A benzofenazina derivada da β-lapachona foi submetida a ozonólise em condições que forneceram seletivamente a lactona macrocíclica 7,7-dimetil-7,8,9,10-tetrahidro-5H-benzo[3,4]oxecino [5,6-b]quinoxalina-5,10-diona, com rendimento de 52%. O efeito de substituintes localizados no anel diidropirânico das fenazinas, no caso C2'-OH, C2'-Br e C2'-I, em reações de oxidação com MCPBA, foi também investigado.The benzophenazine from β-lapachone was submitted to ozonolysis under conditions that selectively furnished the corresponding rigid macrocyclic lactone 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione in an yield of 52%. The effect of substituents located at the dihydropyrane moiety of the phenazines, namely C2'-OH, C2'-Br and C2'-I, in the oxidation with MCPBA, was also investigated.Keywords: β-lapachone, ozonolysis, 10-membered ring macrolide, selectivity, effect of substituent
IntroductionIn general, natural and synthetic phenazines have attracted considerable attention because of their interesting biological activities, 1 including broad-spectrum antibiotic, 2 antimalarial, 3,4 trypanocidal 5 along with anti hepatitis C viral replication activities.6 Benzo[a]phenazines are also efficient DNA intercalating ligands, exhibiting antitumor activity in leukaemia and solid tumors.7 They have also been described as dual inhibitors of topoisomerase I and II. 8 In our search for preparing new derivatives, for synthetic purposes and biological screening, we recently reported 9 that peroxidation of the b-lapachone-derived benzophenazine, named lapazine (1), with m-ClC 6 H 4 CO 2 H/CH 2 Cl 2 generated, unexpectedly, a macrocyclic lactone 2 with a rigid 10-membered ring (27% yield), the corresponding N-oxide 3 (13% yield), and the dihydrobenzophenazine-5-one 4 (35% yield) (Figure 1). Macrocyclic compounds 2 and 3 were formed via oxidative cleavage of the aromatic double bond at the site of fusion of the dihydropyran moiety with the phenazine component. This region (rings C/E, in 1) (Figure 1) would behave as a conjugated enol ether, which, after the expected epoxide formation and fragmentation would lead to 2 and 3 (further oxidation). An acid-catalysed epoxide-acetal or α-hydroxy hemiacetal would furnish 4.
9Compounds 2 and 3 belong to the class of macrolides, an important group of biologically active compounds, especially recognized as antibiotics.
10Among 10-membered macrolactones, the antibiotic activity of apicularen A and B was reported.
11In the present work, considering 2 and 3, the presence of diaza heterocyclic groups close to the ion-binding macrolactone moiety constitutes attractive molecular features.In searching for a more general application of the oxidative cleavage by MCPBA, 9 we have analysed the role of substituent, at C-2', in the dihydropyrane moiety of lapazine, namely -OH (5), -Br (6) and -I (7) (Figure 1). 1075 The Preparation of a 10-Membered Ring Macrolactone Vol. 16, No. 5, 2005 Additionally, in an attempt to develop a more selective and simpler method by...
