Macrocycles template-directed synthesis

The synthetic strategy used for the construction of concave pyridine bislactams 3 (Scheme 1) can also be applied to other concave bases. When instead of a pyridine-2,6-dialdehyde 4, l,10-phenanthroline-2,9-dicarbaldehyde (9) was used in a metal ion template directed synthesis of macrocyclic diimines, after reduction, also macrocyclic 1,10-phenanthroline diamines 10 could be obtained in good yields. Here too, the crude diamines 10 were used in the next reaction step. Bridging of 10 with diacyl dichlorides 8 gave concave 1,10-phenanthroline bislactams 11. Scheme 2 summarizes the synthesis and lists the synthesized bimacrocycles 11 [18]. 

If during the template-directed synthesis of a rotaxane, the location of two identical recognition sites ( stations ) within its dumbbell component can be arranged (Fig. 13.3a and b), a degenerate, coconformational equilibrium state is obtained in which the macrocyclic component spontaneously shuttles back and forth between... 

As already said, catenanes are minimally composed of two interlocked rings. If it is arranged during the template-directed synthesis to have two identical units, that is, recognition sites, located within two different macrocycles, then the resulting... 

Grunewald J, Marahiel MA. Chemoenzymatic and template-directed synthesis of bioactive macrocyclic peptides. Microbiol. Mol. Biol. Rev. 2006 70 121-146. 

The simplest role that a host-guest complex can play is within the context of a template-directed synthesis. For instance, benzo-27-crown-9 receptor 53 can be synthesized using its guest (guanidine) as a template. Similarly, the macrocyclic dibenzo-24-crown-8 55 serves as a receptor for the formation of a host-guest complex with a dialkyl ammonium motif 90—because the alkyl chains... 

Scheme 23. Template-directed synthesis of large macrocycles.

The use of metals for prearranging reaction centers as neighboring groups has a special value in the production of macrocycles (template effect). Although these ligands can be sometimes prepared directly, the addition of metal ion during the synthesis will often increase the yield, modify the stereochemical nature of the product, or even be essential in the buildup of the macrocycle. There have been few mechanistic studies of these processes. The alkali and alkaline-earth metal ions can promote the formation of benzo[18]crown-6 in methanol ... 

Fortunately, more efficient methods for the complexation of macrocyclic hosts with acyclic guest molecules have become available with the advent of supramo-lecular chemistry, resulting in higher yields in rotaxane and catenane synthesis. In the following sections, the preparation of different types of interlocked molecules, with the use of host-guest recognition, is discussed. It should be noted that these template-directed methods differ significantly from the above-mentioned stochastic approach [28]. 

Fig. 8 The two applied approaches to catenane synthesis prior to 1983. (a) The first statistical synthesis [58] relied upon the macrocyclization of a linear compound (7) in the presence of a deuterated cycloalkane (III) to achieve small amounts of the catenane V. (b) The first example [59] of directed synthesis by covalent templation was a catenane that formed after cleaving the covalent bonds around the aromatic core in compound 16. Reproduced with permission from [58] (copyright 1960 American Chemical Society), [59] (copyright 1964 Wiley-VCH)...

The synthesis of macrocycles with the aid of the dilution principle still remains a dominating cyclization method although there have been many attempts to avoid the standard procedure, i.e., the simultaneous addition of reactants to the reaction medium (see Sect. 4). The dilution principle can be avoided in some cases [90,92] by application of template-directed reactions and/or by use of the rigid group principle . 

Scheme 1.2 Synthesis of a bis-imine macrocycle 3 directed by Ni(ll) templation [18].

A new template-directed catenane synthesis was published by Hunter in 1992 [30]. Starting from the intermediate 14 and isophthalic acid dichloride 15, he succeeded in interlocking two identical macrocyclic tetraamides to the catenane type 16 (R=H) in remarkable yield (29 %). 

The one-pot synthesis of polymers via Ugi-4CR can only be performed if either two bifunctional AA-type components or one AB-type component are used. Moreover, highly concentrated reaction mixtures are needed because otherwise ring formations occur, as thoroughly investigated by Wessjohann and coworkers. Here, the directed synthesis of macrocycles or cryptands under classic or pseudo high dilution conditions, or even without dilution exploiting metal template effects were demonstrated [66, 67]. 

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