Crystal structures of resorcin[4]arene and pyrogallol[4]arene complexes with DL-pipecolinic acid. Model compounds for the recognition of the pipecolinyl ring, a key fragment of FK506, through C–H⋯π interaction

• Host–guest complexation of aromatic cyclic tetramers (RCT or PCT) with pipecolinic acid (pipeH) in crystal and in solution.
• Piperidine ring of pipeH incorporated into the cavity of RCT or PCT through C–H⋯π interactions with π-rings of RCT or PCT.
• Ligand-mediated capsule-like dimeric structures, [(RCT or PCT)·L-pipeH·D-pipeH·(RCT or PCT)], are formed.
• A model for the recognition of the pipecolinyl ring of FK506 by its binding protein through C–H⋯π interaction is provided.
• C–H⋯π interaction as a strategy for the structure-based drug design is suggested.

Resorcin[4]arene (resorcinol cyclic tetramer, abbreviated as RCT) or pyrogallol[4]arene (pyrogallol cyclic tetramer, PCT) form host–guest 1:1 complexes with DL-pipecolinic acid (DL-pipeH), RCT·DL-pipeH·EtOH·8H2O (1), PCT DL-pipeH·EtOH·4H2O (2), and PCT·DL-pipeH·3H2O (3), whose crystal structures have been determined. In each complex, the pipeH ligand is incorporated into the bowl-shaped cavity of the RCT or PCT host molecules through C–H⋯π interactions between alkyl protons of the piperidine ring of pipeH and π-rings of RCT or PCT, forming an [(RCT/PCT)·pipeH] structural fragment. In 1 and 3, two [(RCT/PCT) pipeH] fragments self-associate across an inversion center to form a guest-mediated, obliquely declined dimeric structure [(RCT/PCT)·L-pipeH·D-pipeH (RCT/PCT)]. In 2, each PCT-capped pipeH ligand bridges to two adjacent PCT molecules to form guest-mediated, optically-discrete helical polymers [PCT·L-pipeH]n or [PCT·D-pipeH]n. An 1H NMR experiment shows that the complexation through C–H⋯π interaction between the piperidine ring of pipeH and π-rings of RCT or PCT occurs also in solution, with the binding constants of 9.7 ± 0.6 M−1 for RCT and 26.5 ± 1.5 M−1 for PCT. These complexes provide a synthetic model for the recognition of the pipecolinyl-ring moiety, a key constituent of immunosuppressant drugs such as FK506, FK520 or rapamycin, by their binding proteins through C–H⋯π interaction.

Figure optionsDownload as PowerPoint slide