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.

Reactivity and Selectivity of Azaspirocycles in Radical C-H Functionalization.

Investigations of saturated spirocycles toward selective C-H functionalization reactions are scarce, despite their potential applications. In this work, we uncovered fundamental reactivity and selectivity differences between saturated heterocycles and their spirocyclic analogues using a model radical C-H xanthylation coupled with computational analysis. Ultimately, this study sheds light on the fundamental, understudied radical reactivity of spirocycles, thereby allowing for a pronounced chemical tunability that will prove to be advantageous in the expansion of their chemical space and applications in medicinal chemistry.

[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.

A GAP Replacement, Part 2: Preparation of Poly(3-azidooxetane) via Azidation of Poly(3-tosyloxyoxetane) and Poly(3-mesyloxyoxetane).

Despite the variety of energetic polyoxetane binders, the oxirane-based glycidyl azide polymer (GAP) has largely succeeded in the market due to its advantageous properties. Nevertheless, it suffers from various drawbacks such as non-uniform chain termination, possible chlorine content (flame retardant), and toxic epichlorohydrin required for its synthesis. These problems can be bypassed using the structurally related poly(3-azidooxetane). Unfortunately, it is only accessible in moderate yield by polymerization of 3-azidooxetane. Herein, we describe its synthesis by polymer-analogous transformation using the new polymers poly(3-tosyloxyoxetane) and poly(3-mesyloxyoxetane) as precursors. This results in a significantly increased yield and improved safety as handling of the very sensitive 3-azidooxetane is avoided. The aforementioned prepolymers were prepared using boron trifluoride etherate as well as triisobutylaluminum as catalysts. The latter provides polymers of particularly high molecular weight, and the corresponding poly(3-azidooxetane) species was obtained and studied for the first time. In order to shed light on the applicability of poly(3-azidooxetane) as a GAP substitute, it was thoroughly studied with regard to thermal behavior, energetic performance (EXPLO5), plasticizer compatibility, and curing. Moreover, the aquatic toxicity of all involved monomers was analyzed and compared to epichlorohydrin. Here, poly(3-azidooxetane) turned out as a fully adequate, if not more environmentally benign, substitute.

3,3-Dinitratooxetane - an important leap towards energetic oxygen-rich monomers and polymers.

3-Substituted oxetanes are valuable monomers for modern ring-opening polymerizations. A new solid-state oxidizer, 3,3-dinitratooxetane (C3H4N2O7), which has an oxygen content of 62.2% was synthesized by the addition of N2O5 to oxetan-3-one. Monoclinic single crystals suitable for X-ray diffraction (ρ 1.80 g cm-3) were obtained by recrystallization from dichloromethane. In addition, 3-nitratooxetane was prepared by an improved method and 3-nitrato-3-methyloxetane was synthesized for the first time. Theoretical calculations were computed by the EXPLO5 software and additionally sensitivities towards impact and friction were determined.

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.

Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para-Phenyl Bioisosteres.

Bicycloalkyl groups have been previously described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction into complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves aqueous solubility by at least 50-fold, and markedly decreases nonspecific binding (NSB) as measured by CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits regarding NSB or solubility, whereas substitutions with cubane-1,4-diyl showed improvements for both parameters. These results confirm the potential advantages of both BCP and cubane motifs as bioisosteric replacements for optimizing para-phenyl-substituted molecules.

Oxetanyl peptides: novel peptidomimetic modules for medicinal chemistry.

The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics.

A concise and stereoselective synthesis of the A-ring fragment of the gambieric acids.

The A-ring fragment of the gambieric acids has been prepared by a short and efficient route. The key 3(2H)-furanone intermediate has been obtained by [2,3] rearrangement of an allylic oxonium ylide generated from intramolecular reaction of a crotyl ether with a copper carbenoid. A single stereogenic center has been set by using a chiral pool starting material and the other three have been established by using highly diastereoselective substrate-controlled transformations. [reaction--see text]