PROCEDIMIENTOS

An ideal synthetic methodology would endeavour to optimise the following criteria: 1) production o f the target m acrocycle in high yield

2) generation o f a form readily purified and isolated from side-products 3) utilisation o f readily available starting materials

4) employm ent o f a straightforward experimental procedure 5) low financial expenditure

T h e prime focus in the preparation o f macrocyclic compounds is to secure closure o f the correctly sized ring, thereby suppressing production o f ring homologues and polymeric materials. Three major strategies have emerged:

1) Richman-Atkins10* - the Richman-Atkins approach promotes cyclisation between one reagent having two term inal NH2 groups converted into p-toluenesulfonamide sodium salts, -(Ts)N'Na*. and a second reagent with two alcohol groups converted into p-toluenesulfonate ester groups, -OTs. The sodium salts benefit from enhanced nucleophilicity over tosylated amines and the sulfonate esters are more effective leaving groups than halides. A dipolar, aprotic solvent is required.

2) Tem plate110 - By coordinating the linear precursors around a metal ion, so defining their orientation, the tem plate effect ensures that the target ring is obtained in high yield.

3) High D ilution111 - Maintenance of unusually low reactant concentrations limits the occurrence o f further oligomerisation. The entropie terms favouring chain growth over cyclisation become less statistically favoured at high dilution.

There are many review artjc iesn*.>i3.iu.iij.ii*.ii7 pertaining to the synthesis of macrocyclic ligands and so it is intended to simply highlight the field with a few selected examples.

1,4,7-trithiacyclononane

c •

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— O

Figure 1.23 Preparation o f 1,4,7-trithiacyclononane.

Although 9S3 has been prepared by a number o f routes, some in high y ield ,'" the technique shown in Figure 1.23 benefits from its single step ap proach."9 The use o f caesium carbonate to mediate cyclisation reactions was first introduced by Kellogg and co-workers.70 The caesium ions prom ote ring formation by means o f very weak ion-pairing, thereby generating an exceptionally nucleophilic thiolate anion. High reactivity ensures low reactant concentrations so leading to the desired intramolecular reaction. A DMF solution o f 2- mercaptoethyl sulfide and 1,2-dichloroethane is added dropwise to a DMF suspension of

caesium carbonate under a dinitrogen atm osphere. After heating at 100°C for twelve hours, conventional work-up and vacuum sublimation leads to the pure macrocycle in 50% yield.

Figure 1.24 Preparation o f 1,4,8,11-tetrathiacyclotetradecane.

Historically, the development o f polythiamacrocyclic chemistry was hindered by the low synthetic yields obtained from the preparative techniques then available. The synthesis of 14S4 in 1969 serves to illustrate this w ith a yield of ju st 7-5% .67 Using an analogous procedure (see Figure 1.24) combined with hig h dilution conditions the yield was boosted to 5 5 % .170 The sodium salt o f 1,4,8,11-tetrathiaundecane is prepared by addition o f sodium ethoxide to the dithiol. Dropwise addition, o v e r three hours, o f a dilute solution (0 .1 8 mol dm *) dibromoethane to the resulting m ixture produces the desired macrocycle in 55% yield after purification by vacuum sublimation.

1,4,8,11-tetrathiacyclotetradecane

N o O E t/ttO H

l,4,7-triazacyclononaneIJI

This synthesis provides an example o f the Richman-Atkins procedure. The mechanism is quite general and can be used to prepare 9- to 2 1-membered saturated macrocycles containing three to seven donor atoms (nitrogen and/or oxygen). Polymeric side products are negligible and so do not pose a problem. The overall reaction scheme is shown in Figure 1.25. The tosylated derivatives are obtained by reaction o f the diam ine and the diol with p- toluenesulfonyl chloride. Addition o f sodium hydride (50% oil suspension) to the di(p- tolunesulfonyl)ethane-1,2-diamine yields the disodium salt to which the di {p-

toluenesulfonyloxy)ethane can be introduced. The hydrolysis step o f the cyclic tritosylate is efficiently achieved in concentrated sulfuric acid at 120 °C for three days. Final purification is best accomplished using column chromatography.

1,4,8,12-tetraazacyclopentadecane1“

The most commonly used method o f ring closure via the template effect invokes the Schiffs base condensation o f a diketone with the metal-coordinated primary amine groups o f an acyclic multidentate ligand. This preparation is shown schematically in Figure 1.26. N ,N '- bis(3-am inopropyl)-1,3-propanediamine is added to an aqueous solution of nickel(II) chloride, followed by aqueous glyoxal. Hydrogen reduction takes place over Raney nickel during 24 hours. Addition o f N aCN effects decomplexation o f the nickel ion. Conventional work-up procedures then afford the free ligand in 48% yield.

Dihenzo-18-crown-6 and dicyclohexyl-18-crown-^123

The formation o f the eighteen-membered ring is facilitated by the presence o f the sodium ions in this example o f a template synthesis. T h e dicyclohexyl- 18-crown-6 formed contains a mixture o f all stereoisomers. The overall p rocedure is shown in Figure 1.27. Treatment of catechol with base forms the dianion. D ropw ise addition of 2,2'-dichlorodiethyl ether to this nucleophile results in a 'quadruple W illiam son’ reaction. Work up, by extraction, precipitation with acetone and recrystallisation delivers the product in 40% yield. Hydrogenation o f the aromatic derivative req u ires an autoclave. Purification, including an acid-washed alum ina column, leads to the d esired compound as a diastereoisomeric mixture in 60% yield.