Elsevier

Steroids

Volume 76, Issues 10–11, September–October 2011, Pages 1021-1031
Steroids

On the reactivity of 23-methoxycarbonyl furospirostanes

https://doi.org/10.1016/j.steroids.2011.04.006Get rights and content

Abstract

Brønsted and Lewis acid-catalysed reactions of the 23-methoxycarbonyl furospirostanic side chain are described. While bromination, deuteration and BF3·Et2O/AcOH treatment involve regioselective F-ring opening with exclusive participation of Δ22-furostenic intermediates, BF3·Et2O/Ac2O treatment leads to irreversible E- or F-ring cleavage.

Graphical abstract

On the reactivity of 23-methoxycarbonyl furospirostanes. Mariana Macías-Alonso, Marcos Flores-Álamo, Martin A. Iglesias-Arteaga.

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Highlights

► Treatment of the 23-methoxycarbonyl furospirostane with BF3·Et2O in acetic acid produces F ring opening followed by transesterification leading to an E-unsaturated lactone as the sole product. ► Treatment of the 23-methoxycarbonyl furospirostane with BF3·Et2O and acetic anhydride produces both E- or F-ring cleavage leading to a mixture of diacetylated enol ethers. ► Bromination of the 23-methoxycarbonyl furospirostane side chain only occurs at position C-23 and produces a diasteromeric mixture of the brominated compounds. ► Deuteration 23-methoxycarbonyl furospirostane side chain needs the catalysis of a strong acid and exclusively occurs at position C-23. ► Under either Bronsted or Lewis catalysis, the 23-methoxycarbonyl furospirostane side undergoes reversible or irreversible cleavage to produce only the E22-furostenic intermediary.

Introduction

Spiroketals constitute a large family of naturally occurring compounds that have been isolated from both terrestrial and marine organisms. In general the spiroketal moiety is a prevalent structure in a large number of important natural products that have attracted much interest, not only for their wide spectrum of biological activity, but also for their interesting reactivity and usefulness in the preparation of other bioactive compounds [1], [2], [3].

Steroids bearing spiroketal side chains are widespread in both the natural and synthetic domains. Spirostanic sapogenins (see Fig. 1) the reactivity of which has produced a wide variety of interesting reactions [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24] are characterized by the presence of a 16β,22:22,26-diepoxy moiety in the side chain, being 1,6-dioxaspiro[4.5] decane derivatives. Such compounds have been subject of much research due to their intrinsic biological activity [25], [26], [27], [28], [29], [30] as well as their usefulness as starting materials for the synthesis of bioactive compounds such as sex and adrenocortical hormones, [4] ecdysteroids, [31] plant growth stimulators, [32], [33], [34], [35], [36], [37], [38] and cytotoxic steroids, [39], [40], [41], [42], [43], [44], [45] among many others.

It is well known that, in acid media, spirostanic sapogenins present an equilibrium in which the spiroketalic side chain is opened to the oxacarbenium ion I that may lose a proton from either C-20 or C-23 to produce Δ20 or Δ22 enol ethers (see Scheme 1) [4]. Most of the reactivity of the spirostanic side chain can be justified on the basis of these two enolic forms and the oxacarbenium ion I.

Furospirostanes, a smaller and somewhat less known family of steroids bearing a 16β,22:22,25-diepoxy moiety in the chain, may be considered 1,6-dioxaspiro[4.4]nonane derivatives, and includes compounds with antitumor activity as the ritterazines (4), cephalostatines (5) [41], [42], [43], [44], [45], or hippuristanols (68) [46], [47], [48], [49], among others (see Fig. 2).

