Synthesis of Borylated Carbocycles by [2 + 2]-Cycloadditions and Photo-Ene Reactions.

Saturated bicyclic compounds make up a valuable class of building blocks in the development of agrochemicals and pharmaceuticals. Here, we present the synthesis of borylated bicyclo[2.1.1]hexanes via crossed [2 + 2]-cycloaddition. Due to the presence of the C-B bond, a variety of structures can be easily prepared that are not accessible by other methods. Moreover, a rare photo-ene reaction is also disclosed, allowing for the diastereoselective synthesis of trisubstituted borylated cyclopentanes.

Diversification of Simple Arenes into Complex (Amino)cyclitols.

Highly oxygenated cyclohexanes, including (amino)cyclitols, are featured in natural products possessing a notable range of biological activities. As such, these building blocks are valuable tools for medicinal chemistry. While de novo synthetic strategies have provided access to select compounds, challenges including stereochemical density and complexity have hindered the development of a general approach to (amino)cyclitol structures. This work reports the use of arenophile chemistry to access dearomatized intermediates which are amenable to diverse downstream transformations. Practical guidelines were developed for the synthesis of natural and non-natural (amino)cyclitols from simple arenes through a series of strategic functionalization events.

Synthesis of 2-Azanorbornanes via Strain-Release Formal Cycloadditions Initiated by Energy Transfer.

Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2-azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well-defined exit vectors. To achieve the synthesis of 2-azanorbornanes, new strain-release reagent, azahousane, is introduced along with its photosensitized strain-release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2-azanorbornanes with good selectivities.

2,5-disubstituted bicyclo[2.1.1]hexanes as rigidified cyclopentane variants.

Identification of rigid counterparts for common flexible scaffolds is crucial to the advancement of medicinal chemistry. Here we showcase a new class of building blocks, 2,5-disubstituted bicyclo[2.1.1]hexanes that can act as rigidified cis-, or trans-1,3-disubstituted cyclopentanes, common motifs in drugs. The scalable synthesis of these structures was enabled through the use of C-H functionalization logic and cycloaddition reactions.

Preparation of 3,5-Methanobenzo[b]azepines: An sp3-Rich Quinolone Isostere.

The replacement of the aromatic ring in bioactive compounds with saturated bioisosteres has become a popular tactic to obtain novel structures with improved physicochemical profiles. In this paper, we describe an efficient synthesis of 3,5-methanobenzo[b]azepine analogues and suggest them as isosteres of quinolones. Quinolones are heteroaromatic, flat rings and considered as privileged scaffolds. An isosteric version of this scaffold with more 3D character would offer new options to expand their use.

Silver(I)-Catalyzed Synthesis of Cuneanes from Cubanes and their Investigation as Isosteres.

Bridged or caged polycyclic hydrocarbons have rigid structures that project substituents into precise regions of 3D space, making them attractive as linking groups in materials science and as building blocks for medicinal chemistry. The efficient synthesis of new or underexplored classes of such compounds is, therefore, an important objective. Herein, we describe the silver(I)-catalyzed rearrangement of 1,4-disubstituted cubanes to cuneanes, which are strained hydrocarbons that have not received much attention since they were first described in 1970. The synthesis of 2,6-disubstituted or 1,3-disubstituted cuneanes can be achieved with high regioselectivities, with the regioselectivity being dependent on the electronic character of the cubane substituents. A preliminary assessment of cuneanes as scaffolds for medicinal chemistry suggests cuneanes could serve as isosteric replacements of trans-1,4-disubstituted cyclohexanes and 1,3-disubstituted benzenes. An analogue of the anticancer drug sonidegib was synthesized, in which the 1,2,3-trisubstituted benzene was replaced with a 1,3-disubstituted cuneane.

Preparation of new bicyclo[2.1.1]hexane compact modules: an opening towards novel sp3-rich chemical space.

Among the valuable saturated bicyclic structures incorporated in newly developed bio-active compounds, bicyclo[2.1.1]hexanes are playing an increasingly important role, while being still underexplored from a synthetic accessibility point of view. Here, we disclose an efficient and modular approach toward new 1,2-disubstituted bicyclo[2.1.1]hexane modules. Our strategy is based on the use of photochemistry to access new building blocks via [2 + 2] cycloaddition. The system can readily be derivatized with numerous transformations, opening the gate to sp3-rich new chemical space.

