Recent Advances in the Synthesis of Axially Chiral Cycloalkanes

Abstract

Axially chiral cycloalkanes have recently emerged as compelling scaffolds with broad utility in asymmetric catalysis and molecular design. This graphical review provides a concise overview of synthetic strategies for constructing axially chiral cycloalkanes. Representative methods summarized include asymmetric allylic substitution, alkene insertion, carbene cross-coupling, carbonyl condensation/reduction, [2+2] cycloaddition, and deracemization. We offer fundamental insights into this emerging field, aiming to facilitate future research toward novel chiral frameworks.

Key words

axial chirality - alkylidenes - cyclic alkanes - asymmetric transformations - desymmetrization

Biosketches

Tonglin Zhao was born in Xinxiang, Henan Province and obtained his bachelor of science degree from Sichuan University. He is currently pursuing a master’s degree under the supervision of Professor Ying Xia at the same institution.

Ling Chen was born in Dazhou, Sichuan Province and is studying as an undergraduate student at the West China School of Public Health of Sichuan University.

Xufei Yan received his B.S. degree from Sichuan University in 2015. He completed his Ph.D. in inorganic chemistry at Sichuan University under the supervision of Professor Xiangge Zhou in 2020. He is now a postdoctoral fellow in Professor Ying Xia’s laboratory at Sichuan University. His research is focused on the asymmetric synthesis of small-ring molecules.

Ying Xia received his B.Eng. degree from the Beijing Institute of Technology in 2010. He subsequently completed his Ph.D. in organic chemistry at Peking University under the supervision of Professor Jianbo Wang and Professor Yan Zhang. Between 2015 and 2019, he was a postdoctoral fellow in Professor Guangbin Dong’s laboratories at the University of Texas at Austin and the University of Chicago. He began his independent academic career at Sichuan University in 2019. His research interests focus on transition-metal-catalyzed reactions, in particular small-ring transformations and asymmetric catalysis.

Axial chirality represents a fundamental type of chiral element, alongside central, planar, helical, and inherent chirality. In particular, axial chirality in cyclic alkanes remains underexplored, despite the significant potential of these compounds in modern drug discovery. Consequently, sustained and emerging synthetic strategies toward axially chiral alkylidene-cyclic alkanes have attracted growing interest.

Two main approaches have been developed: asymmetric modification of preformed aliphatic carbocycles and cycloaddition between unsaturated precursors. Methods such as enantioselective allylic substitution, carbon–carbon double bond insertion, carbene cross-coupling, carbonyl derivatization, and deracemization have been successfully applied to construct axially chiral four-, five-, and six-membered rings. Additionally, [2+2] cycloadditions involving alkenes and allenes have proven valuable, enabling simultaneous construction of cyclobutane frameworks and axial chirality in a single step.

Despite these advances, scalability and functional group tolerance, broad generality and configurational stability remain challenges. Many existing synthetic methods rely on noble transition metals, which contradicts the principles of sustainable chemistry. Furthermore, these reactions typically proceed via two-electron transfer mechanisms, highlighting the need for innovative approaches such as single-electron processes. In deracemization reactions, expanding the diversity and specificity of chiral photocatalysts represents a key objective. Another important challenge is the precise control of both ring strain in four-membered systems and axial stereochemistry. By focusing on recent progress in the last decade, this graphical review aims to provide mechanistic insights and inspire the development of more efficient and environmentally friendly synthetic strategies toward axially chiral cycloalkanes.

Figure 1 Asymmetric allylic substitution reactions to construct axial chirality in cycloalkanes[1]

Figure 2 Asymmetric insertion of carbon–carbon double bonds to construct axial chirality in cycloalkanes[2]

Figure 3 Asymmetric carbene cross-coupling reactions to construct axial chirality in cycloalkanes[3]

Figure 4 Asymmetric condensation reactions on carbonyl groups to construct axial chirality in cycloalkanes (formation of alkenes)[4]

Figure 5 Asymmetric condensation reactions on carbonyl groups to construct axial chirality in cycloalkanes (formation of oxime ethers or hydrazines)[5]

Figure 6 Asymmetric ketone (or imine) reduction and [2+2] cycloaddition reactions to construct axial chirality in cycloalkanes[6]

Figure 7 Miscellaneous reactions (including deracemization and cyclization) to construct axial chirality in cycloalkanes[7]

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Ms. Xiaoqin Ning in our lab for proofreading this manuscript.

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Publication History

Received: 23 September 2025

Accepted after revision: 03 November 2025

Accepted Manuscript online:
06 November 2025

Article published online:
24 November 2025