Enantioselective synthesis of (+)-8-hydroxy-8-methylidarubicinone q Laurance M. S. Bourghli a,b, * and R. J. Stoodley b a Division of Organic Materials, Royal Scientific Society, Industrial Chemistry Center, Royal Scientific Society, PO Box 1438, Amman 11941, Jordan b Department of Chemistry, UMIST, PO Box 88, Manchester M60 1QD, UK Received 1 October 2003; accepted 19 March 2004 Available online 24 April 2004 Abstract—An asymmetric Diels–Alder reaction methodology was employed to construct the tetracyclic structure of the anthra- cyclinone. A five-step sequence was needed to furnish the target (+)-8-hydroxy-8-methylidarubicinone. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Anthracyclines are antitumour antibiotics that were originally obtained from the cultures of different Strep- tomyces species. 1 Daunorubicin 1 and doxorubicin 2, the most famous anthracyclines, were isolated in the 1960s, and since that time, more than 300 new compounds were produced biosynthetically and more than 2000 ana- logues were synthesized. 2 These differed from the parent drugs either in the tetracyclic structure or in the sugar moiety, or in both. Of the most interesting analogues, which showed advances over the parent drugs, is ida- rubicin 3 (Fig. 1). 3 Since its discovery, several research groups showed interest in manipulating its structure to further enhance its activity and/or to diminish its tox- icity. Arcamone et al. for example, prepared the 8- and 10-fluoro derivatives. 4 We started a research to synthesize derivatives of ida- rubicinone that have a hydroxyl group at C-8 of the tetracyclic structure either alone or in the presence of an alkyl group at the same position. We envisaged that such addition will provide an additional hydrogen bonding capability to the drug and thus add to the sta- bility of the drug–DNA complex, as suggested by the intercalation theory. 5 The effect of these additions on the cytotoxic activity compared to that of the parent com- pound against A2780 tumour cell line (ovarian cancer) was also scheduled. The synthetic methodology is based on a strategy developed in the group and has been in use for 20 years. 6 It is based on an asymmetric Diels–Alder reaction be- tween an oxirane serving as the dienophile and a diene bearing a tetraacetate glucose auxiliary. In this article we wish to report the total synthesis of (+)-8-hydroxy-8- methylidarubicinone 4. 2. Results and discussion Synthesis of the title compound is outlined in Scheme 1. Reaction of the readily available oxirane 7 5 and diene 6 8 in acetonitrile afforded the cycloadduct 7 as a single diastereoisomer in 67% yield after crystallization. 9 The diastereoselectivity of this cycloaddition was attributed to the fact that the diene 6 reacted only by way of the s-cis conformer and the oxirane 5 underwent endo- addition preferentially at the least-hindered top face of the s-cis conformer. 8 q The work presented in this article was carried out at UMIST. *Corresponding author. Fax: +962-6-5344806; e-mail: bourghli@ rss.gov.jo Figure 1. 0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2004.03.047 Bioorganic & Medicinal Chemistry 12 (2004) 2863–2866