[2]-Ladderanes as isosteres for meta-substituted aromatic rings and rigidified cyclohexanes.

Aromatic ring isosteres and rigidified saturated hydrocarbons are important motifs to enable drug discovery. Herein we disclose [2]-ladderanes as a class of meta-substituted aromatic ring isosteres and rigidified cyclohexanes. A straightforward synthesis of the building blocks is presented along with representative derivatization. Preliminary studies reveal that the [2]-ladderanes offer similar metabolic and physicochemical properties thus establishing this class of molecules as interesting motifs.

Strain-Release [2π + 2σ] Cycloadditions for the Synthesis of Bicyclo[2.1.1]hexanes Initiated by Energy Transfer.

Saturated bicycles are becoming ever more important in the design and development of new pharmaceuticals. Here a new strategy for the synthesis of bicyclo[2.1.1]hexanes is described. These bicycles are significant because they have defined exit vectors, yet many substitution patterns are underexplored as building blocks. The process involves sensitization of a bicyclo[1.1.0]butane followed by cycloaddition with an alkene. The scope and mechanistic details of the method are discussed.

Pushing the Frontiers of Accessible Chemical Space to Unleash Design Creativity and Accelerate Drug Discovery.

In highly competitive research environments, the ability to access more complex structural spaces efficiently is a predictor of a company's ability to generate novel IP-protected small molecule candidates with adequate properties, hence filling their development pipelines. SpiroChem is consistently developing new synthetic methodologies and strategies to access complex molecular structure, thereby facilitating and accelerating small molecule drug discovery. Pushing the limits of what are perceived as complex molecular structures allows SpiroChem and its clients to unleash creativity and explore meaningful chemical spaces, which are under-exploited sources of novel active molecules. In this article, we explain how we differentiated ourselves in a globalized R&D environment and we provide several snapshots of how efficient methodologies can generate complex structures, rapidly.

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis.

Herein we report a workflow coupling photoredox-nickel dual-catalyzed N-arylation reactions to benchtop analysis for the efficient generation of fragment-based libraries. Technological advances in photoreactor design facilitated reliable and reproducible experimentation. Knowledge on the reactivity under previously reported reaction conditions of spirocyclic and strained heterocyclic building blocks, viewed as chemistry informers, could thus be rapidly accessed, identifying privileged or challenging scaffolds and paving the way for further exploration.

Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels-Alder Reactions.

Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines, can be exceptionally activated by trifluoroacetylation. This allows a Diels-Alder cycloaddition under very mild reaction conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general and scalable and has an excellent functional group tolerance. A straightforward synthesis of a key intermediate of Bayer's Vericiguat illustrates the potential of this cycloaddition strategy. Quantum mechanical calculations show how the simple N-trifluoroacetylation of 2-hydrazonylpyrimidines distorts the substrate into a transition-state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition.

On water N-arylation of oxetanylamines for the preparation of N-aryl-oxetanylamines; potentially useful aryl-amide isosteres.

A Pd cross-coupling approach for the synthesis of N-aryl-oxetanylamines has been developed. This method provides new building blocks potentially useful in medicinal chemistry as amide bioisosteres. The reactions are conducted in water employing the renewable feedstock surfactant TPGS-750-M.

Domino Pd0 -Catalyzed C(sp3 )-H Arylation/Electrocyclic Reactions via Benzazetidine Intermediates.

The Pd0 -catalyzed C(sp3 )-H arylation of 2-bromo-N-methylanilides leads to unstable benzazetidine intermediates that rearrange to benzoxazines through 4π electrocyclic ring-opening and 6π electrocyclization. The introduction of a bulky, non-activatable amide group on the nitrogen atom was key to favor the challenging reductive elimination step and disfavor undesired reaction pathways.

Efficient and Mild Ullmann-Type N-Arylation of Amides, Carbamates, and Azoles in Water.

A simple, sustainable, efficient, mild, and low-cost protocol was developed for d-glucose-assisted Cu-catalyzed Ullmann reactions in water for amides, carbamates, and nitrogen-containing heterocycles. The reaction was compatible with diverse aryl/heteroaryl iodides, giving highly substituted pyridine, indole, or indazole rings. This method offers an attractive alternative to existing protocols, because the reaction proceeds in aqueous media, occurs at or near ambient temperature, and provides the N-arylated products in good to high yields.

d-Glucose: An Efficient Reducing Agent for a Copper(II)-Mediated Arylation of Primary Amines in Water.

