Three-dimensional Saturated C(sp)-rich Bioisosteres for Benzene

Overview

Journal Nat Rev Chem

Publisher Springer Nature

Specialty Chemistry

Date 2024 Jul 9

PMID 38982260

Authors

Jet Tsien

Chao Hu

Rohan R Merchant

Tian Qin

Affiliations

Soon will be listed here.

Abstract

Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor 'drug-like' properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes. However, until recent discoveries, analogous three-dimensional ortho-substituted and meta-substituted biososteres have remained underexplored, owing to their ring strain and increased s-character hybridization. This Review summarizes the emerging synthetic methodologies to access such saturated motifs and their impact on the application of bioisosteres for ortho-substituted, meta-substituted and multi-substituted benzene rings. It concludes with a perspective on the development of next-generation bioisosteres, including those within novel chemical space.

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References

Shinozuka T, Kobayashi H, Suzuki S, Tanaka K, Karanjule N, Hayashi N . Discovery of DS-1971a, a Potent, Selective Na1.7 Inhibitor. J Med Chem. 2020; 63(18):10204-10220. DOI: 10.1021/acs.jmedchem.0c00259. View

Liang Y, Kleinmans R, Daniliuc C, Glorius F . Synthesis of Polysubstituted 2-Oxabicyclo[2.1.1]hexanes via Visible-Light-Induced Energy Transfer. J Am Chem Soc. 2022; 144(44):20207-20213. DOI: 10.1021/jacs.2c09248. View

Yang Y, Tsien J, Hughes J, Peters B, Merchant R, Qin T . An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates. Nat Chem. 2021; 13(10):950-955. PMC: 8739920. DOI: 10.1038/s41557-021-00786-z. View

Buskes M, Blanco M . Impact of Cross-Coupling Reactions in Drug Discovery and Development. Molecules. 2020; 25(15). PMC: 7436090. DOI: 10.3390/molecules25153493. View

Okude R, Mori G, Yagi A, Itami K . Programmable synthesis of multiply arylated cubanes through C-H metalation and arylation. Chem Sci. 2021; 11(29):7672-7675. PMC: 8159448. DOI: 10.1039/d0sc01909g. View

Measom N, Down K, Hirst D, Jamieson C, Manas E, Patel V . Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA Inhibitor. ACS Med Chem Lett. 2017; 8(1):43-48. PMC: 5238484. DOI: 10.1021/acsmedchemlett.6b00281. View

Guo R, Adak S, Bellotti P, Gao X, Smith W, Le S . Photochemical Dearomative Cycloadditions of Quinolines and Alkenes: Scope and Mechanism Studies. J Am Chem Soc. 2022; 144(38):17680-17691. PMC: 9840784. DOI: 10.1021/jacs.2c07726. View

Xia W, Scheffer J, Botoshansky M, Kaftory M . Photochemistry of 1-isopropylcycloalkyl aryl ketones: ring size effects, medium effects, and asymmetric induction. Org Lett. 2005; 7(7):1315-8. DOI: 10.1021/ol050104k. View

Makarov I, Brocklehurst C, Karaghiosoff K, Koch G, Knochel P . Synthesis of Bicyclo[1.1.1]pentane Bioisosteres of Internal Alkynes and para-Disubstituted Benzenes from [1.1.1]Propellane. Angew Chem Int Ed Engl. 2017; 56(41):12774-12777. DOI: 10.1002/anie.201706799. View

10.

Zhang L, Koreeda M . Total synthesis of (+)-acanthodoral by the use of a Pd-catalyzed metal-ene reaction and a nonreductive 5-exo-acyl radical cyclization. Org Lett. 2004; 6(4):537-40. DOI: 10.1021/ol0363063. View

11.

Brown D, Gagnon M, Bostrom J . Understanding our love affair with p-chlorophenyl: present day implications from historical biases of reagent selection. J Med Chem. 2015; 58(5):2390-405. DOI: 10.1021/jm501894t. View

12.

Collin D, Kovacic K, Light M, Linclau B . Synthesis of -Functionalized 1,4-Cubanedicarboxylate Derivatives through Photochemical Chlorocarbonylation. Org Lett. 2021; . DOI: 10.1021/acs.orglett.1c01702. View

13.

Bolton J, Dunlap T . Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects. Chem Res Toxicol. 2016; 30(1):13-37. PMC: 5241708. DOI: 10.1021/acs.chemrestox.6b00256. View

14.

Feng Y, Liu L, Wang J, Zhao S, Guo Q . Homolytic C-H and N-H bond dissociation energies of strained organic compounds. J Org Chem. 2004; 69(9):3129-38. DOI: 10.1021/jo035306d. View

15.

Bunker K, Sach N, Huang Q, Richardson P . Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction. Org Lett. 2011; 13(17):4746-8. DOI: 10.1021/ol201883z. View

16.

Tkachenko A, Radchenko D, Mykhailiuk P, Grygorenko O, Komarov I . 4-Fluoro-2,4-methanoproline. Org Lett. 2009; 11(24):5674-6. DOI: 10.1021/ol902381w. View

17.

Breitenlechner S, Bach T . A polymer-bound chiral template for enantioselective photochemical reactions. Angew Chem Int Ed Engl. 2008; 47(41):7957-9. DOI: 10.1002/anie.200802479. View

18.

Reinhold M, Steinebach J, Golz C, Walker J . Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space. Chem Sci. 2023; 14(36):9885-9891. PMC: 10510755. DOI: 10.1039/d3sc03083k. View

19.

Frank N, Nugent J, Shire B, Pickford H, Rabe P, Sterling A . Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. Nature. 2022; 611(7937):721-726. DOI: 10.1038/s41586-022-05290-z. View

20.

Zheng Y, Huang W, Dhungana R, Granados A, Keess S, Makvandi M . Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes. J Am Chem Soc. 2022; 144(51):23685-23690. PMC: 10413992. DOI: 10.1021/jacs.2c11501. View