**Mickael Choury, Alexandra Basilio Lopes, Gaëlle Blond and Mihaela Gulea \***

Université de Strasbourg, CNRS, Laboratoire d'Innovation Thérapeutique, LIT UMR 7200, F-67000 Strasbourg, France; mickael.choury@etu.unistra.fr (M.C.); alexandralopesb@yahoo.com.br (A.B.L.); gaelle.blond@unistra.fr (G.B.)

**\*** Correspondence: gulea@unistra.fr

Received: 25 June 2020; Accepted: 7 July 2020; Published: 9 July 2020

**Abstract:** Medium-sized heterocycles (with 8 to 11 atoms) constitute important structural components of several biologically active natural compounds and represent promising scaffolds in medicinal chemistry. However, they are under-represented in the screening of chemical libraries as a consequence of being difficult to access. In particular, methods involving intramolecular bond formation are challenging due to unfavorable enthalpic and entropic factors, such as transannular interactions and conformational constraints. The present review focuses on the synthesis of medium-sized heterocycles by transition-metal-catalyzed intramolecular cyclization, which despite its drawbacks remains a straightforward and attractive synthesis strategy. The obtained heterocycles differ in their nature, number of heteroatoms, and ring size. The methods are classified according to the metal used (palladium, copper, gold, silver), then subdivided according to the type of bond formed, namely carbon–carbon or carbon–heteroatom.

**Keywords:** transition-metal catalysis; intramolecular cyclization; medium-sized heterocycles

#### **1. Introduction**

Heterocyclic compounds are of major importance in pharmaceutical, agrochemical, and materials fields, and as synthetic tools. Among the large variety of methods to synthesize heterocycles, the transition-metal-catalyzed reactions have become a powerful, widely used strategy [1,2]. Most published articles relate to the use of transition metal catalysts for the synthesis of five-, six-, and even seven-membered heterocycles, while the medium-sized counterparts (i.e., eight- to eleven-membered heterocycles) [3,4] are sparsely reported. Indeed, the access to medium-sized rings is particularly difficult because of the high degree of transannular strain and unfavorable entropic factors involved [5,6], particularly when intramolecular cyclization strategies are used. Therefore, from a synthetic point of view, accessing medium-sized heterocycles still represents a challenge. Moreover, some of these heterocycles are structural components of diverse, biologically active natural products and pharmaceuticals (Figure 1).

Several excellent reviews have already covered the topic of synthesis of medium-sized rings, some of them dealing more specifically with ring-closing metathesis [7,8], radical-mediated reactions [9], annulations, ring expansion reactions [10–12], metal-mediated strategies [13–17], microwave-assisted synthesis [18]. Most of them were organized according to the type of the transformation involved to obtain the heterocycle and the structural elements of the heterocycle (i.e., ring size, type and number of heteroatoms).

**Figure 1.** Examples of natural and bioactive compounds containing a medium-sized heterocycle.

The present review focuses on synthetic methods based on transition-metal-catalyzed intramolecular cyclization to access medium-sized heterocycles. The methods are classified according to the metal used as the catalyst (palladium, copper, gold, or silver), then subdivided according to the type of the formed bond, namely carbon–carbon or carbon–heteroatom (C–O, C–N, or C–S). The obtained heterocycles differ in their varied elements, such as the nature of the heteroatoms (O, N, S), the number of heteroatoms (one or more), and their ring size (8 to 11 atoms). The review mostly highlights recent literature (last decade), however some earlier publications are discussed when relevant to the topic or when they represent one of the rare examples described in a category.
