Imine-based macrocycle synthesis

Scheme 1.1 (a) Imine-based macrocycle synthesis templated by ZnCl2 [1J] (b) Fe(ll)-... 

This approach can arguably be traced back to the nineteenth century, and the studies of Emil Fischer on carbohydrates and of Werner on coordination complexes. When Watson and Crick discovered the DNA double hehx in 1953 they reahzed immediately that its repHcation involved a templated synthesis [11]. In retrospect, it is dear that the metal-ion-templated synthesis had been achieved as early as 1926 when Seidel reacted 2-aminobenzaldehyde with ZnCh [12]. An imine-based macrocycle bound to zinc was formed, but was not identified until much later (Scheme 1.1a) [13]. A few years later, Fe(ll) phthalocyanine was formed... 

Manganese(II) has been commonly employed as a templating metal ion for the synthesis of a wide range of other mixed donor (oxygen/nitrogen) Schiff base macrocycles (and/or their imine-reduced derivatives). 

The final example by Severin et al. indicates as to where the dynamic covalent synthesis of superstructures may lead to." Driven by a previous observation that boronic ester-based macrocycles with pendent aldehyde groups could be functionalized with amines, they investigated the possibility of performing boronic ester and imine condensation reactions simultaneously. In the first attempt, a mixture of 3-formylphenylboronic acid 14, pentaerythritol 15, and 1,4-diaminobenzene 16 in tetrahydrofuran/toluene was heated in a flask equipped with a Dean-Stark trap (Figure 8a). Analysis of the formed products revealed the formation of macrocycle 17 as a result of a [4-F2-F2] condensation with a yield of 44%. Prompted by this success, they performed the polycondensation reaction on a mixture of 4-formylphenylboronic acid 18, pentaerythritol 15, and tris(2-aminoethyl)amine 19, rather than the linear 1,4-diaminobenzene (Figure 8b). With a remarkable yield of 82%, the macrobicyclic cage 20 was spontaneously formed as a result of the condensation of six boronic acid molecules, three pentaerythritol molecules, and two triamine molecules. A total of 18 covalent bonds were... 

Fig. 9.15 Synthesis of Schiff base macrocycles a 30, b 32, and c 34 using one-pot macrocyclization reactions aided by hydroxyl groups that form the H-bonds with imine N-atoms and direct the macrocyclization reactions...

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 ... 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

The standard synthesis for cyclam was developed by Barefield and Wagner in 1976.29 They used similar starting materials to the van Alphen procedure but the cyclisation yield is improved through the use of a nickel (II) template. Glyoxal completes the macrocycle by a Schiff base condensation reaction. The resulting imine functionalities are reduced with sodium borohydride to leave the complexed macrocycle. The metal ion is then removed by reaction with cyanide and the free ligand extracted with chloroform (Scheme 3.19). Yields are typically in the region of 60%. 

Fig. 9 (a) Reversible synthesis of a bisiminoboronate-guanosine derivative from guanosine and a bisiminoboronic acid, (b) Dynamic polymeric networks based on reversible boroxine formation, (c) Formation of a macrocycle in a [4 + 4 + 2] condensation via simultaneous reversible formation of imine bonds and boronic esters... 

---