Fuchs and coworkers correlated the cytotoxicity of cephalostatins and their synthetic analogues with that of the potent anti-tumor steroid OSW-1 and hypothesized that the cytotoxic activity of such compounds may be connected with the possibility of the generation of oxacarbenium ions around C-22 [50], [51], [52]. In the light of this hypothesis, the fact that other furospirostanes with different 16β,22:22,25-diepoxy side chains (i.e. hippuristanols 68, Fig. 2) and even steroid sapogenins (13, Fig. 1) with the 16β,22:22,26-diepoxy side chain, (all theoretically able to produce oxacarbeniums ions around C-22), have shown toxic activity against different cancer cell lines, should not be considered a mere coincidence. On the contrary, this fact supports Fuchśs hypothesis, and constitute an invitation to the study of the biological activity and reactivity of other compounds bearing slightly or even drastically modified side chains that still are able to generate oxacarbeniums ions around C-22.

As a part of our project to explore the reactivity of steroid bearing spiroketals side chains, we have found that treatment of 23-oxo-spirostanes with diacetoxyiodobenzene (DIB) and KOH in methanol produces a quasi-Favorskii F-ring contraction that leads to 23-methoxycarbonyl-furospirostanes (see Scheme 2) [10].

This has led us to initiate a program to study the reactivity of the derived compounds as well as their usefulness as starting materials for the synthesis of other potentially bioactive steroids bearing modified spiroketalic side chains. Herein we report on the reactivity of the 23-methoxycarbonyl-16β,22:22,25-diepoxy side chain under both Lewis and Brønsted acid catalysis.

Section snippets

Experimental

Reactions were monitored by TLC on ALUGRAM® SIL G/UV254 plates from MACHEREY-NAGEL. Chromatographic plates were sprayed with a 1% solution of vanillin in 50% HClO4 and heated until color developed. Melting points were measured on a Melt-Temp II equipment and are uncorrected. Mass spectra were registered in a Thermo-Electron spectrometer model DFS (Double Focus Sector). NMR spectra were recorded in CDCl3 solution in a Varian INOVA 400 spectrometer using the solvent signal 7.26 ppm for 1H and 77.00

Reactions under BF3·Et2O catalysis

Acetylation of 10 following the standard Ac2O/pyridine procedure afforded the expected compound 11 that on treatment with BF3·Et2O in acetic acid at room temperature for 10 days underwent transformation to the unsaturated lactone E-12 in 88% yield as the sole product (see Scheme 3).

In the case of E-12, the presence of the conjugated double bond is evidenced by two 13C olefinic signals that were differentiated and assigned to C-22 and C-23 with the aid of a HETCOR experiment (J fixed to 9 Hz)

Conclusion

The obtained results demonstrate that under either Bronsted or Lewis catalysis, the furospirostanic side chain is opened to produce only the Δ22-furostenic intermediary. Moreover, the outcome of all the studied reactions suggests that both reversible and irreversible F-ring opening involve the production of the E geometrical isomer of the Δ22-furostenic intermediate.

The deuteration experiments indicate that, contrary to spirostanic sapogenins in which the order of incorporation of deuterium is

Acknowledgments

The authors thank to the Dirección General de Asuntos del Personal Académico (DGAPA-UNAM) for financial support via project IN221911-3 and CONACyT for scholarship granted to MM-A. Thanks are due to Nuria Esturau Escofet, Georgina Duarte Lisci and Victor Lemus Neri (USAI-UNAM) for recording NMR and MS spectra and Elemental Analysis. We are indebted to Dr. A. J. Boulton for his useful comments and for correcting the manuscript.

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    • Mechanistic insights on the reactivity of furospirostanes with the 16β,22:22,25-diepoxy-23-acetoxymethyl-24-methyl side chain

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      Citation Excerpt :

      The increasing number of naturally occurring bioactive steroids that bear the furospirostane side chain includes compounds that have shown interesting antitumor activity such as ritterazines (1), cephalostatins (2) [6–10], hippuristanols (3) [11–15], as well as the antihypertensive glycosides of nuatigenin (4) [16] among others (see Fig. 2). Unlike spirostanic sapogenins, the side-chain reactivity of which has received considerable attention in the past 70 years selected Ref. [17–37], the studies of the reactivity of the furospirostane side chain are rather scarce [38–42]. In particular, Fuchs and coworkers hypothesized that the cytotoxic activity of cephalostatins may be related to the possibility of the generation of oxacarbenium ions around C-22 [43–44].

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