Naoyuki Kotoku

Trichoderins, novel aminolipopeptides from a marine sponge-derived Trichoderma sp., are active against dormant mycobacteria

Three new aminolipopeptides, designated trichoderins A (1), A1 (2), and B (3), were isolated from a culture of marine sponge-derived fungus of Trichoderma sp. as anti-mycobacterial substances with activity against active and dormant bacilli. The chemical structures of trichoderins were determined on the basis of spectroscopic study. Trichoderins showed potent anti-mycobacterial activity against Mycobacterium smegmatis, Mycobacterium bovis BCG, and Mycobacterium tuberculosis H37Rv under standard aerobic growth conditions as well as dormancy-inducing hypoxic conditions, with MIC values in the range of 0.02-2.0 microg/mL.

Concise asymmetric synthesis of a model compound, (4S,5S,6S)-6-(2,2-dimethoxy)ethyl-4,5-epoxy-6-hydroxy-2-cyclohexenone, for the cyclohexenone core of scyphostatin

Abstract The optically pure cyclohexenone core of scyphostatin ( 1 ) has been synthesized from cyclohexadiene acetal 5 . The crucial aspects of our synthesis include the intramolecular bromoetherification of 5 , the SeO 2 oxidation of 7 , and the enone formation of 13 to 4 in the final step.

Stereoselective Synthesis of Core Structure of Cortistatin A

A stereoselective synthesis of the core structure of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, is described. An 8-oxabicyclo[3.2.1]octene system, a characteristic B-ring structure of 1, was elaborated by a 7-endo selective intramolecular Heck cyclization and a subsequent acid-mediated oxy-Michael reaction.

Shimalactones, neuritogenic polyketides from a marine-derived fungus Emericella variecolor GF10

Shimalactone B (2), a novel polyketide having bicyclo[4.2.0]octadiene and oxabicyclo[2.2.1]heptane units, was isolated as a minor constituent from a cultured marine-derived fungus of Emericella variecolor GF10. The chemical structure of 2 and the structural relationship between shimalactones A and B (2) were determined by detailed NMR and CD spectroscopic analyses and chemical derivatization. Shimalactones A and B (2) induced neuritogenesis against neuroblastoma Neuro 2A cells at 10 μg/mL concentration.

Identification and functional analysis of 2-hydroxyflavanone C-glucosyltransferase in soybean (Glycine max)

C‐Glucosyltransferase is an enzyme that mediates carbon–carbon bond formation to generate C‐glucoside metabolites. Although it has been identified in several plant species, the catalytic amino acid residues required for C‐glucosylation activity remain obscure. Here, we identified a 2‐hydroxyflavanone C‐glucosyltransferase (UGT708D1) in soybean. We found that three residues, His20, Asp85, and Arg292, of UGT708D1 were located at the predicted active site and evolutionarily conserved. The substitution of Asp85 or Arg292 with alanine destroyed C‐glucosyltransferase activity, whereas the substitution of His20 with alanine abolished C‐glucosyltransferase activity but enabled O‐glucosyltransferase activity. The catalytic mechanism is discussed on the basis of the findings.

Asymmetric Desymmetrization of Saturated and Unsaturated meso-1,2-Diols

Abstract An asymmetric desymmetrization of saturated and unsaturated cyclic and acyclic meso-1,2-diols has been developed from the ene acetals, prepared from the norbornene carboxyaldehyde and meso-1,2-diols. The intramolecular haloetherification of the ene acetals as a key step afforded 8-membered acetals in a stereoselective manner just by the reaction of norbornene olefin even when the ene acetals from unsaturated meso-1,2-diols having olefins in the same molecule were used. Subsequent reductive elimination, followed by protecting the hydroxy group and transacetalization, gave optically active 1,2-diol derivatives and the starting ene acetals in good yields.

Asymmetric Total Synthesis of (−)‐Stenine and 9a‐epi‐Stenine

A route for the asymmetric synthesis of (-)-stenine, a member of the Stemona alkaloid family used as folk medicine in Asian countries, is described. The key features of the sequence employed include stereoselective transformations on a cyclohexane ring controlled by a chiral auxiliary unit and an intramolecular Mitsunobu reaction to construct the perhydroindole ring system. By using an intermediate in the route to (-)-stenine, an asymmetric synthesis of 9a-epi-stenine was also executed. The C(9a) stereocenter in 9a-epi-stenine was installed by using a Staudinger/aza-Wittig reaction of a keto-azide precursor followed by reduction of the resulting imine. The results of this effort demonstrate the applicability of the chiral auxiliary based strategy to the preparation of naturally occurring alkaloids that contain highly functionalized cyclohexane cores.

Synthesis of BC-ring model of globostellatic acid X methyl ester, an anti-angiogenic substance from marine sponge.

Concise synthesis of BC-ring model compounds of 13E,17E-globostellatic acid X methyl ester, an anti-angiogenic triterpene derivative from Indonesian marine sponge, was achieved through ynolate olefination and allylic oxidation as key steps. The model compound 5, which was synthesized within 10 reaction steps from commercially available Hajos-Parrish ketone, showed anti-proliferative activity against HUVECs with moderate selectivity.

DESYMMETRIZATION OF UNSATURATED MESO-1,2-DIOLS VIA AN INTRAMOLECULAR HALOETHERIFICATION OF ENE ACETALS : A REMARKABLE KINETIC CONTROL

Abstract Haloetherification reaction of the chiral ene acetals derived from unsaturated meso -1,2-diols and chiral non-racemic norbornene aldehyde proceeded in an intramolecular manner with an unexpectedly high kinetic control. This method has been successfully employed for the desymmetrization of unsaturated meso -1,2-diols leading to their optically pure derivatives.

Structure‐Activity Relationships Study of Bastadin 6, an Anti‐Angiogenic Brominated‐Tyrosine Derived Metabolite from Marine Sponge

A structure‐activity relationship (SAR) study of bastadin 6 (1), a brominated tyrosine‐derived metabolite from Indonesian marine sponge having a potent anti‐angiogenic activity, was executed. The syntheses and their biological evaluation of the oxime‐modified analogues and bromine‐modified analogues revealed that both the oxime moieties and bromine atoms in bastadin 6 (1) play an important role to show the potent and selective anti‐proliferative activity against human umbilical vein endothelial cells (HUVECs).