Direct macrocycle syntheses

A range of direct syntheses have been performed under conditions of moderate to low dilution but have still led to isolation of the required cyclic product in reasonable to high yields. In some of these so-called direct syntheses, ions such as sodium or potassium were present in the reaction solution. It has often been suspected (and has been documented for a number of systems) that these ions may also undertake a template role. In this manner, such syntheses may fall between the extreme direct and in situ categories mentioned at the beginning of this chapter. There is little doubt that such an effect is the source of the larger-than-expected yields obtained in some syntheses of this type. Nevertheless, this is not always the case and there are further mechanisms for assisting cyclization which may operate for particular systems. For such systems, special circumstances usually appear to be present. Examples of this latter type are discussed later in this chapter. 

The above syntheses constitute an extension of earlier work in which precursors of type (53, X = AsCH3 and PC6H5) were employed for the synthesis of a range of three-donor cyclic systems of general structure (55) (Kyba Chou, 1980). Yields for these reactions ranged from 19 to 40%. The arsenic derivatives of type (55) were the first macrocycles incorporating this heteroatom to be reported. 

Cyclizations at moderate to low dilution. A series of A-tosylated (tosyl = p-toluenesulphonyl Ts) macrocycles may be readily prepared by direct means starting from pre-tosylated reactants (Richman Atkins, 1974). Equation [2.3] summarizes an example of this useful reaction type. Reasonable yields (often considerably better than 50%) of such cyclic tosylated products may be achieved in spite of the fact that such reactions are usually performed at moderate dilution. A number of procedures exist for detosylation of these products to yield the corresponding rings containing only secondary nitrogens a common method has been to treat the tosylated intermediate with hot concentrated sulfuric acid for several days. 

Despite the non-use of high-dilution conditions, the reasonable yields of cyclic products from syntheses of the type illustrated by [2.3] are believed to stem, in part, from the influence of the bulky tosyl groups. 

These groups will reduce the number of conformational degrees of freedom (such as bond rotation) in the reactants and/or intermediates. It is this reduction which is thought to facilitate cyclization relative to polymerization for these systems in essence, the enhancement of cyclization can be considered to be largely a consequence of favourable entropy effects. 

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The synthesis of a small library of very large (up to 60-membered) steroid/ peptide hybrid macrocycles has been achieved using double and fourfold Ugi reactions. This type of compound has not previously been described in literature. Neither have multicomponent reactions been used so far to form directly macrocycles of this size. In fact, synthetic macrocycles of this size with this structural complexity are very rare. 

Examples of seven-coordination in pyridine-containing macrocycles have also been osberved. Thus the iron(TI) complexes [Fe(L)X,] xhLO (L = 126 X = halide or pseudohalide) are formed923 when the corresponding seven-coordinate iron(lll) complexes are reduced with aqueous sodium dithionite in the presence of excess NaX or by the direct template synthesis with 2,6-diacetylpyridine and the corresponding tetramine in the presence of iron(IJ). The triimine moiety gives rise to a strong... 

Titanium(rv)-mediated tandem deprotection-cyclodehydration of a protected cysteine A -amide was used in the synthesis of thiazolone- and thiazole-containing heterocycles as building blocks for macrocycle synthesis <20000L3289>. Similarly, the directly connected thiazole-oxazole ring system present in microcin B17 was synthesized from aminoacetonitrile hydrochloride <1996JOC778>. 

Cation-directed synthesis of organic macrocycles such as crown ethers is a well-established procedure that has been widely utilized for many years. However the use of anionic species for this purpose has only recently begun to be exploited. One of the first examples of anion-directed organic synthesis is the oligopyrrolic macrocycle 13 reported by Sessler (see Fig. 4). This macrocycle was... 

Scheme 1.4 An electron-rich dimethoxybenzene template was used to direct the synthesis of a naphthalenediimide-based macrocycle 4 [21]. Addition of dinaphtho-crown ether 6 led to the formation of [2]catenane 5 [22].

A new template-directed catenane synthesis was published by Hunter in 1992 [30]. Starting from the intermediate 14 and isophthalic acid dichloride 15, he succeeded in interlocking two identical macrocyclic tetraamides to the catenane type 16 (R=H) in remarkable yield (29 %). 

In the course of experiments directed at the synthesis of open-chained equivalents of macrocyclic polyethers (see Chap. 7), Rasshofer and Vogtle found that 9 or its derivatives were formed rather than the desired compounds . Although the yields obtained by this method are modest, the facts that the reaction is conducted without the use of high dilution and in one-pot recommend it. 

An attractive approach to cyclocarbon molecules required the preparation of the higher carbon oxides 6-8 followed by either thermal or photochemical CO-elimination (Scheme 2) [41, 521. The direct synthesis of 6-8 by oxidative macrocyclization of 9 was not possible, since all attempts to prepare the latter... 

Template effects have been used in rotaxane synthesis to direct threading of the axle through the wheel. Since macrocycHc compounds such as cyclodextrins, crown ethers, cyclophanes, and cucurbiturils form stable complexes with specific guest molecules, they have been widely used in the templated synthesis of rotax-anes as ring (wheel) components. Here, we briefly discuss macrocycles used in the synthesis of rotaxane dendrimers and their important features. 

Based on studies showing that the close proximity between the porphyrin and the Cm is essential for the observation of an electron transfer process, Fukuzumi and co-workers have prepared the porphyrin-C6o diad 41, in which the C6o-pyrrolidinyl moiety is directly connected to the meso position of the porphyrin macrocycle (Scheme 12) <03JPC(A)8834>. The strategy adopted for the synthesis of the starting porphyrin involved the 2+2 condensation of a maso-unsubstituted dipyrrylmethane with 3,5-di-tert-butylphenyl-substituted dipyrrylmethane and 3,5-di-tert-butylbenzaldehyde, to give 39, in 11.5% yield. Subsequent Ni(II) metallation, followed by Vilsmeier-Haack formylation and demetallation, gave rise to 40 which was used as the 1,3-dipole precursor this dipole in the presence of N-methylglycine and C6o, yielded the expected diad 41. 

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