Chemical Synthesis of Uncommon Natural Bile Acids: The 9α-Hydroxy Derivatives of Chenodeoxycholic and Lithocholic Acids

Abstract

The chemical synthesis of the 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids is reported. For initiating the synthesis of the 9α-hydroxy derivative of chenodeoxycholic acid, cholic acid was used; for the synthesis of the 9α-hydroxy derivative of lithocholic acid, deoxycholic acid was used. The principal reactions involved were (1) decarbonylation of conjugated 12-oxo-Δ 9(11) -derivatives using in situ generated monochloroalane (AlH 2 Cl) prepared from LiAlH 4 and AlCl 3 , (2) epoxidation of the deoxygenated Δ 9(11) -enes using m-chloroperbenzoic acid catalyzed by 4,4′-thiobis-(6-tert-butyl-3-methylphenol), (3) subsequent Markovnikov 9α-hydroxylation of the Δ 9(11) -enes with AlH 2 Cl, and (4) selective oxidation of the primary hydroxyl group at C-24 in the resulting 3α,9α,24-triol and 3α,7α,9α,24-tetrol to the corresponding C-24 carboxylic acids using sodium chlorite (NaClO 2 ) in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and sodium hypochlorite (NaOCl). The 1 H-and 13 C-NMR spectra are reported. The 3α,7α,9α-trihydroxy-5β-cholan-24-oic acid has been reported to be present in the bile of the Asian bear, and its 7-deoxy derivative is likely to be a bacterial metabolite. These bile acids are now available as authentic reference standards, permitting their identification in vertebrate bile acids.

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

“…Nussim, Mazur, and Sondheimer () reported that the hydroxylation of △ 9(11) ‐5α‐steroids with A/B‐ trans junction yielded almost exclusively the corresponding 11α‐alcohols; however, the reaction did not proceed at all for △ 9(11) ‐5β‐steroids with A/B‐ cis junction; on the other hand, the reaction of △ 11 ‐5α‐steroids yielded the corresponding 11α‐ and 12α‐alcohols in a ratio of 1:1. In preliminary experiments, we found that 11α‐hydroxylation of △ 9(11) ‐5β‐cholen‐3α,24‐diol (Iida et al, ) was unsuccessful under various conditions, in analogy with the previous finding of other △ 9(11) ‐5β‐steroids (Nussim et al, ). Furthermore, an attempted reductive cleavage with AlH 2 Cl (Iida et al, ) of methyl 3α‐acetoxy‐11α,12α‐epoxy‐5β‐cholan‐24‐oate, which was easily prepared from 6a intermediate, failed to afford 5β‐cholan‐3α,12α,24‐triol as the major product.…”

“…In preliminary experiments, we found that 11α‐hydroxylation of △ 9(11) ‐5β‐cholen‐3α,24‐diol (Iida et al, ) was unsuccessful under various conditions, in analogy with the previous finding of other △ 9(11) ‐5β‐steroids (Nussim et al, ). Furthermore, an attempted reductive cleavage with AlH 2 Cl (Iida et al, ) of methyl 3α‐acetoxy‐11α,12α‐epoxy‐5β‐cholan‐24‐oate, which was easily prepared from 6a intermediate, failed to afford 5β‐cholan‐3α,12α,24‐triol as the major product. Hydroxylation of 6a , instead of 7a , was also unsatisfactory, yielding a complex mixture of products, probably because of the simultaneous formation of partially hydrolyzed products at C‐3/C‐7 and C‐24 by the alkaline reagent.…”

“…The conclusive evidence for the assigned structure is based on NMR spectra and some cases on X‐ray diffraction. As an example of our work, we have recently reported the preparation of 3α,9α‐dihydroxy‐ and 3α,7α,9α‐trihydroxy‐5β‐cholan‐24‐oic acids (Iida et al, ).…”

Biocatalytic Steroidal 9α‐Hydroxylation and Fragmentation Enable the Concise Chemoenzymatic Synthesis of 9,10‐Secosteroids

“…These results indicate that KSHs could be efficient biocatalysts for steroidal 9α‐hydroxylation. In contrast to the previously reported eight‐step chemical synthesis of related 9α‐hydroxylated steroids (<5% overall yield), [7c] this biocatalytic approach allows for an efficient one‐step enzymatic installation of the 9α‐hydroxyl group with excellent regio‐ and stereospecificity.…”