Synthesis of an isomeric mixture (24RS,25RS) of sodium scymnol sulfate

Abstract

This is the first reported multistep synthesis of the shark bile sterol sodium scymnol sulfate epimeric at the C-24 hydroxyl and C-27 sulfate positions. The starting cholic acid was protected as the tetrahydropyran ether (THP) derivative, reduced to the C-24 alcohol and oxidized to the protected aldehyde. This aldehyde was then coupled with methyl 3-hydroxypropionate using 2 equiv. of lithium diethylamide at −65 °C to produce methyl (24RS,25RS)-24,27-dihydroxy-3α,7α,12α,tris[(tetrahydropyran-2-yl)oxy]-5β-cholestan-26-oate. After protecting the 24 and 27 hydroxyls as the THP derivatives, this fully protected ester was then reduced to the monoalcohol. The monoalcohol was sulfated using the sulfur trioxide–triethylamine complex in dimethylformamide. The protective THP groups were removed with methanolic HCl and the sulfate was converted to the sodium salt with sodium ethoxide in methanol. This general synthetic scheme has application to produce a range of monosulfated sterols.

Introduction

The natural sodium scymnol sulfate has been purified by our group from shark bile by preparative HPLC for use in commercial skin care products [1]. We have investigated many of the wide-ranging biological properties of scymnol and its sulfate including its potent antioxidant [2], [3] and hepatoprotective activities [4], [5]. Ishida et al. have also investigated its protective properties against vascular endothelial cell injury [6], [7], [8].

The sodium scymnol sulfate isolated from shark bile contains the 24R alcohol substituent and either or both of the 27R and 27S sulfate esters [9] (see Fig. 1). Thus, as a further progression in the potential replacement of the natural product with a synthetic product, we designed the synthetic scheme shown in Fig. 2 to allow monosulfation at the C-27 position. This scheme leads to the (24RS,25RS) epimeric mixture of alcohols whereas the natural product comprises the (24R,24R) and/or (24R,25S) epimers. Our group had synthesized epimeric unsulfated (24RS) scymnol [10] previously. (24R) scymnol was synthesized subsequently by Adhikari et al. [11]. However a sulfated form of scymnol had not been previously synthesized.