Bicyclo Pentane Research Articles

Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes.

The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ + 2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines. This transformation not only uses mild and operationally simple conditions but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by simple derivatization reactions.

Cage hydrocarbons as linkers in dimeric drug design: Case studies with trimethoprim and tedizolid

The looming threat of a “post-antibiotic era” has been caused by a rapid rise in antibacterial resistance and subsequent depletion of effective antibiotic agents in the clinic. An efficient strategy to address this shortfall lies in the reengineering of pre-existing and commercially available antibiotic drugs. This is exemplified by dimerization, a design concept in which two pharmacophores are covalently linked to form a new chemical entity. The cage hydrocarbons cubane (1), bicyclo[2.2.2]octane (BCO) (2), adamantane (3), and bicyclo[1.1.1]pentane (BCP) (4) present themselves as an attractive family of linkers in this regard. In this report, all four hydrocarbon cages were employed as linkers in a series of dimers based on the commercially available antibiotics trimethoprim and tedizolid. A detailed synthetic roadmap for the protection and deprotection of each pharmacophore is outlined. Several members of the trimethoprim series showed activity on par with that of their trimethoprim progenitor, although this was not the case for the tedizolid series. The design strategy outlined herein highlights the utility of the group as a platform for the rapid and modular construction of future novel antibiotics.

Advances in nonclassical phenyl bioisosteres for drugstructuraloptimization.

The phenyl group is the most prevalent ring system and plays an essential role as a pharmacophore or scaffold in marketed drugs. However, the indiscriminate employment of phenyl is also a major causeof poor physicochemical properties of active molecules. Nonclassical phenyl bioisosteres (NPBs) have emerged as effectivereplacements for phenyl in structural optimization due to their unique steric structures and physicochemical properties. Herein, the effects of widely reported NPBs on physicochemical properties and biological activities, including bicyclo[1.1.1]pentane (BCP), bicyclo[2.1.1]hexanes (BCH), bicyclo[2.2.2]octane (BCO), cubane (CUB) and closo-carboborane, are reviewed. Issues that require consideration while using NPBs andpractical solutions to problems frequently encountered in structural optimization using NPBsare also discussed.

General and Practical Route to Diverse 1-(Difluoro)alkyl-3-aryl Bicyclo[1.1.1]pentanes Enabled by an Fe-Catalyzed Multicomponent Radical Cross-Coupling Reaction.

Bicyclo[1.1.1]pentanes (BCPs) are of great interest to the agrochemical, materials, and pharmaceutical industries. In particular, synthetic methods to access 1,3-dicarbosubsituted BCP-aryls have recently been developed, but most protocols rely on the stepwise C-C bond formation via the initial manipulation of BCP core to make the BCP electrophile or nucleophile followed by a second step (e.g., transition-metal-mediated cross-coupling step) to form the second key BCP-aryl bond. Moreover, despite the prevalence of C-F bonds in bioactive compounds, one-pot, multicomponent cross-coupling methods to directly functionalize [1.1.1]propellane to the corresponding fluoroalkyl BCP-aryl scaffolds are lacking. In this work, we describe a conceptually different approach to access diverse (fluoro)alkyl BCP-aryls at low temperatures and fast reaction times enabled by an iron-catalyzed multicomponent radical cross-coupling reaction from readily available (fluoro)alkyl halides, [1.1.1]propellane, and Grignard reagents. Further, experimental and computational mechanistic studies provide insights into the mechanism and ligand effects on the nature of C-C bond formation. Finally, these studies are used to develop a method to rapidly access synthetic versatile (difluoro)alkyl BCP halides via bisphosphine-iron catalysis.

Synthesis and Biological Evaluation of Bicyclo[1.1.1]pentane-Containing Aromatic Lipoxin A4 Analogues.

Lipoxins are important drivers of inflammation resolution, suggesting a potential therapeutic benefit. Bicyclo[1.1.1]pentanes (BCPs) are potential isosteric replacements for arenes and/or alkyl groups within drug candidates. We carried out an asymmetric synthesis of four BCP-containing synthetic lipoxin A4 mimetics (BCP-sLXms) in which the key steps were a Suzuki coupling, an asymmetric ketone reduction, and a triethylborane-initiated radical bicyclopentylation. These mimetics were screened for their impact on inflammatory responses, and one imidazolo-BCP-sLXm (6a) was found to possess high anti-inflammatory activity.

Exploiting the sp2 character of bicyclo[1.1.1]pentyl radicals in the transition-metal-free multi-component difunctionalization of [1.1.1]propellane.

