Naoki Toyooka

Enantio- and diastereodivergent synthesis of all four diastereomers of the 2,6-disubstituted 3-piperidinol chiral building block

Abstract Enantio- and diastereodivergent synthesis of all four diastereomers of 2,6-disubstituted 3-piperidinol has been achieved. The versatility of these compounds as the chiral building block for alkaloid synthesis has been demonstrated both by total synthesis of iso-6-cassine and by formal synthesis of prosopinine, cassine, and spectaline.

Construction of 4a,8a-cis-octahydroquinolin-7-one core using an intramolecular aldol type of cyclization: An application to enantioselective total synthesis of lepadin B

Abstract An intramolecular aldol type of cyclization of the piperidine derivative 1 proceeded in highly stereoselective manner to afford the desired 4a,8a- cis -octahydroquinolin-7-one. This key step involves a feature of the use of A (1,3) strain as a control element, in biasing 1 towards the conformer desired for the above cyclization. An application of this aldol reaction to enantioselective total synthesis of the marine alkaloid lepadin B is also described.

Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.

The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 μM with an IC(50) value of about 30 μM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.

The role of a HSV thymidine kinase stimulating substance, scopadulciol, in improving the efficacy of cancer gene therapy.

The most extensively investigated strategy of suicide gene therapy for treatment of cancer is the transfer of the herpes simplex virus thymidine kinase (HSV‐TK) gene followed by administration of antiviral prodrugs such as acyclovir (ACV) and ganciclovir (GCV). The choice of the agent that can stimulate HSV‐TK enzymatic activity is one of the determinants of the usefulness of this strategy. Previously, we found that a diterpenoid, scopadulciol (SDC), produced a significant increase in the active metabolite of ACV. This suggests that SDC may play a role in the HSV‐TK/prodrug administration system.

Model studies toward the total synthesis of halenaquinol and halenaquinone

A strategy for the synthesis of the furan-fused tetracyclic core of halenaquinol and halenaquinone was explored through a model study. The synthesis involved the intramolecular [4+2] cycloaddition reaction of the o-quinodimethane, generated from benzocyclobutene as the key step.

Asymmetric synthesis of the alkaloid 2,6-disubstituted piperidin-3-ols, (−)-cassine and (+)-spectaline

The asymmetric total synthesis of (−)-cassine (1) and (+)-spectaline (2) was achieved by starting with both enantiomers of the homochiral 3-oxygenated 2,6-cis-disubstituted piperidine 3.

Synthesis and antitumor evaluation of arctigenin derivatives based on antiausterity strategy.

A series of new (-)-arctigenin derivatives with variably modified O-alkyl groups were synthesized and their preferential cytotoxicity was evaluated against human pancreatic cancer cell line PANC-1 under nutrient-deprived conditions. The results showed that monoethoxy derivative 4i (PC(50), 0.49 μM), diethoxy derivative 4h (PC(50), 0.66 μM), and triethoxy derivative 4m (PC(50), 0.78 μM) showed the preferential cytotoxicities under nutrient-deprived conditions, which were identical to or more potent than (-)-arctigenin (1) (PC(50), 0.80 μM). Among them, we selected the triethoxy derivative 4m and examined its in vivo antitumor activity using a mouse xenograft model. Triethoxy derivative 4m exhibited also in vivo antitumor activity with the potency identical to or slightly more than (-)-arctigenin (1). These results would suggest that a modification of (-)-arctigenin structure could lead to a new drug based on the antiausterity strategy.

Efficient Approach to 1,2-Diazepines via Formal Diazomethylene Insertion into the C–C bond of Cyclobutenones

Efficient monocyclic 1,2-diazepine formation via a tandem electrocyclization reaction of cyclobutenones with lithiodiazoacetate is demonstrated. The reaction proceeds through an oxy anion-accelerated 4π-ring opening of cyclobutene followed by an 8π-ring closure of the resultant oxy anion-substituted diazo-diene under mild conditions to furnish a 1,2-diazepine via formal diazomethylene insertion into the C-C bond of cyclobutenone.

Asymmetric twin-ring differentiation by lipase-catalyzed enantiotoposelective reaction of the ring-crossed meso glycol: Asymmetric synthesis of a highly functionalized piperidine from the conjoined twin piperidine system

Abstract Both enantiomers of the homochiral 3-oxygenated 2,6-cis-disubstituted piperidine1 were synyhesized by starting with lipase-catalyzed transesterification or hydrolysis of the meso glycol or its diacetate in the conjoined twin piperidine system.

Enantioselective syntheses of (-)- and (+)-monomorine I.

A concise enantioselective total synthesis of unnatural (-)-monomorine I has been achieved starting from lactam 2 in 54% overall yield. Natural (+)-monomorine I was also synthesized.