanistic insights leading to the synthesized products are also proposed and discussed.