Cyclenes, synthesis

Several synthetic routes to cyclen as the starting material for the synthesis of gadoterate are available [20-26]. In Scheme 1 the cyclization of the tosylates 1 and 2 is performed in a high yield since the hydrocarbon segments between the hetero atoms are short, and relatively equal segments of the target macrocycle are condensed. After detosylation of 3 the cyclen 4 is obtained. 

Scheme 3. Synthesis of gadoterate Scheme 1. Synthesis of Cyclen by cyclization...

The synthesis of 11 (an analogue of 7 in which its 12-membered cyclen had been replaced by 14-membered cyclam rings) was reported in 1998 using the tri-N-tosylamide derivative of cyclam and l,3,5-tris(bromomethyl)benzene as precursors [24], The trinuclear Hg(II) derivative was shown to selectively recognise and bind a tripodal tris(histidine) ligand in which the three (S)-histidines are 12 A apart. The system was seen as a model for peptide recognition. 

Another group of cyclene-based molecules interacting with nucleic acids was described by us. [12] In this case, cyclene nitrogen atoms were substituted with carbamoyl groups which irreversibly reduced the basicity and binding abilities but were useful for the synthesis of more complex molecules (Scheme 14). Simple carbamoyl-substituted cyclenes were obtained by standard protection - acylation - deprotection... 

In 1974 a DuPont patent- disclosed the synthesis of cyclen phosphine oxide, 2,— by hydrolysis of cyclen fluorophosphorane, 1. 

This chapter does not cover cyclic amides and peptides, since their number would enormously expand this text. They are reviewed only if they serve as reaction intermediates during synthesis of cyclic amines. In addition, metal ions complexation will be presented in required minimum, for example, if it serves for template formation during ring synthesis or as a main topic in some application. In this chapter, most of the sections deal with the literature data for all cycle types, except Section 14.11.6, which focuses mainly on chemistry of cyclen and cyclam and their analogs and derivatives. In Section 14.11.8, we give only a brief overview of the utilizations and provide a reader with reviews where more detailed information may be found. 

Another general method for the synthesis of these macrocycles is the reaction of amines with (active) esters of carboxylic acids leading to oxoderivatives of the cycles. The amides can be reduced to amines or directly used for further transformations or complexation of metal ions. Two cyclens 55 and 56, as intermediates for the synthesis of bifunctional DOTA derivatives, were obtained by condensation shown in Scheme 10 between appropriate diamine-amide and active ester of AT-BOC-iminodiacetic acid (BOC = /-butoxycarbonyl), followed by deprotection and reduction <2003NMB581>. 

A big improvement has been made in synthesis of cyclen. For a long time, the amine has been available mostly through classical so-called tosylamide synthesis <1974JA2268>. The method is atom noneffective , as most of molecular mass disappears by removal of the sulfonate group. Furthermore, harsh deprotection conditions can interfere with numerous functional groups. The method is time consuming when the protection-deprotection strategy is used. 

Another example described in Section 9.5.3 reports the synthesis and screening of a synthetic receptor library aimed at transition metal binding. Other similar examples have been reported recently. Burger and Clark Still (211) prepared ionophoric, cyclen-based libraries decorated by amino acid units and screened them for their ability to complex copper and cobalt ions Malin et al. (212) identified novel hexapeptidic technetium-binding sequences from the screening of cellulose-bound libraries and... 

Borbas, K.E. and Bruce, J.I. (2007) Synthesis of asymmetrically substituted cyclen-based ligands for the controlled sensitisation of lanthanides. Organic and Biomolecular Chemistry, 5, 2274. 

Chiral phosphoramides, particularly C2-symmetric examples, are widely used in asymmetric synthesis (see section 3.2). One example is the asymmetric catalysis of Aldol reactions, where the phosphoramide catalyst is used in combination with a Lewis base. A solid state and solution study of the structure of chiral phosphoramide-tin complexes used in such reactions has now been reported. A number of chiral, non-racemic cyclic phosphoramide receptors (387) have been synthesised and their interactions with homochiral amines studied using electrospray ionisation MS. Although (387) bind the amines strongly, no evidence of chiral selectivity was found. Evidence from a combination of its X-ray structure, NMR, and ab initio calculations suggests that the cyclen phosphorus oxide (388) has an N-P transannular interaction in the solid state. A series of isomers of l,3,2-oxazaphosphorino[4,3-a]isoquinolines(389), containing a novel ring-system, have been prepared and their stereochemistry and conformation studied by H, C, and P NMR spectroscopy and X-ray crystallography... 

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