18 The Mitsunobu Reaction in the Synthesis of Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . 420
18.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
18.2 12-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
18.3 13-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
18.4 14-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
18.5 15-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
18.6 16-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
19 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
Abstract A wide variety of natural products exhibit a macrocyclic lactone motif
with a large spectrum of biological properties ranging from perfumery, over
phytotoxicity, pheromone, or insecticide activity to medicinal (antibiotic, cytotoxic, antiangiogenesis) properties. These molecules feature a wide range of cyclic
structures up to 60-membered rings. For this reason, the devise of new macrolactonization methods is always of general interest. The objective of this chapter is not
only to present an overview of the macrolactonization of seco-acids in the total
synthesis of natural products but to present other new effective procedures for the
ring closure of 12- to 16-membered ring lactones.
Keywords 12- to 16-membered • Macrolactones • Lactones • Macrolactonization •
Metathesis • Natural products • Total synthesis
1 Introduction
Macrolactones are frequently observed structural motifs in natural products in
general and polyketides in particular. Often the macrocyclic structure is one
prerequisite of their biological activity and it is proposed that the so-obtained
conformational restriction might be a general strategy for pre-orientation and
ultimately optimal binding of ligands to their biological target. Additionally, the
so-obtained conformational restriction might add to the chemical stability of natural
products due to unfavorable stereoelectronic effects that disfavor retro-aldol processes and other transformations that could potentially lead to decomposition. In
that respect, macrocyclization strategies are pivotal elements for natural products
syntheses. For polyketides the macrocyclization takes place at the very end of their
biosynthesis and has therefore to tolerate a variety of functional groups and
protecting groups. That leads in turn to different macrocyclization strategies
beyond obvious lactonizations, such as RCM, RCAM, intramolecular crosscoupling, Nozaki–Hiyama–Kishi, Wittig, and HWE methods. This review will
cover different strategies and comment on advantages as well as disadvantages
for natural products syntheses, providing a starting point for the evaluation of
synthetic routes.
Synthesis of 12- to 16-Membered-Ring Lactones
371
18.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
18.2 12-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
18.3 13-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
18.4 14-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
18.5 15-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
18.6 16-Membered Macrocyclic Lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
19 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
Abstract A wide variety of natural products exhibit a macrocyclic lactone motif
with a large spectrum of biological properties ranging from perfumery, over
phytotoxicity, pheromone, or insecticide activity to medicinal (antibiotic, cytotoxic, antiangiogenesis) properties. These molecules feature a wide range of cyclic
structures up to 60-membered rings. For this reason, the devise of new macrolactonization methods is always of general interest. The objective of this chapter is not
only to present an overview of the macrolactonization of seco-acids in the total
synthesis of natural products but to present other new effective procedures for the
ring closure of 12- to 16-membered ring lactones.
Keywords 12- to 16-membered • Macrolactones • Lactones • Macrolactonization •
Metathesis • Natural products • Total synthesis
1 Introduction
Macrolactones are frequently observed structural motifs in natural products in
general and polyketides in particular. Often the macrocyclic structure is one
prerequisite of their biological activity and it is proposed that the so-obtained
conformational restriction might be a general strategy for pre-orientation and
ultimately optimal binding of ligands to their biological target. Additionally, the
so-obtained conformational restriction might add to the chemical stability of natural
products due to unfavorable stereoelectronic effects that disfavor retro-aldol processes and other transformations that could potentially lead to decomposition. In
that respect, macrocyclization strategies are pivotal elements for natural products
syntheses. For polyketides the macrocyclization takes place at the very end of their
biosynthesis and has therefore to tolerate a variety of functional groups and
protecting groups. That leads in turn to different macrocyclization strategies
beyond obvious lactonizations, such as RCM, RCAM, intramolecular crosscoupling, Nozaki–Hiyama–Kishi, Wittig, and HWE methods. This review will
cover different strategies and comment on advantages as well as disadvantages
for natural products syntheses, providing a starting point for the evaluation of
synthetic routes.
Synthesis of 12- to 16-Membered-Ring Lactones
371