Macrocycles intramolecular cyclisation

When the copper complex of 7.62 reacts with ICH2(CH2OCH2)4CH2l in the presence of base, an intramolecular cyclisation occurs to form the macrocyclic ether 7.63. However, because of the arrangement of the starting ligands about the copper(i) centre, the two macrocycles are interlinked, and the consequence is the formation of the copper(i) complex of the catenand (catenand = catenane ligand) (Fig. 7-41). 

As we considered above, one of the fundamental problems associated with the preparation of macrocyclic ligands is concerned with the orientation of reactive sites such that they give intramolecular (cyclic) rather than intermolecular (acyclic) products. This is associated with the conformation of the reactants and the reactive sites, and so we might expect that judicious location of donor atoms might allow for metal ion control over such a cyclisation process. This is known as a template synthesis, and the metal ion may be viewed as a template about which the macrocyclic product is formed. This methodology was first developed in the 1960s, and has been very widely investigated since that time. At the present, template reactions usually prove to be the method of choice for the synthesis of many macrocyclic complexes (with the possible exceptions of those of crown ethers and tetraazaalkanes). When the reactions are successful, they provide an extremely convenient method of synthesis. 

In the diterpene series a notable recent example of semisynthesis is that (ref.24) of pachiclavularolide (28) a substance isolated from the soft coral, Pachiclavularia violacea. starting from S-citronellal readily available from S-citronellol. The key step in the formation of the macrocycle is an intramolecular palladium-catalysed diyne cyclisation following initially a Mislow-Evans rearrangement of a sulphinyl ester from S-citronellal. ... 

Macrolides and Related Compounds.- The total synthesis of amphoteronolide B (166) and amphotericin B (167) has been reported in a series of papers by Nicolaou s group.The method uses the phosphonate-based olefination of (164) with (165) to form the basic carbon skeleton which is cyclised by an intramolecular phosphonate-based olefination. A Wittig reaction of the ylide (168) is a key step in the synthesis of the cytotoxic macrocycle riccardin C (169). 

The outstanding challenge in this area is the synthesis of the natural macrocyclic diester alkaloids. A first step in this direction was taken by Robins and Sakdarat 251), when they managed to reconstruct an 11-membered macrocyclic diester (85) from (+)-retronecine and 3,3-dimethyl-glutaric anhydride. The mixture of 7- and 9-monoesters of retronecine initially produced was cyclised intramolecularly via the corresponding 2-pyridinethiol esters. 

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