Alpha-hydroxylation at C-15 and C-16 in cholesterol: synthesis of (25R)-5alpha-cholesta-3beta,15alpha,26-triol and (25R)-5alpha-cholesta-3beta,16alpha,26-triol from diosgenin

[reaction: see text] (25R)-5alpha-cholesta-3beta,16alpha,26-triol 7b and (25R)-5alpha-cholesta-3beta,15alpha,26-triol 10b were synthesized, via (25R)-5alpha-cholesta-3beta,16beta,26-triol 5a, from diosgenin 3 in 52% yield over six steps and 47% yield over eight steps, respectively. An efficient method for inversion of a C-16beta hydroxyl to the C-16alpha position and a short method for transposition of a C-16beta hydroxyl to the C-15alpha position via the unexpected beta-reduction of a C-15 ketone in a steroid are reported.     

Potential bile acid metabolites. 25. Synthesis and chemical properties of stereoisomeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids

Epimeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids and some related compounds were synthesized from chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), respectively. The key reaction involved one-step remote oxyfunctionalization of unactivated methine carbons at C-17 of CDCA and at C-14 of UDCA as their methyl ester-peracetate derivatives with dimethyldioxirane (DMDO). After dehydration of the resulting 17alpha- and 14alpha-hydroxy derivatives with POCl(3) or conc. H(2)SO(4), the respective Delta(16)- and Delta(14)-unsaturated products were subjected to hydration via hydroboration followed by oxidation to yield the 3,7,16- and 3,7,15-triketones, respectively. Stereoselective reduction of the respective triketones with tert-butylamine-borane complex afforded the epimeric 3alpha,7alpha,16- or 3alpha,7alpha,15-trihydroxy derivatives exclusively. A facile formation of the corresponding epsilon-lactones between the side chain carboxyl group at C-24 and the 16alpha- (or 16beta-) hydroxyl group in bile acids is also clarified.     

Zur Konfiguration des Vitamin-D3-Metaboliten 25, 26-Dihydroxycholecalciferol: Synthese von (25S,26)- und (25R,26)-Dihydroxycholecalciferol

Configuration of the Vitamin-D₃-Metabolite 25,26-Dihydroxycholecalciferol: Synthesis of (25S,26)- and (25R,26)-Dihydroxycholecalciferol For selective synthesis of the title compounds, (25S)- 1b and (25R)- 1b (Scheme 1), the protected cholesterol precursors (25S)- 6 and (25R)- 6 were prepared from stigmasterol-derived steroid-units 4a-d and C₅-side chain building blocks 5a–d by Grignard- or Wittig-coupling (Scheme 2), the configuration at C(25) of the target compounds being already present in the C₅-units. Conversion of the cholesterol intermediates to the corresponding vitamin-D₃ derivatives was carried out via the 7,8-didehydrocholesterol compounds (25S)- 2b and (25R)- 2b (Scheme 1), using the established photochemical-thermal transformation of the 5,7-diene system to the seco-triene system of cholecalciferol. The configuration at C(25) of the cholesterol precursors as assigned on basis of the known configuration of the C₅-units used, was found to be in agreement with the result of a single crystal X-ray analysis on compound 11 . The configuration at C(25) remained untouched on conversion of the cholesterol ring system to the seco-triene system of vitamin D₃ as evident from comparison of the lanthanide-induced CD. Cotton effects observed for (25S)- 3b and (25S) 1b . 25,26-Dihydroxycholecalciferol observed as a natural vitamin-D₃ metabolite has (25S)-configuration.     

Asymmetric total synthesis of 14(R),15(S)-, 14(S),15(R)-, 14(R),15(R)-, and 14(S),15(S)-epoxyeicosatrienoic acids

The four chiral stereoisomers of 14,15-oxido-5Z, 8Z, 11Z-eicosatrienoic acid were synthesized. The absolute stereochemistry in each case was derived from an asymmetric epoxidation of E-2-octen-1-ol.     

