Cyclisation templates

Synthesis of cyclic porphyrin tetramer 4 from linear tetramer 6 using y4Porph and Bipy as positive cyclisation templates. 

The oxazinones 74 and 79, already described as chiral glycine templates in Section 11.11.6.3, have been prepared by the PET cyclisation of 252 by irradiation in the presence of 1,4-dicyanonaphthalene as the electron acceptor and methyl viologen as electron-transfer mediator. When the reaction was carried out under strictly anhydrous conditions, compound 79 was isolated, whereas when the reaction was carried out in wet MeCN, compound 74 was the exclusive product (Scheme 33). In any case, the products were obtained with high stereoselectivity, which is the condition required to use them as chiral auxiliaries <2000EJ0657>. 

Brady, R. A. Sanders, J. K. M. Thermodynamically controlled cyclisation and interconversion of oligocholates Metal ion templated living macrolac-tonisation. J. Chem. Soc. Perkin 11997, 3237-3253. 

R. Nouguier, C. Lesueur, E. De Riggi, M. P. Bertrand, and A. Virgili, Stereoselective free-radical cyclisation on a sugar template. Hie sulphonyl radical as a synthetic tool for functionalized glycosides. Tetrahedron Lett. 37 3541 (1990). 

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. 

Figure 6-5. A metal-ion-templated cyclisation of a compound containing two donor atoms (filled circles) and two reactive groups (open circles). The co-ordination of the open-chain ligand to the metal ion brings the reactive sites into close proximity and favours the intramolecular reaction.

There are also potential disadvantages associated with the use of template methodology for the formation of macrocyclic ligands. Perhaps the most important is the observation that not all metal ions can act as templates for the specific cyclisation reactions of interest. In many cases it may not be trivial to find an appropriate template ion (if indeed... 

Figure 6-9. The action of a potassium template ion in the formation of 18-crown-6 from open-chain precursors. The important feature is the way in which the metal ion holds the alkoxide and tosylate groups in proximity in the intermediate immediately before the cyclisation.

Probably one of the commonest reactions encountered in the template synthesis of macrocycles is the formation of imine C=N bonds from amines and carbonyl compounds. We have seen in the preceding chapters that co-ordination to a metal ion may be used to control the reactivity of the amine, the carbonyl or the imine. If we now consider that the metal ion may also play a conformational role in arranging the reactants in the correct orientation for cyclisation, it is clear that a limitless range of ligands can be prepared by metal-directed reactions of dicarbonyls with diamines. The Tt-acceptor imine functionality is also attractive to the co-ordination chemist as it gives rise to strong-field ligands which may have novel properties. All of the above renders imine formation a particularly useful tool in the arsenal of preparative co-ordination chemists. Some typical examples of the templated formation of imine macrocycles are presented in Fig. 6-12. 

The template method may be extended to derivatives of imines, and hence to the synthesis of cyclic hydrazones. An example of a templated cyclisation leading to a cyclic hydrazone is shown in Fig. 6-13. 

The formation of cyclic ligands by template reactions has another associated complexity which we encountered in Section 6.3.3. This concerns the number of reacting molecules involved in the formation of the cyclic products and the overall stoichiometry of the reaction. We have not yet considered the control of stoichiometry of the cyclisation reactions in any great detail. 

The formation of macrocyclic ligands by template reactions frequently involves the reaction of two difunctionalised precursors, and we have tacitly assumed that they react in a 1 1 stoichiometry to form cyclic products, or other stoichiometries to yield polymeric open-chain products. This is certainly the case in the reactions that we have presented in Figs 6-8, 6-9, 6-10, 6-12 and 6-13. However, it is also possible for the difunctionalised species to react in other stoichiometries to yield discrete cyclic products, and it is not necessary to limit the cyclisation to the formal reaction of just one or two components. This is represented schematically in Fig. 6-19 and we have already observed chemical examples in Figs 6-4, 6-11 and 6-18. We have already noted the condensation of two molecules of 1,2-diaminoethane with four molecules of acetone in the presence of nickel(n) to give a tetraaza-macrocycle. Why does this particular combination of reagents work Again, why are cyclic products obtained in relatively good yield from these multi-component reactions, rather than the (perhaps) expected acyclic complexes We will try to answer these questions shortly. 

The thermodynamic stability of the macrocyclic complex provides one of the driving forces for cyclisation in template reactions. In a way, co-ordination of the macrocycle to the metal ion provides a thermodynamic sink into which the reaction product can fall. This is clearly of importance when we consider the reactions such as the formation of metal... 

Clearly it is possible to exert relatively subtle control over the direction of cyclisation reactions by a judicious choice of template ion, even if the effects may not be fully quantified or understood. 

One of the more interesting hole size effects arises when the metal ion successfully acts as a template, but is labilised in the macrocyclic complex that is formed. The consequence of this is that the metal ion acts as a transient template. The metal ion may be viewed as pre-organising the reactants to form the macrocyclic products, but then finding itself in an unfavourable environment after the cyclisation. The effect is best observed when a small metal ion is used as a template for a reaction that can only give one product (or at least, only one likely product). What happens to the metal ion when it finds itself in an environment that does not match up to its co-ordination requirements The most useful consequence would be labilisation of the metal ion, with resultant demetallation and formation of the metal-free macrocycle. This would overcome one of the major disad-... 

In order to achieve the final cyclisation step in the spherand syntheses, a new synthetic ring-closure procedure was developed, which proceeds according to Equation 3.2 (acac = acetylacetonato, CH(COMe)2 ). The aryl lithium compound produced by action of butyl lithium is oxidised by the Fe (III) complex to give an aryl biradical, which then undergoes a template cyclisation about the Li+ ion (see Section 3.9.1 for an explanation of the template effect). In the case of 3.33, this method resulted in the isolation of the complex in 28 % yield from the reaction shown in Scheme 3.9. 

Figure 3.45 Kinetic studies of the template effects of metal ions on cyclisation to form benzo [18] crown-6. ( Wiley-VCH Verlag GmbH Co. Reproduced with permission).

The standard synthesis for cyclam was developed by Barefield and Wagner in 1976.29 They used similar starting materials to the van Alphen procedure but the cyclisation yield is improved through the use of a nickel (II) template. Glyoxal completes the macrocycle by a Schiff base condensation reaction. The resulting imine functionalities are reduced with sodium borohydride to leave the complexed macrocycle. The metal ion is then removed by reaction with cyanide and the free ligand extracted with chloroform (Scheme 3.19). Yields are typically in the region of 60%. 

Carbon-carbon bond forming reactions such as Wurtz coupling and 1,6-elimination, e.g. synthesis of [2.2] paracyclophane (Scheme 6.9). Here the lack of templation means that competing cyclisation and polymerisation is a significant problem. 

Cryptophane synthesis is accomplished by one of two methods. Initial procedures employed a covalent template effect in which one CTV-derived bowl preorganised the cyclisation of the second under high dilution conditions (Scheme 6.16a). More recently, a much more straightforward procedure has been developed in which cryptophanes are formed directly in a double trimerisation reaction (Scheme 6.16b). 

A limited number of syntheses are templated by one or more protons wherein a hydrogen-bonding network may function as a template, correctly predisposing the electrophilic and nucleophilic components for the cyclisation step. 

The following procedure is representative of a proton-templated cyclisation reaction. 

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