Biocatalytic asymmetric construction of secondary and tertiary fluorides from β-fluoro-α-ketoacids

Fluorine is a critical element for the design of bioactive compounds, but its incorporation with high regio- and stereoselectivity using environmentally friendly reagents and catalysts remains an area of development. Stereogenic tertiary fluorides pose a particular synthetic challenge and are thus present in only a few approved pharmaceuticals such as fluticasone, solithromycin, and sofosbuvir. The aldol reaction of fluorinated donors provides an atom-economical approach to asymmetric C-F motifs via C-C bond formation. Here we report that the type II pyruvate aldolase HpcH and engineered mutants thereof are biocatalysts for carboligation of ß-fluoro-α-ketoacids (including fluoropyruvate, ß-fluoro-α-ketobutyrate, and ß-fluoro-α-ketovalerate) with many diverse aldehydes. The reaction proceeds with kinetic resolution in the case of racemic donors. The reactivity of HpcH towards these new donors, which are non-native in both steric and electronic properties, grants access to enantiopure fragments with secondary or tertiary fluoride stereocenters. In addition to representing the first asymmetric synthesis of tertiary fluorides via biocatalytic carboligation, the afforded products could improve the diversity of fluorinated building blocks and enable the synthesis of fluorinated drug analogs.

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

gem-Difluoroalkenes are readily available fluorinated building blocks, and the fluorine-induced electronic perturbations of the alkenes enables a wide array of selective functionalization reactions. However, many reactions of gem-difluoroalkenes result in a net C–F functionalization to generate monofluorovinyl products or addition of F to generate trifluoromethyl-containing products. In contrast, fluorine-retentive strategies for the functionalization of gem-difluoroalkenes remain less generally developed, and is now becoming a rapidly developing area. This review will present the development of fluorine-retentive strategies including electrophilic, nucleophilic, radical, and transition metal catalytic strategies with an emphasis on key physical organic and mechanistic aspects that enable reactivities.

Supramolecular Alloys from Fluorinated Hybrid [4+6] Imine Cages

To create innovative materials, efficient control and engineering of pore sizes and their characteristics, crystallinity and stability is required. Eight hybrid [4+6] imine cages with a tuneable degree of fluorination and one fully fluorinated [4+6] imine cage are investigated. Although the fluorinated and the non-fluorinated building blocks used herein differ vastly in reactivity, we are able to gain control over the outcome of the self-assembly process, by carefully controlling the feed ratio. This represents the first hybrid material based on fluorinated/hydrogenated porous organic cages (POCs). These alloys with unlimited miscibility in the solid state were obtained as highly crystalline samples after recrystallization and even showed retention of the crystal lattice. All alloys and the fully fluorinated [4+6] imine cage were analysed by MALDI-MS, SCXRD, PXRD and in regards to thermal stability (TGA). <br>

Supramolecular Alloys from Fluorinated Hybrid [4+6] Imine Cages

To create innovative materials, efficient control and engineering of pore sizes and their characteristics, crystallinity and stability is required. Eight hybrid [4+6] imine cages with a tuneable degree of fluorination and one fully fluorinated [4+6] imine cage are investigated. Although the fluorinated and the non-fluorinated building blocks used herein differ vastly in reactivity, we are able to gain control over the outcome of the self-assembly process, by carefully controlling the feed ratio. This represents the first hybrid material based on fluorinated/hydrogenated porous organic cages (POCs). These alloys with unlimited miscibility in the solid state were obtained as highly crystalline samples after recrystallization and even showed retention of the crystal lattice. All alloys and the fully fluorinated [4+6] imine cage were analysed by MALDI-MS, SCXRD, PXRD and in regards to thermal stability (TGA). <br>

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

A study exploring halofluorination and fluoroselenation of some cyclic olefins, such as diesters, imides, and lactams with varied functionalization patterns and different structural architectures is described. The synthetic methodologies were based on electrophilic activation through halonium ions of the ring olefin bonds, followed by nucleophilic fluorination with Deoxo-Fluor®. The fluorine-containing products thus obtained were subjected to elimination reactions, yielding various fluorine-containing small-molecular entities.

A fluoride-responsive genetic circuit enables in vivo biofluorination in engineered Pseudomonas putida

Fluorine is a key element in the synthesis of molecules broadly used in medicine, agriculture and materials. Addition of fluorine to organic structures represents a unique strategy for tuning molecular properties, yet this atom is rarely found in Nature and approaches to integrate fluorometabolites into the biochemistry of living cells are scarce. In this work, synthetic gene circuits for organofluorine biosynthesis are implemented in the platform bacterium Pseudomonas putida. By harnessing fluoride-responsive riboswitches and the orthogonal T7 RNA polymerase, biochemical reactions needed for in vivo biofluorination are wired to the presence of fluoride (i.e. circumventing the need of feeding expensive additives). Biosynthesis of fluoronucleotides and fluorosugars in engineered P. putida is demonstrated with mineral fluoride both as only fluorine source (i.e. substrate of the pathway) and as inducer of the synthetic circuit. This approach expands the chemical landscape of cell factories by providing alternative biosynthetic strategies towards fluorinated building-blocks.

Carbenoid-Mediated Homologation Tactics for Assembling (Fluorinated) Epoxides and Aziridines

Homologation strategies provide highly versatile tools in organic synthesis for the introduction of a CH2 group into a given carbon skeleton. The operation can result in diverse structural motifs by tuning of the reaction conditions and the nature of the homologating agent. In this Account, concisely contextualizing our work with lithium carbenoids (LiCH2X, LiCHXY etc) for homologating carbon-centered electrophiles, we focus on the assembly of three-membered cycles featuring fluorinated substituents. Two illustrative case studies are considered: (1) the development and employment of fluorinated carbenoids en route to rare α-fluoroepoxides and aziridines, and (2) the installation of up to halomethylenic groups on trifluoroimidoylacetyl chlorides (TFAICs) for preparing CF3-containing halo- and halomethylaziridines. Collectively, we demonstrate that the initial homologation event generated by the installation of the carbenoid, upon modulation of the conditions, serves as a tool for creating fluorinated building blocks in a single operation.

Pauson–Khand reaction of fluorinated compounds

The Pauson–Khand reaction (PKR) is one of the key methods for the construction of cyclopentenone derivatives, which can in turn undergo diverse chemical transformations to yield more complex biologically active molecules. Despite the increasing availability of fluorinated building blocks and methodologies to incorporate fluorine in compounds with biological interest, there have been few significant advances focused on the fluoro-Pauson–Khand reaction, both in the inter- and intramolecular versions. Furthermore, the use of vinyl fluorides as olefinic counterparts had been completely overlooked. In this review, we collect the advances both on the stoichiometric and catalytic intermolecular and intramolecular fluoro-Pauson–Khand reaction, with special attention to the PKR of enynes containing a fluoride moiety.