Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long-sought-after mimetics for ortho/meta-substituted arenes.

ABSTRACT: The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

SUBMITTER: Zhao JX

PROVIDER: S-EPMC8285974 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Synthesis of Sulfur-Substituted Bicyclo[1.1.1]pentanes by Iodo-Sulfenylation of [1.1.1]Propellane.

Project description:Thiols easily react with [1.1.1]propellane to give sulfur-substituted bicyclo[1.1.1]pentanes in radical reactions, but this reactivity is not replicated in the case of heterocyclic thiols. Herein, we address this issue by electrophilically activating [1.1.1]propellane to promote its iodo-sulfenylation with 10 classes of heterocyclic thiols in two protocols that can be conducted on a multigram scale without exclusion of air or moisture.

| S-EPMC9531248 | biostudies-literature

Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes.

Project description:Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.01,3]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/tert-butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.

| S-EPMC6001403 | biostudies-literature

Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes.

Project description:Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis.

| S-EPMC7955048 | biostudies-literature

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

Project description:Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp3-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or "scaffold hop", between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to "scaffold hop" between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance.

| S-EPMC10281541 | biostudies-literature

Synthesis of All-Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron-Catalyzed Kumada Cross-Coupling.

Project description:1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p-substituted arenes and alkynes. Access to all-carbon disubstituted BCPs via cross-coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3-C-disubstituted BCPs from 1-iodo-bicyclo[1.1.1]pentanes (iodo-BCPs) by direct iron-catalyzed cross-coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo-BCPs as electrophiles in cross-coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3-C-disubstituted BCPs including various drug analogues.

| S-EPMC7383991 | biostudies-literature

1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of <i>ortho</i>-substituted benzene.

Project description:Bicyclo[2.1.1]hexanes have been synthesized, characterized, and biologically validated as saturated bioisosteres of the ortho-substituted benzene ring. The incorporation of the 1,2-disubstituted bicyclo[2.1.1]hexane core into the structure of fungicides boscalid (BASF), bixafen (Bayer CS), and fluxapyroxad (BASF) gave saturated patent-free analogs with high antifungal activity.

| S-EPMC10718076 | biostudies-literature

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

Project description: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.

| S-EPMC10412002 | biostudies-literature

Sodium Bicyclo[1.1.1]pentanesulfinate: A Bench-Stable Precursor for Bicyclo[1.1.1]pentylsulfones and Bicyclo- [1.1.1]pentanesulfonamides.

Project description:Herein, we present the synthesis of the bench-stable sodium bicyclo[1.1.1]pentanesulfinate (BCP-SO2 Na) and its application in the synthesis of bicyclo[1.1.1]pentyl (BCP) sulfones and sulfonamides. The salt can be obtained in a four-step procedure from commercially available precursors in multigram scale without the need for column chromatography or crystallization. Sulfinates are known to be useful precursors in radical and nucleophilic reactions and are widely used in medicinal chemistry. This building block enables access to BCP sulfones and sulfonamides avoiding the volatile [1.1.1]propellane which is favorable for the extension of SAR studies. Further, BCP-SO2 Na enables the synthesis of products that were not available with previous methods. A chlorination of BCP-SO2 Na and subsequent reaction with a Grignard reagent provides a new route to BCP sulfoxides. Several products were analyzed by single-crystal X-ray diffraction.

| S-EPMC7187227 | biostudies-literature

Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates.

Project description:Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure-activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.1]pentane (BCP) motif has increasingly received attention as a bioisosteric replacement of benzene rings due to its ability to improve the physicochemical properties of prospective drug candidates, but studying the SARs of C2-substituted BCPs has been heavily restricted by the need for multistep de novo synthesis of each analogue of interest. Here we report a programmable bis-functionalization strategy to enable late-stage sequential derivatization of BCP bis-boronates, opening up opportunities to explore the SARs of drug candidates possessing multisubstituted BCP motifs. Our approach capitalizes on the inherent chemoselectivity exhibited by BCP bis-boronates, enabling highly selective activation and functionalization of bridgehead (C3)-boronic pinacol esters (Bpin), leaving the C2-Bpin intact and primed for subsequent derivatization. These selective transformations of both BCP bridgehead (C3) and bridge (C2) positions enable access to C1,C2-disubstituted and C1,C2,C3-trisubstituted BCPs that encompass previously unexplored chemical space.

| S-EPMC10922318 | biostudies-literature

A general strategy toward aromatic 1,2-ambiphilic synthons: palladium-catalyzed ortho-halogenation of PyDipSi-arenes.

Project description: Not available

| S-EPMC3132816 | biostudies-literature