Macrocyclic imines, reduction

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. 

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.

The reverse reaction, namely hydrogenation, has also frequently been used to decrease the degree of unsaturation present in macrocyclic systems - typically converting imine linkages to amine groups. Such hydrogenations have usually been performed catalytically (for example, using H2 in the presence of Raney nickel or a precious metal catalyst) or by means of chemical reductants such as sodium borohydride. 

Secondary and tertiary amines can be obtained if the hydroformylation of olefins is conducted in the presence of primary and secondary amines under elevated hydrogen partial pressures. Here the rhodium catalyst is involved in both steps, the hydroformylation of an olefin as well as the hydrogenation of the imine or enamine resulting from a condensation of the oxo-aldehyde with the amine (Scheme 14). This combination of hydroformylation and reductive amination is also known as hydroaminomethylation and has been applied to the synthesis of various substrates of pharmaceutical interest [55-57] as well as to the synthesis of macrocycles [60-63] and dendrimers [64,65]. 

A number of pendant arm ligand derivatives based on hexamine macrocyclic backbones have been reported." One such species was formed by the [2 -f 2] Schiff base condensation between 3,3-iminobis(propylamine) and diformyl-p-cresol followed by sodium borohydride reduction of the four imine functions so generated. Potentiometric studies indicate that a range of both mononuclear and dinuclear species are formed in solution with manganese(II) incorporating various both protonated and nonprotonated forms of the ligand. 

The reactions of simple imine complexes are mainly restricted to hydrogenation or reduction by hydrides or by addition of nucleophiles such as alcohols. For example, complexes of macrocycles (18) undergo catalytic reduction to generate two chiral centres.66 Sodium borohydride has been used to reduce the imine complexes shown in equation (3).67 This technique enables convenient removal of the metal and the consequent synthesis of the reduced free macrocycles. Complexes of the aldimine (20) undergo nucleophilic addition of alcohols.49... 

Curtis-type macrocyclic complexes are sufficiently stable to undergo a variety of oxidation and reduction processes to yield a range of complexes containing from zero to four imine linkages (Scheme 10).40 66 84 85 96 The oxidative dehydrogenation process is metal-ion dependent, as illustrated by the alternative ligand structure developed from the iron(II) complex (equation 14) 97 9S... 

The metal ion does, however, introduce a new subtlety into these reductions. The reduction of the two imine groups in the nickel(n) complex 4.10 is readily achieved with Na[BH4], The free tetraamine ligand would be expected to exhibit a facile pyramidal inversion at each nitrogen atom, whereas in the nickel(n) complex this inversion is not possible without significant weakening (or breaking) of the Ni-N bonds. In macrocyclic complexes it is very often found that the complex obtained by the reduction of a co-ordinated imine does not possess the same stereochemistry as that obtained by the direct reaction of the free amine with metal ion. 

Figure 6-15. The reduction of a co-ordinated imine macrocycle may lead to a number of different diastereomers of the complex of the saturated macrocyclic ligand...

Stoddart and coworkers have used imine condensation in two different contexts to form interlocked molecules. The authors have modified the crown ether component of their dialkylammonium / D B24C8 system to incorporate reversible imine subunits which allow for dynamic clipping around dialkylammonium cation 91 [60], Three diformyl spacers (92-94) have been investigated with the same acyclic diamine 95 for their thermodynamic stability and kinetics of macrocyclization (96). However, reduction with BH3 to the kinetically trapped macrocyclic secondary diamine has only been reported for reaction of the 2,6-diformylpyridine derivative (Scheme 10.19 97) [60a]. 

Another recent innovation regarding the use of imine chemistry in DCC relies on an original way to freeze the equilibrating mixture by Ugi reactions [27]. In other words, this consists in conjugating a reversible reaction of imine condensation with an irreversible Ugi reaction. The latter step therefore represents an alternative to the more widespread reduction of imines with borohydrides. Wessjohann and coworkers recently prepared a library of macrocyclic oligoimines by condensation... 

Diastereoselective reaction of diimines with sodium in ether leads to the formation of macrocyclic ethers of the type (32 equation 67) and (33 equation 68) in modest yields, However, there are no reports of examples using the templating effect of low-valent transition metals, as used to good effect for intramolecular carbonyl couplings. Electrochemical reduction of imines has been used to produce a variety of bicyclic structures via cyclization-aromatization (equation 69) or transannular cyclization (equation 70). ... 

A limited number of asymmetrical compartmental macrocycles having two amine and two imine donors, prepared by partial reduction of the tetraimine macrocycle, are also known. Thus, a partially reduced macrocycle is obtained by the reaction of (57a) and (57b) with o-phenilenedia-mine in methanol.14 The reduction of two imine groups takes place during the synthetic procedure. The nature of this macrocycle was confirmed by X-ray determination.14... 

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