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Oxidative thymine damage was investigated using a new non-heme oxygenation model, Fe(MeCN)6(2+)-H2O2-Ac2O, based on high-spin Fe(MeCN)6(2+) in a non-aqueous solution, Ac2O-MeCN. Thymine and 1,3-dimethylthymine oxidized by the system gave the corresponding trans-thymine glycol derivatives in good yield. Thymineglycol is equivalent to an oxidative product as a measure of oxidative DNA damage in living cells. It is suggested that the activation of Fe(MeCN)6(2+)-H2O2-Ac2O in Ac2O-MeCN forms the oxoiron O=Fe(IV)(AcO)(MeCN)4(+) as an active species via a hetelolytic two-electron mechanism, not a Haber-Weiss-Fenton-type reaction with a one-electron process by treatment with a radical scavenger. In addition, we also demonstrated the transition state (TS) for the interaction between thymine and O=Fe(IV)(AcO)(MeCN)4(+) in the triplet spin (spin multiplicity; M=3). This model of oxidative thymine damage may provide new insight into the oxidative mechanism of thymine glycol production in non-aqueous reactions of thymine.

A simple method for the direct synthesis of 2,2′-binaphthols 2 and dinaphtho[1,2-b;2′,1′-d]furans 3 under mild conditions was developed, utilizing a biaryl coupling reaction via electron donor–acceptor complexes of 1-naphthols with SnCl4. Heating of the complex in a sealed tube for (18–24 h) afforded the corresponding o–o coupled product 2 in excellent yield. Prolonged reaction (56–65 h) under the same conditions afforded 3 in high yield in one step. We also found that in the case of α-naphthol without substituents other than a hydroxyl group at the C-1 position, regioselective o–o coupling reaction proceeded. The products 2a, 2b and 2g should be useful as synthetic intermediates for naturally occurring 3,3′-bijuglone, 3,3′-biplumbagin and elliptinone.

The first total and biomimetic synthesis of violet-quinone ( 1 ), which has a dinaphthofuranquinone (DNFQ) framework, is described. This synthesis features the oxidative dimerization of 1-naphthol 4 and the construction of the DNFQ framework by photochemical ring closure of 2,2′-binaphthoquinone 7 as a key intermediate. Compound 7 was prepared by the novel oxidative dimerization of 4 with a semiconductor (such as ZrO 2 ) in the presence of dioxygen, followed by oxidation of the resulting 2,2′-binaphthyl-1,1′-quinone 6 with HNO 3 .

The Stille coupling reaction of stannylindole 12 with 4-iodoimidazole 13 (or 24) in the presence of PdCl(2)(PPh(3))(2) gave the corresponding indole-imidazole coupling product 14 (or 25), thereby affording a new synthetic approach to the alkaloid granulatimide (7), isolated from the Brazilian ascidian Didemnum granulatum, as well as its structural analogues, 10-methylgranulatimide (23), 17-methylgranulatimide (30), 10,17-dimethylgranulatimide (31).

Sulfur substituted 3-vinylpyrrole 10 was prepared from 3-thio-acetylpyrrole 9 by alkylation with alkyl halide in the presence of propylene oxide. Functionalized 4-alkylthioindoles were made by Diels-Alder reaction of the 3-vinylpyrrole 10 with dienophiles. Chuangxinmycin analogues were synthesized by using some of the functionalized 4-alkylthioindoles as key intermediates.

The reaction of oleanane triterpenoid 1b with a FeIII(PA; picolinate)3/H2O2/MeCN system (reagent system A), a simple model system for mono-oxygenase, gave the 11 alpha-hydroxyl derivative 3 as major product, along with 11-oxo derivative 4 and 12-oxo derivative 6. The reaction of lupane triterpenoid 2b with reagent system A gave only oxidative rearrangement compounds, (20R)-aldehyde 8 and (20S)-aldehyde 9 were epimeric isomers. Then, we have found that iron(III) picolinate complex, FeIII(PA)3 is efficient in effecting the rearrangement of triterpenoid epoxides 5 and 7 into the corresponding carbonyl compounds, 6, 8 and 9 with 1,2-shift of the hydride.

