Organofluorine compounds are central in synthetic chemistry, medicinal chemistry and material chemistry. In this review, we summarize the investigations on the synthesis of organofluorine compounds with acylsilanes. For the non-fluorinated acylsilanes, the in situ generation of difluoroenoxysilanes from the reactions of the acylsilanes with trifluoromethylation reagents is the major pathway, leading to the facile preparation of various α,α-difluoroketones. For the fluoroalkylacylsilanes, apart from the in situ generation of difluoroenoxysilanes through anion Brook rearrangement, radical Brook rearrangement of the photoexcited acylsilanes and the selective control of the reactivities of the biradicals pave the way for the synthesis of a variety of organofluorine compounds. In general, most of these reactions gave racemic products, and the asymmetric synthesis of organofluorine compounds with acylsilanes is still rare, which would be a potential direction of this field.

Comprehensive Summary

Organofluorine compounds are central in synthetic chemistry, medicinal chemistry and material chemistry. In this review, we summarize the investigations on the synthesis of organofluorine compounds with acylsilanes. For the non-fluorinated acylsilanes, the in situ generation of difluoroenoxysilanes from the reactions of the acylsilanes with trifluoromethylation reagents is the major pathway, leading to the facile preparation of various α,α-difluoroketones. For the fluoroalkylacylsilanes, apart from the in situ generation of difluoroenoxysilanes through anion Brook rearrangement, radical Brook rearrangement of the photoexcited acylsilanes and the selective control of reactivities of the biradicals pave the way for the synthesis of a variety of organofluorine compounds. In general, most of these reactions gave racemic products, and the asymmetric synthesis of organofluorine compounds with acylsilanes is still rare, which would be a future direction of this field.

Key Scientists

In 1957, the first acylsilane compound, triphenylsilyl phenyl ketone was reported by Brook group. In 1991, Portella and coworkers reported the reaction of non-fluorinated acylsilanes and perfluoroorganometallic reagents without Brook rearrangement, resulting in the formation of alcohols as the products. In 1992, Xu and coworkers carried out the first investigation on fluoroalkylacylsilanes for the preparation of difluoroenoxysilanes through anion Brook rearrangement. In 1994, Portella group reported the synthesis of difluoroenoxysilanes with non-fluorinated acylsilanes and Ruppert-Prakash reagent. In 2009, Otaka and coworkers reported a NHC-mediated intramolecular redox reaction to prepare (Z)-fluoroalkene dipeptide isosteres (FADIs) from γ,γ-difluoro-α,β- enoylsilane. Until 2022, the application of radical Brook rearrangement of fluoroalkylacylsilanes for the generation of fluoroalkylsiloxycarbenes was achieved by Shen group, enabling the synthesis of fluoroalkylated cyclopropenols. In 2022, Shen and coworkers successfully achieved the trapping of biradical intermediates generated from fluorine-containing acylsilanes, leading to the facile preparation of fused gem-difluorooxetanes. In the same year, Shen group reported the first asymetric reactions of fluoroalkylacylsilanes to prepare enantiomerically enriched fluoroalkyl alcohols and difluoroenoxysilanes.

[Fe^III(H-5-Br-thsa)(5-Br-thsa)]·H₂O, which exists in two polymorphic forms that exhibit SCO, is reported. Polymorph 1 exhibits three-step SCO, while polymorph 2 exhibits five-step SCO, which effectively regulates multi-step SCO behavior. Polymorphs 1 and 2 crystallize in different space groups during the entire spin-transition process, and two-step symmetry breaking was observed (Pbcn → Pnc2 → Pbcn for polymorph 1; P2₁/n → Pn → P2₁/n for polymorph 2).

