Synthesis of the cryptand

The macrocyclization step involving the two bifunctional compounds 2 and 3 is performed under high-dilution conditions. For this reaction there is a need to use a specially adapted apparatus illustrated in Fig. 5.3. The crucial features of this reaction are the precision addition funnels which have to deliver the solutions at a low and constant rate and the vigorous stirring ensured by a high-speed motor and by the creased flask. 

One can note that for this step the ratio of reagents 3 2 is 2 1, the excess diamine, 3, playing the role of base which takes up the hydrogen chloride liberated by the coupling reaction. The separation of the monocyclic diamide 4 from the reaction mixture containing amide oligomers is easy as the latter 

The bicyclization step is accomplished under identical conditions to the first macrocyclization step, the base being in this case added triethylamine. The reduction of the bicyclic amide 6 has to be realized with diborane (LiAlH4 cleaves the macrobicyclic system). Note that there is no need to isolate the intermediate aminoborane 7 the crude mixture obtained after 

Caution Carry out all procedures in a well-ventilated hood, and wear disposable vinyl or latex gloves and chemical-resistant safety goggles. Oxalyl chloride is a very dangerous material. 

Introduce with care the stirring bar in the 500 mL round-bottomed flask. Fill the drying tube with drierite. 

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Template synthesis of the cryptand L1488 is carried out under phase-transfer catalysis conditions, using tetrabutylammonium iodide (Eq. 6.59) [168]. 

The synthesis of 1,10-diaza-l 8-crown-6 (9) has been an important problem because this is the key starting material in the synthesis of numerous cryptands (see Chap. 8). Although first synthesized some years ago, the process has recently been patented. Di-azacrown 9 is prepared by a high dilution condensation of 1,8-diamino-3,7-dioxaoctane with ethylene glycol diacetyl chloride. The resulting diamide is then reduced with lithium aluminum hydride to give 9 in 56% overall yield from the open-chained diamine. The synthesis is illustrated In Eq. (4.8), below. 

It should be noted here that the brevity of this section is due in part to the fact that essentially this single method is utilized in the synthesis of most cryptands which have... 

An interesting alternative approach to the synthesis of a cryptand having nitrogen atoms in the bridges was presented by Newkome and coworkers. This group condensed triethanolamine with 2,6-dichloropyridine in a relatively straightforward but low yield (5%) nucleophilic aromatic substitution to form 7, illustrated below in Eq. (8.6). The identity of the compound was confirmed by X-ray structural analysis. 

We have noted above (Sect. 8.3) that certain substituted benzoic acids have been used in the synthesis of endolipophilic cryptands but it is the glycerol and penta-erythritol units which have been used most commonly in this application. These are discussed separately, below. 

The various possible strategies for the synthesis of macropolycyclic cryptands are outlined in Figure 14. 

As seen in Figure 14 the ellipsoidal cryptands may be prepared by the simultaneous formation of three bridges. This route has found limited use due to low yields but has been employed in the synthesis of some cryptands including the tris-pyridino system (36) (81TL3035) and bis-tren (18) (80UP52100). 

Jean-Marie Lehn synthesis of the first cryptands... 

Amide formation via reaction of amines with an acid chloride as in the synthesis of various cryptands (Scheme 3.6). 

Menif, R. Reibenspies, J. Martell, A. E. Synthesis, protonation constants, and copper(II) and cobalt(II) binding constants of a new octaaza macrobicylic cryptand (MX)3crystal structures of the cryptand and of the carbonato-bridged dinuclear copper(II) cryptate, Inorg. Chem. 1991, 30, 3446-3454. 

The synthesis of macropolycyclic cryptands generally involves stepwise, straightforward pathways (18, 20, 33) based on the successive construction of systems of increasing cyclic order macrocyclic, macrobicyclic, and so on. Newkome has recently reported a satisfactory quaternization-dealkylation procedure, facilitating the synthesis of 8 (34). Unlike the synthetic approaches to simple crown ethers (10,... 