The reaction of cholesteryl acetate 1 with a Fe III (PA; picolinate) 3 /H 2 O 2 /MeCN system (reagent system A), a simple model system for mono-oxygenases, gave mainly the 7α-hydroxylation product 2a, along with 7-ketonization product 3 and the 5,6-epoxidation product 4. On the other hand, reaction of 1 using a Fe(PA) 3 /peracetic acid (AcOOH)/MeCN system (reagent system C) or a Fe III (ClO 4 ) 3 .9H 2 O-picolinic acid(PAH)-pyridine(Py)/AcOOH MeCN system (reagent system F), provided 4 predominantly without formation of 2a. The former reaction may proceed via the dimeric Fe III -Fe V manifold complex, (PAH)(PA) 2 Fe III -O-O-Fe V =O(PA)2 (VII) as a hypothetically active species and a nonradical pathway, and the latter may proceed through monomeric iron complexes, [(PAH)(PA) 2 Fe v =O] + (IX) and [(PAH)(PA) 2 Fe v (OH)(OOH)] (X).

Oxidation of N, N-dimethylaniline (1) utilizing the Fe(PA)3/H2O2/MeCN system and the Fe(ClO4)3·9H2O/PHA-Py/H2O2/MeCN system, simple model systems for mono-oxygenases, in the presence of acetic anhydride (Ac2O) afforded predominantly the N-acetylative demethylation product, N-methylacetanilide (4), along with a few other compounds.

We investigated the structural requirements for the induction of hepatic microsomal cytochrome P450 2B1/2 (P450 2B1/2) and cytochrome P450 1A1/2 (P450 1A1/2) by imidazole- and pyridine-containing compounds in rats. Clotrimazole, an azole antifungal drug, and 1-diphenylmethylimidazole preferentially induced P450 2B1/2 in a dose-dependent manner, and slightly induced P450 1A1/2. 1-Benzylimidazole preferentially induced P450 1A1/2. 1-Phenylimidazole, which lacks the methylene bridge of 1-benzylimidazole, only induced P450 1A1/2. In turn, loss of aromaticity of the N-substituted moiety of imidazole, as in 1-cyclohexylmethylimidazole and 1-tert-butylimidazole, resulted in a preferential induction of P450 2B1/2. Likewise, various pyridine-containing compounds showed structure-dependent induction of P450 species. Namely, 4-diphenylmethylpyridine induced P450 2B1/2. 4-Benzylpyridine induced both P450 2B1/2 and P450 1A1/2. 4-Cyclohexylmethylpyridine and 4-tert-butylpyridine predominantly induced P450 2B1/2. 4-Phenylpyridine preferentially induced P450 1A1/2 rather than P450 2B1/2. Oxygenation products at the methylene bridge, 4-benzoylpyridine and phenyl-4-pyridylmethanol, could not induce P450 1A1/2. In turn, 2,4'-dipyridyl induced both P450 2B1/2 and P450 1A1/2, but not 2,2'-dipyridyl. 4,4'-Trimethylenedipyridine preferentially induced P450 1A1/2 at very low doses. These findings indicate that imidazole- and pyridine-containing compounds having lipophilic groups are inducers of hepatic P450, and that such compounds having aromatic groups and taking coplanar conformational structures are potent inducers of P450 1A1/2.

A simple method for the direct synthesis of 2,2′-binaphthols was developed, utilizing aryl–aryl coupling reaction via electron donor–acceptor complexes of 1-naphthols with SnCl 4 . Heating of the complex in a sealed tube afforded the corresponding o - o coupling product in excellent yield. This method was utilized for a biomimetic synthesis of the binaphthoquinone, 3,3′-biplumbagin, isolated from Plumbago zeylanica .

Stereoselective 7α-hydroxylation reaction of Δ5-steroids by a Fe(PA; picolinate)3/H2O2/MeCN system is presented. The 7α-hydroxylation reactions were achieved in 33-40% yields by addition of 30%-H2O2 to a solution of 3β-acetoxy-Δ5-steroids 1a-1d and a crystalline of Fe(PA)3 in MeCN.

