New steroid-fused P-heterocycles: Part I. Synthesis and conformational study of dioxaphosphorino[16,17-d]estrone derivatives
Introduction
Monocyclic and condensed six-membered P-heterocycles have been thoroughly studied from both stereochemical and pharmacological points of view [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. The main driving force in these investigations was the desire to clarify the mode of action of cyclic nucleotides (e.g. cAMP) which contain a dioxaphosphorinane moiety and play important roles in hormone action and cell communication [11], [12], [13], [14]. Earlier studies have demonstrated that the stereostructures of P-hetero rings are significantly different from those of cyclohexanes, and the P-rings relatively easily adopt conformations other than a chair [15], [16], [17]. The equilibria of the possible conformers have been found to be strongly influenced by the steric and electronic properties of the P-substituent. In this regard, conformational analyses of cycloalkane-condensed heterocycles have revealed interesting details about the stereostructures of these ring systems. Besides their biological importance, the high sensitivity of the conformational behaviour of dioxaphosphorinane-oxides on the substitution pattern makes them excellent model compounds for study [18], [19].
The intensive research on novel steroidal compounds has recently focused on the development of new, potentially pharmacologically active heterocyclic derivatives [20], [21], [22], [23], [24], [25], [26], [27]. Surprisingly, only a few P-containing ring systems that are of importance from a pharmacological aspect have been described so far [28], [29].
We report here the syntheses and conformational analyses of novel D-ring-fused dioxaphosphorinane-oxides in the estrone series, in which the rigid framework, the five-membered ring D and the angular methyl group at position 13 of the sterane skeleton, together with the P-substituent, were expected to exert a considerable influence on the conformation of the fused hetero ring.
Section snippets
General
Melting points (mp) were measured on a Kofler hot-stage apparatus and are uncorrected. The NMR spectra were recorded on a Bruker DRX 300 or a Bruker DRX 400 spectrometer in CDCl3, with TMS (1H and 13C NMR) as an internal and 85% H3PO4 (31P NMR) as an external standard. 13C and 31P NMR spectra were measured at 75 (or 100 MHz) and 121 MHz, respectively. For determination of the 13C NMR multiplicities, the APT pulse sequence was used. Assignments were supported by 1D-NOE and 2D heteronuclear HMQC
Synthetic studies
We earlier reported the formation of the epimers of P-phenyl D-ring-fused dioxaphosphorinane oxide 4 in excellent yield in a nearly 1:1 ratio [34] by the reaction of 17β-hydroxy-16β-hydroxymethylestrone 3-methyl ether [35], [36] 3 and phenylphosphonic dichloride (Scheme 1). In order to study the influence of the substituents on the conformation of the hetero ring, the analogous phosphorylation reactions of 3 with phenyl dichlorophosphate and bis(2-chloroethyl)phosphoramidic dichloride were
Acknowledgments
The authors thank I. Simon (University of Szeged, Hungary) for the NMR spectra, and Gy. Udvarnoki (University of Göttingen, Germany) for the mass spectra. The financial support by the Hungarian Scientific Research Fund (OTKA T 049366 and T 042479 and in part T 042642) is gratefully acknowledged. The authors are grateful to the NIIF Supercomputer Centre, Budapest, for the computational possibility.
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2012, SteroidsCitation Excerpt :On the other hand the successful application of oxathiaphospholane and dithiaphospholane derivatives (five-membered rings) as reactive precursors of sulfur-modified oligonucleotides has raised interest in their synthesis and molecular geometry, in particular in the conformation of the heterocyclic ring [13–15]. To the best of our knowledge, amongst a number of potentially effective heterocyclic steroid compounds only a few phosphorus-containing systems have been synthesized so far [15–22]. Lawesson’s reagent (LR: 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) [23–25], commonly utilized as a thionating agent, has been used to build five- and six-membered phosphorus heterocycles, such as oxathiaphospholes, oxathiaphospholidine-2-thiones, oxazaphosphorin-4-thione-2-sulfides, and sulfur containing heterocycles thienothiazines and benzothiazoles [24].