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The total synthesis of the 2-azaanthraquinone alkaloid, scorpinone (4), isolated from the mycelium of a Bispora-like tropical fungus, has been completed in nine steps. The two key steps involve a microwave-assisted thermal electrocyclic reaction for the synthesis of an 8-oxygenated isoquinoline skeleton from a 1-aza 6π-hexatriene system, and a regioselective microwave-assisted [4+2] cycloaddition for the construction of a 2-azaanthraquinone framework.

We synthesized 9alpha-fluoromedroxyprogesterone acetate (FMPA) in order to test whether it is a more potent anti-angiogenic agent than medroxyprogesterone acetate (MPA), which has been widely used as a therapeutic agent for breast and endometrium cancers. FMPA was previously synthesized in 10 steps (total yield: 1%). An efficient synthesis of FMPA has been achieved in 6 steps (total yield: 12%). We examined the anti-tumor effect of FMPA, complexed with dimethyl-beta-cyclodextrin (DM-beta-CyD), on rat mammary carcinomas induced by 7,12-dimethylbenz[a]anthracene (DMBA). FMPA showed great anti-tumor effect on DMBA-induced rat mammary carcinomas.

We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4×10(-6)-1.2×10(-7) M.

The total syntheses of beta-carboline alkaloids, (R)-(-)-pyridindolols (1, 5, and 6) are described. The two key steps involved are (1) a thermal electrocyclic reaction of the 3-alkenylindole-2-aldoxime 10 and (2) a thermal cyclization of 3-alkynylindole-2-aldoxime 11 to construct the beta-carboline N-oxides 8, which upon heating with acetic anhydride and sequential treatment with trifluoromethanesulfonic anhydride gave the triflates 18. The Stille coupling reaction of 18 with vinylstannane, followed by cleavage of MOM ether, afforded the 1-ethenyl-3-hydroxymethyl-beta-carboline (7a). Subsequent acetylation of 7a yielded the acetate 7b, which was subjected to the Sharpless asymmetric 1,2-dihydroxylation by AD-mix-beta to produce (R)-(-)-pyridindolol K2 (6). Selective acetylation of 6 was effected by Ac(2)O and collidine to form (R)-(-)-pyridindolol K1 (5). By contrast, hydrolysis of 6 provided (R)-(-)-pyridindolol (1).

The formal total synthesis of murrayaquinone A (1) and the total synthesis of furostifoline (5) were completed by the construction of 4-oxygenated 3-methylcarbazoles 7 based on a new type of electrocyclic reaction through 2-alkenyl-3-allenylindole intermediates 8 derived from the 2-alkenyl-3-propargylindoles 9, starting from 2-chloroindole-3-carbaldehyde (11). The N, O-bisbenzyloxymethyl group of 16c and 22 underwent a Birch reduction followed by treatment with Triton B to produce the known 4-hydroxy-3-methylcarbazole (7a) and 4-hydroxy-3-methylfuro[3, 2-a]carbazole (7b) as precursors of murrayaquinone A (1) and furostifoline (5), respectively. The trifluoromethanesulfonyloxy-3-methylfuro[3, 2-a]carbazole (24), prepared from 7b, was subjected to reductive cleavage to provide furostifoline (5).

A new and versatile synthetic route to a benzophenanthridine alkaloid was developed by a bond formation between C4b and N5 on the benzo[c]phenanthridine nucleus, using a microwave-assisted electrocyclic reaction of the aza 6π-electron system. This strategy was successfully used to synthesize nornitidine (1b), noravicine (1d), and isodecaline (1f).

The formal total synthesis of murrayaquinone A (1) and the total synthesis of furostifoline (5) were completed by the construction of 4-oxygenated 3-methylcarbazoles 7 based on a new type of electrocyclic reaction through 2-alkenyl-3-allenylindole intermediates 8 derived from the 2-alkenyl-3-propargylindoles 9, starting from 2-chloroindole-3-carbaldehyde (11). The N, O-bisbenzyloxymethyl group of 16c and 22 underwent a Birch reduction followed by treatment with Triton B to produce the known 4-hydroxy-3-methylcarbazole (7a) and 4-hydroxy-3-methylfuro[3, 2-a]carbazole (7b) as precursors of murrayaquinone A (1) and furostifoline (5), respectively. The trifluoromethanesulfonyloxy-3-methylfuro[3, 2-a]carbazole (24), prepared from 7b, was subjected to reductive cleavage to provide furostifoline (5).

