Synlett

The present article presents a personal account on the synthesis of heterocycles by the combination of regioselective Pd-catalyzed cross-coupling reactions of polyhalogenated heterocycles, i.e., Suzuki–Miyaura and Sonogashira reactions, with alkyne-carbonyl-metathesis (ACM) reactions. The products, which show interesting optical, electronic or medicinal properties, are not readily available by other methods.

The dithioacetalization of lactaldehyde derivatives with ethane-1,2-, propane-1,3-, butane-1,4-, and pentane-1,5-dithiols in the presence of 4 mol% of scandium triflate has been described. A series of cyclic dithioacetals were obtained with yields ranging from quantitative to 37%. The dithioacetalization of lactaldehyde derivatives with butane-1,4-dithiol and pentane-1,5-dithiol groups are accompanied by the formation of 14- and 16-membered macrocyclic sulfur structures with yields of 3% and 18%, respectively. In the case of a cyclic dithioacetal derivative with three methylene groups, a diastereoisomeric pair of enantiomers was obtained, the structure of which was confirmed by single-crystal X-ray diffraction analysis. Dithioacetals are useful building blocks in the synthesis of complex chemical structures. Macrocyclic compounds can be used to complex metal ions.

Irisquinone is a tumor radiotherapy sensitizer and has been found to have broad-spectrum antitumor activity in recent years. The current acquisition method of extracting and purifying from semen irisis has greatly limited its wide application and activity study deeply. In this work an efficient route for the synthesis of the irisquinone was investigated to solve the source of it. The target compound was synthesized by 5-step reactions to Wittig reaction, reduction, oxidation, Wittig reaction, and oxidation using 3,5-dimethoxycarboxaldehyde as the starting material with an overall yield of 48%. The key factors such as the ratio of raw materials, temperatures, solvents, reaction times, and types of base for the main reactions were optimized. In addition, the deprotection and reduction were completed with Pd/C catalytic simultaneously when compound 2 was synthesized from compound 1. In the last reaction, the 3,5-dimethoxybenzene moiety of compound 4 was directly oxidized to 6-methoxy-1,4-benzoquinone by K3[Fe(CN)6]/H2O2 without the need to selectively remove the methyl protecting group, which were the innovative points in the experimental route design of the irisquinone synthesis. This work has opened new perspectives for the artificial synthesis and the development of irisquinone.

We have been interested in the differences between the properties of low-coordinated carbon compounds and their heavier homologues based on elements of group 14, e.g., Si and Ge. Fundamental research on the synthesis and characterization of divalent and multiply bonded compounds of heavier group 14 elements has led to a variety of isolated low-coordinated species of heavier group 14 elements that can replace transition metals in small-molecule transformations. We have focused on low-coordinated germanium compounds with double or triple bonds between germanium atoms, as well as germanium-containing aromatic compounds. Once isolated, the reactivity of these low-coordinated germanium compounds was examined with regard to small-molecule activation. In this account, the reactivity patterns of these compounds will be described.1 Introduction2 1,2-Dibromodigermenes and Bromogermylenes3 Digermynes4 1,2-Digermacyclobutene5 1,3-Digerma-2-silaallene6 Digerma-Aromatic Compounds7 Germanium-Catalyzed Cyclotrimerization of Alkynes8 Summary

The field of C–H functionalization chemistry has experienced rapid growth in the past twenty years, with increasingly powerful applications in organic synthesis. Recognizing the potential of this emerging field to impact drug discovery, a dedicated effort was established in our laboratories more than ten years ago, with the goal of facilitating the application of C–H functionalization chemistries to active medicinal-chemistry programs. Our approach centered around the strategy of late-stage functionalization (LSF) wherein C–H functionalization chemistry is employed in a systematic and targeted manner to generate high-value analogues from advanced drug leads. To successfully realize this approach, we developed broadly useful LSF chemistry platforms and workflows that increased the success rates of the C–H functionalization chemistries and accelerated access to new derivatives. The LSF strategy, when properly applied, enabled a rapid synthesis of molecules designed to address specific medicinal-chemistry issues. Several case studies are presented, along with descriptions of the group’s platforms and workflows.1 Introduction2 Building an LSF Chemistry Toolbox2.1 C–H Borylation2.2 Minisci Platforms2.3 Automated Direct-Metalation Platform3 Building an LSF Workflow4 LSF Application Case Studies4.1 BTK Inhibitor Program4.2 GPR40 Agonist Program5 Conclusions

