Steroid glycosides have been a subject of study for the synthetic chemist for many years. 1 The construction of the glycoside-steroid linkage has been successfully accomplished by several groups. Every recorded synthesis used the most common method of glycoside bond formation, namely electrophilic activation of the anomeric carbon of the carbohydrate followed by its trapping with a steroidal alcohol. Our laboratory has been exploring an alternate approach to glycosyl transfer, 2 shown by the general cycloaddition in Scheme 1.We were interested to discover if our concept could be applied to the glycosidation of steroids. Our planning was based on our earlier demonstration that the structural element required for a successful heterocycloaddition was a 1,3-dioxo-2-thiono assembly such 1, which is symmetrical, and 2, where the carbonyls were differentiated electronically. Thus, our proposed steroid heterodiene 3 led to an interesting question: would there be selectivity between the carbonyls at C-1 and C-3 in the cycloaddition? ResultsThe first task was to prepare cholestane-1,3-dione (4), which was to be the precursor to heterodiene 3. Dione 4 had been reported by Tamm, 3 using the sequence shown in Scheme 2. We repeated the work with one significant change. In our hands, the Grieco modification of the Yang method using t-BuOOH for the epoxidation of the enone 6 produced the desired 7 in 53% yield, compared to 16% yield in our hands, when alkaline hydrogen peroxide was the reagent. 4 Scheme 3 illustrates the cycloaddition chemistry. Thus, steroid dione 4 was cleanly phthalimidosulfenylated to afford sulfenyl dione 8, the ultimate precursor to our heterodiene 3, which was generated and trapped in situ in the presence of 0.5 equiv of tribenzyl glucal 9. Two cycloadducts were obtained in identical yield and were separable by flash chromatography on silica gel. That both adducts had arisen from heterodiene attack on the bottom or R face of the glucal was clear from proton NMR data. In particular, the axial H at C-2′ (δ 3.2), adjacent to sulfur, is quite diagnostic in all our cycloadducts. In order to differentiate between the two adducts, an undecoupled 13 C NMR spectrum of each material was used. Thus, the product assigned structure 10 exhibited a triplet for the resonance at δ 162.1 assigned to the vinyl carbon at C-3, whereas the material assigned structure 11 revealed a distorted triplet for the CdO at δ 194.7. Desulfurization of 10 and 11 with Raney nickel in benzene afforded the novel steroid glycosides 12 and 13 in 57% and 21% yield, respectively. DiscussionThe absence of regioselectivity in the cycloaddition step of diene 3 was surprising at first glance since the 2-D representation implies that congestion might exist near the C-1 carbonyl. However, a simple calculation of the ground-state geometry of heterodiene 3 corrected our naive first impression. Figure 1 shows that, indeed, the C-1 carbonyl carbon is somewhat blocked by the angular methyl. But, the A ring is quite twisted, presumably to avoid eclipsing o...
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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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