Crystallographic study and molecular modeling on the oxidation product of N-[(8R)-2-methoxy-5,6,7,8,9,10-hexahydro-6,9-methanocyclohepta[b]indol-8-yl]acetamide

Abstract

Crystallization of N- [(8R)-2-methoxy-5,6,7,8,9,10-hexahydro-6,9-methanocyclohepta[b]indol-8-yl]acetamide was accompanied by oxidation at the C 5a -C 10a bond with formation of N- [(5S)-10-methoxy-2,8-dioxo-1,2,3,4,5,6,7,8-octahydro-3,6-methano-1-benzazecin-5-yl]acetamide whose structure was determined by X-ray analysis. Docking of this compound into melatonin-binding pocket of MT 1A receptor was simulated by computer-assisted molecular modeling.While performing studies on conformationally rigid melatonin analogs, we synthesized a series of indole derivatives fused to bicyclic structures [1-3]. Some compounds, including amide I [2], were studied by X-ray analysis [4]. In the present work we made an attempt to perform X-ray analysis of an analog of I containing a methoxy group in the indole fragment. The structure of methoxy derivative II was unambiguously confirmed by NMR, IR, and mass spectra and elemental analysis [2]. However, during preparation of a single crystal of II for X-ray analysis by slow crystallization from a colorless solution in anhydrous CH 2 Cl 2 pale rose crystals separated. The X-ray diffraction data (Fig. 1) allowed us to identify this compound as N- [(5S)-10-methoxy-2,8-dioxo-1,2,3,4,5,6,7,8-octa-hydro-3,6-methano-1-benzazecin-5-yl]acetamide (III) which was formed as a result of oxidative cleavage of the double C 5a -C 10a bond in II (Scheme 1).

Spectroscopic, crystallographic, and Hirshfeld surface characterization of nine-membered-ring-containing 9-methoxy-3,4,5,6-tetrahydro-1H-benzo[b]azonine-2,7-dione and its parent tetrahydrocarbazole

“…A search for compounds similar to compound (I) in the Cambridge Structural Database (Groom et al, 2016) found a single structure (CSD refcode COMBEO) which contains the nine-membered ring with an additional acetamide-containing group bridging the 3-and 5-position methylene C atoms of the title compound (Baranova et al, 2012). The additional bridging group in COMBEO positions the amide carbonyl and N-H groups cis to one another, with an O-C-N-H torsion angle of 7.37 � , allowing for the formation of an R 2 2 (8) graph-set centrosymmetric hydrogen-bonding dimer, whereas in compound (I), they are oriented trans, with an O-C-N-H torsion angle of 170.69 � , which precludes hydrogen bonding via a similar dimer, and (I) forms a one-dimensional hydrogenbonding chain.…”