Synthesis of <i>Ortho</i>-Functionalized 1,4-Cubanedicarboxylate Derivatives through Photochemical Chlorocarbonylation

Collin, Diego E.; Kovacic, Kristina; Light, Mark E.; Linclau, Bruno

doi:10.1021/acs.orglett.1c01702

Cited by 19 publications

(14 citation statements)

References 55 publications

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“…However, cubanes have only been explored as replacements for terminal and parasubstituted phenyl rings, presumably a function of poorly developed synthetic accessibility to cubanes with unsymmetrical substitution patterns that might offer mimicry of ortho-and meta-substituted phenyl rings. 73 This is analogous to the still evolving circumstance surrounding bicyclo[1.1.1]pentane (BCP) as a phenyl ring mimetic (vide infra), where the development of new synthetic methodologies is facilitating broader exploration and application. 74,75 Several recent studies have investigated the potential of cubane as a substitute for a phenyl ring in either marketed drugs or compounds in the lead optimization phase.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 96%

“…As a caged hydrocarbon, cubane offers expanded three-dimensional character and eight attachment points that can be exploited to mimic different spatial arrangements of substituted phenyl rings. However, cubanes have only been explored as replacements for terminal and para -substituted phenyl rings, presumably a function of poorly developed synthetic accessibility to cubanes with unsymmetrical substitution patterns that might offer mimicry of ortho - and meta -substituted phenyl rings . This is analogous to the still evolving circumstance surrounding bicyclo[1.1.1]pentane (BCP) as a phenyl ring mimetic ( vide infra ), where the development of new synthetic methodologies is facilitating broader exploration and application. , …”

Section: Bioisosteric Replacement Of Terminal Phenyl Ringsmentioning

confidence: 99%

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Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 96%

Section: Bioisosteric Replacement Of Terminal Phenyl Ringsmentioning

confidence: 99%

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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“…In order to avoid laborious installation and removal of a directing group, we decided to start with the symmetrical, commercially available dimethyl cubane-1,4-dicarboxylate (8). Inspired by a cubane C-H carboxylation reported by Bashir-Hashemi 39,40 , we utilized a light-mediated onepot C-H carboxylation/ esterification sequence. Deprotection of the sterically exposed methyl ester of 9 yielded the monoacid 10.…”

Section: Synthesis Of 1-tert-butyl-2-methyl Cubane-12-dicarboxylatementioning

confidence: 99%

“…Moreover, many functional groups, including the metal-sensitive isoxazole-moiety (33), were tolerated, demonstrating the mildness of the reaction. Under slightly modified conditions, aryl and heteroaryl bromides were also coupled with cubane (39)(40)(41)(42)(43)(44)(45)(46) and synthetically useful functional groups such as cyanides (39) and aryl chlorides (42,44) were preserved. Of note is the tolerance of an ortho-substituent in the coupling with the sterically hindered, tertiary cubyl radical (43).…”

Section: C-c Cross Coupling Of Cubanesmentioning

confidence: 99%

General access to cubanes: ideal bioisosteres of ortho-, meta-, and para-substituted benzenes

Wiesenfeldt

Rossi‐Ashton

Perry

et al. 2023

Preprint

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The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well-suited since the ring strain imparts high bond strength and thus metabolic stability on its C–H bonds. Cubane is the ideal bioisostere since it provides the closest geometric match to benzene. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings. This is due to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the incompatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalyzed valence isomerization. Herein, we disclose expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C–H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C–N, C–C(sp3), C–C(sp2), and C–CF3 cross-coupling protocols. Our research enables facile elaboration of all cubane isomers into drug candidates thus enabling ideal bioisosteric replacement of ortho-, meta-, and para-substituted benzenes.

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“…The extremely strained yet remarkably stable cubane system has been attracting unflagging scientific attention , since its planful synthesis in 1964. − Some of its potential applications include pharmaceuticals (a rigid cubane cage is considered a phenyl bioisoster), − fuels, explosives, , building blocks in material chemistry, , etc. The recently published decagram synthesis of one of the key building blocks, dimethyl cubane-1,4-dicarboxylate, in combination with the rapid development of new chemical tools allowing the functionalization of its scaffold , clearly indicates that the synthesis of cubane derivatives has not reached its end yet.…”

Section: Introductionmentioning

confidence: 99%

Chlorinated Cubane-1,4-dicarboxylic Acids

et al. 2023

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Herein, we report radical chlorination of cubane-1,4-dicarboxylic acid leading preferentially to one monochlorinated cubane dicarboxylate (ca. 70%) that is accompanied by four dichlorinated derivatives (ca. 20% in total). The exact positions of the chlorine atoms have been confirmed by X-ray diffraction of the corresponding single crystals. The acidity constants of all dicarboxylic acids in water were determined by capillary electrophoresis (3.17 ± 0.04 and 4.09 ± 0.05 for monochlorinated and ca. 2.71 ± 0.05 and 3.75 ± 0.05 for dichlorinated cubanes). All chlorinated derivatives as well as the parent diacid showed high thermal stability (decomposition above 250 °C) as documented by differential scanning calorimetry. The probable reaction pathways leading to individual isomers were proposed, and the energies of individual transition states and intermediates were obtained using density functional theory calculations (B3LYP-D3BJ/6-311+G(d,p)). The relative strain energies for all newly prepared derivatives as well as for hypothetical hexahalogenated (fluorinated, chlorinated, brominated, and iodinated) derivatives of cubane-1,4-dicarboxylic acids were predicted using wavefunction theory methods. The hexafluorinated derivative was identified as the most strained compound (57.5 kcal/mol), and the relative strain decreased as the size of halogen atoms increased (23.7 for hexachloro, 16.7 for hexabromo, and 4.0 kcal/mol for the hexaiodo derivative).

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Synthesis of Ortho-Functionalized 1,4-Cubanedicarboxylate Derivatives through Photochemical Chlorocarbonylation

Cited by 19 publications

References 55 publications

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

General access to cubanes: ideal bioisosteres of ortho-, meta-, and para-substituted benzenes

Chlorinated Cubane-1,4-dicarboxylic Acids

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