Cuneanes as Potential Benzene Bioisosteres Having Chirality

Hiyori Takebe; Seijiro Matsubara

doi:10.1055/a-2403-1860

Synthesis, Table of Contents

Synthesis 2025; 57(08): 1441-1447
DOI: 10.1055/a-2403-1860

short review

Bioisosteres

Cuneanes as Potential Benzene Bioisosteres Having Chirality

Hiyori Takebe∗

^aDepartment of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan

^bMitsui Chemicals & Kyoto University Digital Chemical Laboratory, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan

,

Seijiro Matsubara ∗

^bMitsui Chemicals & Kyoto University Digital Chemical Laboratory, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan

^cInstitute for Liberal Arts and Science, Kyoto University, Yoshida-Nihonmatsu, Sakyo, Kyoto 606-8510, Japan

› Author Affiliations

Abstract

All articles of this category

Abstract

Cuneane, a structural isomer of cubane, possesses C _2v symmetry, unlike the O_h symmetry of cubane. It can exhibit chirality with only a single substituent, differentiating it from cubane. Consequently, cuneane is being explored as a potential benzene bioisostere in pharmaceutical molecules, adding complexity such as chirality through isomerization of the cubane skeleton. Although there has been limited research on the synthesis of cuneane, recent years have seen increased attention devoted to this cage hydrocarbon. In this short review, we will discuss recent advances in the synthesis, utilization, and transformations of the cuneane framework into other cage hydrocarbons.

1 Introduction: Absolute Configuration Notation

2 Preparation of 1,3- and 2,6-Disubstituted Cuneanes by Constitutional Isomerization of 1,4-Disubstituted Cubanes

3 Preparation of 1,2-Disubstituted Cuneanes from 1-Cuneanecarboxamide via Directed ortho-Metalation

4 Investigation of the Potential as a Benzene Bioisostere

5 Asymmetric Synthesis of Cuneanes

6 Cuneane Scaffold Editing

7 Conclusion

Key words

cuneane - cubane - benzene bioisostere - chirality - asymmetric synthesis

Full Text

References

References
1 Criegee R, Askani R. Angew. Chem., Int. Ed. Engl. 1968; 7: 537

2a Eaton PE, Cole TW. Jr. J. Am. Chem. Soc. 1964; 86: 962
2b Eaton PE, Cole TW. Jr. J. Am. Chem. Soc. 1964; 86: 3157
2c Bliese M, Tsanaktsidis J. Aust. J. Chem. 1997; 50: 189

3 Cassar L, Eaton PE, Halpern J. J. Am. Chem. Soc. 1970; 92: 6366
4 Roux MV, Dávalos JZ, Jiménez P, Notario R, Castaño O, Chickos JS, Hanshaw W, Zhao H, Rath N, Liebman JF, Farivar BS, Bashir-Hashemi A. J. Org. Chem. 2005; 70: 5461

5a Son J.-Y, Aikonen S, Morgan N, Harmata AS, Sabatini JJ, Sausa RC, Byrd EF. C, Ess DH, Paton RS, Stephenson CR. J. J. Am. Chem. Soc. 2023; 145: 16355
5b Ma Y. J. Org. Chem. 2024; 89: 3430

6a Takebe H, Matsubara S. Eur. J. Org. Chem. 2024; 27: e202300891
6b Takebe H, Matsubara S. Synthesis 2024; 56: 16
6c Yoshino N, Kato Y, Shimada Y, Williams CM, Matsubara S. Isr. J. Chem. 2021; 61: 380
6d Yoshino N, Kato Y, Mabit T, Nagata Y, Williams CM, Harada M, Muranaka A, Uchiyama M, Matsubara S. Org. Lett. 2020; 22: 4083

7a Takebe H, Matsubara S. Eur. J. Org. Chem. 2022; e202200567
7b Takebe H, Muranaka A, Uchiyama M, Matsubara S. Chem. Lett. 2022; 51: 754

8a Smith E, Jones KD, O’Brien L, Argent SP, Salome C, Lefebvre Q, Valery A, Böcü M, Newton GN, Lam HW. J. Am. Chem. Soc. 2023; 145: 16365
8b Fujiwara K, Nagasawa S, Maeyama R, Segawa R, Hirasawa N, Hirokawa T, Iwabuchi Y. Chem. Eur. J. 2024; 30: e202303548

9 Takebe H, Matsubara S. Chem. Lett. 2023; 52: 358
10 Rohbogner CJ, Clososki GC, Knochel P. Angew. Chem. Int. Ed. 2008; 47: 1503

11a Chalmers BA, Xing H, Houston S, Clark C, Ghassabian S, Kuo A, Cao B, Reitsma A, Murray C.-EP, Stok JE, Boyle GM, Pierce CJ, Littler SW, Winkler DA, Bernhardt PV, Pasay C, De Voss JJ, McCarthy J, Parsons PG, Walter GH, Smith MT, Cooper HM, Nilsson SK, Tsanaktsidis J, Savage GP, Williams CM. Angew. Chem. Int. Ed. 2016; 55: 3580
11b Houston SD, Fahrenhorst-Jones T, Xing H, Chalmers BA, Sykes ML, Stok JE, Soto CF, Burns JM, Bernhardt PV, De Voss JJ, Boyle GM, Smith MT, Tsanaktsidis J, Savage GP, Avery VM, Williams CM. Org. Biomol. Chem. 2019; 17: 6790

12a Yeh N.-H, Chen C.-W, Lee S.-L, Wu H.-J, Chen C.-h, Luh T.-Y. Macromolecules 2012; 45: 2662
12b Benyei G, Jalsovszky I, Demus D, Prasad K, Rao S, Vajda A, Jakli A, Fodor-Csorba K. Liq. Cryst. 2006; 33: 689

13 Hassenrück K, Martin H.-D, Walsh R. Chem. Ber. 1988; 121: 369
14 Takebe H, Umemura T, Matsubara S. Chem. Lett. 2024; 53: in press

15a Hasegawa T, Kuwatani Y, Higuchi H, Ueda I. Bull. Chem. Soc. Jpn. 1993; 66: 3009
15b Eaton PE, Yip YC. J. Am. Chem. Soc. 1991; 113: 7692

16 Takebe H, Matsubara S. Chem. Eur. J. 2024; 30: e202303063