Strained bicyclic substructures are increasingly relevant in medicinal chemistry discovery research because of their role as bioisosteres. Over the last decade, the successful use of bicyclo[1.1.1]pentane (BCP) as a para-disubstituted benzene replacement has made it a highly valuable pharmacophore. However, various challenges, including limited and lengthy access to useful BCP building blocks, are hampering early discovery research. Here we report a single-step transition-metal-free multi-component approach to synthetically versatile BCP boronates. Radicals derived from commonly available carboxylic acids and organohalides perform additions onto [1.1.1]propellane to afford BCP radicals, which then engage in polarity-matched borylation. A wide array of alkyl-, aryl- and alkenyl-functionalized BCP boronates were easily prepared. Late-stage functionalization performed on natural products and approved drugs proceeded with good efficiency to generate the corresponding BCP conjugates. Various photoredox transformations forging C-C and C-N bonds were demonstrated by taking advantage of BCP trifluoroborate salts derived from the BCP boronates.

Dicarbofunctionalization of [1.1.1]Propellane Enabled by Nickel/Photoredox Dual Catalysis: One-Step Multicomponent Strategy for the Synthesis of BCP-Aryl Derivatives

Bicyclo[1.1.1]pentane (BCP) motifs as para-disubstituted aryl bioisosteres are playing an emerging role in pharmaceutical, agrochemical, and materials chemistry. The vast majority of these structures is obtained from a BCP electrophile or nucleophile, which are themselves derived from [1.1.1]propellane via cleavage of the internal C-C bond through the addition of either radicals or metal-based nucleophiles. Compared with the current stepwise approaches, a multicomponent reaction that provides direct access to complex and diverse disubstituted BCP products would be more attractive. Herein, we report a single-step, multicomponent approach to synthetically versatile arylated BCP products via nickel/photoredox catalysis. Importantly, this three-component process allows two C-C bonds to be formed in a single step and sets three quaternary centers, unprecedented in any previously reported methods. The method has been demonstrated to allow access to complex BCP architectures from aryl halide and radical precursor substrates.

On-DNA Hydroalkylation to Introduce Diverse Bicyclo[1.1.1]pentanes and Abundant Alkyls via Halogen Atom Transfer.

DNA-encoded libraries have proven their tremendous value in the identification of new lead compounds for drug discovery. To access libraries in new chemical space, many methods have emerged to transpose traditional mol-scale reactivity to nmol-scale, on-DNA chemistry. However, procedures to access libraries with a greater fraction of C(sp3) content are still limited, and the need to "escape from flatland" more readily on-DNA remains. Herein, we report a Giese addition to install highly functionalized bicyclo[1.1.1]pentanes (BCPs) using tricyclo[1.1.1.01,3]pentane (TCP) as a radical linchpin, as well as other diverse alkyl groups, on-DNA from the corresponding organohalides as non-stabilized radical precursors. Telescoped procedures allow extension of the substrate pool by at least an order of magnitude to ubiquitous alcohols and carboxylic acids, allowing us to "upcycle" these abundant feedstocks to afford non-traditional libraries with different physicochemical properties for the small-molecule products (i.e., non-peptide libraries with acids). This approach is amenable to library production, as a DNA damage assessment revealed good PCR amplifiability and only 6% mutated sequences for a full-length DNA tag.

Radical Multicomponent Alkyl Alkynylation of Propellane via Synergistic Photoredox and Copper Catalysis.

Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of aryl, tert-butyl groups, and internal alkynes that can impact key physicochemical properties on drug candidates. Herein, we describe a novel and efficient reaction to synthesize alkyl-alkynyl-substituted BCP derivatives by synergistic photoredox and copper catalysis at room temperature. The mild reaction conditions, simple protocol, broad functional group tolerance, and high efficiency of this procedure make it a valuable strategy for accessing alkynyl-substituted BCPs.

Radical Acylation of [1.1.1]Propellane with Aldehydes: Synthesis of Bicyclo[1.1.1]pentane Ketones.

Bicyclo[1.1.1]pentanes (BCPs) are widely utilized in drug design as sp3-rich bioisosteres for tert-butyl, internal alkynes, and aryl groups. A general and mild method for radical acylation of [1.1.1]propellane with aldehydes has been developed. The protocol provides straightforward access to bicyclo[1.1.1]pentane ketones with a broad substrate scope. The synthetic utility of this methodology is demonstrated by the late-stage modification of bioactive molecules and the versatile transformation of bicyclo[1.1.1]pentane ketones, making it useful for drug discovery.

Synthesis and Use of Bicyclo[1.1.1]pentylaldehyde Building Blocks.