Comprehensive Summary

Regulating spin crossover (SCO) behavior, especially controlling the spin transition steps, is an important scientific issue, mainly because people aim to control spin bistability and multistability. Presently, SCO bistability can be regulated by changing the ligand-modifying species, non-coordinated anions, guest molecules, and metal-ion dopant. However, the control of multistability is extremely challenging, especially in Fe(III) SCO compounds. Here, we report that [Fe^III(H-5-Br-thsa)(5-Br-thsa)]·H₂O (5-Br-thsa = (5-bromo-2-hydroxybenzylidene)hydrazinecarbothioamide), a compound we have reported before, exists in two polymorphic forms: polymorph 1 exhibits three-step SCO, and polymorph 2 shows five-step SCO, with multi-step SCO behavior effectively regulated by polymorphism. According to single-crystal and powder X-ray diffractometry, polymorphs 1 and 2 crystallize in different space groups during their spin transitions, with two-step symmetry breaking observed (Pbcn → Pnc2 → Pbcn for polymorph 1; P2₁/n → Pn → P2₁/n for polymorph 2). We realized that the behavior of these two polymorphs depends significantly on the structure, including (i) the average Fe—N bond distance, (ii) deformation of octahedral Fe^III atoms, and (iii) distinct crystal packing, which account for the large differences observed in magnetic properties.

Valbenazine (Ingrezza), a potent compound that selectively inhibits VMAT2 through an active metabolite HTBZ, has been approved for the treatment of tardive dyskinesia and very recently for chorea associated with Huntington's disease. In this report, a practical synthesis of HTBZ and valbenazine has been achieved, featuring a highly stereoselective 1,3-dipolar cycloaddition and an enzymatic kinetic resolution. The cascade process toward pyrido[2,1-a]isoquinoline including cycloaddition, cleavage of the N—O bond, and lactamization proved to be operationally feasible. The allure of enzymatic resolution developed in this work provides a rapid access to THIQ-fused piperidine in various bioactive substances.

Comprehensive Summary

Valbenazine (Ingrezza), a potent and highly selective inhibitor of vesicular monoamine transporter type 2 (VMAT2) through the active metabolite hydrotetrabenazine (HTBZ), has been approved for the treatment of tardive dyskinesia and, very recently, for chorea, which is associated with Huntington's disease. Despite numerous synthetic efforts dedicated to the synthesis of HTBZ, the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone reduction. Herein, we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3-dipolar cycloaddition and enzymatic kinetic resolution. The cascade process includes cycloaddition, N—O bond cleavage, and lactamization, which proved to be operationally simple. The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline (THIQ)-fused piperidine in the production of medically significant compounds, such as yohimbine and reserpine.

Inspired by the skin of Osteichthyes fishes, a Janus hydrogel coating consisting of slippery and sticky layers is successfully prepared by a two-step UV light irradiation at room temperature. The slippery layer replicates the structure of cycloid scales, while the nature of hydrogel mimics the mucus on fish skin. The Janus hydrogel coating possesses prominent mechanical, anti-fouling and drag reduction properties. More details are discussed in the article by Xue et al. on page 867—872.

Inspired by the skin of Osteichthyes fishes, a Janus hydrogel coating consisting of slippery and sticky layers is successfully prepared by a two-step UV light irradiation at room temperature. The slippery layer replicates the structure of cycloid scales, while the nature of hydrogel mimics the mucus on fish skin. The Janus hydrogel coating possesses prominent mechanical, anti-fouling and drag reduction properties. More details are discussed in the article by Xue et al. on page 867—872.

As classic molecular magnets with magnetic bistability, spin-crossover (SCO) compounds have potentially important application value in molecular electronics, sensing, and information storage. Multistable control of SCO compounds is more difficult than bistability control. In this paper, we propose a strategy to control the number of spin-transition steps to further understand the control of the multistability of SCO compounds. More details are discussed in the article by Li et al. on page 879—886.

As classic molecular magnets with magnetic bistability, spin-crossover (SCO) compounds have potentially important application value in molecular electronics, sensing, and information storage. Multistable control of SCO compounds is more difficult than bistability control. In this paper, we propose a strategy to control the number of spin-transition steps to further understand the control of the multistability of SCO compounds. More details are discussed in the article by Li et al. on page 879—886.

