Cynaropicrin (1) is a sesquiterpene lactone natural product isolated from artichokes (Cynara scolymus). 1 has attractive biological activity including anti-trypanosomal activity, inhibition of NF-κB activation, antihepatitis C activity, etc. Herein, we report the first total synthesis of cynaropicrin 1. The structure activity relationship study is also described.

The synthesis involved stereoselective Favorskii rearrangement and indium-promoted diastereoselective Barbier reaction. At first, 8 was obtained from commercially available (S)-α-pinene 9 in three steps. Diol 7 was then obtained in two steps from 8. Protection of primary and secondary hydroxyl groups of 7 gave Favorskii rearrangement precursors 10, 11, and 12. The investigation of Favorskii rearrangement with NaOMe in MeOH was then performed to afford 13. 5-Membered ring 13 was subjected to 8-steps reactions including a [2,3]-sigmatropic rearrangement for the construction of the exo-olefin to give an aldehyde 5.

Next, the Barbier reaction between the obtained 5 and the prepared bromolactone 4 was examined. In this reaction, using indium in THF and H₂O gave moderate yield with good stereoselectivity. To construct the main skeleton of 3, 4-step reactions including intramolecular ene reaction for compound 19 were conducted to afford 3. Prepared side chain 2 was then introduced into the hydroxyl group of 3 via a Mitsunobu-Mukaiyama reaction. Removal of PMB groups gave cynaropicrin 1. Spectroscopic data of synthesized 1 showed good agreement with natural 1. The first total synthesis of 1 was thus achieved in 2.6% overall yield over 23-steps from 9.

Structure activity relationship studies on Trypanosoma brusei and NF-κB were also carried out. It was turned out that natural product 1 holds the most potent biological activity.

The central role of dolichyl-phosphate N-acetylglucosamine-phosphotransferase 1 (DPAGT1) suggests that its inhibition could affect the glycosylation of many essential biological systems. The tunicamycins are the only DPAGT1 inhibitors known and biochemical studies with these DPAGT1 inhibitors are limited by their promiscuous toxicities. The tunicamycins kill a wide range of cancer and healthy cells in a non-selective manner. In sharp contrast, selective DPAGT1 inhibitors identified in our program display strong cytostatic effect against solid cancers which require the overexpression of DPAGT1 in their progression, but do not affect cell viability of healthy cells. The identified DPAGT1 inhibitors possess impressive anti-metastatic ability in various solid cancer cell lines and induce their mitochondrial structural changes. This review summarizes our discovery of novel DPAGT1 inhibitors with drug-like properties and proof-of-pharmaceutical concept studies of a novel DPAGT1 inhibitor in xenograft and orthotopic anticancer mouse models.

Isonitrile (R-NC) is a regioisomer of the corresponding nitrile (R-CN), whose C-terminus has carbene like property. Isonitriles have been deeply investigated from the viewpoint of their use. In contrast to the usability, the synthesis of isonitriles themselves are not sufficiently studied. In this manuscript, we describe our findings on catalytic nucleophilic isocyanation using cyanide with precise control of the ambident reactivity. We successfully demonstrated Pd-catalyzed allylic isocyanation. A wide variety of allylic isonitriles were obtained by this method, in high yield with good linear selectivity. Allylic nitriles were not observed at all, which were the possible side products in the reaction. Even though the reaction is the Pd-catalyzed allylic substitution, no π-allyl Pd(II) intermediate is involved in the catalytic cycle. Pd salt, such as Pd(OAc)₂ and Pd(CN)₂, was just the precursor of catalytic active species. It was reversibly converted into the ate complex, (Me₃Si)[Pd-(CN)₃], with excess amount of trimethylsilyl cyanide (Me₃SiCN). The ate complex plays dual roles: 1) The Me₃Si group activates phosphate leaving group on the allylation electrophile. 2) The [Pd(CN)₃]^- part reacts as the nucleophile with its N-terminus because the strong interaction between Pd center and C-terminus of cyanide suppresses the C-nucleophilicity. Benzylic isocyanation was successfully catalyzed by Ag₂O. Both primary and secondary benzylic isonitriles were obtained in high yield. Pd-catalyzed synthesis of α-aryl-α-isocyanoacetamide derivative was also demonstrated. This catalytic procedure was appropriate to the sequential transformation into the trisubstituted oxazole without isolation of the isonitrile intermediate. Mechanistic investigations revealed that the nucleophilic isocyanation proceeded through a S_N1-type substitution predominantly.

Isoxazole is a five-membered heteroaromatic ring that is a highly important framework with widespread applications in pharmaceuticals and agrochemicals. Indeed, the isoxazole ring has desirable pharmacological activity because its two contiguous electronegative heteroatoms (nitrogen and oxygen atoms) contribute to hydrogen bonding with various target enzymes and receptors inaccessible by other ring systems. This unique and significant utility has led to great interest in the synthesis of functionalized isoxazoles, and various synthetic approaches have been developed for this class of compounds. Current synthetic approaches are classified into following four groups: (a) 1,3-dipolar cycloaddition, (b) condensation, (c) cycloisomerization, and (d) direct functionalization. Despite the recent much effort on synthetic researches, however, direct functionalization of isoxazoles (approach d) has still been immature to produce a variety of multifunctionalized isoxazoles. We herein describe our recent studies on direct functionalization of isoxazoles based on the generation of 4-isoxazolyl anion species and the subsequent gold (I)-catalyzed electrophilic aromatic substitution type reactions and rhodium (III)-catalyzed carboxylate-directed C-H activation. These developed functionalization methodologies enabled access to novel isoxazole derivatives that are not readily synthesized by other means. In addition, our interest in photolysis of isoxazoles led us to find photochemical conversion of isoxazoles into 5-hydroxyimidazolines.

Development of a new synthetic method for the construction of quaternary carbon centers with a trifluoromethyl group was realized by way of smooth 1,6-addition of various active methylene compounds to highly reactive δ-trifluoromethylated p-quinone methides generated in situ only with a catalytic amount of a base. A variety of aldehydes also behaved as nice nucleophiles with the aid of a NHC catalyst and the resultant products were further converted to such congested structures as the consecutive quaternary-tetrasubstituted carbons in a highly stereoselective manner. This method was also extended for the incorporation of heteroatoms like nitrogen, oxygen, and sulfur atoms.

Allylic amination reactions of alkenes are useful tools to construct N-functionalized molecules and now one of the main research targets in the field of allylic oxidation reaction. Although many reactions using transition metal catalysts have been developed, the examples of metal-free systems are relatively limited. This short review focuses on recent reports about metal-free allylic C-H amination, and three types of the reactions, (1) enantioselective reactions using organobase catalysts, (2) iodine-mediated reaction systems, and (3) selenium-catalyzed reactions will be described.