Six-membered rings are ubiquitous structural motifs in bioactive compounds and multifunctional materials. Notably, their thermodynamically disfavoured isomers, like disubstituted cyclohexanes featuring one substituent in an equatorial position and the other in an axial position, often exhibit enhanced physical and biological activities in comparison with their opposite isomers. However, the synthesis of thermodynamically disfavoured isomers is, by its nature, challenging, with only a limited number of possible approaches. In this Review, we summarize and compare synthetic methodologies that produce substituted six-membered rings with thermodynamically disfavoured substitution patterns. We place particular emphasis on elucidating the crucial stereoinduction factors within each transformation. Our aim is to stimulate interest in the synthesis of these unique structures, while simultaneously providing synthetic chemists with a guide to approaching this synthetic challenge.

六元环是生物活性化合物和多功能材料中普遍存在的结构基序。值得注意的是，它们的热力学不利异构体，例如一个取代基位于赤道位置，另一个取代基位于轴向位置的二取代环己烷，与相反的异构体相比，通常表现出增强的物理和生物活性。然而，热力学上不利的异构体的合成本质上是具有挑战性的，可能的方法数量有限。在这篇综述中，我们总结并比较了产生具有热力学不利取代模式的取代六元环的合成方法。我们特别强调阐明每个转化中关键的立体诱导因素。我们的目标是激发人们对合成这些独特结构的兴趣，同时为合成化学家提供应对这一合成挑战的指南。