Saturated Bioisosteres of ortho‐Substituted Benzenes

Denisenko, Aleksandr V.; Garbuz, Pavel; Шишкина, Светлана В.; Voloshchuk, Nataliya; Mykhailiuk, Pavel K.

doi:10.1002/ange.202004183

Cited by 31 publications

(21 citation statements)

References 66 publications

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“…2 Recently, Mykhailiuk and co-workers reported the synthesis of bicyclo[2.1.1]hexanes as the first example of saturated bioisosteres of ortho-disubstituted benzenes. 4 Conversely, there is still a gap in the literature for the synthesis of 1,2-difunctionalized BCP skeletons that would act as ortho-and/or meta-disubstituted benzenes ( Figure 1B). Our foray into the synthesis of such compounds started with a directed C-H activation strategy where a bridgehead amide direction group was installed to activate the side position of the BCP.…”

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confidence: 99%

1,2-Difunctionalized Bicyclo[1.1.1]pentanes: Long Sought After Bioisosteres for ortho/meta-Substituted Arenes

Zhao¹,

Chang²,

Elleraas³

et al. 2020

Preprint

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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 synthesis of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles has been achieved from a simple common intermediate. Several ortho and/or meta-substituted benzene analogues as well as simple molecular matched pairs have also been prepared using this platform. In-depth biological and computational studies are currently in progress to validate the ortho and/or meta-character of these new bioisosteres. Results of these investigations will be reported in due course.

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confidence: 99%

1,2-Difunctionalized Bicyclo[1.1.1]pentanes: Long Sought After Bioisosteres for ortho/meta-Substituted Arenes

Zhao¹,

Chang²,

Elleraas³

et al. 2020

Preprint

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“…Bicyclo[1.1.1]pentanes (BCPs) containing substitutions at bridgehead positions (C1, C3) are now widely recognized as saturated bioisosteres for para-substituted benzenes 4 . Analogously, related caged scaffolds with differentiated substitutions (Figure 1A) are expected to be ideal bioisosteres of ortho-or meta-substituted benzenes 5,6 . Currently BCPs are synthesized from the highly strained [1.1.1]propellane (6) (the strain energy of the C-C bond = ~59~65 kcal/mol) 7-9 , using methodologies pioneered by Wiberg 7 , Michl 10 , Baran 11 , and others 12-20 , wherein 6 is transformed to symmetric and asymmetric BCPs using either single-or two-electron transfer pathways (Figure 1B).…”

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confidence: 99%

Synthesis of Multi-Substituted Bicycloalkyl Boronates: An Intramolecular Coupling Approach to Alkyl Bioisosteres

Yang¹,

Tsien²,

Hughes³

et al. 2021

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Bicyclic hydrocarbons, bicyclo[1.1.1]pentanes (BCPs) in particular, play an emerging role as saturated bioisosteres in pharmaceutical, agrochemical, and material 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. This work describes a novel approach to accessing multi-substituted BCPs via a new type of intramolecular cyclization. In addition to the C1, C3-disubstituted BCPs, this method also enables the construction of yet underexplored tri-substituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this cyclization is examined through synthesis of a variety of caged bicyclic molecules, ranging from [1.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead Bpin resulted from the cyclization is demonstrated via several downstream functionalizations, highlighting the ability of this approach for programmed and divergent synthesis of multi-substituted bicyclic hydrocarbons.

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“…In stark contrast, saturated bicyclic hydrocarbons mimicking ortho-and meta-substituted benzenoids have only recently been advanced or predicted by DFT calculations (structures D-H, Figure 1B) 8 ; thus highlighting the need for efficient methods for their synthesis in order to validate their bioactivity. Within the last year, elegant synthetic routes by Baran 18 and Qin 19 have provided access to 1,2-difunctionalized BCPs D; while seminal work by Mykhailiuk has identified difunctionalized bicyclo[2.1.1]hexanes (BCHs) 8,20 -and related structures 21 -as attractive candidates for both ortho-and meta-substituted benzene bioisosteres, depending on their substitution pattern (E-H) 8 . In a recent study, Mykhailiuk incorporated the BCH core E into compounds 5 and 7 (analogues of the anti-hypertensive drug valsartan 6 and the antifungal fluxapyroxad 8, respectively) at the expense of the corresponding ortho-disubstituted benzene cores 20 .…”

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confidence: 99%

A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres

Agasti

Beltran

Kaltsoyannis

et al. 2022

Preprint

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C(sp3)-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo[1.1.1]pentanes (BCPs), play an increasingly high-profile role as saturated bioisosteres of benzenoids in medicinal chemistry and crop science. Substituted bicyclo[2.1.1]hexanes (BCHs) are new emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, which to date remain difficult to access. Therefore, a general synthetic route to BCHs is urgently needed, if their potential as bioisosteres is to be realized. Here, we describe a broadly applicable catalytic approach that delivers substituted BCHs by a highly atom-economical intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2–catalyzed process embraces a wide range of electron-deficient alkenes and substituted BCB ketones, operates with loadings of SmI2 as low as 5 mol%, and is underpinned by a radical-relay mechanism that is supported by DFT calculations. The product BCH ketones have been shown to be versatile synthetic intermediates through selective downstream manipulation, and the expedient synthesis of a saturated hydrocarbon analogue of the broad spectrum antimicrobial, phthalylsulfathiazole. Our findings have provided the first general catalytic approach to the substituted BCH scaffold, and serve as a launchpad for the widespread use of this largely unexplored family of bioisosteres in medicinal chemistry.

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Saturated Bioisosteres of ortho‐Substituted Benzenes

Cited by 31 publications

References 66 publications

1,2-Difunctionalized Bicyclo[1.1.1]pentanes: Long Sought After Bioisosteres for ortho/meta-Substituted Arenes

1,2-Difunctionalized Bicyclo[1.1.1]pentanes: Long Sought After Bioisosteres for ortho/meta-Substituted Arenes

Synthesis of Multi-Substituted Bicycloalkyl Boronates: An Intramolecular Coupling Approach to Alkyl Bioisosteres

A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres

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