Ring closure methods in the synthesis of macrocyclic natural products

Abstract

Macrocyclization methods by means of ring closure from linear bifunctional precursors are critically reviewed. The scope of this article is limited to macrocyclic natural products and, to some extent, their model compounds. However, not only macrolides, but all kinds of macrocyclic natural products which have been synthesized by ring closure reactions are covered. The commonly used ring closure methods in recent literature include those involving lactonization, lactamization, C-C bond formation, C=C bond formation, ether formation, amine formation, and exo ring formation. The activation of one or both interacting sites of the bifunctional linear precursor is the central issue of some ring closure methods. Stereochemistry plays an important role in ring closure reactions. Only when the stereochemistry of the linear precursor allows its two interacting sites to reach each other occurs a successful ring closure. If the adopted conformation of a linear precursor sufficiently resembles that of the corresponding macrocycle a ring closure can be very facile.