Yoshiki Morimoto

Chemical investigation of the soft coral Stereonephthya sp., collected from Kagoshima, Japan, led to the isolation of two previously undescribed 4α-methylated sterols, (3β,4α,22E,24R)-4,23-dimethylergosta-6,8(14),22-trien-3-ol (1) and (3β,4α,24S)-4-methylergosta-6,8(14)-dien-3-ol (2), together with the known sterol 4α-methyl-ergosta-6,8(14),22E-trien-3β-ol (3). Their structures were elucidated using a comprehensive spectroscopic analysis. Compound 1 was characterized as a conjugated 6,8(14)-diene system with a 24-methylated side chain containing a 22E double bond, whereas compound 2 was identified as its 22,23-dihydro-30-nor analog. The relative configurations of the steroidal nuclei and side chains were established by nuclear Overhauser effect spectroscopy experiments, density functional theory (DFT)-based conformational analysis and comparison of the nuclear magnetic resonance chemical shifts with those of related sterols. Their absolute configurations were determined by comparing the experimental electronic circular dichroism (ECD) spectra with time-dependent DFT-calculated spectra. The absolute stereochemical assignment of the known sterol 3 was also supported by its ECD spectrum. Bioassay-guided fractionation of the crude extract, which inhibited nitric oxide production in lipopolysaccharide-stimulated RAW 264 macrophages, identified monogalactosyl monoacylglycerol (4) and arachidonic acid (5) as the principal active constituents. In contrast, sterols 1–3 did not significantly inhibit nitric oxide production at 80 μM. These findings expand the chemical diversity of 4α-methylated marine sterols and the known secondary metabolite profile of Stereonephthya sp.

The red algal genus Portieria is a prolific producer of halogenated monoterpenoids. In this study, we isolated and characterised monoterpenoids from the Okinawan red algae Portieria hornemannii. A new polyhalogenated cyclic monoterpenoid, 2(R)‐chloro‐1,6(S)‐dibromo‐3(8)(Z)‐ochtoden‐4(R)‐ol (1), along with three known monoterpenoids, (2R,3(8)E,4S,6R)‐6‐bromo‐2‐chloro‐1,4‐oxido‐3(8)‐ochtodene (2), 1‐bromo‐2‐chloroochtoda‐3(8),5‐dien‐4‐one (3), and 2‐chloro‐1‐hydroxyochtoda‐3(8),5‐dien‐4‐one (4) were isolated from the methanol extract of three populations of P. hornemannii. These compounds were characterised using a combination of spectroscopic methods and chemical synthesis, and the absolute stereochemistry of compounds 1 and 2 was determined. In addition, all isolated compounds were screened for their anti‐biofouling activity against the mussel Mytilus galloprovincialis, and 1 exhibited strong activity. Therefore, halogenated monoterpenoids have the potential to be used as natural anti‐biofouling drugs.

The asymmetric total synthesis of toxicodenane A, a sesquiterpenoid expected to be promising for diabetic nephropathy, was achieved. In the synthesis, a samarium iodide (SmI₂)-induced Barbier-type cyclization and a regio- and stereoselective allylic oxidation followed by a dehydration cyclization were employed as key steps. Furthermore, the first asymmetric syntheses of both enantiomers were accomplished using the previously mentioned synthetic strategy. Finally, the synthetic compounds significantly inhibited lipotoxicity-mediated inflammatory and fibrotic responses in mouse renal proximal tubular cells.

There are marine cytotoxic bromotriterpenoids, named the thyrsiferol family that are structurally characterized by some tetrahydropyran (THP) and tetrahydrofuran (THF) rings. The thyrsiferol family belongs to natural products that are often difficult to determine their stereostructures even by the current, highly advanced spectroscopic methods, especially in acyclic systems including stereogenic tetrasubstituted carbon centers. In such cases, it is effective to predict and synthesize the possible stereostructures. Herein, to elucidate ambiguous stereostructures and unassigned absolute configurations of aplysiol B, laurenmariannol, and saiyacenol A, members of the thyrsiferol family, we carried out their asymmetric chemical syntheses featuring 6‐exo and 5‐exo oxacyclizations of epoxy alcohol precursors and 6‐endo bromoetherification of a bishomoallylic alcohol. In this paper, we report total assignments of their stereostructures through their asymmetric chemical syntheses and also their preliminary cytotoxic activities against some tumor cells. These results could not have been achieved without depending on asymmetric total synthesis.

Feroniellin analogs isolated from Feroniella lucida possess a furanocoumarin skeleton connected to monoterpenic five‐ to seven‐membered ethereal rings by an ether linkage and exhibit a broad spectrum of biological activities. In this contribution, we intended to establish a “ring‐size‐divergent” synthetic strategy for the monoterpenic five‐ to seven‐membered ethereal rings through the chemical sythesis of feroniellins. The short and comprehensive synthesis of feroniellins was achieved in only two steps from easily available bergamottin based on the “ring‐size‐divergent” strategy. In addition, these syntheses resulted in revision of the proposed structures for feroniellins A and B and the determination of all the absolute configurations of feroniellins; their preliminary anti‐inflammatory activities were investigated as well.

Histrionicotoxin (HTX) alkaloids isolated from the poison arrow frogs possess a unique structure characterized by a 1‐azaspiro[5.5]undecane skeleton common to the HTX family. The unique molecular architecture of HTXs and the interest as potential target drugs have prompted synthetic chemists to promote the total synthesis so far. However, all of the synthetic strategies to access the 1‐azaspiro[5.5]undecane framework of HTXs take a multistep approach from linear starting materials due to stepwise construction of either six‐membered carbo‐ or azacycle. Herein, we report the direct one‐step construction of the 1‐azaspiro[5.5]undecane skeleton from linear amino ynone substrates bearing an N‐methoxycarbonyl group utilizing our mercuric triflate (Hg(OTf)₂)‐catalyzed cycloisomerization reaction. The utility of this novel methodology was demonstrated by the total and formal syntheses of HTX‐235A and HTX‐283A, respectively, from the azaspirocycle.

In this contribution, we propose a new synthetic approach to tetrodotoxin (TTX), one of the most famous marine toxins that, after first preparing a functionalized linear substrate, forms a cyclohexane core from the substrate utilizing our mercuric triflate (Hg(OTf)₂)-catalyzed cycloisomerization reaction. The concept was applied to the synthesis of 11-nor-6,7,8-trideoxyTTX and 11-nor-4,9-anhydro-6,7,8-trideoxyTTX, which are unnatural TTX analogues, demonstrating the validity of our new approach.