Oxidation of N, N-dimethylaniline (1) utilizing the Fe(PA)3/H2O2/MeCN system and the Fe(ClO4)3·9H2O/PHA-Py/H2O2/MeCN system, simple model systems for mono-oxygenases, in the presence of acetic anhydride (Ac2O) afforded predominantly the N-acetylative demethylation product, N-methylacetanilide (4), along with a few other compounds.

The reaction of cholesteryl acetate 1 with a Fe III (PA; picolinate) 3 /H 2 O 2 /MeCN system (reagent system A), a simple model system for mono-oxygenases, gave mainly the 7α-hydroxylation product 2a, along with 7-ketonization product 3 and the 5,6-epoxidation product 4. On the other hand, reaction of 1 using a Fe(PA) 3 /peracetic acid (AcOOH)/MeCN system (reagent system C) or a Fe III (ClO 4 ) 3 .9H 2 O-picolinic acid(PAH)-pyridine(Py)/AcOOH MeCN system (reagent system F), provided 4 predominantly without formation of 2a. The former reaction may proceed via the dimeric Fe III -Fe V manifold complex, (PAH)(PA) 2 Fe III -O-O-Fe V =O(PA)2 (VII) as a hypothetically active species and a nonradical pathway, and the latter may proceed through monomeric iron complexes, [(PAH)(PA) 2 Fe v =O] + (IX) and [(PAH)(PA) 2 Fe v (OH)(OOH)] (X).

The reaction of oleanane triterpenoid 1b with a FeIII(PA; picolinate)3/H2O2/MeCN system (reagent system A), a simple model system for mono-oxygenase, gave the 11α-hydroxyl derivative 3 as major product, along with 11-oxo derivative 4 and 12-oxo derivative 6. The reaction of lupane triterpenoid 2b with reagent system A gave only oxidative rearrangement compounds, (20R)-aldehyde 8 and (20S)-aldehyde 9 were epimeric isomers. Then, we have found that iron(III) picolinate complex, FeIII(PA)3 is efficient in effecting the rearrangement of triterpenoid epoxides 5 and 7 into the corresponding cargonyl compounds, 6, 8 and 9 with 1, 2-shift of the hydride.

Oxidative thymine damage was investigated using a new non-heme oxygenation model, Fe(MeCN)6(2+)-H2O2-Ac2O, based on high-spin Fe(MeCN)6(2+) in a non-aqueous solution, Ac2O-MeCN. Thymine and 1,3-dimethylthymine oxidized by the system gave the corresponding trans-thymine glycol derivatives in good yield. Thymineglycol is equivalent to an oxidative product as a measure of oxidative DNA damage in living cells. It is suggested that the activation of Fe(MeCN)6(2+)-H2O2-Ac2O in Ac2O-MeCN forms the oxoiron O=Fe(IV)(AcO)(MeCN)4(+) as an active species via a hetelolytic two-electron mechanism, not a Haber-Weiss-Fenton-type reaction with a one-electron process by treatment with a radical scavenger. In addition, we also demonstrated the transition state (TS) for the interaction between thymine and O=Fe(IV)(AcO)(MeCN)4(+) in the triplet spin (spin multiplicity; M=3). This model of oxidative thymine damage may provide new insight into the oxidative mechanism of thymine glycol production in non-aqueous reactions of thymine.

Sulfur substituted 3-vinylpyrrole 10 was prepared from 3-thio-acetylpyrrole 9 by alkylation with alkyl halide in the presence of propylene oxide. Functionalized 4-alkylthioindoles were made by Diels-Alder reaction of the 3-vinylpyrrole 10 with dienophiles. Chuangxinmycin analogues were synthesized by using some of the functionalized 4-alkylthioindoles as key intermediates.

The Stille coupling reaction of stannylindole 12 with 4-iodoimidazole 13 (or 24) in the presence of PdCl2(PPh3)2 gave the corresponding indole–imidazole coupling product 14 (or 25), thereby affording a new synthetic approach to the alkaloid granulatimide (7), isolated from the Brazilian ascidian Didemnum granulatum, as well as its structural analogues, 10-methylgranulatimide (23), 17-methylgranulatimide (30), 10,17-dimethylgranulatimide (31).

