Synthesis of ligand

The high-yield syntheses of macrocyclic polyoxoethers are characterized by the strong template effects that arise from oxygen coordination by alkali metal ions during cyclization of polyoxo units (96, 106,157, 

The low affinity of sulfur for alkali metal ions, however, renders template effects of less consequence in the synthesis of polythia macrocycles. Thus, the competition between cycli-zation and linear polymerization is more statistically defined, with cyclization kinetically favored only at high dilution 64,65,66). Consequently, most of the synthetic methods for the synthesis of polythia rings involve high-dilution techniques coupled with relatively long reaction times. Historically, the study of the coordination chemistry of macrocyclic thioethers has been hindered by difficulties in the synthesis of the free ligands. The synthesis of [BJaneSa, first reported by Ochrymowycz and co-workers in 1977 101), illustrates this well. 

By combining the procedures of Ochrymowycz and co-workers (151) with the high-dilution CS2CO3/DMF cyclization developed later by 

Buter and Kellogg 62, 63), large-scale synthesis of thioether macrocycles can now be achieved in good yields (2 77,223,224,226). Octathia Ss-donor macrocycles have been synthesized as 2 -t- 2 products from the cyclization reactions employed to form tetrathia S4-donor ligands 59, 61,83,147,209). 

A range of mixed-donor thia macrocycles have also been prepared using related techniques (5, 57, 58, 59, 60, 62, 63, 93,123,150, 213) water-soluble thioether macrocycles incorporating hydroxy-groups on the carbon back-bone have also been reported (163). 

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Chiral amines and diamines are readily available substrates for the synthesis of ligands for transition metal-catalysed reactions since they can easily be transformed into chiral ureas and thioureas. Therefore, several groups have prepared chiral symmetrical ureas and thioureas, dissymmetrical ureas and thioureas, amino-urea and thiourea derivatives. Finally polyureas and non-soluble polythioureas were also prepared and tested as ligands for asymmetric catalysis. 

General procedures for the synthesis of ligands and metal complexes are shown in Scheme 1. For file synthesis of 2a acenaphthenequinone (0.38 g, 2.1 mmol) and a,a-bis(4-amino-3,5-dimethylphenyl)-toluene(Kccess) were dissolved in 50 mL of CH3OH in a round-bottom flask. Five drops of formic acid were added, and the sealed solution was stirred at 50 C overnight. After filtration, the red solid was washed with hot methanol and dried to give 1.2 g of red powder in 50 % yield. 

It will not be lost on the reader that, while PHOTOFRIN and compounds (3), (5) and (6) contain no metal, they would be expected to be excellent ligands. Are metal complexes useful as PDT photosensitizers Indeed, they are, and may be expected in the future to become more important. The rest of this chapter is about this aspect it will emphasize metal complex formation and properties in relation to PDT. The synthesis of ligands, while of crucial importance, will not usually be treated here in detail, but leading references to relevant synthetic organic chemistry will be provided. The synthesis of porphyrins and related compounds has been considered in several monographs and reviews (porphyrins,46 47 phthalocyanines48). 

In model studies involving Fe(n) species, three broad approaches have been used to mitigate the problem of autoxidation of the iron (Hay, 1984). These are (i) the use of low temperatures so that the rate of oxidation becomes very slow (ii) the synthesis of ligands containing steric barriers such that dimerization of the iron complex is inhibited, and (iii) immobilization of the iron complex on a solid surface such that dimerization once again will not be possible. 

During the synthesis of ligands for the vesicular acetylcholine transporter, a octahy-droquinoline nucleus 361 was prepared via a ring-expansion rearrangement followed by a hydride reduction (equation 140). The yield was moderate but only one lactam 360 was produced by the Beckmann rearrangement. 

For reviews on classical bidentate ligand library construction see Ref. [3] and Lavastre, O., Bonnette, F. and Gallard, L. (2004) Parallel and combinatorial approaches for synthesis of ligands. Curr. Opin. Chem. Biol., 8, 311-318. 

Consideration of synthetic utility of reactions of coordinated ligands must therefore take into account the synthesis of ligands promoted by metal coordination, in addition to direct reactions of metal complexes. 

DESIGN AND SYNTHESIS OF LIGANDS AND ANTAGONISTS OF SIGLECS AS IMMUNE RESPONSE MODIFIERS... 

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