The preparation of a 10-membered ring macrolactone by selective ozonolysis and the role of the dihydropyran-substituent on the MCPBA-oxidation reaction profile of beta-lapachone phenazines

Abstract

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...

Chemoselective oxidation of benzophenazines by m-CPBA: n-oxidation vs. oxidative cleavage

“…1 Hydroxy and bromo derivatives of 1, respectively, 5 and 6, were also submitted to oxidation in the same conditions and furnished substituted 10 membered macrolactones: 7 from 5 and 8 from 6. 2 Based on that initial study, 1 some papers dealing with modifications of the methodology and a more general view of the synthetic aspects have appeared in the literature, showing the large potential of this macrolide synthetic approach. 3,4 Macrolides are an attractive class of compounds that have shown a wide variety of bioactivities, 5 especially recognized as antibiotics.…”