Kaoru Omura

Regioselective dehydrogenation of 3-keto-steroids to form conjugated enones using o-iodoxybenzoic acid and trifluoroacetic acid catalysis.

Mild and regioselective conversion of 3-keto-5α- and 3-keto-5β-steroids (trans A/B- and cis A/B-ring juncture, respectively) to the corresponding enones (Δ(1)- and Δ(4)-3-ketones) by treatment with o-iodoxybenzoic acid (IBX) catalyzed by trifluoroacetic acid (TFA) in DMSO, is described. The IBX-mediated reaction involved dehydrogenation of the α- and β-hydrogen atoms of the 3-ketones to give the enones regioselectively in good isolated yields without concomitant formation of related dienones and trienones.

An efficient synthesis of 7α,12α-dihydroxy-4-cholesten-3-one and its biological precursor 7α-hydroxy-4-cholesten-3-one: Key intermediates in bile acid biosynthesis

This paper describes a method for the chemical synthesis of 7α,12α-dihydroxy-4-cholesten-3-one (1a) and its biological precursor, 7α-hydroxy-4-cholesten-3-one (1b), both of which are key intermediates in the major pathway of bile acid biosynthesis from cholesterol. The principal reactions involved were (1) building of the cholesterol (iso-octane) side chain by 3-carbon elongation of the cholane (iso-pentane) one, (2) oxidation sequence to transform the 3α-hydroxy group of the steroidal A/B-ring to the desired 4-en-3-one system, and (3) appropriate protection strategy for hydroxy groups in the positions at C-7 and C-12 in the steroid nucleus. The absolute structure of 1a and 1b were confirmed by NMR and X-ray crystallography. The targeted compounds 1a and 1b, prepared in 11 steps from 2a and 2b respectively, should be useful for biochemical studies of bile acid biosynthesis or clinical studies of bile acid metabolism, as plasma levels of 1b (also termed C4) have been shown to correlate highly with the rate of bile acid biosynthesis in man.

Chemical Synthesis of Rare Natural Bile Acids: 11α-Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids

A method for the preparation of 11α-hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12α-mesyloxy group of the methyl esters of 3α-acetate-12α-mesylate and 3α,7α-diacetate-12α-mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting △11 -3α-acetoxy and △11 -3α,7α-diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11α-hydroxylation of the △11 -3α,24-diol and △11 -3α,7α,24-triol intermediates with B2 H6 /tetrahydrofuran (THF); and (4) selective oxidation at C-24 of the resulting 3α,11α,24-triol and 3α,7α,11α,24-tetrol to the corresponding C-24 carboxylic acids with NaClO2 catalyzed by 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and NaClO. In summary, 3α,11α-dihydroxy-5β-cholan-24-oic acid and 3α,7α,11α-trihydroxy-5β-cholan-24-oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis.

Solvent-Free Synthesis of 2-Alkylbenzothiazoles and Bile Acid Derivatives Containing Benzothiazole Ring by Using Active Carbon/Silica Gel and Microwave

A highly efficient and simple method for the synthesis of 2-alkylbenzothiazoles through the condensation of 2-aminothiophenol and aliphatic aldehydes in the presence of active carbon/silica gel is described. The reaction proceeded under solvent-free and microwave irradiation to afford 2-alkylbenzothiazoles in high yields. This method was extended to the synthesis of bile acid derivatives containing a benzothiazole ring and obtained the desired products in high yields. The anti-inflammatory activity and cytotoxicity of the newly synthesized benzothiazole derivatives of bile acid were tested; the results showed that anti-inflammatory activities of all tested compounds tested were higher than that of standard drugs, such as indomethacin.

3,4-Seco-12α-hydroxy-5β-cholan-3,4,24-trioic Acid, a Novel Secondary Bile Acid: Isolation from the Bile of the Common Ringtail Possum (Pseudocheirus peregrinus) and Chemical Synthesis

The major bile acids present in gallbladder bile of the common ringtail possum (Pseudocheirus peregrinus), an Australian marsupial, were isolated by preparative HPLC and identified by NMR and by comparison with synthetic standards. The major compound present (52%) was 3α,12α-dihydroxy-7-oxo-5β-cholan-24-oic acid (7-oxodeoxycholic acid), about three fourths conjugated with taurine. Also present was 3α,7β,12α-trihydroxy-5β-cholan- 24-oic acid (20%; ursocholic acid) largely in unconjugated form. In addition, 3,4-seco-12α-hydroxy-5β-cholan-3,4,24- trioic acid was present in unconjugated form and constituted 8% of biliary bile acids. Proof of the structure of this novel 3,4-seco acid was obtained by its chemical synthesis from deoxycholic acid via an intermediary 3β,4β-dihydroxy derivative that was then oxidatively cleaved with sodium periodate. As all primary bile acids have a hydroxyl or oxo substituent at C-7, the absence of such in the seco-bile acid suggests that it is a secondary bile acid, synthesized by bacterial enzymes present in the intestine.

Two Major Bile Acids in the Hornbills, (24R,25S)-3α,7α,24-Trihydroxy-5β-cholestan-27-oyl Taurine and Its 12α-Hydroxy Derivative.

Two major bile acids were isolated from the gallbladder bile of two hornbill species from the Bucerotidae family of the avian order Bucerotiformes Buceros bicornis (great hornbill) and Penelopides panini (Visayan tarictic hornbill). Their structures were determined to be 3α,7α,24-dihydroxy-5β-cholestan-27-oic acid and its 12α-hydroxy derivative, 3α,7α,12α,24-tetrahydroxy-5β-cholestan-27-oic acid (varanic acid, VA), both present in bile as their corresponding taurine amidates. The four diastereomers of varanic acid were synthesized and their assigned structures were confirmed by X-ray crystallographic analysis. VA and its 12-deoxy derivative were found to have a (24R,25S)-configuration. 13 additional hornbill species were also analyzed by HPLC and showed similar bile acid patterns to B. bicornis and P. panini. The previous stereochemical assignment for (24R,25S)-VA isolated from the bile of varanid lizards and the Gila monster should now be revised to the (24S,25S)-configuration.