Ivana Ozimec Landek

2,8-dithia-dibenzo〔e,h〕azulenes and their 8-oxa analogs: synthesis and anti-inflammatory activity

Synthesis of 2, 8-dithia-dibenzo[e, h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1 two novel classes of fused heterocyclic compounds, is described. Starting 11H-dibenzo[b, f]thiepin-10-one, 11H-dibenzo[b, f]oxepin- 10-one and its 2-chloro derivative (1a-c) were oxidized to 1, 2-diketones (2a-c) which subsequently reacted with 2, 2’ -dimethyl thiodiglycolate to form fused thiophene ring by Hinsberg cyclization reaction. Substituents at positions C(1) and C(3) were then further transformed in order to obtain aminoalkoxy derivatives 8-11. Structures of regioisomers 6c and 6d were elucidated using two-dimensional NMR techniques. All compounds with tetracyclic skeleton were tested in vitro for their anti-inflammatory activity.

Conformational properties and chiral separation of dibenzo[b,f]thieno[3,4-d]-fused oxepines and thiepines

The dynamic properties of planar chiral 1-hydroxymethyl-substituted dibenzo[b,f]thieno[3,4-d]-fused oxepine and thiepine derivatives have been investigated by use of variable-temperature nuclear magnetic resonance spectroscopy combined with line-shape analysis, chiral column chromatography, and molecular modelling. NMR data and computational studies revealed the height of the energy barrier for ring inversion in thiepine derivatives was sufficient to enable the existence of a pair of conformational enantiomers at ambient temperature. Their resolution was achieved by chiral column high-performance liquid chromatography (HPLC). The absolute conformation of the enantiomers is proposed. This is the first chromatographic separation of planar chiral enantiomers of [b,d,f]-fused thiepine derivatives.Graphical Abstract

Synthesis of naphtho〔2,3-b〕- and naphtho〔1,2-b〕-fused thieno〔2,3-d〕〔1〕benzoxepins and thieno〔2,3-d〕〔1〕benzothiepins

Synthesis of four novel classes of structurally related fused hetero-pentacyclic compounds, naphtho[2,3-b]thieno[2,3-d][1]benzothiepins (Ia), naphtho[1,2-b]thieno[2,3-d][1]benzothiepins (IIa), naphtho[2,3-b]thieno[2,3-d][1]benzoxepins (Ib,c) and naphtho[1,2-b]thieno[2,3-d][1]benzoxepins (IIb,c), is described. The key intermediates were the tetracyclic ketones, benzo[b]-naphtho[f]-fused thiepinones 1a,b and oxepinones 1c-f, formed by intramolecular cyclization of the corresponding 2-naphthalenylthio- (2a,b) and 2-naphthalenyloxy-substituted (2c-f) phenylacetic acid derivatives. Reaction of ketones 1a-f with Vilsmeier reagent provided β-chlorovinyl aldehydes 10a-f that readily cyclized with ethyl 2-mercaptoacetate to form thieno[2,3-d]-fused derivatives of benzo-naphtho-thiepins 11a,b and benzo-naphtho-oxepins 11c-f. Reduction of ester group of 11a-f afforded final hydroxymethyl derivatives 12a-f.