Synthesis of 3alpha,7alpha,14alpha-trihydroxy-5beta-cholan-24-oic acid: a potential primary bile acid in vertebrates

A method for the synthesis of 3alpha,7alpha,14alpha-trihydroxy-5beta-cholan-24-oic acid which is a possible candidate of bile acid metabolite in vertebrates was developed. The principal reactions involved were 1). stereoselective remote-hydroxylation of methyl ursodeoxycholate diacetate with dimethyldioxirane, 2). site-selective protection at C-3 by tert-butyldimethylsilylation of the resulting 3alpha,7alpha,14alpha-trihydroxy ester, 3). oxidation of the diol with pyridinium dichromate adsorbed on activated alumina, 4). stereoselective reduction of the 7-ketone with zinc borohydride, and 5). cleavage of the protecting group at C-3 with p-toluenesulfonic acid. A facile elimination of the 14alpha-hydroxy group under an acidic or neutral condition is also described. The synthetic reference compound is now available for comparison with unidentified biliary bile acids detected in vertebrate bile.     

Stereoselective synthesis of the nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid from (4S,5S)-4-formyl-5-vinyl-2-oxazolidinone

(4S,5S)-4-Formyl-5-vinyl-2-oxazolidinone (4b), which is readily obtained via a zinc-silver-mediated reductive elimination of alpha-d-lyxofuranosyl phenyl sulfone (3b), is successfully converted to the naturally occurring, nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid (2). Also in this study, a facile "oxazolidinone rearrangement" reaction is uncovered during the attempted formation of the (methylthio)thiocarbonate derivative of the oxazolidinone alcohol 7.     

Synthese von (22R,25S)-16β-Amino-22,26-epiminocholestanen

By reacting the known 16-bromo-N-cyano-22,26-epimino-cholestanes (e.g.2) with NaN₃ inDMF 16-azido-N-cyano-22,26-epimino-cholestanes (e.g.4) were obtained. Reduction of4 with LiAlH₄ gives 16-amino-22,26-epimino-cholestane (9). Some acylated derivatives of9 are described, e.g. the known derivatives11 and13, which prove the stereochemistry at C-16.

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Herrn Prof. Dr.K. Kratzl mit den besten Wünschen zum 60. Geburtstag von der Abteilung für Pharmazeutisch-chemische Forschung der Chemie Linz AG gewidmet.     

Totally selective synthesis of enantiopure (3S,5S)- and (3R,5R)-4-amino-3,5-dihydroxypiperidines from aminodiepoxides derived from serine

The transformation of enantiopure (2R,4R)- and (2S,4S)-N,N-dibenzyl-1,2:4,5-diepoxypentan-3-amine, 1 and 2, into the corresponding enantiopure (3S,5S)- and (3R,5R)-3,5-dihydroxy-3-aminopiperidines, 3 and 4 respectively, is described. The opening of the two epoxide rings with a range of amines takes place with total regioselectivity and high yields, in the presence of LiClO4. A mechanism to explain this transformation is proposed.     

(+)-Colletodiol : Synthesis from (S,S)-tartaric acid and (R)-3-hydroxy-butyric acid

E-(R)-5-Hydroxy-2-hexenoic acid (4) and the acetonide of E-(4R,5R,7R)-trihydroxy-2-octenoic acid (3) are joined to give, after deprotection, (+)-colletodiol (1). The syntheses of the two hydroxy-acids from poly-(R)-3-hydroxy-butanoate (PHB) and (?)-tartaric acid, respectively, are outlined.     

Stereoselective synthesis of (2R,3S,4S,5R)-trans-3,4-dihydroxy-5-(4-fluorophenoxymethyl)-2-(1-N-hydroxyureidyl-3-butyn-4-yl)tetrahydrofuran and (2R,3S,4S,5R)-trans-5-ethynyl-2-(4-fluorophenoxymethyl)-3,4-O-isopropylidene tetrahydrofuran from mannose diacetonide

Stereoselective synthesis of pharmaceutically interesting chiral tetrahydrofurans starting from mannose diacetonide is reported. A 1,4-diol system derived from mannose diacetonide, through a Mitsunobu reaction was stereospecifically cyclized to give chiral tetrahydrofurans. Both the C-1 and C-4 centers of d-mannose are successfully exploited to install the requisite side chains.