To monitor tumor response to capecitabine therapy noninvasively, Zheng and co-workers, from the Indiana University School of Medicine, developed the synthesis of the fluorine- 18-labeled capecitabine as a potential radiotracer for positron emission tomography (PET) imaging of tumors.28 Cytosine (20) was nitrated at the C-5 position with nitric acid in concentrated sulfuric acid at 85°C, followed by neutralization to provide 5-nitrocytosine (27) in moderate yield. This nitro pyrimidine was then carried through the glycosylation and carbamate formation steps, as shown in the Scheme below, to provide the 6/s-protected 5-nitro cytidine 28 in 47% for the three-step process. Precursor 28 was then labeled by nucleophilic substitution with a complex of 18F-labeled potassium fluoride with cryptand Kryptofix 222 in DMSO at 150 °C to provide the fluorine-18-labe led adduct. This intermediate was not isolated, but semi-purified and deprotected with aqueous NaOH in methanol to provide [l8F]-capecitabine in 20-30% radiochemical yield for the 3-mg-scale process. The synthesis time for fluorine-18 labeled capecitabine (including HPLC purification) from end of bombardment to produce KI8F to the final formulation of [18F]-1 for in vivo studies was 60-70 min. 

Very successful results in the synthesis of simple cryptands stimulated more systematic studies in this field. First of all, it was interesting to test the influence of the length of the bridging component on the yield obtained for the double-quatemization reaction41. ... 

The saturated aza-oxa crown ethers were first synthesised as intermediates in the synthesis of the nitrogen cryptands.1 The reaction conditions used for the formation of these macrocycles involved the high-dilution technique. In this versatile method, a diamine and a diacid chloride are simultaneously added in the presence of triethylamine to a large volume of solvent, usually toluene, over an extended period of time. The major product from such a reaction is the [1+1] cyclised product, although the [2+2] adduct can often be isolated as well, in low yield. Whilst this method is still sometimes used,2,3 particularly for cryptand synthesis (Chapter 5), it has been superseded by methods that are more convenient and which proceed under medium dilution. 

The cryptands were first prepared in 1969 and form a series of well-defined complexes (cryptates) with alkali and alkaline-earth cations. In this chapter the synthesis of the first cryptand, 8, a macrobicyclic ligand, will be described1,2. The schematic representation (Fig. 5.1) shows that one deals with a multi-step synthesis. The major drawback of this approach is the rather large number of synthetic steps, but the route offers the advantage of being able to construct unsymmetrical compounds (A B C). 

Scheme 1 The synthesis of simple cryptands via the high-dilution addition of acyl chlorides to azacrownethers...

Recently the synthesis of the macrocyclic tetramine below (Scheme 3) was reported [5]. The encrypted nitrogens are very basic (pK, 24.9 in MeCN) and it was observed that chloroform is dehydrohalogenated in its presence to give dichlorocarbene. Because this new cryptand and related cage structures shown below (such as the diamine [6], the commercially available diamine triether [7] and the pentamine [8], Scheme 3) have thus far not experienced significant application in organic methodology, they will not be further treated herein. 

Park and Simmonds Katapinand anion hosts 1969 — Jean-Marie Lehn Synthesis of the first cryptands... 

Following these preliminary studies, it was possible to design host molecules of the type shown in 15, based upon diaza-12-crown-4 and diaza-15-crown-5 receptors, which would form inclusion complexes with either one bisalkylammonium cation H3N (CH2) N H3 21 or two simple primary alkylammonium cations RN+H3 22. The use of tricyclic compounds of this type has been described elsewhere [23]. The cryptands 23, which are based upon two identical diaza-crown ether moieties, were synthesised by the simple one step procedure shown in Scheme 1, whereas it was necessary to use the stepwise procedure [24] summarised in Scheme 2 for the synthesis of analogous cryptands 24 in which the two diaza crown ether moieties are different. 

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