The success of a given macrocyclization reaction involves a very delicate balance of many different factors. First, a proper understanding of the basic thermodynamic and kinetic concepts underlying these processes is essential in defining the strategies to obtain the targeted cyclic structures and the experimental elements to be optimized. essential element for achieving high yields in a macrocyclization process is the appropriate selection of the disconnection site. This defines the reaction used for the key step, which will clearly affect the overall process, but also delineates the nature and structure of the immediate linear precursor. The presence of structural elements, including configurational elements, able to induce a favorable folding of this linear precursor in such a way that both reactive ends approach with the proper orientation provides significant enhancements in macrocyclizations. The use of templates of very different natures is a versatile strategy to overcome the limitations of the other macrocyclization strategies. The use of templates has allowed the preparation of a variety of macrocyclic structures in better yields and usually in shorter reaction times, and often allows easier purification protocols.Financial support of the Spanish Ministry of Science and Innovation (CTQ2012-38543-C03) and Generalitat Valenciana (PROMETEO/2012/020) is acknowledged. V.M.-C. thanks the Spanish Ministry of Science and Education for a predoctoral fellowship (FPU AP2007-02562) and Generalitat Valenciana for a VALi+d postdoctoral fellowship (APOSTD/2013/041). M.D.P. thanks the Spanish Ministry of Education for a postdoctoral fellowship and UGC India for a Startup Grant

Cage compounds offer unique binding pockets similar to enzyme-binding sites, which can be customized in terms of size, shape, and functional groups to point toward the cavity and many other parameters. Different synthetic strategies have been developed to create a toolkit of methods that allow preparing tailor-made organic cages for a number of distinct applications, such as gas separation, molecular recognition, molecular encapsulation, hosts for catalysis, etc. These examples show the versatility and high selectivity that can be achieved using cages, which is impossible by employing other molecular systems. This review explores the progress made in the field of fully organic molecular cages and containers by focusing on the properties of the cavity and their application to encapsulate guests.

The Diels–Alder (DA) reaction is a cornerstone of synthesis, yet Nature does not use catalysts for intermolecular [4+2] cy-cloadditions. Attempts to create artificial “Diels–Alderases” have also met with limited success, plagued by product inhibi-tion. Using a simple Pd₂L₄ capsule we now show DA catalysis that combines efficient turnover alongside enzyme-like hall-marks. This includes excellent activity (kcat/kuncat > 10³), selec-tive transition-state (TS) stabilization comparable to the most proficient DA catalytic antibodies, and control over regio- and chemo-selectivity that would otherwise be difficult to achieve using small-molecule catalysts. Unlike other catalytic approach-es that use synthetic capsules, this method is not defined by entropic effects; instead multiple H-bonding interactions modu-late reactivity, reminiscent of enzymatic action.

We provide an overview of coordination cage catalysis, highlighting how mechanistic understanding can help address the challenges in this area leading to new opportunities in non-covalent reactivity.

Self-assembled metallo-organic cages have emerged as promising biomimetic platforms that can encapsulate whole substrates akin to an enzyme active site. Extensive experimental work has enabled access to a variety of structures, with a few notable examples showing catalytic behavior. However, computational investigations of metallo-organic cages are scarce, not least due to the challenges associated with their modeling and the lack of accurate and efficient protocols to evaluate these systems. In this review, we discuss key molecular principles governing the design of functional metallo-organic cages, from the assembly of building blocks through binding and catalysis. For each of these processes, computational protocols will be reviewed, considering their inherent strengths and weaknesses. We will demonstrate that while each approach may have its own specific pitfalls, they can be a powerful tool for rationalizing experimental observables and to guide synthetic efforts. To illustrate this point, we present several examples where modeling has helped to elucidate fundamental principles behind molecular recognition and reactivity. We highlight the importance of combining computational and experimental efforts to speed up supramolecular catalyst design while reducing time and resources.