Masayoshi Tsubuki

Stereocontrolled syntheses of novel styryl lactones, (+)-goniodiol, (+)-goniotriol, (+)-8-acetylgoniotriol, (+)-goniofufurone, (+)-9-deoxygoniopypyrone, (+)-goniopypyrone, and (+)-altholactone from common intermediates and cytotoxicity of their congeners

Abstract Concise syntheses of (+)-goniodiol, (+)-goniotriol, (+)-8-acetylgoniotriol, (+)-goniofufurone, (+)-9-deoxygoniopypyrone, (+)-goniopypyrone, and (+)-altholactone and their congeners from chiral lactonic aldehydes 27 and 36 as common intermediates are described. The key features in the syntheses are based on the in situ generation of unstable aldehydes 27 and 36 followed by their chemoselective reaction with triisopropoxyphenyltitanium to afford both diastereomers 28, 29 and 37, 38 at the C-8 positions. The cytotoxicity of styryl lactone congeners against P388 murine leukemia cells was examined.

Construction of a chiral quaternary carbon center by enantioselective deprotonation : application to the formal synthesis of (+)-α-cuparenone

Abstract Construction of a chiral quaternary carbon center was achieved by employing an enantioselective deprotonation with chiral bases and this strategy was applied to the formal synthesis of (+)-α-cuparenone.

SYNTHESIS AND BIOLOGICAL EVALUATION OF EXTRA-HYDROXYLATED BRASSINOLIDE ANALOGS

Abstract Brassinolide (BL) analogs with an extra hydroxyl (OH) group(s), 14α-OH-BL ( 2 ), 25-OH-BL ( 4 ) and 14α,25-di-OH-BL ( 7 ) were synthesized from BL ( 1 ) via direct hydroxylation of the C-14 and/or −25 positions with methyl(trifluoromethyl)dioxirane, and (25 S )-26-OH-BL ( 5 ) from a known lactone ( 16 ). The biological evaluation of these compounds together with (20 R )-20-OH-BL ( 3 ), 28-OH-BL ( 6 ) and (20 R )-20,28-di-OH-BL ( 8 ) by the rice lamina inclination test suggested that hydroxylations at C-14, −20, −25 and −26 are inactivation steps in BL metabolism, and that C-28 position of 1 is a promising accessory site for assembling BL-based molecular probes to investigate brassinosteroid-receptors.

Chiral synthesis of 3-substituted and 3,3-disubstituted γ-butyrolactones by enantioselective deprotonation strategy

Abstract Chiral synthesis of 3-substituted and 3,3-disubstituted γ-butyrolactones was achieved by employing an enantioselective deprotonation of the corresponding cyclobutanone derivatives with chiral bases as a key reaction.

Stereocontrolled synthesis of the brassinolide side chain via a pyranone derivative

Abstract A new method for assembling the brassinolide side chain from 20-carboxaldehyde 2 was developed via the stereoselective construction of the pyranone moiety as key steps.

Inhibition of Hepatitis C Virus NS3 Helicase by Manoalide

The hepatitis C virus (HCV) causes one of the most prevalent chronic infectious diseases in the world, hepatitis C, which ultimately develops into liver cancer through cirrhosis. The NS3 protein of HCV possesses nucleoside triphosphatase (NTPase) and RNA helicase activities. As both activities are essential for viral replication, NS3 is proposed as an ideal target for antiviral drug development. In this study, we identified manoalide (1) from marine sponge extracts as an RNA helicase inhibitor using a high-throughput screening photoinduced electron transfer (PET) system that we previously developed. Compound 1 inhibits the RNA helicase and ATPase activities of NS3 in a dose-dependent manner, with IC(50) values of 15 and 70 μM, respectively. Biochemical kinetic analysis demonstrated that 1 does not affect the apparent K(m) value (0.31 mM) of NS3 ATPase activity, suggesting that 1 acts as a noncompetitive inhibitor. The binding of NS3 to single-stranded RNA was inhibited by 1. Manoalide (1) also has the ability to inhibit the ATPase activity of human DHX36/RHAU, a putative RNA helicase. Taken together, we conclude that 1 inhibits the ATPase, RNA binding, and helicase activities of NS3 by targeting the helicase core domain conserved in both HCV NS3 and DHX36/RHAU.

Enantioselective Synthesis of (−)-Canadensolide

Abstract Chiral synthesis of canadensolide has been achieved by using the Sharpless kinetic resolution of the 2-furylcarbinol derivative( 11 ), followed by its oxidative conversion into the corresponding pyranone( 12 ) as key reactions.

Synthesis of (±)-pisiferin, (±)-pisiferol, and related compounds by intramolecular [4 + 2]cycloaddition

Thermolysis of the olefinic benzocyclobutene (17) afforded the tricyclic compounds (18a) and (18b), whose sequential reduction, via the aldehyde (19), gave rise to the pisiferol derivatives (20a) and (20b). Since (20a) was transformed into pisiferol (2), pisiferic acid (3), and methyl pisiferate (4), this synthesis constitutes their formal synthesis. Wolff–Kishner reduction of the hydrazone of (19b) yielded the known tricyclic compound (21), which has previously been transformed into xanthoperyl methyl ether (22). Furthermore, the predominantly cis used mixture of compound (18)(a/b= 1 : 4) was converted into the predominantly trans-fused mixture (a/b= 3 : 1) using catalytic hydrogenation of the enone (24) as a key reaction. Finally, a skeletal rearrangement of an abietane-type into a 9(10→20)abeo-abietane-type compound was demonstrated. Dehydration of the alcohol (20a) afforded the methyl ether (26) and its isomer (27) in the ratio of 3 : 1 as an inseparable mixture. Demethylation of the mixture (26) and (27) provided pisiferin (1) and compound (28). Interestingly, rearrangement of the cis-fused compound (20b) formed the methyl ether (27) as a sole product, which was converted into isopisiferin (29).

Synthesis and structure elucidation of a novel ecdysteroid, gerardiasterone

The structure of a novel ecdysteroid, gerardiasterone, is elucidated as 2a by its synthesis employing a diastereoselective dihydroxylation of the E-olefin 22 as a key step.

Enantioselective synthesis of bislactone structure: A formal synthesis of (−)-canadensolide

Abstract An enantioselective synthesis of the canadensolide-type bislactone ( 12 ) via the versatile pyranone ( 4 ) derived from the chiral furylcarbinol ( R ) −3 has been accomplished. A formal synthesis of (−)-canadensolide ( 1 ) is also described.