Isotopically labelled geometric isomers of vinyl groups: reconstructive synthesis of (Z)- and (E)-[7′-2H]rotenone

Abstract

Rotenone with its 7′-methylene specifically labelled with hydrogen isotope in the (Z)- or (E)-position offers utility in both biochemical and chemical experiments, and the chemical shifts of the protons in question were identified by NOE experiments. Since an approach to stereospecific synthesis through introduction of a trimethylsilyl-substituted methylene by the Wittig reaction proved unsatisfactory, 12a-β-hydroxyrotenone (rotenolone) trimethylsilyl ether was treated with benzenesulfenyl chloride to give, on desilylation, anti-Markownikov addition products diastereoisomeric at C-6′. On heating, these were converted into the Markownikov diastereoisomers which, by dehydrohalogenation, produced 7′-phenylthiorotenolone as a mixture of (E)- and (Z)-isomers (∼85:15). The latter were separated, and the (E)-isomer was desulfurised by deactivated [²H₂]-Raney nickel to give (E)-[7′-²H₂]rotenolone, though deuterium incorporation was incomplete (∼60%). To obtain a higher isotopic content, [7′-²H₂]rotenolone trimethylsilyl ether was synthesized and subjected to similar treatment with benzenesulfenyl chloride to give 7′-phenylthio-[7′-²H]rotenolone as (E)-/(Z)-isomers. Separation and treatment of the (E)-isomer with [¹H₂]-Raney nickel now produced (Z)-[7′-²H]rotenolone having a >95% incorporation of deuterium with >90% positional integrity. Removal of the blocking 12a-hydroxy group with zinc and acetic acid gave the desired (Z)-[7′-²H]rotenone.

Although 12a-methylrotenone having the unnatural trans-B/C fusion formed both the required anti-Markownikov and Markownikov addition products, unwanted removal of ring-E protons by hindered bases from the now more accessible α-face brought about extensive elimination, forming a conjugated diene.