Synthetic macrocycles cyclophanes

The properties of natural macrocycles, the cyclodextrins, has stimulated interest in the preparation of synthetic macrocycles. Three basic types have been made macrocyclic amines, cyclophanes, and cyclic peptides. Hersh-field and Bender (33) prepared a bicyclic amine with hydroxamate sub-... 

A hallmark in supramolecular chemistry came in 1967, when Pedersen created the first crown ethers. These were entirely synthetic, macrocyclic, and capable of recognizing and binding small ions. Crowns opened the door to many possibilities. Most importantly, new ideas began to flood, and a new field was created, called host-guest chemistry. Donald J. Cram was among the first to recognize the potential of crowns, and he assimilated his knowledge of cyclophanes, crowns, cyclo-... 

The first examples reported of totally synthetic uncharged host-uncharged guest intramolecular inclusion complexes elucidated by x-ray crystal structures were the calixarenes (125,126). This class of macrocyclic cyclophanes contains phenolic residues in a cyclic array linked by methylene groups all ortho to the hydroxy groups (Figure 2.53). 

Much related work has occxured based on organized catalysis in natural and synthetic macrocycles, polymers, and modified surfaces, which can only be hinted at briefly in such a review. We highlight Lehn s application of crown-ethers (83) and (84) in the catalysis of hydrolysis of chiral dipeptide esters (S R up to 50 1) and hydride transfer to ketones, respectively, Knowles s successful preparation of specifically substituted a-cyclodextrins (85) and their involvement in phosphate ester hydrolysis, and Murakami s syntheses of catalytically active p-cyclophanes. " The long-standing contribution of... 

MacrocycHc isophthalamides (the tetralactam macrocycles) have been used as a host to build rotaxanes and catenanes by Vogtle and others [15]. Structurally analogous to cyclophanes, their initial usage as a synthetic receptor was for... 

Macrocycles containing isoxazoline or isoxazole ring systems, potential receptors in host—guest chemistry, have been prepared by multiple (double, triple or quadruple) 1,3-dipolar cycloadditions of nitrile oxides, (prepared in situ from hydroxamoyl chlorides) to bifunctional calixarenes, ethylene glycols, or silanes containing unsaturated ester or alkene moieties (453). This one-pot synthetic method has been readily extended to the preparation of different types of macrocycles such as cyclophanes, bis-calix[4]arenes and sila-macrocycles. The ring size of macrocycles can be controlled by appropriate choices of the nitrile oxide precursors and the bifunctional dipolarophiles. Multiple cycloadditive macrocy-clization is a potentially useful method for the synthesis of macrocycles. 

In more recent works, Zhu and coworkers synthesized a variety of para-cyclophanes and biarylether containing macrocycles (14c and d) using a reaction sequence consisting of an Ugi reaction followed by an intramolecular Sj Ar cyclization (Scheme 14) [76-78]. Many linear precursors (14a and b) were achieved with the Ugi reaction by employing varied primary amines. This synthetic planning allowed the introduction of four points of diversity within the resulting scaffolds, thus producing a small library of cyclopeptoids. 

Cyclodextrins and calixarenes are members of a general class of macrocycles commonly referred to as cyclophanes, although the naturally occurring CDs are usually considered separately from the synthetic members of the cyclophane family of compounds. The properties and guest-host complexes of cyclophanes... 

The present volume is intended to provide this knowledge, showing synthetic principles and creative strategies for the above-mentioned classes of macrocycles with stress on crowns, strained and cavityshaped cyclophanes, expanded porphyrins and macrolide antibiotics. 

Wilcox, C S, Cowart, M D, New approaches to synthetic receptors. Studies on the synthesis and properties of macrocyclic C-glycosyl compounds as chiral, water-soluhle cyclophanes, Carbohydr. Res., 171, 141-159, 1987. 

Amino acids may be bound in water by molecules with hydrophobic cavities. Cyclodextrin derivatives were studied extensively. Enantioselectivities are usually modest, with some exceptions. For example, a diphenoxyphos-phoryl-substituted p-cyclodextrin bound serine with 3.6 1 enantioselectivity " and an a-cyclodextrin with a pyr-idinium substituent showed 10 1 enantioselectivity toward the same substrate.Synthetic cyclophanes were also used. The bipyridinium-based macrocycle 36 bound DOPA 37 with 13 R S selectivity in acidic aqueous solution. 

With water as solvent, hydrophobic interactions can be used to drive complex formation. Cyclodextrins were widely used to study hydrophobic binding, and they often show enantioselectivity. However, strong enantiodiscrim-ination is rare, especially for less-functionalized substrates. synthetic water-soluble receptors gave similar results. For example, cyclophane 65 bound the enantiomers of menthol 66 in the ratio 5 4. - while macrocycle 67 bound Naproxen derivatives 68 in D20/Me0H (60 40) with 1.9 ] enantioselectivity. " ... 

Despite some uncertainty in the expected olefin geometry, the utility of the RBR is anply demonstrated by its application to the synthesis of many diverse targets. These include dendrimers, cyclophanes, modified carbohydrates such as C-glycosides and exoglycals, alkaloids, terpene derivatives, enediynes, amino acids, stilbenes, and macrocycles.The remainder of this chapter presents examples of the RBR that are pertinent to the strategic considerations oudined previously and illustrate its scope as a versatile and powerful synthetic method. 

The synthesis of q clophanes requires the closure of a ring system to avoid polymerisation or oligermerisation. As cyclophanes cover many different complex macrocycles, it is not possible to cover all of the types of synthetic procedures. Broadly speaking, the preparation of cyclophanes can be classified under fhree different methodologies, as follows ... 

Synthetic methods for the preparation of azacycloalkanes and -cyclophanes also include modification of a preformed macrocycle. This is commonly performed by means of conventional functionalization reactions which do not follow particular strategies and are adequately described in the cited literature. Conversely, a large strategic effort has been dedicated to the preparation of topologically constrained ligands and linked-ring systems. The... 

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