Investigation on the synthesis of 25-hydroxycholesterol.

A very efficient and environmentally benign method has been developed for the synthesis of 25-hydroxycholesterol. The reaction was performed in THF-water (4:1, v/v) using NBS as the brominating agent, followed by the easy reduction of C-Br with lithium aluminum hydride in THF, to yield the final product corresponding to a Markovnikov's rule. Excellent yields and regioselectivity have been obtained.

Synthesis and biological activity of (24E)- and (24Z)-26-hydroxydesmosterol.

Using 3ß-hydroxychol-5-en-24-oic acid (4) as starting material, the diastereoisomeric allylic alcohols (24E)-26-hydroxydesmosterol (2) and (24Z)-26-hydroxydesmosterol (3) have been synthesised in six steps with 67% and 12% overall yield, respectively. Both of these isomers are found in newborn mouse brain where sterol synthesis is high. Unlike desmosterol (1), neither of these isomers is a ligand to the liver x receptors and thus represents a novel biological deactivation mechanism avoiding cholesterol synthesis.

First synthesis of ent-desmosterol and its conversion to ent-deuterocholesterol.

We report the first synthesis of the unnatural enantiomer of desmosterol (ent-desmosterol). The sterol nucleus was constructed enantiospecifically, followed by stepwise addition of the side chain. Beginning with ent-androst-4-ene-3,17-dione, ent-desmosterol was synthesized in 13 steps and 20% yield. Protected ent-desmosterol was subjected to catalytic deuteration to afford ent-deuterocholesterol. Ent-desmosterol and ent-deuterocholesterol will be used to study the importance of sterol absolute configuration for sterol-lipid interactions in biophysical studies and in biological systems.

Further studies on the synthesis of 24(S),25-epoxycholesterol. A new, efficient preparation of desmosterol.

Efforts to improve the synthesis of 24(S),25-epoxycholesterol (1) from stigmasterol (3) have included identification of 6 alpha-hydroxy-i-steroid 11 as a byproduct from the ozonolysis of 9 and an attempt to effect conversion of sulfone 14 to diol 18 via Payne rearrangement and nucleophilic trapping of epoxide 25, which led instead to 27 and 28 (97% yield). A more efficient synthesis of 1 was achieved via coupling of cuprate 21 with allylic acetate 31 to give 73% of 16, in the most efficient conversion yet of a C22 intermediate to desmosterol (5) or its acetate 6.

Synthesis of desmosterol and epidesmosterol from hyodeoxycholic acid.

A new synthesis of desmosterol was described using hyodeoxycholic acid (3alpha,6alpha-dihydroxy-5beta-cholanic acid) as a starting material. Epidesmosterol (3alpha-hydroxycholesta-5,24-diene) was also synthesized for the first time from the same starting material.