The highly tumor inhibitory cephalostatins (e.g., cephalostatin 1), a marine natural product isolated from Cephalodiscus gilcristi, have attracted us to synthesize biologically active analogues. The goal of this study is to shed more light on selective desymmetrization of a symmetrical starting analogue through the F-ring opening route applied to certain analogues using different borane complexes. Previously, we have reported a selective opening of the spiroketal in the northern part of an analogue using catechol-borane and D-(N-tosyl) valine-borane complexes. We demonstrate here the possibility of opening the southern part of the same analogue using salicylic acid-borane complex by which extra flexibility is harvested. In contrast, a different reaction type took place when another analogue was treated with 3,4-diaminobenzonitrile-borane complex, which give after H 2 O 2 oxidation, products arising from Δ 14 bond hydration. This led us to conclude that the geometry of both borane complex and substrate govern the regioselectivity of the products. However, the electronic nature of both substrate and borane-complex govern the chemoselectivity.During the 1990s, Winterfeldt's group was busy in the synthesis of symmetrical and asymmetrical analogues [5]. Meanwhile, Fuchs and co-workers reported the first total synthesis of 1 and other cephalostatin members [6][7][8]. Very recently, Shair et al. have reported the second total synthesis of 1 using an elegant allylic oxidation method of C-18 [9]. The work of these groups depends on asymmetrical coupling of the proper steroidal parts to generate a rigid desired synthetic target. Despite the number of synthetic procedures in the literature, the interest in alternative and more convenient procedure for the synthesis of 1 is high. Thus, our philosophy is completely different. Based on desymmetrizing of the gram-scaled symmetrical diketone (2) followed by remote interconversion methods, we build up our strategy aiming at either the synthesis of flexible analogues or perhaps the natural product itself. This strategy enables us to gather a lot of information about the behavior of the active centers in such complicated structures along with building a helpful spectral database.
M. M. NAWASREHScheme 1 Different-side spiroketal opening of 3. (i) 16 equiv a, abs THF, 0-7 °C, two weeks; (ii) 10 equiv b, abs THF, 0-2 °C, four weeks.
M. M. NAWASREHScheme 2 Regioselective spiroketal opening of 6. (i) 1.5 equiv c, 24 h/0-5 °C; (ii) 10 equiv d/3 days/78 %.Scheme 3 Hydroboration-oxidation of 8 using the complex e. (i) 16 equiv e, abs THF/H 2 O 2 , 0-8 °C.Scheme 4 Regioselective hydration of 11. (i) 5 equiv BH 3 ؒTHF, 0-7 °C.