The total synthesis of the 2-azaanthraquinone alkaloid, scorpinone (4), isolated from the mycelium of a Bispora-like tropical fungus, has been completed in nine steps. The two key steps involve a microwave-assisted thermal electrocyclic reaction for the synthesis of an 8-oxygenated isoquinoline skeleton from a 1-aza 6π-hexatriene system, and a regioselective microwave-assisted [4+2] cycloaddition for the construction of a 2-azaanthraquinone framework.

The first enantioselective synthesis of a β-carboline alkaloid, dichotomine C, possessing antiallergic effects, was achieved by constructing a β-carboline framework based on the microwave-assisted thermal electrocyclic reaction of a 1-azahexatriene system, followed by the Sharpless asymmetric dihydroxylation.

An asymmetric synthesis of the core carbazole structure, 6-desprenyl-carquinostatin 3 and 6-descycloavandulyl-lavanduquinocin 3, toward a total synthesis of carquinostatin A (1) and lavanduquinocin (2), has been established. Lipase QLM (Meito) catalyzed enantioselective acetylation of the racemic alcohol 6 gave the (-)-acetate 7 and the (+)-alcohol 6 with high enantioselectivity. The absolute stereochemistry of the (-)- and (+)-alcohol 6 have been determined to be R- and S-configurations, respectively, by the advanced Mosher method. In the same manner, the (-)-acetate 13 and the (+)-alcohol 12 have been obtained from the racemic alcohol 12. The (R)-(-)-acetate 13, derived from the (R)-(-)-acetate 7, was the same as the (-)-acetate 13, which has been determined to be (R)-configuration. Oxidation of the (R)-(-)-acetate 13 followed by hydrolysis afforded (R)-(-)-6-desprenyl-carquinostatin [and (R)-(-)-6-descycloavandulyl-lavanduquinocin] 3. In addition, oxidation of the (S)-(+)-alcohol 12 provided (S)-(+)-3, which is the enantiomer of 6-desprenyl-carquinostatin A (R)-(-)-3.

9alpha-Fluoromedroxyprogesterone acetate (FMPA) is a synthetic analog of medroxyprogesterone acetate (MPA). FMPA exhibited more potent anti-tumor and anti-angiogenic activities in some assay systems than the parent agent, MPA. Exudative age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). Anecortave acetate, an angiostatic steroid, is clinically efficacious in patients with exudative AMD. Betamethasone is an anti-angiogenic steroid. Therefore, we examined the effects of FMPA, anecortave acetate and betamethasone on laser-induced CNV in rats. Anecortave acetate and betamethasone were included as positive controls. Crypton laser was applied to the fundus in Brown Norway rats. Laser photocoagulations were performed in each eye between the major retinal vessels of the superior retina. Subconjunctival injection of FMPA, anecortave acetate or betamethasone was performed once just after the photocoagulation (on day 0). The incidence of CNV formation was evaluated by fluorescein angiography (FAG) on day 14. On the next day, examination of the retinal function was performed by electro retinogram (ERG). Subconjunctival injection of FMPA at doses of 300, 1000 and 3000 microg/eye dose-dependently inhibited the incidence of CNV formation. Significant differences were observed at doses of 1000 and 3000 microg/eye of FMPA as compared with the control group. Anecortave acetate and betamethasone significantly inhibited the incidence of CNV formation. FMPA at the doses used in this study did not affect the retinal function in rats, as determined by ERG. FMPA appeared to be effective in a rat model of CNV, so it was demonstrated that FMPA might be useful in the treatment of AMD.

A biomimetic approach to calothrixin B via a hypothetical metabolite, 6-formylindolo[2,3-a]carbazole, is described. The construction of a suitable indolo[2,3-a]carbazole ring system was carried out using an allene-mediated electrocyclic reaction involving two [b]-bonds of indoles as the key step.

A total synthesis of a new furo[3,2-h]isoquinoline alkaloid TMC120-B (2), isolated from Aspergillus ustus together with two related compounds, has been completed in sixteen steps. The key step is the synthesis of the appropriate 3,7,8-trisubstituted isoquinoline framework (23) based on a thermal electrocyclic reaction of the 1-aza 6pi-electron system involving the benzene double bond. In addition, the microwave assisted electrocyclic reaction of this system was newly performed.