A copper-catalyzed Ullmann-type amination with primary amines in water with a combination of copper(II) triflate [Cu(OTf)2 ], dipivaloylmethane, and d-glucose is reported. The mild conditions and the use of an inexpensive catalyst as well as a renewable feedstock (d-glucose and the surfactant TPGS-750-M, which is derived from vitamin E) make this protocol a safe and convenient strategy for efficient C-N bond formation. This easy-to-handle procedure is extremely competitive compared to palladium-based reactions and may be used to synthesize N-containing molecules, such as drugs or organic light-emitting diodes (OLEDs).

Smart tools and orthogonal click-like reactions onto small unilamellar vesicles: Additional molecular data.

We present here the synthetic routes and the experimental data (NMR and MS spectra) for model reactions for copper-free Huisgen 1,4-cycloaddition, Staudinger ligation and for addition of a dithiol on a dibromomaleimide ring. Starting materials were synthesized from the commercially available 4-chlorophenethylamine, previously described 2-(cyclooct-2-yn-1-yloxy)acetic acid, 1-fluorocyclooct-2-ynecarboxylic acid, commercial 2-(diphenylphosphino)terephthalic acid 1-methyl 4-pentafluorophenyl diester and dibromomaleimide. In all cases, the expected compounds were obtained with good yield (50% to quantitative). A novel synthesis of the lipid anchor DOGP3NH2 is also described. These data were used as basis for the study reported in the article "Smart Tools and Orthogonal Click-like Reactions onto Small Unilamellar Vesicles" in Chemistry and Physics of Lipids [1].

Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells.

Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication.

Smart tools and orthogonal click-like reactions onto small unilamellar vesicles.

Click-based reactions were conducted at the surface of small unilamellar vesicles (SUVs) to provide onto-vesicle chemistry with efficient innovative ready-for-use tools. For that purpose, four amphiphilic molecules were designed to insert into bilayers while presenting a reactive functional head. In this manner, a dioleylglycero-ethoxy-ethoxy-ethoxy-ethanamine (DOG-PEG4-NH2) was chosen as a common platform while the reactive amine head was converted into several electrophilic functions. Thus, two dioleylglycerol-based cyclooctyne anchors were prepared: cyclooct-1-yn-3-glycolic acid-based anchor (DOG-COA) and 1-fluorocyclooct-2-ynecarboxylic acid-based anchor (DOG-FCOA). The last one differed from the first one in that a fluorine atom reinforces the electrophilic properties of the unsaturated bond. In addition, a third dioleylglycerol-based triphenylphosphine (DOG-PPh3) was synthesized for the first time. These three innovative amphiphilic anchors were designed to react with any azide-based biomolecule following copper-free Huisgen 1,4-cycloaddition and Staudinger ligation, respectively. A fourth anchor bearing a 3,4-dibromomaleimide ring (DOG-DBM) was also unprecedentedly synthesized, to be further substituted by two thiols. Model reactions conducted in solution with either model biotinyl azide or model biotinyl disulfide gave good to total conversions and excellent isolated yields. The four new anchors were inserted into SUVs whose formula is classically used in in vivo biology. Stability and surface overall electrostatic charge were in the expected range and constant over the study. Then, the functionalized liposomes were ligated to biotin-based reagents and the experimental conditions were finely tuned to optimize the conversion. The biotinyl liposomes were demonstrated functional and totally accessible in an affinity test based on biotin scaffold quantification. Finally, DOG-FCOA's reactivity was confronted to that of DOG-DBM in a 'one-pot' orthogonal reaction. (Biotin-S)2 and TAMRA-N3 (tetramethylcarboxyrhodamine azide) were successively conjugated to the liposome suspension in a successful manner. These data implement and reinforce the interest of bioorthogonal click-like reactions onto lipid nanoparticles.

Benzofuran derivatives as anticancer inhibitors of mTOR signaling.

A series of 32 derivatives and isosteres of the mTOR inhibitor 2 were synthesized and compared for their cytotoxicity in radioresistant SQ20B cancer cell line. Several of these compounds, in particular 30b, were significantly more cytotoxic than 2. Importantly, 30b was shown to block both mTORC1 and Akt signaling, suggesting insensitivity to the resistance associated to Akt overactivation observed with rapamycin derivatives currently used in clinic.