Resiniferatoxin (1) belongs to a daphnane diterpenoid family, and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. We accomplished three radical-based total syntheses of 1 to streamline the overall route. In the first-generation synthesis, we implemented a novel radical three-component coupling reaction. This transformation formed the hindered linkage between the A and C-rings and extended the carbon chain in a stereoselective fashion. The 7-membered B-ring was cyclized by the second radical reaction. In the second-generation synthesis, we improved the efficacy and practicality by reorganizing the reaction sequence and retaining the intermediates of the first route. Thus, we utilized intermolecular radical allylation, Stille coupling, and photocatalytic decarboxylative radical cyclization as the three key transformations. In the third-generation synthesis, we designed a specific intermediate based on the common substructure of not only 1, but also structurally related diterpenoids, and established a unified strategy. The common intermediate was efficiently built by exploiting the bridgehead radical cyclization and derivatized into 1 through efficient C-ring functionalizations. These three total syntheses of 1 together demonstrate the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multi-step target-oriented synthesis.

Alkaloids with fused polycyclic skeletons are attractive targets for synthetic organic chemists due to their structural complexity and biological activity. Developing efficient synthetic strategies for these compounds is one of the key challenges in the field of synthetic research. When planning the synthesis of natural products with such complex three-dimensional structures, the key challenge is to introduce the appropriate functional group at the desired position while building the three-dimensional framework of the natural product. Various strategies and synthetic methodologies are needed to face these challenges. Herein, we disclose the synthesis of fused polycyclic alkaloids based on the dearomative oxidative phenolic coupling reaction of phenols followed by regioselective intramolecular aza-Michael reactions of dienones, allowing the efficient synthesis of a series of hasubanan alkaloids. In this study, three hasubanan alkaloids ((−)-Metaphanine, (+)-Stephadiamine, and Cepharatines) were synthesized by the late diversification of their C and D ring moieties based on regioselective aza-Michael reaction of dienones obtained by dearomative oxidative phenolic coupling reaction of phenols. The synthesis of (−)-metaphanine was achieved through an efficient construction of the Hasubanan skeleton by utilizing the regioselective aza-Michael reaction at C14. (+)-Stephadiamine was synthesized employing an aza-benzylic acid-type rearrangement reaction to contraction of C ring. Additionally, cepharatines were successfully synthesized through the reorganization of the D ring, which involved a cascade reaction featuring a retro aza-Michael reaction and subsequent aminal formation.

The exploration for novel functional organic materials using hetero-elements has been advancing. As a result of the consideration of a diverse range of elements, those incorporated have reached as far as the heavy elements. However, arsenic is one element that has been left behind in this trend. Arsenic, located in the fourth period of group 15, is indispensable for a systematic understanding of p-block elements. Furthermore, arsenic, with its stereochemical and chemical stability and heavy atom effect, has potential as a key element for functional materials. Nevertheless, research on organoarsenic compounds has significantly stagnated due to the volatility and toxicity of their synthetic precursors. We have developed various routes to synthesize organoarsenic compounds from non-volatile precursors, and have pioneered functional organoarsenic chemistry. We have conducted research on the optical and electronic properties of conjugated molecules and polymers, the structure, function, and reaction of metal complexes with arsenic ligands, and organocatalysts. This review outlines these areas.

Non-alternant hydrocarbons, such as azulene, pentalene, and heptalene, are intriguing compounds. The π-conjugations within these consecutive odd-membered carbocycles provide unique physical properties not shared by alternant-benzenoid hydrocarbons. Incorporating these non-alternant frameworks into polycyclic aromatic hydrocarbons (PAHs) is a curious strategy to develop unusual optical/magnetic properties, such as near-IR absorption/emission, (anti)aromaticity, and spin polarization. The design of a relatively simple and efficient methodology to construct polycyclic systems with odd-membered rings is in high demand. We have been demonstrating the efficient synthesis of π-extended molecules with non-alternant frameworks using the interactions of Lewis acidic metals with sp-hybridized carbon-carbon bonds to promote tandem annulations. Among the rich chemistry of non-alternant hydrocarbons, pursuing the non-alternant isomers of pyrene, which has seven possible non-alternant isomers, has been the most significant project. Through enormous dedication by many pioneering works, six of the seven possible non-alternant isomers of pyrene have been isolated and characterized as stable aromatic molecules. However, the only unsynthesized isomer, bis-periazulene (cyclohepta[def]fluorene), had remained an uncharacterized hydrocarbon until 2022, despite many synthetic and theoretical investigations since it was first reported in 1955. This article describes the synthesis and characterization of bis-periazulene derivatives. The historical perspectives, synthetic approaches employing Lewis acid-mediated cyclization, fundamental properties, and comparisons to related systems are documented.

Hypervalent iodine compounds have been widely used in organic synthesis due to their high reactivity, low toxicity, and ease of availability. Recently, the transformation of complex molecules with hypervalent iodine compounds is gathering great attention. In this account, we report the synthesis of cyclic alkynyl benziodoxolones, ethynylbenziodoxolone, ethynylbenziodoxole, and diynylbenziodoxolone, and the development of electrophilic alkynylation and alkenylation of nitrogen nucleophiles derived from complex molecules such as amino acid and peptide with cyclic alkynyl benziodoxolones. This methodology provides the amino acid- and peptide-derived ynamide, enamide, and 4-imidazolidinone under mild reaction conditions due to the high electron-withdrawing nature and hyper-leaving-group character of the λ³-iodanyl group. Mechanistic investigation for the synthesis of 4-imidazolidinone with DFT calculation is also described.

The regioselective functionalization of C-H bonds in pyridines is in high demand due to their wide-ranging application in bioactive compounds, materials, and ligands. This short review provides a recent development of the 4-selective functionalization of pyridines via pyridylphosphonium salts. These transformations involve the regioselective installation of phosphonio groups at the 4-position of pyridines, enabling subsequent bond-forming reactions.