Synthesis of [19- 2H3]-analogs of dehydroepiandrosterone and pregnenolone and their sulfates.
Deuterated analogs of pregnenolone and pregnenolone sulfate with three atoms of deuterium in position 19 were prepared. The synthetic approach was developed on derivatives of dehydroepiandrosterone, where initial intermediates were well characterized, and then applied to the pregnenolone series. Starting 19-hydroxy compounds were transformed into 3alpha,5-cycloderivatives to simplify the Jones oxidation into the corresponding 19-oic acids. After oxidation, rearrangement to 3-hydroxy-5-enes, and suitable protection, two deuterium atoms were introduced by lithium aluminum deuteride reduction. Mesylate exchange by iodide in the presence of zinc and deuterium oxide added third deuterium atom. Deprotection gave title analogs with about 93-95% content of d3-derivative, the rest was mainly not fully deuterated d2-analogue as followed from the mass spectra analysis. Thus, 3beta-hydroxy[19-2H3]androst-5-en-17-one was prepared in 14 steps from 19-hydroxy-17-oxoandrost-5-en-3beta-yl acetate in 8.9% yield, the analogous sequence in the pregnenolone series gave 3beta-hydroxy[19-2H3]pregn-5-en-20-one in 7.3% yield. Corresponding sulfates were prepared via pyridinium salts in 53 and 57% yields, respectively. Fully assigned NMR data of selected pregnenolone derivatives were given.
Cerný
Ivan
I
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic.
Pouzar
Vladimír
V
Budesínský
Milos
M
Bicíková
Marie
M
Hill
Martin
M
Hampl
Richard
R
D000731:Androstanes / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D003903:Deuterium / Q000737:chemistry; D015394:Molecular Structure; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011284:Pregnenolone / Q000138:chemical synthesis* / Q000737:chemistry
D000731:Androstanes; C018370:pregnenolone sulfate; D003687:Dehydroepiandrosterone; D011284:Pregnenolone; D003903:Deuterium; D011280:Pregnanolone; C033936:androstane