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

Denisenko, Aleksandr; Garbuz, Pavel; Makovetska, Yelyzaveta; Shablykin, Oleh; Lesyk, Dmytro; Al-Maali, Galeb; Korzh, Rodion; Sadkova, Iryna V.; Mykhailiuk, Pavel K.

doi:10.1039/d3sc05121h

Cited by 28 publications

(15 citation statements)

References 39 publications

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“…While this agreement extends to the substituent scaffold angles φ 2 and φ 3 , the 58° dihedral angle of 1,2-BCH (+)-23 is significantly larger than the 0° found in telmisartan. An exit vector analysis of 1,2-BCHs and ortho -benzene independently reported by Mykhailiuk and co-workers confirms these geometrical trends [ 36 ].…”

Section: Reviewsupporting

confidence: 67%

“…Comparison of physicochemical data of 1,2-BCHs and ortho -benzenes was reported by Mykhailiuk and co-workers ( Figure 5 ) [ 36 ]. Lipophilicity of 1,2-BCHs was measured by experimental distribution coefficient (SF logD) and calculated partition coefficient (clogP).…”

Section: Reviewmentioning

confidence: 60%

“…B: Fessard, Salomé and co-workers’ derivatization of 1,2-BCHs [ 40 ]. C: Mykhailiuk and co-workers’ synthesis of 1,2-BCHs as ortho -substituted benzene isosteres [ 36 ]. TBS = tert -Butyldimethylsilyl, ITX = 2-isopropylthioxanthone, DMP = Dess–Martin periodinane, DPPA = diphenylphosphoryl azide.…”

Section: Reviewmentioning

confidence: 99%

“…Recently, Mykhailiuk and co-workers also reported the synthesis of 1,2-BCHs using an intramolecular crossed [2 + 2] cycloaddition strategy ( Scheme 4C ) [ 36 ]. They were able to avoid purification by column chromatography by transformation of BCH ester (±)-53 into BCH acid (±)-54 , allowing isolation of pure 1,2-BCH (±)-54 by crystallisation.…”

Section: Reviewmentioning

confidence: 99%

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(Bio)isosteres of ortho- and meta-substituted benzenes

Diepers,

Walker

2024

Beilstein J. Org. Chem.

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Saturated bioisosteres of substituted benzenes offer opportunities to fine-tune the properties of drug candidates in development. Bioisosteres of para-benzenes, such as those based on bicyclo[1.1.1]pentane, are now very common and can be used to increase aqueous solubility and improve metabolic stability, among other benefits. Bioisosteres of ortho- and meta-benzenes were for a long time severely underdeveloped by comparison. This has begun to change in recent years, with a number of potential systems being reported that can act as bioisosteres for these important fragments. In this review, we will discuss these recent developments, summarizing the synthetic approaches to the different bioisosteres as well as the impact they have on the physiochemical and biological properties of pharmaceuticals and agrochemicals.

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Section: Reviewsupporting

confidence: 67%

Section: Reviewmentioning

confidence: 60%

Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

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(Bio)isosteres of ortho- and meta-substituted benzenes

Diepers,

Walker

2024

Beilstein J. Org. Chem.

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“…More recently, the group of Mykhailiuk used other types of substituted dienes under EnT photocatalysis with benzophenone 122 , to rapidly yield 1,2‐disubstituted [2.1.1]BCHs [63] …”

Section: Photochemical Synthesis And/or Functionalization Of Other Ar...mentioning

confidence: 99%

Light‐Driven Synthesis and Functionalization of Bicycloalkanes, Cubanes and Related Bioisosteres

Cuadros,

Paut,

Anselmi

et al. 2024

Angew Chem Int Ed

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Bicycloalkanes, cubanes and their structural analogues have emerged as bioisosteres of (hetero)arenes. To meet increasing demand, the chemical community has developed a plethora of novel synthetic methods. In this review, we assess the progress made in the field of light‐driven construction and functionalization of such relevant molecules. We have focused on diverse structural targets, as well as on reaction processes giving access to: (i) [1.1.1]‐bicyclopentanes (BCPs); (ii) [2.2.1]‐bicyclohexanes (BCHs); (iii) [3.1.1]‐bicycloheptanes (BCHeps); and (iv) cubanes; as well as other structurally related scaffolds. Finally, future perspectives dealing with the identification of novel reaction manifolds to access new functionalized bioisosteric units are discussed.

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Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes

Sujansky,

2024

Asian J Org Chem

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Within a medicinal chemist’s toolbox, one of the most effective strategies to improve the overall properties of a biologically active compound is bioisosteric replacement. Ever since the first example of replacing benzene with a bicyclo[1.1.1]pentane (BCP) group was published in the late 1990s, the medicinal chemistry community has continually been expanding the scope of such phenyl bioisosteric replacements. Recent interest from academia has focused on novel synthetic strategies to access C(sp3)‐rich bicyclic hydrocarbons with expanded ring sizes. Herein, we summarize some of these transformations and reveal that most rely on strain releasing cycloadditions with bicyclo[1.1.0]butane (BCB) and bicyclo[2.1.0]pentane (housane). We have organized this review based on the mechanism of such strain release strategies, namely, carbene cycloadditions, energy transfer photocatalyzed cycloadditions, electron transfer catalyzed cycloadditions, and polar cycloadditions.

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1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene

Abstract: 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...

Cited by 28 publications

References 39 publications

(Bio)isosteres of ortho- and meta-substituted benzenes

(Bio)isosteres of ortho- and meta-substituted benzenes

Light‐Driven Synthesis and Functionalization of Bicycloalkanes, Cubanes and Related Bioisosteres

Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes

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