Stereoselective 7α-hydroxylation reaction of Δ5-steroids by a Fe(PA; picolinate)3/H2O2/MeCN system is presented. The 7α-hydroxylation reactions were achieved in 33-40% yields by addition of 30%-H2O2 to a solution of 3β-acetoxy-Δ5-steroids 1a-1d and a crystalline of Fe(PA)3 in MeCN.

Oxidative dimerization of 1-naphthols 1 with dioxygen in the presence of a semiconductor, such as SnO2, ZrO2, or activated charcoal, as a catalytic mediator takes place selectively to give the corresponding 2,2′-binaphthols 2 or 2,2′-binaphthyl-1,1′-quinones 3 in excellent yields without light irradiation. The catalytic activity of SnO2 could be fully restored by appropriate reactivation treatment after the oxidation. In addition, SnO2 without dioxygen catalyzes selective O-demethylation of the enol-ethers 3 to 4 .

The combination of electrolysis and the Fe I I I (PA) 3 /O 2 /CH 3 CN system was investigated for allylic hydroxylation of octahydronaphthalene derivatives. Substrates with a bridgehead double bond gave the allylic alcohol with α-preference, while non-bridgehead olefin did not react smoothly. This system is a useful tool for α-selective allylic hydroxylation of octahydronaphthalene derivatives with a bridgehead double bond as model compounds for the AB fused ring of cholesterols.

We investigated the reactions of various 1-naphthols (NPOHs; 1) with p-benzoquinones (Qs), such as 1,4-benzoquinone (BQ) and p-chloranil (CA), as pi-electron acceptors. With electron-rich NPOHs 1a-c, oxidative biaryl coupling and subsequent dehydrogenation reaction took place selectively to give the corresponding 2,2'-binapthyl-1,1'-quinones 3a-c in excellent yield. In the case of electron-deficient NPOHs 1e, f, two different types of reactions occurred in the presence of SnCl4 and ZrO2 under similar conditions: SnCl4 mediated oxidative dimerization and trimerization of NPOH, while ZrO2 promoted electrophilic arylation of Qs with NPOH. The resulting products 3 would be useful synthetic intermediates for naturally occurring diosindigo B, biramentaceone and violet-quinone.

This paper describes research performed in the Laboratory of Organic Chemistry, Showa Pharmaceutical University. Oxidation reactions involving the oxidase can be divided roughly into two kinds of reactions: The first involves electron removal from an aromatic ring or an active CH-bond. The other reaction involves hydrogen abstraction from an inactive CH-bond. The oxidase models, Fe(DMF)(3)Cl(2)(1+) and Fe(AN)(6)(3+)/AN, which we have synthesized, have been shown to work by the former mechanism, and the models Fe(AN)(6)(3+)-IO(4)(-)/AN, Fe(AN)(6)(2+)-Ac(2)O-H(2)O(2)/AN, Fe(AN)(6)(2+)-2PAH-5Py-Ac(2)O-H(2)O(2)/AN, Fe(PA)(3)(OH(2))-H(2)O(2)/AN and Fe(PA)(3)(OH(2))-O(2)-electrolysis/AN do so by the latter mechanism. Further, we found some iron (II or III)picolinate-H(2)O(2)/AN complexes have the 7 alpha-hydroxylase-like activity.

A novel and efficient oxidative dimerization of 1-naphthols 1 with dioxygen in the presence of several semiconductors including SnO 2 , ZrO 2 , and activated charcoal as catalytic mediators took place selectively to give the corresponding 2,2 ′ -binaphthols 2 or 2,2 ′ -binaphthyl-1,1 ′ -quinones 3 in excellent yields without light irradiation. Among these semiconductors, the catalytic activity of SnO 2 could be fully restored by appropriate reactivation treatment after oxidation. The products 2 and 3 should be useful as synthetic intermediates for natural binaphthyls.

