Azamacrocycles, synthesis

B. Konig, T. Fricke, A. Wa/imann, U. Krallmann-Wenzel, and T. K. Lindhorst, y-Mannosvl clusters scaffolded on azamacrocycles Synthesis and inhibitory properties in the adhesion of type 1 fimbriated Escherichia coli to guinea pig erythrocytes, Tetrahedron Lett., 39 (1998) 2307-2310. 

The one-pot synthesis of 9 described above appears to afford only modest yields of azacrowns. One might wonder why any crown at all would be formed under non-high dilution conditions intended to yield only open-chained material. Vogtle suggests that this can be explained in terms of template, steric and entropy effects . These factors are of doubtless significance, but it is interesting to note that in the synthesis of poly-azamacrocycles, Richman and Atkins found that there was no significant template effect observed. The question of the template effect in Ihe syntheses of 9 has recently been addressed by Kulstad and Malmsten They conclude that the formation of 9 is assisted by the presence of alkali metal cations. 

Synthesis and metal complexes of azamacrocycles with pendant arms having additional ligating groups. T. A. Kaden, Top. Curr. Chem., 1984,121,157-179 (54). 

Imine metathesis has continued to be a popular exchange reaction for DCLs. Various groups have found novel systems in which the reaction can be applied, as well as interesting ways to halt the equilibration. For example, Wessjohann and coworkers have demonstrated that Ugi reactions can efficiently halt equilibration of an imine DCL, combining an irreversible diversification process with areversible library selection [24]. Xu and Giusep-pone have integrated reversible imine formation with a self-duplication process [25], and Ziach and Jurczak have examined the ability of ions to template the synthesis of complex azamacrocycles [26]. The mechanistically related reactions of hydrazone [27] and oxime [28] exchange have also been explored as suitable foundations for DCL experiments. 

The main emphasis of our EC project is in electrocatalytic C02 reduction, where we explore synthetic pathways for novel binuclear Co complexes with tetra-azamacrocyclic ligands and their use in electrochemical measurements and synthesis. Although several routes for ligand synthesis have been briefly described in the literature, we find upon repeated attempts that well-characterised samples are hard to obtain. In one case (bis-dioxocyclam XI) We have obtained a pure product. In addtion, the rotating-ring disk electrode has been introduced in this study for obtaining kinetic information on mono-and binuclear complexes. For their use in anhydrous media, water-free compelxes have been prepared. 

The appropriate conditions for the synthesis of tris-azamacrocyclic clathrochelates containing dioximate fragments in polyazamacrocyclic rings were not selected. Attempts to use open-chain polyamines, as well as their complexes with transition metals, primarily Ni2+, gave no desired results. 

Important areas of growth since the publication of CCC (1987) in 1987 have included the synthesis of macrocycles with amide and amidate functions, the cyclization of metal-amine compounds by Mannich reactions, the preparation of polycyclic and of linked azamacrocycles, and the preparation of azamacrocycles with a diversity of functionalized A- and C-substituents. Much recent interest has been focused on azamacrocycles functionalized in some fashion, and much of the research has only marginally been about the coordination chemistry which is the primary focus of this chapter. 

A bicyclic azamacrocycle (127) has been prepared from [bisiV-(2-aminoethyl)-tacn)Cun] by reduction of the aminal formed with glyoxal (Scheme 30). The tricyclic ligands (128) and (129) formed by Richman-Atkins synthesis from tetrakis(3-aminopropyl)- and tetrakis(2-aminoethyl)-cyclam, respectively, form binuclear compounds.174... 

Bridget, G.J., Skerlj, R.T., Padmanabhan, S., Martellucci, S.A., Henson, G.W., Struyf, S., Witvrouw, M., Schols, D. and De Clerq, E. (1999) Synthesis and structure-activity relationships of phenyle-nebis(methylene)-linked bis-azamacrocycles that inhibit HTV-l and HTV-2 replication by antagonism of the chemokine receptor CXCR4. J. Med. Chem. 42 3971-3981. 

Azamacrocycles with two hydroxyethyl side chains attached at the nitrogen atoms (53) have also been prepared by the same method (Equation (23)) <90TL1077>. An analog synthesis produces the 14-membered macrocycle, which can be reduced to the amine, thus giving the possibility to obtain cyclam derivatives in high yield <90tlio77>. 