The bicyclo[1.1.1]pentane (BCP) motif is an emerging scaffold in medicinal chemistry because of its bioisosterism to 1,4-phenylene and 1,2-alkynyl functions. The current drawback of its use is the lack of stable versatile synthetic building blocks. Aldehydes are among the most useful functionalities in organic chemistry. In this paper, a simple one-pot procedure from aryl-halides and [1.1.1]propellane is described. Preparation of various BCP molecules is conducted to showcase the versatility of these stable intermediates.

One step synthesis of unsymmetrical 1,3-disubstituted BCP ketones via nickel/photoredox-catalyzed [1.1.1]propellane multicomponent dicarbofunctionalization.

Bicyclo[1.1.1]pentanes (BCPs), utilized as sp3-rich bioisosteres for tert-butyl- and aryl groups as well as internal alkynes, have gained considerable momentum in drug development programs. Although many elegant methods have been developed to access BCP amines and BCP aryls efficiently, the methods used to construct BCP ketones directly are relatively underdeveloped. In particular, the preparation of unsymmetrical 1,3-disubstituted-BCP ketones remains challenging and still requires multiple chemical steps. Herein, a single-step, multi-component approach to versatile disubstituted BCP ketones via nickel/photoredox catalysis is reported. Importantly, installing a boron group at the carbon position adjacent to the BCP structure bypasses the limitation to tertiary BF3K coupling partners, thus expanding the scope of this paradigm. Further transformation of disubstituted-BCP ketones into a variety of other BCP derivatives demonstrates the synthetic value of this developed method.

Enantioenriched BCP Benzylamine Synthesis via Metal Hydride Hydrogen Atom Transfer/Sulfinimine Addition to [1.1.1]Propellane.

The stereoselective synthesis of bicyclo[1.1.1]pentane (BCP) benzylamine derivatives from [1.1.1]propellane and mesityl sulfinimines via metal hydride hydrogen atom transfer (MH HAT) is reported. Medicinally relevant heterocyclic BCP methanamines are prepared with high diastereoselectivity. The strategic impact of the method is demonstrated via the streamlined synthesis of the BCP analogue of a key levocetirizine intermediate. Mechanistic evidence for a competitive H2 evolution pathway and the importance of controlled silane addition during reaction initiation are disclosed.

Synthesis and Applications of Polysubstituted Bicyclo[1.1.0]butanes

Bicyclo[1.1.0]butanes (BCBs) are valuable substrates in the "strain release" synthesis of polysubstituted four-membered ring systems, with applications including bioconjugation agents. The introduction of substituents onto the BCB bridges is challenging due to limitations in current methods for the preparation of this bicyclic scaffold, typically necessitating linear syntheses with limited functional group tolerance and/or substituent scope. Here, we report the synthesis of tri- and tetrasubstituted BCBs via directed metalation of readily accessed BCB amides; this straightforward "late stage" approach generates a wide variety of bridge-substituted BCBs that can be easily converted into other useful small ring building blocks. Access to a monodeuterated BCB afforded unprecedented insight into the mechanism of dihalocarbene insertion into BCBs to afford bicyclo[1.1.1]pentanes (BCPs).

Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen-Substituted Bicyclo[1.1.1]pentanes.

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron‐neutral nucleophiles such as anilines and azoles to give nitrogen‐substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen‐Substituted Bicyclo[1.1.1]pentanes

AbstractStrategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron‐neutral nucleophiles such as anilines and azoles to give nitrogen‐substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Synthesis of α-Quaternary Bicyclo[1.1.1]pentanes through Synergistic Organophotoredox and Hydrogen Atom Transfer Catalysis.

Bicyclo[1.1.1]pentanes (BCPs) are important in drug design as sp3-rich bioisosteres of arenes and tert-butyl groups; however, the preparation of BCPs with adjacent quaternary carbons is barely known. We report a facile synthesis of α-quaternary BCPs using organophotoredox and hydrogen atom transfer catalysis in which α-keto radicals, generated through oxidation of β-ketocarbonyls, undergo efficient addition to [1.1.1]propellane. The BCP products can be transformed into a variety of useful derivatives, including enantioenriched BCPs featuring α-quaternary stereocenters.

An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates.

Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons.

Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives

Abstract“Escaping from flatland”, by increasing the saturation level and three‐dimensionality of drug‐like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert‐butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well‐documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This Minireview aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years.

Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives.

“Escaping from flatland”, by increasing the saturation level and three‐dimensionality of drug‐like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert‐butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well‐documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This Minireview aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years.