Tadachika Miyasaka

Hemiketal D2 (HKD2) is a recently identified eicosanoid produced from arachidonic acid via a crossover pathway involving 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2), and has been shown to stimulate angiogenesis by inducing endothelial cell tubulogenesis. However, its limited availability by enzymatic reactions has hindered detailed biological investigation. Herein, we report the first total synthesis of HKD2 through a convergent coupling of three segments bearing all required stereogenic centers. Key transformations include addition of dithiane anion to a lactone segment to construct the hemiacetal moiety and a late-stage cross metathesis with carboxylic acid segment to complete the synthesis.

Tetrodotoxin (TTX) is a potent neurotoxin widely distributed among marine and terrestrial animals, yet how terrestrial vertebrates acquire this toxin has been debated for decades. Here, we identify oribatid mites as the primary dietary sources of TTX for the Japanese fire-bellied newt, Cynops pyrrhogaster. We detect TTX and its analogs in the mites Scheloribates processus and Galumna sp. KM1, which are preferentially consumed by terrestrial newts. In a controlled toxification experiment, juvenile newts accumulated TTX after consuming TTX-bearing mites, directly demonstrating dietary acquisition. Our results support that the early terrestrial stage is critical for lifelong TTX acquisition in the C. pyrrhogaster. Notably, we also detect pumiliotoxin, a poison-frog alkaloid, in S. processus, suggesting that newts and poison frogs have convergently evolved to exploit toxin-bearing microarthropods for chemical defense. We propose a “terrestrial toxic web” hypothesis in which oribatid mites act as a shared environmental reservoir linking putative microbial toxin production to vertebrate chemical defense, highlighting microarthropods as potential key mediators in terrestrial toxin flow.

Eight-membered cyclic alkyne 3 was synthesized from 1, bearing an N-tosyl-o-alkynylanilide and alkyl bromide, by a high-temperature treatment in the presence of a base. This is the first example of the direct synthesis of an eight-membered cyclic alkyne containing a nitrogen atom from the corresponding linear alkyne. The structural requirements for this cyclization were also investigated. Eight-membered cyclic alkyne 3 reacted with benzyl azide without a copper(I) salt to give triazoles 17 and 18 at room temperature.

Total syntheses of Cep-212 and Cep-210, predicted biosynthetic intermediates of tetrodotoxin isolated from the Japanese toxic newt, have been accomplished from geraniol by an intramolecular hetero Diels–Alder reaction as a key step in a highly stereoselective manner. The success of these syntheses enabled us to determine their absolute configurations by using a chiral normal-phase HPLC/MS analysis of the bis-dinitrobenzene derivative of natural Cep-212 and reference derivatives prepared from chemically synthesized enantiomers.