SYNTHESIS AND CONFORMATIONAL-ANALYSIS OF A SERIES OF 1-BENZOPYRANO[3,4-B]-[1,4]OXAZINES STRUCTURALLY RELATED TO CROMAKALIM

A series of 1-benzopyrano[3,4-b][1,4]oxazines 2a-c structurally relate d to the potassium channel activator cromakalim (1) were synthesized a nd the energetically minimized conformations were compared. Synthesis of 2a-c was achieved via selective N-acylation of the aminochromanol 3 with chloroacetylchloride and subsequent cyclization using sodium hyd ride. This two step procedure proved to give better overall yields tha n a one pot reaction previously published for analogous compounds. Geo metry optimization of all molecules was performed using quantumchemica l ab initio calculations on the 3-21G level. Comparison of the molecul ar shapes of the newly synthesized compounds 2a-c with those of the le ad compound 1 shows, that there are only slight differences mainly dep ending on the substituent on the nitrogen atom. Superposition of all f our compounds by a least squares fit procedure demonstrates that the r elative positioning of the carbonyl oxygen to the benzene moiety is ne arly identical in all the four molecules.