With intention to formulate a potentially general synthetic strategy generating a collection of skeletally diverse scaffolds without simplifying a structural feature of natural products, we devised an artificial assembly line of terpenoid indole alkaloids and its variants. Inspired by the key biosynthetic intermediate, dehydrosecodine, responsible for divergent intramolecular cyclizations, a “multipotent intermediate” with improved stability and versatile reactivity was designed to establish a streamlined divergent synthetic process. A newly developed copper-catalyzed cyclization protocol allowed rapid formation of the sensitive dihydropyridine system. By harnessing the versatile reactivity of the multipotent intermediate, three types of bioinspired [4＋2] cycloadditions as well as two types of oxidation-triggered cyclizations were successfully implemented to generate five distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and unnatural tetracyclic framework within 6-9 steps from tryptamine. Furthermore, simple manipulations of the [4＋2] products allowed total synthesis of (−)-catharanthine, (±)-vincadifformine and (±)-andranginine, demonstrating a structural relevance of our compound collections to the natural products.

This review describes the development of nitrile N-oxide-based click agents to fabricate multi-component organic architectures. Central to the technique to create the agents is the kinetic stabilization of nitrile N-oxide. We first describe the structure of nitrile N-oxide in solution, estimated by the ¹³C NMR and UV spectroscopic studies of ¹³C-labelled nitrile N-oxides. The results indicate the temperature-dependent dynamic character of nitrile N-oxide in solution. The stable nitrile N-oxides exhibit high reactivity to various dipolarophiles without self-decomposition reactions. We next introduce the intramolecular cycloaddition reactions of nitrile N-oxide moiety to the neighboring benzene ring, along with the structural optimization of molecular ligation tool. Based on the results, we developed the nitrile N-oxide-based click agents, such as homoditopic nitrile N-oxides, orthogonal agents possessing both a nitrile N-oxide and an electrophile, and nitrile N-oxide-terminated polymers. These agents undergo catalyst- and solvent-free cycloaddition reactions to unsaturated bond-containing compounds, polymers, and material surfaces, enabling catalyst-free polycycloaddition, modification and cross-linking of polymers, and polymer-grafting.

Inhibition of sodium glucose co-transporter 2 (SGLT2) in vivo increases urinary glucose excretion (UGE) and controls blood glucose levels in hyperglycemic animals. T-1095 is the first orally active SGLT2 inhibitor, and it was discovered by optimizing the natural glucosyl product phlorizin. We focused on aryl-C-glucosides and optimized the analogs, resulting in the discovery of canagliflozin, which is metabolically more stable than T-1095. Canagliflozin markedly induced UGE compared with that of T-1095 because of its excellent pharmacokinetic properties in vivo and its high potency for inhibiting SGLT2. Canagliflozin was selected as a clinical candidate for treating type 2 diabetes mellitus and was approved in the USA and EU in 2013 and in Japan in 2014. In this study, we describe the synthesis of new C-glucoside analogs using a palladium-catalyzed cross-coupling reaction of glucal boronate and its application as an SGLT2 inhibitor.

Regio- and stereoselective allylic substitution is an important tool for the synthesis of complex organic molecules. Due to the high branched-product selectivity, iridium gives a new opportunity in enantioselective synthesis. Iridium-catalyzed enantioselective allylic substitution is one of the most reliable methods for the synthesis of chiral building blocks. This review gives a comprehensive survey of iridium-catalyzed enantioselective allylic substitution. Iridium catalysts are divided into two types; iridacycle and bidentate (P, alkene) iridium complex. Iridacycle catalyst is suitable for the reaction of primary allylic electrophiles. On the other hand, bidentate (P, alkene) iridium catalyst is suitable for the reaction of racemic secondary allylic electrophiles.

Azadirachtin (1), which was isolated from the Indian neem tree in 1968, exhibits potent antifeedant and growth inhibitory activities against many insects. Because of its complicated structure, only the Ley group has completed the synthesis of 1. In this article, we describe the second synthesis of 1. The Diels-Alder reaction-decarboxylation-Claisen rearrangement approach was used to construct the basic structure of the left-hand segment. The correct stereochemistry at C4 was established by an oxidative ring-opening reaction and a subsequent aldol reaction. The right-hand segment was prepared from the known cyclopentenone derivative. After a coupling of both segments, the key tandem radical cyclization reaction was performed to elaborate the full carbon framework of 1. The cyclized product could be converted into Ley’s intermediate in 9 steps, resulting in the formal synthesis of 1. Our synthesis with a longest linear sequence of 39 steps is highly efficient.

A metal carbenoid is a highly active carbon species that exhibits divergent reactivity. The control of the reactivity still remains a challenging task in carbenoid chemistry. Recently, several groups have succeeded in controlling the chemoselectivity of these reactions. This mini-review highlights substrate-controlled chemoselective arene cyclopropanation over C-H insertion reaction, and catalyst-controlled C-H functionalization of electron-rich aromatic compounds.