Macrocycles imines

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

It should be noted that while TE domains represent the most common solution in releasing macrocyclic NRPs and PKs, other pathways are known. For instance, in the biosynthesis of cyclosporine, the cyclization is proposed to be catalyzed by the most downstream C-domain [48]. Macrocyclization can also occur under reduction of a carbonyl group mediated by a reduction domain (R-domain) as proposed in the synthesis of the macrocyclic imine nostocyclopeptide [49]. The synthetic utility of these cyclization strategies has not yet been reported. 

Imines derived from macrocyclic ketones (C10 to C 15 ) and (- )-(S)-a-(methoxymcthyl)benzene-ethanamine are successfully deprotonated using LDA ( —25 JC. THF. 1 h)9. In contrast to azaenolates of C0- to C8-membered cyclic ketones, which show only E geometry, Z-isomers are observed with macrocyclic imines. As evident from H-NMR data, azaenolates of cyclodecanone imines generated under these conditions are a mixture of E- and Z-isomers (33 66), whereas azaenolates of cyclododecanone and cyclopenladecanone imines arc formed as the pure. E-isomers (see Table 3). Upon heating the solutions of metalated imines to reflux for 1 hour, complete isomerization to the thermodynamically more stable Z-isomers occurs. 

The stereoselective synthesis of bis-(3-lactams grafted macrocycles has been described [109]. Macrocyclic imine and phenoxy acetyl chloride in the presence of triethylamine produced a diastereomeric mixture of cis macrocyclic bis-(3-lac-tams (Scheme 36) by the Staudinger reaction. 

In a similar way, formation and subsequent hydrolysis of bis-p-lactams provide a route to peripheral functionalization of macrocyclic imines. For example, racemic bis-p-lactam 15, Scheme 5, which is formed upon Staudinger reaction of imine 14 and the ketene originated from phenoxyacetyl chloride and triethylamine, led to C2 symmetric amino acid 16 in high yield [59]. 

Figure 6-14. The reduction of co-ordinated macrocyclic imines provides a method for the preparation of macrocyclic amines. The reaction above illustrates one of the standard methods for the preparation of cyclam. The metal ion may be removed from the nickel(n) complex by prolonged reaction with cyanide.

Enantiopure fused oxopiperazino-/3-lactams have been produced by application of the Staudinger reaction with 5,6-dihydropyrazin-2-(l/7)-ones and the /3-lactams were converted to the 2-oxopiperazine-3-acetic acid esters in good yield with no epimerization (Equation 86) <2006TL8911>. Fused /3-lactams have been formed from macrocyclic imines by use of the Staudinger reaction (see Section 2.04.9.7). When phenoxyacetyl chloride and triethylamine were used, the best yields (45-52%) of the fused /3-lactams were obtained with dry dichloromethane as solvent <2006TL8855>. 

In the beginning of the macrocycle chemistry era, thiaaza-crown macrocycles in the form of cyclic bis Schiff bases were prepared by template-assisted ring-closure reactions. In general, the imine double bonds were not reduced and the template metal ions were not removed (Thompson and Busch, 1964 Urbach and Busch, 1973). These macrocyclic imine complexes, which may be used as starting materials for the preparation of thiaaza-crowns, are not listed in the tables at the end of this chapter because this book describes only saturated macrocycles. The two general methods used to prepare the thiaaza-crown macrocycles are listed here. 

All the macrocyclic imines possess several characteristics in common (1) a six- or seven-membered imino ring (2) a cyclohexenyl ring with spiro linkage to the cyclo-imine (except for the prorocen-trolides with condensed rings) (3) para-substitution on the cyclohexenyl ring (4) a macrocycle... 

Diagnostic Structural Features of the Major Macrocyclic Imine Subgroups... 

All of the cyclic imine toxins (except spiro-prorocentrimine) may be structurally classihed as macrocyclic polyethers. Although the elucidation of biosynthetic pathways for polyether dino-flagellates toxins is limited to the ladder frame polyether brevetoxins [40], the linear polyether dinophysistoxins DTX4 and DTX5 [11,41] and the macrocyclic imine des-methyl spirolide C... 

The environmental effects on production of macrocyclic imines are also poorly understood in the race to discover yet more new derivatives. Current evidence suggests that these compounds are constitutively produced, that is, a given strain is either toxigenic or not—these are not classic stress metabolites that can be induced by nutrient or light deprivation. Nevertheless, most of these conclusions are based upon relatively few studies, mostly on spirolides, and these comparative investigations must be extended to the other toxin groups. 

Finally, the oral toxicity and risks to human health posed by macrocyclic imine toxins has not yet been resolved. There have been no long-term trials on the affects of chronic sublethal exposure to cyclic imines in any animal model or even any concerted attempt to predict such consequences based upon pharmacological first principles reported in the literature. Development of a rational and precautionary strategy for human health protection will require more comprehensive knowledge on the toxicology and pharmacological implications of these compounds than is currently accessible. 

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