Templates for macrocyclization

The use of metal ions as templates for macrocycle synthesis has an obvious relevance to the understanding of how biological molecules are formed in vivo. The early synthesis of phthalocyanins from phthalonitrile in the presence of metal salts (89) has been followed by the use of Cu(II) salts as templates in the synthesis of copper complexes of etioporphyrin-I (32), tetraethoxycarbonylporphyrin (26), etioporphyrin-II (78), and coproporphyrin-II (81). Metal ions have also been used as templates in the synthesis of corrins, e.g., nickel and cobalt ions in the synthesis of tetradehydrocorrin complexes (64) and nickel ions to hold the two halves of a corrin ring system while cycliza-tion was effected (51), and other biological molecules (67, 76, 77). 

Maximum value of templates will be achieved only through an intimate understanding of how they function. As pointed out in the discussion of Fig. 2, a template for macrocycle formation need only consist of a molecular turn, an anchor, and a complementary reagent to link the two ends of the turn. Anchors and turns recur repeatedly in template reactions and are among the most important... 

As mentioned already, Curtis reported the first (Curtis, 1960) of a number of pioneering template reactions for macrocyclic systems which were published in the period 1960 to 1965. In the Curtis synthesis, a yellow crystalline product was observed to result from the reaction of [Ni(l,2-diaminoethane)3]2+ and dry acetone. This product was initially thought to be a bis-ligand complex of the diimine species (58). However, the stability of the product in the presence of boiling acid or alkali was... 

Kinetic aspects of the use of alkali metals as templates for the formation of other crowns have been studied in some depth (Mandolini Masci, 1984). The results of such investigations parallel the previous observations - namely, that the catalytic efficiency of such ions in promoting cyclization shows a strong tendency to parallel their strength of binding with the crown products (this in turn often correlates with the fit of the metal ion for the macrocyclic cavity in the product). 

In the following sections, examples of hydrogen-bonding templates for the synthesis of macrocycles, cages, interlocked species, helicates and for the photochemical reaction of olefins will be discussed. The use of hydrogen-bonding templates in dynamic combinatorial libraries will also be presented. 

Macrocyclization of esters of allylglycine with diols has been successfully used to prepare derivatives of 2,7-diaminosuberic acid [861,864]. The latter are surrogates of cystine, and therefore of interest for the preparation of peptide mimetics. For unknown reasons protected allylglycine derivatives can not be directly dimerized by self metathesis [864]. However, catechol [864], ethylene glycol [861], and 1,2- or 1,3-di(hydroxymethyl)benzene derivatives [860] of allylglycine are suitable templates for the formal self metathesis of this amino acid via RCM. 

The reaction sequence outlined in Scheme 12 illustrates how macrocyclic polyether-thiono diesters such as RR)-lfi6 can be prepared (184) from 0,0-dimethyl 2,6-pyridinedicaibothiolate and (RR)-S4, Potassium thiocyanate forms a 1 1 crystalline complex with (RR)-1S6 and presumably the potassium ion serves as a template for the (1 -I-1) cyclization. Raney nickel desulfurization of (/ R)-186 yields the chiral pyridino-18-crown-6 derivative RR)-191. 

Aminobenzaldehyde structural fragments have been incorporated into diatninodialdehydes, which can act as precursors for macrocyclic complexes. The initial work in this area involved template reactions between dialdehydes and diamines in the presence of hydrated metal(II) acetates in methanol (equation 26).153-155 Benzene-1,2-diamines could also be used in these syntheses. 

The construction of suitable dialdehydes for macrocycle formation by metal template methods has more recently been extended to include a range of oxamides. In the first case, the simple 2,2 -(oxalyldiimino)bisbenzaldehyde underwent rather sluggish template reactions but yielded extremely stable macrocyclic complexes (Scheme 31).167 168 These products could be sulfonated in oleum, without destruction of the macrocyclic structure. This general synthetic route has been extended to include reactions of diketones and the formation of complexes of macrocyclic ligands such as (70) and (71). Attempts to incorporate a malonamide fragment in place of the oxamide... 

There are also potential disadvantages associated with the use of template methodology for the formation of macrocyclic ligands. Perhaps the most important is the observation that not all metal ions can act as templates for the specific cyclisation reactions of interest. In many cases it may not be trivial to find an appropriate template ion (if indeed... 

In this section we will consider the choice of particular metal ions for particular template syntheses. We noted earlier that not all metal ions could act as templates for a particular reaction. What criteria can we use to match a potential template ion to a given macrocyclic product To a certain extent, the choice of a template ion is dictated by experience, intuition and prejudice. In reality, macrocyclic chemists have their own favourite metal ions that they tend to try first of all Very often, the first choice of a template ion is nickel(n), and this probably partly explains the vast number of nickel(n) macrocyclic complexes which have been prepared. 

The pentadentate nitrogen donor ligand 6.30 has a hole size of about 0.7 A and we predict that we could use a first-row transition metal ion as the template for its synthesis. The macrocycle is best prepared by the condensation of 6.31 with glyoxal about a nickel(n) template. In this condensation, most other metal ions are ineffective as templates. 

In many cases it is possible to utilise the hole size effects for the synthesis of specific types of macrocycle. Thus, a tetradentate macrocycle (6.33) is expected to be obtained from a template condensation of 2,6-diacetylpyridine with 1,5,9-triazanonane in the presence of small, first-row transition metal dications. The hole size of 6.33 closely matches the size of these metal ions. This is indeed what happens when Ni2+ (r = 0.8 A) is used as a template for the condensation and the nickel(n) complex of 6.33 is obtained in good yield (Fig. 6-32). However, when Ag+ (r = 1.0 A) is used as a template, the metal ion... 

One of the more interesting hole size effects arises when the metal ion successfully acts as a template, but is labilised in the macrocyclic complex that is formed. The consequence of this is that the metal ion acts as a transient template. The metal ion may be viewed as pre-organising the reactants to form the macrocyclic products, but then finding itself in an unfavourable environment after the cyclisation. The effect is best observed when a small metal ion is used as a template for a reaction that can only give one product (or at least, only one likely product). What happens to the metal ion when it finds itself in an environment that does not match up to its co-ordination requirements The most useful consequence would be labilisation of the metal ion, with resultant demetallation and formation of the metal-free macrocycle. This would overcome one of the major disad-... 

Jeremy K.M. Sanders Gdansk, Poland The Ins and Outs of Templating A Dynamic Future for Macrocyclic Chemistry... 

However, produced a neutral [2]catenane (Scheme 11.5) [lib] bearing a mechanically interlocked bis-NDI macrocycle in 53% yield. This yield is far more attractive for a bis-NDI macrocycle than the 10% yield originally obtained in macrocycles [30a]. This approach involved an oxidative coupling of two acetylenic naphthalene diimides in the presence of crown ether. The efficiency of the catenation can be attributed to the crown ether component acting as a permanent template for the forming cyclophane. 

The most common template syntheses have been for macrocycles containing the donor atoms in the ratio of 2 2, e.g., reaction of the Ni(II) complexes (LXXXV), formed by condensation of oc-diketones with /i-mercaptoamines in the presence of Ni(II) ions, with a,a -dibromo-o-xylene affords LXXXVI through a kinetic template effect (see Section II,A) (136-138). Reaction with acetone links the coordinated amine groups of dithiodiamine to form the macrocycle complex LXXXVII (23). 

An effective template metal ion binds strongly to the donor atoms of the macrocycle or its precursors, e.g., K+ is the most common template for synthesis of crown ethers and forms definite complexes with a wide variety of crown ethers. 

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