Described is a deprotonative α-arylation reaction of Meyers’s chiral bicyclic lactams (MCBLs) under palladium catalysis, and a substrate-dependent post-transformation. When the bridgehead carbon of the MCBLs is substituted with a methyl or an ethyl group, the initial arylation product undergoes a further rearrangement reaction to give a conjugated framework. On the other hand, substrates bearing a bridgehead isopropyl or aryl group are converted into the corresponding exo-arylation products. Preliminary studies indicated that the rearrangement pathway was promoted by deprotonation and was independent of palladium catalysis. In addition to mechanistic interests, this study demonstrates a modular and divergent synthesis of functionalized lactams.

The synthesis of polysubstituted 4H-pyran derivatives has attracted considerable attention due to its wide application in agrochemicals, pharmaceuticals, and other functional molecules. We report an N-heterocyclic carbene-catalyzed [3+3] annulation reaction of β-ketone esters with enynals for rapid access to pentasubstituted 4H-pyran derivatives through a regioselective activation of the ynal. A series of 4H-pyran derivatives bearing various substituents were obtained in moderate to excellent yields. This method could find further applications in the synthesis of structurally diverse 4H-pyran-derived functional molecules from readily available starting materials.

1-Phenyl-3-azaarenyl-propan-1-amine structural moieties have been widely incorporated in pharmaceuticals and biologically active compounds; however, current synthetic methods to access these compounds need multiple steps and proceed with low efficiency. Herein, we reported an efficient photocatalytic carbamoyl radical transfer approach that allows the preparation of these compounds in high yields (up to 88%). The reaction easily runs on a gram-scale and was applied for the preparation of pheniramine in two steps with 72% total yield.

Chikusetsusaponin IVa butyl ester (CS-IVa-Be) is a triterpene saponin that acts as a novel IL6R antagonist for inducing breast cancer cell apoptosis. However, the structure–activity relationship for this class of saponins remains unclear. Here, we report a gram-scale synthesis of CS-IVa-Be and the efficient preparation of eight of its analogues. CS-IVa-Be was demonstrated to have significant antitumor activities against MDA-MB-231, HepG2, and A549 cells. When one of the sugar residues at either the 3-OH or 28-COOH position of CS-IVa-Be was cleaved, or the length of the alkyl chain on the d-glucuronic acid residue of CS-IVa-Be was changed, these analogues showed varied inhibitory activities against the cancer cell lines. Notably, the carboxylic acid form of CS-IVa-Be exhibited a stronger antitumor activity against MDA-MB-231 cells. Furthermore, the carboxylic acid form of CS-IVa-Be inhibited MDA-MB-231 cell proliferation in a dose-dependent manner by arresting the cell cycle at the G2/M phase.

The cyclization of various nucleophiles, such as 1,3-dicarbonyl compounds, 1,3-bis(silyloxy)-1,3-butadienes, hydrazones, hydroxylamine, amidines, thioglycolic esters, heterocyclic enamines and others, with 4-chlorocoumarins, containing an electron-withdrawing group at position 3, allows for a convenient synthesis of a great variety of benzo[c]coumarins and related fused coumarins. Suzuki–Miyaura reactions of coumarin-derived bis(triflates) result in formation of arylated coumarins with excellent regioselectivity that is controlled by electronic and steric features of the substrate. The combination of Suzuki–Miyaura with lactonization reactions of carba- and heterocyclic substrates allows for the synthesis of benzo[c]coumarins and of other fused coumarins. Domino Michael–retro-Michael–lactonization reactions of 1,3-bis(silyloxy)-1,3-butadienes with chromones provide a convenient access to hydroxylated benzo[c]coumarins. In a related approach, fused coumarins were prepared by domino reactions of heterocyclic enamines with chromone-3-carboxylic acids.1 Introduction2 Reactions of 3-Acceptor-4-chlorocoumarins3 Reactions of Coumarin Triflates4 Synthesis of Fused Coumarins5 Conclusions