Hetaryl-substituted bicyclo[1.1.1]pentanes (microreview)

Grygorenko, Oleksandr O.; Kokhan, Serhii O.

doi:10.1007/s10593-019-02558-7

Cited by 4 publications

(4 citation statements)

References 15 publications

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“…[33] All the bi-or polycyclic ring systems shown in Figure 5 can be used as isosteres of monosubstituted and p- disubstituted benzene derivatives; in addition to that, they were proposed as analogues of tert-butyl group and internal alkyne moiety. The subject or its various aspects have been surveyed many times in recent years; [33,[392][393][394][395][396][397][398][399] the reader is referred to the cited reviews for detailed discussion of synthetic approaches, as well as applications in medicinal chemistry and other areas. If shortly, the isosteric replacements were typically aimed at increasing of the aqueous solubility and metabolic stability of the optimized compounds; this is especially true for the bicyclo [1.1.1]pentane (BCP) derivatives (Figure 6).…”

Section: Non-classical Sp 3 -Enriched Benzene Isosteres: An Escape From Flatlandmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well-overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp 3 -enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non-classical sp 3 -enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gemdifluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed.

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Section: Non-classical Sp 3 -Enriched Benzene Isosteres: An Escape From Flatlandmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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“…The chemistry of bicyclo[1.1.1]pentanes (BCPs) has been experiencing a huge boom in recent years, as clearly demonstrated by numerous articles and reviews. − Much effort has been directed into the development of modern synthetic techniques that allow incorporation of these cages into complex systems using various cross-coupling reactions on the bridgehead carbon atoms. − Such 1,3-disubstituted BCPs thus not only appeared as the biologically active substances − but also became important players in the field of supramolecular chemistry. − …”

Section: Introductionmentioning

confidence: 99%

Polyhalogenated Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acids

Rončević

Dračínský

et al. 2021

J. Org. Chem.

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Herein we report the highly selective radical chlorination of 2,2-difluorobicyclo[1.1.1]pentane-1,3-dicarboxylic acid. Together with radical hydrodechlorination by TMS3SiH, four new bicyclo[1.1.1]pentane cages carrying two fluorine and one to three chlorine atoms in bridge positions have been obtained. The exact positions of all halogen atoms have been confirmed by X-ray diffraction. The acidity constants (pK a) for all new derivatives have been determined by capillary electrophoresis, and these experimental values show excellent agreement with pK as predicted by DFT methods. Extensive DFT calculations have been used to rationalize the selective formation of four out of nine possible F2Cl1–4 isomers of bridge-halogenated bicyclo[1.1.1]pentanes and to obtain relative strain energies for all possible isomers.

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“…[1][2][3][4] A number of saturated bicyclic bioisosteres were proposed to replace flattened aromatic rings such as benzene, bicyclo[1.1.1]pentane (BCP) being one of the most renown ones. [5][6][7][8][9][10][11][12][13][14][15] Recently, Mykhailiuk and co-workers proposed another closely related benzene isostere -2-oxabicyclo[2.1.1]hexane (Figure 1A). [16] It was shown that derivatives of this scaffold have improved aqueous solubility and hydrophilicity as compared to their benzene-and BCP-derived counterparts.…”

Section: Introductionmentioning

confidence: 99%

4‐(Di‐/Trifluoromethyl)‐2‐heterabicyclo[2.1.1]hexanes: Advanced Fluorinated Phenyl Isosteres and Proline analogues

et al. 2021

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A gram-scale synthesis, physico-chemical characterization, and lead-likeness assessment of 4-di/trifluoromethyl-2-heterabicyclo [2.1.1]hexanes as fluorinated bicyclic proline analogues and phenyl isosteres are disclosed. The key step of the synthesis included iodocyclization of fluorinated 3-hydroxy-/3aminomethyl methylenecyclobutanes; with the amino derivatives, the reaction was accompanied with carboxylation and further cyclization. Apart from the corresponding 4-di/ trifluoromethyl-2,4-methanoprolines, a series of fluorinated oxabicyclo[2.1.1]hexane-derived building blocks relevant to medicinal chemistry (i. e. primary iodides, carboxylic acids, alcohols, azides, primary amines, sulfonyl chlorides, and alkynes) were prepared. For representative derivatives of the resulting fluorinated 2-oxabicyclo[2.1.1]hexanes, pK a and logP values were measured to clarify their potential as the possible phenyl isosteres. Apart from the somewhat increased acidity, finetuned lipophilicity intermediate between that of non-fluorinated or aromatic counterparts was observed. Finally, the potential of the title building blocks was demonstrated by generation of virtual compound libraries using the LLAMA software. The resulting libraries fitted perfectly the lead-like chemical space, had higher three-dimensionality, and showed lower mean lead-likeness penalty as compared to those obtained from either non-fluorinated or aromatic derivatives.

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Hetaryl-substituted bicyclo[1.1.1]pentanes (microreview)

Cited by 4 publications

References 15 publications

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Polyhalogenated Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acids

4‐(Di‐/Trifluoromethyl)‐2‐heterabicyclo[2.1.1]hexanes: Advanced Fluorinated Phenyl Isosteres and Proline analogues

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