The synthesis of C-substituted polyazamacrocycles generally needs a precursor, which already has the side chain incorporated, prior to cyclization. Using the Tabushi et al. approach <77TL1049> for the condensation of polyamines with substituted malonate diesters, several C-substituted tetra-azamacrocycles (62) have been prepared, in which R and/or R are alkyl groups <83IC2055> or one or two fluorine atoms (Scheme 6) <88JA3679>. 

The benzyloxycarbonyl protecting group, commonly used in peptide synthesis, has also been used in the preparation of azamacrocycles. Sutherland and co-workers <76CC639> prepared a benzodiaza-15-crown-4 derivative from a,a -dibromo-/w-xylene <79JCS(P1)1089>. Although not specified in the report, deprotection was presumably accomplished using standard conditions (HBr/HOAc). 

Although a great variety of oxa-azamacrocyclic receptors has been examined in the search for synthetical host molecules, only few attempts have been devoted to the synthesis of macrocyclic structures containing both polyoxa and polyaza subunits as potentially hard and soft binding sites. To this purpose we have synthesized some new compartmental oxa-aza macrocyclic receptors, as reported in Figure 4, which display two different binding sites (one N5 and one O2 or O3 subunits), located at opposite side of the same macrocycle. 

The similarities in chemical behaviour across the lanthanides mean that kinetically stable lanthanide complexes offer a degree of control that cannot readily be achieved through selective self-assembly of small building blocks. Azamacrocycle complexes derived from cyclen amino-carboxylates are particularly suited to this, and ternary complexes can be used to study the photophysical behaviour of lanthanide complexes. We initially used such an approach to probe the effectiveness of chromophores as sensitizers for lanthanides without recourse to extensive synthesis (as illustrated in Fig. 7). This approach can be used with simple chromophores to probe the mechanism of energy transfer. For instance, tetrathiafulvalene... 

In 1937, van Alphen described the synthesis of the aza-cycloalkane (saturated azamacrocycle) 1,4,8,11-tetraazacy-clotetradecane (6), more commonly known as cyclam, obtained by reaction of 1,3-dibromopropane and 1,4,8,11-tetraazaundecane in the presence of an alkali. Twenty-four years later, Stetter and Mayer synthesized the ligand by a different route and showed that the material described by van Alphen contained only a small amount of the claimed ligand, but it took another five years for the first metal complex with cyclam to be reported. After these early works, a huge number of saturated azamacrocycles were synthesized, making the azacycloalkanes one of the most studied class of macrocyclic ligands. " ... 

Metal ion complexes with azamacrocycles, and, in particular, complexes with transition metal ions, have turned out to have special properties since the synthesis of the first similar ligands performed by template reactions in the... 

Pappalardo, S., F. Bottino, P. Finocchiaro, A. Mamo and F. R. Fronczek - Synthesis of symmetrical H-tosyldi-azamacrocycles and complexation properties of their derivatives... 

The presence of the benzamide moiety appears essential for mesophase production. If the benzamides are reduced to the benzyl-amines [240], or straight-chain amides (C,, Hi3CO) [241] are used, all mesophase behaviour disappears. Some smaller ring azamacrocycles 66-68 have been prepared and found to give discotic phases. Their synthesis is wholly similar to that of the hex-acyclens. Benzamides of larger macrocycles (e.g. [30] N,o [241]) have also been synthesized, but these show only monotropic mesophases. 

Cycloaddition reaction of two molecules of alkyne and alkene is a direct route for the synthesis of substituted cyclohexadiene derivatives, which are important components of the Diels-Alder reaction. Therefore, the reaction cycloisomerization of enediyne azamacrocycles represents a pathway to the synthesis of highly functionalized tetra-condensed cyclo-hexadienes in a single step. The synthetic variety of such reactions is... 

Unsaturated Azamacrocyclic Enediynes Synthesis, Structural Analysis and Thermal Behavior... 

Gonzalez, 1., Roglans, A., Benet-Buchholz, J. and Rourac, P. (2006) New unsaturated azamacrocyclic enediynes synthesis, structural analysis and thermal behavior. Synlett, (18), 3041-3044. 

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