Investigation on the flexibility of chiral tricyclic derivatives

Abstract

In the perspective of generating libraries for broad screening purposes, the inversion barrier of enantiomeric conformers of various tricyclic compounds, characterized by a seven-membered ring featuring a lactam group with two aromatics condensed at its opposite sides, has been investigated by ab initio calculations and NMR spectroscopy. Solid-state structure characterizations by single-crystal X-ray diffraction have been also carried out. The aim was to assess if moving from ethers to sulfides and sulfones derivatives, causes the racemization barrier to vary. Investigation was also extended to thiolactam congeners. Structural and electronic effects were investigated on the energetics of the inversion process and structure-property relationships evidenced. Results suggest that the ring inversion of the oxo derivatives is easier with respect to the corresponding S/SO 2 ones. Also amide molecules have, on the whole, smaller barriers with respect to the corresponding thioamide ones.

Dibenzo[b,f][1,4]thiazepin-11-yl-diethyl-amine

“…For the clinical use of dibenzothiazepine derivatives, see: Ganesh et al (2011); Pettersson et al (2009); Riedel et al (2007); Warawa et al (2001). For structure-property relationships in (6,7,6)-tricyclic ring systems, see: Ravikumar & Sridhar (2005); Altamura et al (2008Altamura et al ( , 2009Altamura et al ( , 2011. For geometrical data and descriptors, see: Duax et al (1976); Bertolasi et al (1982); Allen et al (1987).…”

“…In fact the dibenzothiazepine skeleton has a broad spectrum of medical applications; its derivatives are used to treat schizophrenia and also find applications as neuroleptics, antidepressants, antihistaminic, just to name a few (Ganesh et al 2011;Pettersson et al 2009;Riedel et al 2007;Warawa et al 2001). Within our programme research concerning the structural elucidation of tricyclic molecules in order to gain further insights into structure-property relationships (Altamura et al, 2008;Altamura et al, 2009;Altamura et al, 2011) we investigated the crystal and molecular structure of the title compound. The overall shape of the tricyclic skeleton is controlled both by the conformation of the central seven-membered ring and the relative arrangement of the aromatic rings bound to it.…”

Uncommon crystal motif of brucine in its diastereomeric salt with (11-oxo-11H-dibenzo[b,f][1,4]thiazepin-10-yl)-acetic acid: a case of possible crystallization-induced dynamic resolution

“…16,17 Brucine was chosen for the enantiomer separation of compounds 1-3 (Fig. 1), which are members of a well known and pharmaceutically useful class of compounds 18 and which were recently synthesized and studied 19 as a part of a commitment directed to the design of chemical libraries based on the control of internal motions of the pool members. 20 The results obtained to date 19 suggested that the enantiomeric interconversion barrier increases on passing from compound 1 to compound 3 (Fig.…”

“…With these compounds at hands, we reasoned that, in principle, the entrapment of their single enantiomers in suitable crystal lattices could be useful to enlarge the scope of the hypothetical library. 21 Compounds 1-3 having not shown the tendency to crystallize as conglomerates, 19 we oriented our attention to diastereomeric salt formation. As described in this paper, we found that brucine in acetone solution is an effective resolving agent, though for compound 2 only.…”

“…Finally, the molecular structure of the acetate anion (H À1 2 hereafter) in salt 4 is compared with that of the corresponding neutral species. 19 In addition, the results from a modelling study, set up to test the role played by the acetic side chain in stabilizing the overall conformation in the crystal, a study we extended to the congener ether and sulfone derivatives, are also briefly discussed.…”