New steroid-fused P-heterocycles: Part I. Synthesis and conformational study of dioxaphosphorino[16,17-d]estrone derivatives

doi:10.1016/j.steroids.2007.02.002

Steroids

Volume 72, Issue 5, May 2007, Pages 437-445

https://doi.org/10.1016/j.steroids.2007.02.002 Get rights and content

Abstract

D-ring-fused dioxaphosphorinanes (4–6) in the estrone series were synthetized as epimeric pairs and investigated by NMR and computational methods in order to determine their stereostructures and predominant conformations. The study was performed to evaluate the influence of the rigid sterane framework on the geometry of the condensed hetero ring, with regard to the possible steric effect of the angular methyl group at position 13. Additionally, the steric and electronic effects of the P-substituents on the conformational equilibrium were examined. The distorted-boat conformation of the hetero ring of dioxaphosphorinoestrone 3-methyl ether 4a was confirmed by single-crystal X-ray analysis. This is in good agreement with the observation in solution that, in the case of the boat conformation, the anisotropic shielding effect of the phenyl group of cyclic phosphonate 4a generates an upfield shift for 17-H, as compared with the corresponding chemical shift for epimer 4b. A similar boat conformation was substantiated for derivatives 4b, 5a, 5b and 6b on the basis of the J(H, H) and J(H, P) coupling constants and also ab initio calculations, regardless of the P-configuration. At the same time, the hetero ring of 6a seems to tilt towards a chair-like conformation due to the strong equatorial preference of the N-bis(2-chloroethyl) group.

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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New steroid-fused P-heterocycles: Part I. Synthesis and conformational study of dioxaphosphorino[16,17-d]estrone derivatives

Abstract

Introduction

Section snippets

General

Synthetic studies

Acknowledgments

Tetrahedron

Bioorg Med Chem Lett

Tetrahedron Lett

Tetrahedron

Tetrahedron

Prog Med Chem

Tetrahedron Asymmetry

Steroids

Steroids

Steroids

Tetrahedron

Tetrahedron Lett

J Chromatogr A

J Magn Reson A

Tetrahedron

Tetrahedron Lett

The question of chair-twist equilibria for the phosphate rings of nucleoside cyclic 3′,5′-monophosphates. Proton NMR and X-ray crystallographic study of the diastereomers of thymidine phenyl cyclic 3′,5′-monophosphate

J Am Chem Soc

Thermochemical identification of the structural factors responsible fort he thermodynamic instability of 3′,5′-cyclic nucleotides

J Am Chem Soc

Conformational equilibria of phosphoranes with 5-alkyl-substituted 1,3,2-dioxaphosphorinane rings attached diequatorially to five-coordinated phosphorus. Are boat/twist conformations populated?

J Am Chem Soc

Phenyl phosphorodichloridate in the synthesis of cyclic phosphate diesters of biological interest

Can J Chem

Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect Prodrugs) useful for targeting phosph(on)ate-based drugs to the liver

J Am Chem Soc

Studies on organophosphorus compounds XXVI. New aspects on the synthetic study of some cyclic esters of alkylphosphonic acids

Synthesis

6-Membered P-heterocycles: 1,2-dihydro-, 1,2,3,6-tetrahydro- and 1,2,3,4,5,6-hexahydrophosphinine 1-oxides

Curr Org Chem

Synthesis of psicofuranine cyclic 4′,6′-monophosphate

J Org Chem

Design, synthesis, and characterization of a series of cytochrome P₄₅₀ 3A-activated prodrugs (HepDirect Prodrugs) useful for targeting phosph(on)ate-based drugs to the liver