A method for the synthesis ofaza-crown compounds by the intramolecular cyclization of co-amino acids with subsequent reduction of the lactam to a macrocyclic amine was developed. 1,8-Diazacyclotetradecane and 1,8dioxa-4,11-diazacyclotetradecane were synthesized in preparative yields. The structural assignments' were made using the IR, 1H and 1~C NMR, and mass spectra.
A significant number of the heretofore described methods for the synthesis of macroheterocyclic compounds make it possible to construct molecules, the structural formulas of which have relatively high symmetry (no lower than C2v ). "Symmetrical" reagents, i.e., reagents, the structural formulas of which have a plane of symmetry, are commonly used for unambiguous macrocyclization. Attempts to use "unsymmetrical" reagents lead to difficult-to-separate mixtures of isomers.
The method that we propose to synthesize macroheterocycles does not have the indicated drawbacks. It makes it possible to obtain aza-crown compounds with any symmetry (also including those with rather low symmetries --C 2 and lower) with arbitrary ring sizes, sets of heteroatoms, and side groups. The method consists in the realization of the intramolecular cyclization of co-amino acids to the corresponding lactams with subsequent reduction of the amide to a macrocyclic amine [1].
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The use of co-amino acids for the synthesis of terminal diamines, which are converted to macrocyclic tetraamides by reaction with activated dicarboxylic acid esters, has been described [2].
We used our method to synthesize two cyclam analogs --1,8-diazacyclotetradecane (XIV) and 1,8-dioxa-4,11diazacyclotetradecane (XXIII). In the course of the synthesis of XIV we tested various protective and activating groups and varied the cyclization and reduction conditions. These experiments made it possible to select the optimum conditions for the reactions presented in the scheme.
For the construction of diaza-crown compounds by the proposed method one must have a sufficiently long co-amino acid with a protected amino group and an activated COOH group.
The desired 13-aminotridecanoic acid derivatives were obtained by condensation of N(6)-protected derivatives of 6aminohexanoic acid with 6-aminohexanoic acid and its benzyl ester.
The methyl (I) and benzyl (II) esters of 6-aminohexanoic acid were synthesized in 95 % and 98 % yields, respectively. The reaction of tert-butyloxycarbonyl azide (Boc azide) with 6-aminohexanoic acid in the presence of magnesium oxide gave Boc-aminohexanoic acid (III) in high yield. Treatment of 6-aminohexanoic acid with benzyloxycarbonyl chloride (ZC1) under the conditions of the Schotten--Baumann reaction gives Z-aminohexanoic acid (IV) in 83 % yield. Compound III was converted to N-hydroxysuccinimidyl ester V [by reaction with N-hydroxysuccinimide in the presence of N,Nl-dicyclohexylcarbodiimide (DCC)], the condensation of which with 6-aminohexanoic acid led to Boc-protected amino acid VII. An alternative pathway to VII included aeylation of benzyl ester II by V and removal of the protective benzyl group by catalytic hydrogenolysis.