Chemical Synthesis of (22E)-3.ALPHA.,6.ALPHA.,7.ALPHA.,12.ALPHA.-Tetrahydroxy-5.BETA.-chol-22-en-24-oic Acid and Its N-Acylamidated Conjugates with Glycine or Taurine: Precursors of the [22,23-3H] Labelled Tracers

Abstract

(22E)-3a,6a,7a,12a-Tetrahydroxy-5b-chol-22-en-24-oic acid and its N-acylamidated conjugates with glycine or taurine were synthesized from cholic acid. The key reactions employed are: 1) degradation of the side chain in intermediary C 24 3a,6a,7a,12a-tetrahydroxylated bile acid to the corresponding C 22 23,24-dinor-aldehyde, followed by Wittig reaction with methyl (triphenylphosphoranylidene)acetate and 2) N-acylamidation of the unconjugated tetrahydroxy-D 22-5b-cholenoic acid with glycine (or taurine) in the presence of diethylphosphorocyanide and triethylamine as coupling reagents.Key words bile acid; tetrahydroxy-D 22-5b-cholenoic acid; gycine conjugate; taurine conjugate; Wittig reaction; N-acylamidation Chem. Pharm. Bull. 58(8) 1103-1106 (2010) © 2010 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: takaiida@chs.nihon-u.ac.jp Fig. 1. Structure of (22E)-3a,6a,7a,12a-Tetrahydroxy-5b-chol-22-en-24-oic Acid and Its Glycine and Taurine Conjugates (1a-c)

The discovery of 12β-methyl-17-epi-18-nor-bile acids as potent and selective TGR5 agonists

“…Upon formyl protection of the two hydroxy groups of 17 [47] and 43, the side chain was first subjected to a bis(acetoxy)iodobenzene (BAIB)/copper(II) acetate-mediated oxidative decarboxylation to yield the olefins 80 and 85 [54]. These were then dihydroxylated by means of osmium tetroxide and N-methylmorpholine N-oxide (NMO) and the resulting vicinal diols 81 and 86 underwent oxidative cleavage to the desired 17-epi-18,23,24-trisnor-BAs 83 and when treated with BAIB and catalytic amounts of TEMPO [55,56]. Final conjugation of 83 and 88 with taurine (22) was accomplished by using DPPA as the coupling reagent [51].…”

“…25, 71.09, 54.56, 51.51, 50.69, 49.00, 47.78, 46.93, 42.84, 39.88, 37.70, 37.41, 36.79, 36.67, 36.58, 36.55, 34.68, 34.41, 31.31, 30.54, 29.78, 25.61, 25.40, 23.93, 23.46, 21.97, 20.28, 12.03; HRMS (ESI) m/z calcd for C 29 H 50 NO 6 S − 540.3364, found 540.3360. 3α-Hydroxy-12β-methyl-7-oxo-17-epi-25-homo-18-nor-5βcholan-25-oic acid (55). Employing Method A as described for the preparation of compound 28, bleach (2 M, 3.5 mL) was introduced slowly into a mixture of compound 20 [47] (2.51 g, 6.17 mmol) and potassium bromide (39.6 mg, 0.33 mmol) in a 1:1 mixture of acidic acid (40 mL) and ethyl acetate (40 mL) at 10-14 • C to afford 2.14 g (86%) of 55 as a colorless foam along with 296 mg (12%) of the corresponding diketone by-product 54.…”

Chemical Synthesis of the Epimeric (23R)‐ and (23S)‐Fluoro Derivatives of Bile Acids via Horner–Wadsworth–Emmons Reaction

“…When 6a and 6b were subjected to the Horner-Wadsworth-Emmons reaction with triethyl 2-fluoro-2-phosphonoacetate in the presence of LiCl and 1,8-diazabicyclo [5,4,0]undec-7-ene (DBU) as base-sensitive reagents [17], the reaction proceeded smoothly to give the more thermodynamically stable (E)-isomer of the C 24 α-fluoro-α,β-unsaturated esters (7a and 7b) in reasonable isolated yields of 70 and 72 %. The stereochemical configuration of the Δ 22 -bond in 7a and 7b was conclusively determined as the E-form, on the basis of a multiplet 1 H signal at 22-H appearing at 5.68-5.73 ppm in the 1 H NMR spectra [18][19][20]. The characteristic 13 Catalytic hydrogenation of the α-fluoro-α,β-unsaturated esters (7a and 7b) in the presence of Pd/C as a catalyst yielded an epimeric mixture of the (23R)-and (23S)-23-fluoro-peracetate esters (8a and 8b) nearly quantitatively.…”