Selected Topics in the Syntheses of Bicyclo[1.1.1]Pentane (BCP) Analogues

Ma, Xiaoshen; Pham, Luu Nhat

doi:10.1002/ajoc.201900589

Cited by 93 publications

(34 citation statements)

References 119 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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“…Surprisingly, none of the works of Baran, Ma or Qin considers the synthesis of BCP derivatives containing bridge nitrogen substituents. This is in contrast to the considerable progress made towards installation of nitrogen atoms at the bridgehead positions, [17b, 69, 70, 77] for example, for bioisosteric replacement of anilines, common structural alerts and toxicophores in drug design. To date, nitrogen has only been installed on the bridge positions of BCP derivatives through Schmidt rearrangement of carboxylic acid 59 (Schemes 12 and 19) by Wiberg [35b] .…”

Section: Nitrogen Substituentsmentioning

confidence: 90%

Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives

et al. 2021

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“Escaping from flatland”, by increasing the saturation level and three‐dimensionality of drug‐like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert‐butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well‐documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This Minireview aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years.

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“…SHELXT-2015; [51] structure refinement, SHELXL-2015. [52] 2-Cyano-1,1-difluoropropan-2-yl acetate (8). TMSCN (350 g, 3.53 mol) was added in portions to a mixture of 1,1-difluoroacetone (332 g, 3.53 mol) and Sc(OTf) 3 (8.68 g, 17.7 mmol) under 30 °C with external water cooling bath.…”

Section: Methodsmentioning

confidence: 99%

“…[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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Selected Topics in the Syntheses of Bicyclo[1.1.1]Pentane (BCP) Analogues

Abstract: This Minireview focuses on selected topics in the syntheses of bicyclo[1.

Cited by 93 publications

References 119 publications

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives

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

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