The oxygenation reaction of cholesteryl acetate 1 was examined with the Fe(III)(PA)(3)/O(2)/MeCN system using an electrochemical method. The constant potential technique gave mainly the 7-hydroxylated product stereoselectively, along with the 7-oxo product. This oxygenation system is mechanistically unique, requiring iron catalyst, dioxygen, and both cathode and anode.

A simple method was developed for the direct synthesis of 2,2′-binaphthoquinones and dinaphtho[1,2-b;2′,1′-d]furans, utilizing an oxidative reaction via electron donor–acceptor complexes of 1-naphthols with SnCl4 in the absence or presence of dioxygen. As an application of this method to natural product synthesis, we describe a facile biomimetic synthesis of several binaphthoquinones, 3,3′-bijuglone, 3,3′-biplumbagin and elliptinone.

The Stille coupling reaction of the stannylindole 13 with the 5-iodoimidazole derivative 14 (or 27) in the presence of PdCl(2)(PPh(3))(2) gave the corresponding indole-imidazole coupling product 15 (or 28), thereby affording a synthetic approach to 10-methylgranulatimide (7), 15-methylgranulatimide (11), and 10, 15-dimethylgranulatimide (12), as well as 10-methylisogranulatimide B (5).

The oxygenation reaction of (+)-camphor with a simple model reagent, Fe(MeCN)2+6-H2O2-Ac2O, for mono-oxygenase was investigated in connection with its bio-oxygenation. The products 1b, 2b, 3b, 5, 10, 11, and 12 were obtained.

We examined the effect of 1-benzylimadazole on the induction of cytochrome P -450 1A1/2 ( P -450 1A1/2) and cytochrome P -450 2B1/2 ( P -450 2B1/2) in normal, castrated, ovariectomized and hypophysectomized male rats, and in castrated rats treated with testosterone. 1-Benzylimadazole markedly increased P -450 content in male and female rats. Parallell to the dose-dependent increase in P -450 content, 1-benzylimidazole produced a significant increase in P -450 2B1/2 in male rats, but not in female rats. 1-Benzylimidazole failed to induce P -450 2B1/2 in castrated male and ovariectomized female rats. Treatment of castrated male rats with testosterone restored the induction of P -450 2B1/2 by 1-benzylimidazole. Treatment of ovariectomized female rats with 1-benzylimidazole or phenobarbital led to the increase in P -450 content, accompanying by the inductino of P -450 2B1/2 by the latter treatment, but not ther former. In hypophysectomized male rats, 1-benzilimidazole was able to induce P -450 2B1/2 in contrast to castrated male rats. Neonatal male and female rats responded well to the induction of P -450 2B1/2 by 1-benzylimidazole. The present findings suggest that P -450 2B1/2 induction by 1-benzylimidazole would be coupled with circulating testosterone regulated by hypophysis-testis axis. 1-Benzylimidazole produced sex-differentiated induction of P -450 2B1/2 in pubertal rats, but not in neonatal animals. The present findings would be provide information on a unique effect ot 1-benzylimidazole on P -450 2B1/2 induction in rats.

Oxazoles having functionalized carbon substituents at the C-2 position were synthesized in one step by the oxidation of ketones with iron(III) solvates of nitriles, i.e., Fe(RCN)6(ClO4)3 (solvate A) or Fe(RCN)6(FeCl4)3 (solvate B), in the corresponding nitriles.

The reaction of a solution obtained by anodic oxidation of tetraethylammonium perchlorate in MeCN with 5, 7, 4'-trimethoxyflavanone or 7-methoxycoumarin afforded a chlorinated derivative 1 and the nitrated derivatives 2, 3, and 4, or 6-nitro-7-methoxycoumarin.

Combined oxidizing reagent systems of Fe (AN)6 (ClO4)3 (AN=acetonitrile) with halogen oxyacids were investigated. In particular, reactions of paraffin hydrocarbons with a combined reagent system of Fe (AN)3+6-IO-4 were explored because of the high reactivity of this system in the oxidation of adamantane (Table I). Oxidations of bornane, norbornane, cyclohexane, and n-hexane gave the corresponding acetamides and acetates (Table II). These results show that the title reagent system can efficiently oxidize organic substrates which have onset potentials of anodic current of ca. 2.7V vs. saturated calomel electrode.

