The synthesis of C2-symmetric 1,4,7-triazacyclononane ligands derived from chiral aziridines

Abstract

An efficient synthetic route for the synthesis of C 2 -symmetric derivatives of 1,4,7-triazacyclononanes 14 from chiral pool amino acids has been developed. These investigations have shown that competitive formation of piperazines 7 occurs when inappropriate nitrogen protecting groups are employed. It is apparent that the formation of the piperazines occurs as a result of an intramolecular nucleophilic attack followed by a belimination. This appears to only be relevant for the formation of the [9]-N 3 ring, as the larger [12]-N 4 macrocycle, 11, is formed via a Richman-Atkins cyclisation in the presence of the same benzylic protected nitrogen atom. The single crystal X-ray structures of piperazine 7a and 1,4,7-triazacyclononanes 14a both reveal that weak intermolecular C-HÁ Á ÁO=S interactions occur in the solid state in these systems.

NMR investigation into the dynamic behaviour of a novel C2‐symmetric macrocyclic ligand

“…Such hindered N-S bond rotation for the tosyl groups at positions N-1 and N-7 is more likely than for the unique tosyl group at position N-4, since the X-ray structure of 5 reveals 4 greater planarity for nitrogens N-1 and N-7 (sum of the bond angles at nitrogen are 356°and 354°), compared with nitrogen N-4 (sum of bond angles is 340°). Off-diagonal contours in red give ROE correlations, whereas the black off-diagonal correlation peaks are due to slow chemical exchange.…”

“…When the sulfur atom is effectively tetrahedral (as seen in the X-ray structure 4 ), this can generate two environments for the aromatic ring if the molecule does not possess a plane of symmetry which includes the trigonal nitrogen plane of canonical form II.…”

“…Two distinct dynamic processes were quantified for 3b, one of which was assigned to hindered amide-like rotation about the N-S bond of the N-tosyl groups. We 4,6 and others 1 -3 have subsequently turned our attention to the development of alternative enantiomerically pure ligands, such as 4, derived from chiral pool amino acids, principally owing to their greater ease of preparation and the range of ligand precursors that are readily available. As a result, we were keen to investigate the solution behaviour of one of the sulfonamide analogues, 5, by VT-NMR to ascertain whether our postulate for the unexpectedly complex solution behaviour of 3 was indeed due to the fused bicyclic nature of the structures.…”

Synthesis of Previously Inaccessible Derivatives of 1,4,7‐Tri‐R‐1,4,7‐Triazacyclononane, Including Chiral Examples, and a Rapid Synthesis of the HCl Salts of H3tacn and H4dtne

“…One of the longest standing challenges in tacn synthesis is the development of effective chiral derivatives for asymmetric catalysis. To date, synthetic routes to chiral R 3 tacn derivatives have proceeded by one of two routes: (1) substitution of H 3 tacn with an epoxide[6g] or lactone or (2) introduction of annulet (ring) substituents during the Richman–Atkins synthesis of an H 3 tacn derivative . Tacn compounds generated by the former method possess a beta‐N chiral center that is too remote to produce a significant stereoinductive influence on the coordination sphere of a coordinated metal, while the latter have stereocenters on the tacn annulus (ring), which projects in the opposite direction of the coordination sphere.…”

“…(3) Current routes to chiral derivatives of R 3 tacn are very limited and have found limited success, likely owing to the non‐ideal chiral environment established by ligands synthesized by current routes. These include (1) derivatives with chiral R groups where the chiral center is removed from the nitrogen atoms by one methylene unit,[6g], and (2) derivatives where chirality comes from chiral centers on the nine‐membered heterocycle, where such chiral groups do not project toward the coordination sphere of the ligated metal.…”