The tail-to-head terpene (THT) cyclization is a biochemical process that gives rise to many terpene natural product skeletons encountered in nature. Historically, it has been difficult to achieve THT synthetically without using an enzyme. In this protocol, a hexameric resorcin[4]arene capsule acts as an artificial enzyme mimic to carry out biomimetic THT cyclizations and related carbocationic rearrangements. The precursor molecule bears a leaving group (usually an alcohol or acetate group) and undergoes the THT reaction in the presence of the capsule catalyst and HCl as a cocatalyst. Careful control of several parameters (including water content, amount of HCl cocatalyst, temperature and solvent) is crucial to successfully carrying out the reaction. To facilitate the application of this unique capsule-catalysis methodology, we therefore developed a very detailed procedure that includes the preparation and analysis of all reaction components. In this protocol, we describe how to prepare two different terpenes: isolongifolene and presilphiperfolan-1β-ol. The two procedures differ in the water content required for efficient product formation, and thus exemplify the two common use cases of this methodology. The influence of other crucial reaction parameters and means of precisely controlling them are described. A commercially available substrate, nerol, can be used as simple test substrate to validate the reaction setup. Each synthetic procedure requires 5–7 d, including 1–5 h of hands-on time. The protocol applies to the synthesis of many complex terpene natural products that would otherwise be difficult to access in synthetically useful yields.

尾到头萜烯（THT）环化是一种生化过程，可产生自然界中遇到的许多萜烯天然产物骨架。从历史上看，不使用酶很难合成 THT。在该方案中，六聚间苯二酚[4]芳烃胶囊充当人工酶模拟物，以进行仿生 THT 环化和相关的碳阳离子重排。前体分子带有离去基团（通常是醇基或乙酸基），并在胶囊催化剂和 HCl 作为助催化剂的存在下进行 THT 反应。仔细控制几个参数（包括水含量、HCl 助催化剂的量、温度和溶剂）对于成功进行反应至关重要。为了促进这种独特的胶囊催化方法的应用，我们开发了一个非常详细的程序，包括所有反应组分的制备和分析。在本协议中，我们描述了如何制备两种不同的萜烯：isolongiolene 和 presilphiperfolan-1β-ol。这两个程序在有效形成产品所需的水含量方面有所不同，因此举例说明了该方法的两个常见用例。描述了其他关键反应参数的影响以及精确控制它们的方法。市售底物橙花醇可用作简单的测试底物来验证反应设置。每个合成过程需要 5-7 天，其中包括 1-5 小时的动手时间。该协议适用于许多复杂萜烯天然产物的合成，否则这些产物很难以合成有用的产量获得。