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The preparation and reactions of B-norsteroidal 6-ketones and their relatives

Posted on 30. September, 2011.

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B-norsteroids are involved in the the apoptopic activity of the marine sterol orostonal and the anti-tubercular activity of the parguesterols, and are used in the synthesis of hormone analogues.  The preparation and reactivity of the heavily substituted cyclopentanone B-norsteroidal 6-ketones, which have formed precursors for the synthesis of ring B-azasteroids, are reviewed by Cavit Uyanik and James R. Hanson in the September issue of Journal of Chemical Research. They suggest further areas for investigation of these modified steroids.

The preparation and reactions of B-norsteroidal 6-ketones and their relatives are reviewed in the context of the stability of the A/B and B/C ring junctions and the stereochemistry of the addition reactions to the carbonyl group. This review is a sequel to a previous article on the reactions of B-norsteroidal 4- and 5-enes (C. Uyanik and J.R. Hanson, J. Chem. Res, 2009, 713.)

There has been renewed interest in the B-norsteroids following the discovery of the apoptopic activity of the marine sterol orostonal (1) and the anti-tubercular activity of the parguesterols (e.g. 2).4 B-Norsteroids have been used in the synthesis of hormone analogues. Thus B-norsteroidal 6-ketones have formed precursors for the synthesis of ring B azasteroids such as azapregnanolone analogues of neuroactive steroids. The reactivity of steroidal ketones is often used as a model for understanding the reactions of ketones in more complicated environments. As will become apparent from the following, the reactivity of the cyclopentanone ring B differs significantly from that of the cylohexanone C-6 and C-7 ketones of the normal steroids. The synthesis, chemistry and biological activity of Bnorsteroids has been reviewed previously. This review is is concerned primarily with B-norsteroidal 6-ketones.

The generalisation that a cis-fused hydroindanone is more stable than the trans isomer is explored in the context of the stability of the A/B and B/C ring junctions. Whilst this generalisation is broadly satisfied in this context, there are exceptions which reveal the importance of considering all the possible interactions within a molecule. It suggests that there are further factors such as the stereochemistry at C-9, C-10 and C-14 as well as the presence of carbonyl groups at other positions which may need to be examined. The potential for conformational distortions implicit in these isomerisations may affect the binding of the steroids to different receptors and their consequent biological activity. Studies on the biological activity of B-norsteroids and related azasteroids as potential inhibitors of human steroidal 5α-reductase,43 the 3β-hydoxy steroid dehydrogenase of Mycobacterium tuberculosis44 and as analogues of neuroactive steroids45 suggest that there are further areas for investigation of these modified steroids.

In picture: James Hanson (left) and Cavit Uyanik (right).

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