Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel-[1,5]-hydride shift cyclization reaction

László Tóth; Yan Fu; Hai Yan Zhang; Attila Mándi; Katalin E Kövér; Tünde-Zita Illyés; Attila Kiss-Szikszai; Balázs Balogh; Tibor Kurtán; Sándor Antus; Péter Mátyus

doi:10.3762/bjoc.10.272

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel-[1,5]-hydride shift cyclization reaction

Beilstein J Org Chem. 2014 Nov 6:10:2594-602. doi: 10.3762/bjoc.10.272. eCollection 2014.

Authors

Affiliations

¹ Department of Organic Chemistry, Semmelweis University, Hőgyes u. 7., 1092 Budapest, Hungary, ; Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 20, 4010 Debrecen, Hungary.
² CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China.
³ Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 20, 4010 Debrecen, Hungary.
⁴ Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4010 Debrecen, Hungary.
⁵ Department of Organic Chemistry, Semmelweis University, Hőgyes u. 7., 1092 Budapest, Hungary.
⁶ Department of Organic Chemistry, University of Debrecen, Debrecen, P. O. Box 20, 4010 Debrecen, Hungary ; Porfirin Ltd., Mikszáth K. u. 7. III/3, 4032 Debrecen, Hungary.

Abstract

Condensed O,N-heterocycles containing tetrahydro-1,4-benzoxazepine and tetrahydroquinoline moieties were prepared by a regio- and diastereoselective domino Knoevenagel-[1,5]-hydride shift cyclization reaction of a 4-aryl-2-phenyl-1,4-benzoxazepine derivative obtained from flavanone. The relative configuration of products were determined by the correlation of (3) J H,H coupling data with the geometry of major conformers accessed by DFT conformational analysis. Separated enantiomers of the products were characterized by HPLC-ECD data, which allowed their configurational assignment on the basis of TDDFT-ECD calculation of the solution conformers. Two compounds showed neuroprotective activities against hydrogen peroxide (H2O2) or β-amyloid25-35 (Aβ25-35)-induced cellular injuries in human neuroblastoma SH-SY5Y cells in the range of those of positive controls.

Keywords: 1,4-benzoxazepine; TDDFT-ECD calculation; diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization; neuroprotective; tert-amino effect.