Reaction control macrocyclic compounds

Under the controlled reaction conditions, macrocyclic compounds, calix[n]arenes, were prepared using para-substituted phenolic monomers. When l,2-dialko ybenzenes are used as monomers, the reaction sites are the 4- and 5-positions of l,2-dialko3Q benzenes, but not the 3- and 6-positions (Scheme 2.4b). This is because the electron density at the 4- and 5-positions is higher than that at the 3- and 6-positions. Steric hindrance of alkojgr... 

As with any modern review of the chemical Hterature, the subject discussed in this chapter touches upon topics that are the focus of related books and articles. For example, there is a well recognized tome on the 1,3-dipolar cycloaddition reaction that is an excellent introduction to the many varieties of this transformation [1]. More specific reviews involving the use of rhodium(II) in carbonyl ylide cycloadditions [2] and intramolecular 1,3-dipolar cycloaddition reactions have also appeared [3, 4]. The use of rhodium for the creation and reaction of carbenes as electrophilic species [5, 6], their use in intramolecular carbenoid reactions [7], and the formation of ylides via the reaction with heteroatoms have also been described [8]. Reviews of rhodium(II) ligand-based chemoselectivity [9], rhodium(11)-mediated macrocyclizations [10], and asymmetric rho-dium(II)-carbene transformations [11, 12] detail the multiple aspects of control and applications that make this such a powerful chemical transformation. In addition to these reviews, several books have appeared since around 1998 describing the catalytic reactions of diazo compounds [13], cycloaddition reactions in organic synthesis [14], and synthetic applications of the 1,3-dipolar cycloaddition [15]. 

The basic reactions which are involved in the synthesis of macrocyclic compounds are very simple and of a very few types. In this section we shall consider the basic organic chemistry of macrocyclic ring-closures and how a metal ion may activate or control these reactions. In most cases, these reactions involve the formation of heteroatom-carbon bonds. 

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

The complexation of coordination compounds may make it possible to control their photochemical behaviour via the structure of the supramolecular species formed. For instance, the binding of cobalt(m) hexacyanide by macrocyclic polyammonium receptors markedly affects their photoaquation quantum yield in a structure-dependent manner [8.73-8.77]. It thus appears possible to orient the photosubstitution reactions of transition-metal complexes by using appropriate receptor molecules. Such effects may be general, applying to complex cations as well as to complex anions [2.114]. 

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. 

A very surprising and fruitful result was obtained when a control experiment related to an amide templated synthesis was made. Dibromo compound 19 utilized in the reaction looked similar to the axle centerpiece used in the amide template synthesis but lacked the amide in the middle which was crucial for this purpose. However, when the reaction was complete, it was found that rotaxane 24 was formed with 80-95% yield [12] (Figure 9). It seemed reasonable to assume that this time not the axle but the stopper coordinated to the macrocycle [27], This suggestion was supported by the high binding constant of the deprotonated stopper-wheel complex 21 18 (> 105 M"1) derived from H NMR titrations. In the rotaxane synthesis, this complex reacts with the semiaxle 23 producing a rotaxane. 

No example has so far been reported of a shuttling process controlled by electron transfer chemical reactions. There are, however, very interesting examples of shuttling processes controlled by acid/base reactions. One case is that of the previously discussed compound 13 " (see Figure 14), in which the shuttling of the macrocycle component can be controlled not only electrochemically, but also by protonation/ deprotonation of the benzidine unit [43]. 

Kaiser et al. have reported a general entry for the selective synthesis of dimeric macrocycles like cyclostellettamines and for polymeric natural products [41]. It uses the Zincke reaction by which it is possible to control the number of units in a 3-alkylpyridinium polymer. As summarized in Fig. (33), the reaction of the free amine 89 with the Zincke salt 88 gives the dimer 90 (route b) which, after terminal amine deprotection and DNB functionalization at the A-pyridine centre, gives the cyclic dimer, as in the synthesis of cyclostellettamine B. Otherwise, compound 90 furnishes both the protected dimer 91 and the free linear dimer, which, refluxed together in butanol, give the linear tetramer (route c). By the same iterative sequence, the linear octamer was obtained from the tetramer, and from the latter the hexadecamer. 

In order to obtain the desired macrocyclic diaiyl ethers, the effect of halogen substituents is utilized to control the directions of intramolecular cyclization reactions mediated by TTN. As shown in Scheme 166, on TTN-mediated oxidation of a compound... 

Extended conjugated systems of jr-electrons make these compounds promising candidates for various elecfronic devices [49, 50] and solar cell compo-nenfs [51,52]. These macrocycles provide a variefy of subsfifufion sifes which can be used fo create compounds with controlled electron donor/acceptor properties [53, 54]. In nature, metal-containing macrocycles are present as central structural units in many substances involved in biochemical redox reactions [55]. 

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