Synthesis of fluorinated analogues of the neurosteroid GABA(A) receptor antagonist, 17-PA

The steroid 17-PA is a GABA(A) receptor antagonist which is finding use as a tool in evaluating agonistic/antagonistic activity at GABA(A) receptors. Compounds with improved efficacy over 17-PA would be are advantageous for such studies. Accordingly a series of novel analogues of the neurosteroid 17-PA have been prepared and a convenient two-step route is presented which is amenable to the synthesis of analogues with electron-donating para-aromatic substituents including fluorine. However, for the metafluoro analogue then the original four-step route to 17-PA remains more efficient overall. The paper describes these syntheses and discusses the electronic factors which influence this synthetic chemistry. (c) 2008 Elsevier B.V. All rights reserved.