The biomimetic synthesis of some spirodienone-type natural alkaloids (oxocrinine, oxomaritidine, amurine, flavinantine, pallidine, cryptopleurine and colchicine etc.) by anodic oxidation is reviewed.The effectiveness of fluoboric acid as electrolyte in the electrochemical synthesis of some spirodienones is also described.

(±)-lsopodophyllotoxone 6a and the related lactones 8a and 9a were synthesized by a biomimetic procedure from the ester 5a by oxidation with a CrO3-HBF4-MeCN reagent system in one step. 4'-Benzyl-isopodophyllotoxone 6b, 4'-benzyl-picropodophyllone 7b, and the γ-lactones 8b and 9b were also synthesized from the ester 5b by oxidation with the same reagent system.

The iron (III) complexes Fe (S)6(ClO4)3, S=solvent, were prepared from Fe (H2O)6(ClO4)3 in the donor solvents. Reactions of alkylbenzenes with Fe(AN)6(ClO4)3 (AN=acetonitrile) were explored because the AN complex has the highest formal redox potential, E°=1.73 V vs. SCE, among these complexes. Oxidation of the primary alkylbenzenes by the iron (III) AN complex gave the corresponding acetamides (Table II). Oxidation of the secondary alkylbenzenes, namely, cumene, 2-phenylbutane, and 2-exo-phenylnorborane, afforded the corresponding acetates and acetamides (Charts 2 and 3), consuming over 4 mol eq of reagent. Reactions of p-xylene and hexamethylbenzene with Fe (CH2=CHCN)6(ClO4)3 also yielded the amides 31a and 31b. These results demonstrate the applicability of the iron (III) AN complex as a powerful reagent to oxidize organic substrates which have onset potentials of anodic current of ca. 2.0 V vs. SCE.

Oxidations of 1-aryl-1-propenes with new reagent systems, CrO3-HBF4-MeCN and CrO3-HClO4-MeCN, gave the 4-aryltetralones 1a and 1c, and the tetrahydrofuran 4, which are precursor molecules for aryltetrahydronaphthalene and tetrahydrofuran neo-lignans.

Oxygenation reactions of olefins having an endo- or exo-cyclic double bond, namely, cyclohexene, norbornene, camphene, longifolene, and ent-kaurene, with a simple model reagent, Fe(MeCN)2+6-H2O2-Ac2O, for mono-oxygenase were investigated in connection with their biotransformations.

Oxygenation reactions of olefins having an endo- or exo-cyclic double bond, namely, cyclohexene, norbornene, camphene, longifolene, and ent-kaurene, with a simple model reagent, Fe(MeCN)2+6-H2O2-Ac2O, for mono-oxygenase were investigated in connection with their biotransformations.

The alkaloid (±)-colchicine (1) was synthesized by a methylene transfer reaction from the spirodienone (3b), followed by acid catalysed rearrangement and dehydrogenation to give deacetamido-isocolchicine (7).

The iron (III) complexes Fe (S)6(ClO4)3, S=solvent, were prepared from Fe (H2O)6(ClO4)3 in the donor solvents. Reactions of alkylbenzenes with Fe(AN)6(ClO4)3 (AN=acetonitrile) were explored because the AN complex has the highest formal redox potential, E°=1.73 V vs. SCE, among these complexes. Oxidation of the primary alkylbenzenes by the iron (III) AN complex gave the corresponding acetamides (Table II). Oxidation of the secondary alkylbenzenes, namely, cumene, 2-phenylbutane, and 2-exo-phenylnorborane, afforded the corresponding acetates and acetamides (Charts 2 and 3), consuming over 4 mol eq of reagent. Reactions of p-xylene and hexamethylbenzene with Fe (CH2=CHCN)6(ClO4)3 also yielded the amides 31a and 31b. These results demonstrate the applicability of the iron (III) AN complex as a powerful reagent to oxidize organic substrates which have onset potentials of anodic current of ca. 2.0 V vs. SCE.