The bifunctional fluorescent probe Mito-Q can not only effectively detect mitochondrial viscosity changes and mitophagy, but also be successfully applied to observe the fusion of mitochondrial-containing autolysosomes and autophagosomes (FMAA).

Comprehensive Summary

Autophagy is a multi-step cell metabolism process in which cells remove damaged and unwanted materials. During autophagy, autophagosomes fuse with lysosomes to form autophagosomes. Autophagosomal membrane components are recycled from autolysosomes through the autophagosomal components recycling (ACR), while lysosomal components circulate on the autolysosomal surface through the autophagic lysosome reformation (ALR) process. Autolysosomes contain components from autophagosomes and lysosomes. However, whether there is a fusion between autolysosome and autophagosome or lysosome at the organelle level remains unknown. In this study, a pH and viscosity dual-controlled mitochondria-targeting fluorescent probe Mito-Q was designed based on an asymmetric norcyanine to achieve the high-contrast imaging of mitochondria-containing autolysosomes. Mito-Q not only effectively detected mitochondrial viscosity changes and mitophagy with high sensitivity, but more importantly, the fusion of mitochondria-containing autolysosomes and autophagosomes (FMAA) was observed during autophagy by the real-time confocal imaging of HeLa cells.

Comprehensive Summary

Eight rare capnosane-type cembranoids, sarcocinerenoids A—H (1—8) and two new cage-type cembranoids sarcocinerenoids I—J (9—10) were isolated from the soft coral Sarcophyton cinereum. The 5/11 bicyclic carbon skeleton is the same in Sarcocinerenoids A—H (1—8), and they collocate distinctive oxygen rings. Sarcocinerenoids I—J (9—10) with a cage-type structure have been discovered to have an oxygen bridge and an uncommon seven-membered ring. Extensive spectroscopic investigation, X-ray diffraction analysis, estimated ECD, and DP4+ probability assessments were used to ascertain the structures of the two types of diterpenoids. Moreover, compounds 1, 4 showed promoting angiogenesis activity in zebrafish assays.

Azepine ring is a prominent structural scaffold in biologically significant molecules. This study demonstrates a Ni(II)-catalyzed alkyne functionalization/cyclization cascade reaction of alkyne-tethered malononitriles, involving intermolecular regioselective arylation of the alkynes and desymmetrizing addition onto the nitrile group, to access azepine derivatives. This strategy introduces an all-carbon quaternary stereocenter and an unprotected imine functionality simultaneously to the azepine scaffold, showing great promise for subsequent transformations. More details are discussed in the article by Liu et al. on page 873—878.

Azepine ring is a prominent structural scaffold in biologically significant molecules. This study demonstrates a Ni(II)-catalyzed alkyne functionalization/cyclization cascade reaction of alkyne-tethered malononitriles, involving intermolecular regioselective arylation of the alkynes and desymmetrizing addition onto the nitrile group, to access azepine derivatives. This strategy introduces an all-carbon quaternary stereocenter and an unprotected imine functionality simultaneously to the azepine scaffold, showing great promise for subsequent transformations. More details are discussed in the article by Liu et al. on page 873—878.

Palladium-catalyzed dipolar [4+2] and [6+2] cycloaddition reactions of benzo[d]isothiazole 1,1-dioxides (BDs) have been developed for the construction of of BD-fused 1,3-oxazinanes and 1,3-oxazocanes derivatives, respectively.

Comprehensive Summary

The Pd-catalyzed dipolar cycloaddition represents a significant synthetic strategy for the construction of useful heterocyclic compounds. This study developed the dipolar [4+2] and [6+2] cycloaddition reactions of benzo[d]isothiazole 1,1-dioxides (BDs) leading to the synthesis of BD-fused 1,3-oxazinane and 1,3-oxazocane derivatives, respectively. In particular, the synthesis of BD-fused 1,3-oxazinanes demonstrated regio- and enantioselective characteristics, resulting in products with good yields, enantioselectivity and regioselectivity (if applicable). Furthermore, the [6+2] cycloaddition reaction developed in this work represented the first strategy for the synthesis of medium-sized ring compounds based on BDs.