Synthesis of [3,4-13C2]-enriched bile salts as NMR probes of protein-ligand interactions

Gregory P. Tochtrop, Gregory T. DeKoster, David P. Cistola, Douglas F. Covey

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18 Scopus citations

Abstract

Synthetic methodology that allows for incorporation of isotopic carbon at the C-3 and C-4 positions of bile salts is reported. Three [3,4-13C2]-enriched bile salts were synthesized from either deoxycholic or lithocholic acid. The steroid 3α-OH group was oxidized and the A-ring was converted into the Δ4-3-ketone. The C-24 carboxylic acid was next converted into the carbonate group and selectively reduced to the alcohol in the presence of the A-ring enone. Following protection of the 24-OH group, the Δ4-3-ketone was converted into the A-ring enol lactone. Condensation of the enol lactone with [1,2-13C2]-enriched acetyl chloride and subsequent Robinson annulation afforded a [3,4-13C2]-enriched Δ4-3-ketone that was subsequently converted back into a 3α-hydroxy-5β-reduced bile steroid. C-7 hydroxylation, when necessary, was achieved via conversion of the Δ4-3-ketone into the corresponding Δ4,6-dien-3-one, epoxidation of the Δ6-double bond, and hydrogenolysis/hydrogenation of the 5,6-epoxy enone system. The [3,4-13C2]-enriched bile salts were subsequently complexed to human ileal bile acid binding protein (I-BABP), and 1H-13C HSQC spectra were recorded to show the utility of the compounds for investigating the interactions of bile acids with I-BABP.

Original languageEnglish
Pages (from-to)6764-6771
Number of pages8
JournalJournal of Organic Chemistry
Volume67
Issue number19
DOIs
StatePublished - Sep 20 2002

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