Letters in Organic Chemistry, 2008, 5, 17-21 17 1570-1786/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Steroidal -Alkenyl Oximes as Ambident Nucleophiles: Electrophile- Induced Formation of Oxazepane Derivatives in the Bis-Estrone Series Erzsébet Mernyák a , Zsolt Bikádi b , Eszter Hazai b , László Márk c , Gyula Schneider a and János Wölfling* ,a a Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary b Virtua Drug Ltd, Csalogány utca 4C., H-1015 Budapest, Hungary c Department of Biochemistry and Medical Chemistry, University of Pécs, Szigeti út 12., H-7624 Pécs, Hungary Received August 07, 2007: Revised October 10, 2007: Accepted October 12, 2007 Abstract: Electrophile-induced cyclization of steroidal -alkenyl oximes and oxime ethers and subsequent hydride reduc- tion of the cyclic nitrones led to new halogenated or selenylated N-hydroxy- or N-benzyloxy-aza-D-homo-estrones. Start- ing from a 13-D-secoestrone oxime or oxime ether, steroidal dimers were isolated in intermolecular 1,3-dipolar cycload- dition of the cyclic nitrone to the C=N double bond of the oxazepine intermediates. Keywords: Selenium, oxazepane, 1,3-dipolar cycloadditions, stereoselectivity, dimeric steroids, estrone derivatives. Dedicated to Prof. B. Schönecker on the occasion of his 70 th birthday. Electrophile-induced cyclization of alkenyl oximes is a known procedure for the formation of cyclic nitrones. Since the internal nucleophile is an ambident group, it can act with either N or O as the reactive site, depending on the co- reagents, the solvent and the pH of the reaction mixture [1]. It was observed by Dondas et al. [1b] and Tiecco et al. [2] that, on treatment of the two isomeric -alkenyl oximes with electrophilic selenylating reagents, five-membered cyclic nitrones were formed, 1,2-oxazines were only present in traces. -Alkenyl oximes led to six-membered cyclic ni- trones, the appropriate oxazepines were not isolated under the same reaction conditions. They concluded that the two isomeric oximes undergo interconversion and that formation of the 1,2-oxazine is a reversible process [2]. Thus, longer reaction times are associated with a shift in the process to- wards formation of the thermodynamically more stable cy- clic nitrone. We recently reported on the halogen-induced synthesis of nitrones from steroidal -alkenyl oximes in the 13- and 13-estrone series and the 1,3-dipolar cycloaddi- tions of the steroidal nitrones with N-phenylmaleimide (NPM) [3]. The reactions were highly stereoselective, yield- ing condensed aza-D-homo-estrone derivatives. We now describe the halogen and PhSeBr-induced cycli- zations of -alkenyl oximes and oxime ethers in the 13- and 13-estrone series and subsequent hydride reduction of the corresponding oxyiminium or iminium salts. In view of the findings of Dondas et al. [4] (reactions only with PhSeBr), slow fragmentation of the oxyiminium salts formed from the oxime ethers was expected to furnish cyclic iminium salts, hydride reduction of which would yield 16-substituted aza- D-homo-estrones. D-Ring-substituted aza-D-homo-13- estrones have not been described in the literature to date. *Address correspondence to this author at the Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary; E-mail: wolfling@chem.u-szeged.hu 13-Estrone derivatives substituted with alkyl- or arylse- lenyl groups in rings B, C or D were previously synthetized in order to investigate the non-invasive differentiation of hormone-dependent and hormone-independent mammary tumours. Some of those compounds exhibited greater rela- tive binding affinities for the estrogen receptor than that of estradiol itself [5]. 75 Se-containing selenosteroids have been used as potential radiopharmaceuticals in breast tumour im- aging [5]. No selenyl 13-homo-estrones appear to have been synthetized so far. Electrophile-induced cyclization of steroidal oximes and oxime ethers was carried out in MeCN, using different alkene halogenating agents or PhSeBr. In the 13-estrone series, the reactions proceeded in an unexpected manner (Scheme 1, Table 1). When oxime 1 was reacted with 1 equiv. of N-bromo-succinimide (NBS) under stirring, a pre- cipitate was formed after some minutes. The starting product had completely reacted (monitoring by TLC). After 0.5 h of stirring, the precipitate was filtered off and washed with cold MeCN. NMR measurements showed it to be a non- symmetrical steroidal dimer (14a), consisting of D- piperidino and D-oxazepano moieties. When oxime 1 was treated in the same way with 1 equiv. of PhSeBr, the same type of product (14b) was isolated [6]. With N-iodo- succinimide (NIS) as electrophile, dimer (14c) formation was not observed, but 11c or 11d was isolated, depending on the conditions of the hydride reduction. Such reactions of oxime 1 demonstrated the competition between the O and N of the internal ambident nucleophile. Under the conditions employed, the trapping of the intermediate halonium (3a,c; 5a,c) or seleniranium ion (3b, 5b) proceeded via the N atom in the case of the E-oxime, and via the O atom in the case of the Z-oxime. The oxazepine derivative (10a,b) was formed immediately and reacted as a dipolarophile with the cyclic nitrone (9a,b) in the 1,3-dipolar cycloaddition [7]. The dimer (14a,b) proved to be stable in the solid state, but in solution