The total synthesis of renierone, mimocin, renierol, renierol acetate, renierol propionate, and 7-methoxy-1,6-dimethylisoquinoline-5,8-dione was successfully achieved by the regioselective oxidation of 5-oxygenated isoquinoline. The synthetic method of the 5-oxygenated isoquinoline is based on the thermal electrocyclic reaction of 1-azahexatriene system involving the benzene 1,2-bond.

A new deprotection procedure regarding the N-methoxymethyl (MOM) group was revealed during the total synthesis of oxopropalines D and G. We describe the deprotection method of N-MOM-heterocyclic compounds and its utilization.

The reaction of the β-methylsulfanylacroleins, derived from alkenyl sulfides by the Vilsmeier reaction, with 6-aminouracils or 2,6-diaminouracil, provides a new synthetic route to the 6-substituted pyrido[2,3-d]pyrimidines by two methods, the reaction mechanisms of which were examined by a deuterium-labeled thioacrolein.

The specific optical rotations of (R)-oxopropaline D calculated by two ab initio MO methods were +52+/-31 degrees and +61+/-29 degrees, respectively, and (+)-oxopropaline D (3) was presumed to have an R-configuration. On the basis of this theoretical result, the reaction of 1-litio-beta-carboline with (R)-glyceraldehyde acetonide followed by oxidation with MnO(2) gave (R)-oxopropaline D acetonide (4a), which was consistent with the previously synthesized (+)-oxopropaline D acetonide (4) in all respects. From the results of theoretical calculations and the experimental synthesis, we determined that natural (+)-oxopropaline D (3) has an R-configuration.

The first enantioselective synthesis of a beta-carboline alkaloid, dichotomine C, possessing antiallergic effects, was achieved by constructing a beta-carboline framework based on the microwave-assisted thermal electrocyclic reaction of a 1-azahexatriene system, followed by the Sharpless asymmetric dihydroxylation.

The total synthesis of bioactive calothrixin B (2) was completed which two kinds of carbazoles using three approaches. The common strategy was based on an allene-mediated electrocyclic reaction of a 6π-electron system involving one or two indole [b]-bonds for the construction of an appropriate 4-oxygenated 2,3,4-trisubstituted carbazole 28 or a 6-oxygenated 5-methylindolo[2,3-a]carbazole 39, respectively. Oxidation of the methyl group of 28 followed by reduction of the nitro group of 21 afforded the pentacyclic phenol 5, which was oxidized with CAN to give calothrixin B (2). In a biomimetic pathway, the fully protected 5-formylindolo[2,3-a]carbazole 40 with a methoxymethyl group provided calothrixin B (2) through N-methoxymethyl-calothrixin B 43.

We synthesized 6-methylindole-4,5-quinone (1b) in order to clarify the structure of natural product, 5-methylindole-4,5-quinone (la) isolated from Drupella fragum. The synthesis features the construction of the indole ring based on an electrocyclic reaction of a 3-alkenyl-2-propargylpyrrole intermediate. Two synthetic methylindolequinones and their related compounds were examined in human lung cancer cell line NCI-H460 and human breast cancer cell line MDA-MB-231.

A highly efficient synthesis of a phenanthridine alkaloid, trispheridine (1) has been achieved in a 74% overall yield in a four-step sequence. The key step is the construction of a tetrahydrophenanthridine based on a microwave -assisted thermal electrocyclic reaction of an aza 631-electron system including the benzene double bond.

A new synthesis of an indole ring based on an electrocyclic reaction of a 2-alkenyl-3-allenylpyrrole intermediate generating from 2-ethenyl-3-propargylpyrrole was established. A synthesis of 5-methylindole-4,7-quinone (1)was completed in seven steps from the 4-oxygenated 5-methylindole (13a). It was demonstrated that the structure of natural product (1), isolated from Dropella fragum, is not at least 5-methylindole-4,7-quinone (1).

A total synthesis of a new furo[3,2-h]isoquinoline alkaloid, TMC-120B (2) has been completed in sixteen steps. The key step is the synthesis of 7,8-disubstituted isoquinoline (17) based on the thermal electrocyclic reaction of 1-azahexatriene system involving the benzene 1,2-bond.