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

Abstract

The paper reports on the molecular and crystal structure of the diastereomeric salt (4) formed by the (11-oxo-11H-dibenzo[b,f][1,4]thiazepin-10-yl)-acetate (H À1 2) and the brucinium resolving agent. Experimental evidences suggest that the salt was obtained by a crystallization-induced dynamic resolution of the tricyclic compound 2, which seems to constitute the first example of successful application of this technique to tricycles of this kind. A systematic comparison with already published structural data of compounds containing brucine (molecule/ion) evidences that in 4 the resolving cation assembles in an unusual host framework. A review of the solid state structures containing brucine/ brucinium moieties available in the literature provides some simple rules which help to exclude/identify a priori the supramolecular host (brucine molecule/ion) framework.

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…Tricyclic compounds 211 – 213 form enantiomeric species, with an increasing interconversion barrier on passing from 211 to 213 (Scheme 80). [148] Paoli et al. explored conditions for their resolution with brucine in acetone, however, crystalline material was obtained only for compound 212 .…”

Dibenzothiazepine Based MCR Chemistry

“…The unusual conformational equilibrium, which has been reported multiple times, [4,5,17–19] affords atropisomers. Those atropisomers, which depend on the substitution pattern can have high energy interconversion and can be separated, are non‐superimposable mirror images thus, enantiomers.…”

“…[4,5] Many commercial drugs consist of a benzothiazepine core, including quetiapine, metiapine and clotiapine with an antipsychotic mechanism of action [6][7][8][9] and bioactive compounds [2,3] such as Ca 2 + channel blockers, [10] antiviral, [11,12] antimicrobial, [13] antifungal, [14] histone deacetylase 6 (HDAC6) inhibitors [15] and even molecules with interesting electronic properties (Figure 1C). [16] The unusual conformational equilibrium, which has been reported multiple times, [4,5,[17][18][19] affords atropisomers. Those atropisomers, which depend on the substitution pattern can have high energy interconversion and can be separated, are non-superimposable mirror images thus, enantiomers.…”

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.…”