Intramolecular hydrogen bonding and structure of stereoisomeric 20(22)-hydroxy-22(23)-isoxazolinyl steroids

Abstract

We have used IR spectroscopy and the quantum chemical AM1 method to study stereoisomeric 22(23)-isoxazolinyl steroids with a hydroxyl group at C 20 or C 22 , in order to establish the spectral features that will allow us to identify their stereoisomers. We have carried out a conformational analysis of isoxazolinyl steroid stereoisomers, and we have calculated the populations of their stable conformers. We have assigned the bands in the IR spectra of the stereoisomers in the region of the stretching vibrations of OH groups, and have analyzed the possibility of intramolecular hydrogen bond formation between the OH groups and proton-acceptor centers of the isoxazoline ring. Introduction.As was shown earlier in [1-6], 1,3-dipolar cycloaddition of nitrile oxides to form terminal steroid 22-enes and 23-enes leads to stereoisomeric isoxazolinyl steroids, which are of interest as potential bioregulators and also are valuable intermediates in synthesis of a number of natural steroids with a polyfunctionalized side chain. It is a complicated problem to study the structures of isoxazolinyl steroids and in particular to establish the stereochemistry of asymmetric centers on the side chains of the stereoisomers formed, requiring that we draw on a number of physicochemical methods. We have successfully used NMR spectroscopy [1, 2, 4-6], x-ray diffraction [3,7,8], and circular dichroism [9] to solve this problem.In this work, with the aim of determining the spectral features allowing us to identify the stereoisomers with the simple and accessible IR spectroscopy method, we have carried out an IR spectroscopy study and conformational analysis of the stereoisomers 5a-12c of 22(23)-isoxazolinyl steroids with a hydroxyl group at C 20 or C 22 :

Stereochemical assignments of 22-isoxazolinylsteroids using circular dichroism

“…The different effect of an IeHB and IaHB on the geometry of the isoxazoline ring can be explained logically because an IeHB tends to stretch the heterocycle whereas an IaHB contracts it. Rupture of the relatively weak IaHB [13] in 6 and 14 and the IeHB in 15 under CD measurement conditions in ethanol will restore the "normal" geometry of the isoxazoline ring. This was confirmed by the similar absolute values of [θ] for the n-π * -transition band of the C=N bond for 6 and 3 (Table 1).…”

“…We constructed molecular models of stereoisomers taking into account the details noted aobve for the molecular structures of stereomers 3 and 6 and using dihedral angles from their x-ray structures and from structures of stereoisomeric isoxazolinylsteroids calculated separately by us here and previously [13] in order to make stereochemical assignments for the 22-isoxazolinylsteroids 1-12. Application of the rule of octants to the azomethine bond in the molecular models of the stereoisomers enabled the sign and value of the CE in the range 208-215 nm to be linked to the placement in the octant diagram of asymmetric C-5′ and other asymmetric centers and their substituents.…”