7a-hydroxy derivatives

After hydroxylation of a steroidal substrate has taken place, fission of caibon-carbon bonds may occur. Thus 9a-hydroxylation is the first stage in the fission of the B-ring. This process can be suppressed by restriction of metals (such as iron). This has been accomplished using 2,2-bipyiidyl, either alone or in combination with an absorbent such as Amberlite XAD-7. Very substantial enhancements in yield aro possible. For example 3-ketobisnorcholenol (68) gave <10% yield of the 7a-hydroxy derivative with Botryodiploida theobromae in the absence of these materials, but up to 45% vriien diey were added together (equation 23). ... 

Oxidation of hydrazones. The hydrazone of 3/3-hydroxy-A24-lanostene-7-one (1) is oxidized in CH2C12 at 0-5° by lead tetraacetate to give 3/3-hydroxy-7a-acetoxy-A24-lanostene (2) as the major product. The A7 M-diene (3) is a minor product.6 The reaction is useful, since 7a-hydroxy derivatives have been used to... 

If the pathway of biosynthesis of alio bile acids from cholestanol is similar to that proposed for the 5p bile acids from cholesterol, 7a-hydroxyla-tion should be the next step. The microsomal fraction of rat liver properly fortified with NADPH and oxygen was observed to hydroxylate cholestanol and cholesterol to the respective 7a-hydroxy derivatives at equivalent rates (127). With cholestanol the 7 -hydroxylase was inhibited by the product, or the 7j3-ol or 7-keto sterol. The rate of hydroxylation could be enhanced by prior treatment of the rats with cholestyramine (a bile acid sequestrant) and/or phenobarbital. A C5 double bond was not considered a requirement for enzymatic hydroxylation at C7. 

Common sage and rosemary (see Table 8.32), plants of the Lami-aceae family, contain the diterpenes camosic acid, also known as rosmaricin (8-259), derived from ent-caurene, and bitter carnosol (picrosalvin, 8-260), which are potent antioxidants. Carnosic acid is a major component of fresh rosemary tops (1-2%), but is unstable and is enzymatically transformed into carnosol. These two diterpenoids represent about 15% w/w of plants haulm extracts and exhibit about 90% of extract antioxidant activity. Other transformation products of carnosic acid are rosmanol (7a-hydroxy derivative, 8-261), epirosmanol (7P-isomer, 8-262) and similar compounds. 

From the study of a microbially mediated oxidation of arteether 28b, sufficient quantities of 7a-hydroxy 180 and 15-hydroxy derivatives 182 were obtained to employ them as intermediates for the preparation of fluorinated compounds. The hydroxyl groups were oxidized to the corresponding aldehyde 187, or ketone 188, with catalytic quantities of tetra- -propylammonium perruthenate (TPAP) in the presence of excess iV-methylmorpholine A -oxide. On reaction with DAST, 187 and 188 were converted into the corresponding geminal difluoro derivatives, 189 (63%) and 190 (42%). In addition to 190, a monofluoro olefin 191 was obtained in 25% yield from 188 on reaction with DAST <1995JME4120>. 

The second method of preparation (shown in Scheme 2) depends on treating dehydroepiandrosterone (prepared from cholestrol or sitosterol) with acetylene to form the 17a-ethnyl-17p-hydroxy derivative, which is carbonated to the 17a-propionic acid. Reduction of the unsaturated acid in alkaline solution yields the saturated acid, which cyclizes to the lactone on acidification. Bromination to the 5,6-dibromo-compound, followed by oxidation of the hydroxyl group to the ketone, and then dehydro-bromination to the 7a-hydroxyl derivative, produces spironolactone when esterified with thiolacetic acid. 

Androstenolone, 1, can be transformed microbiologically to the 7a,15a-dihy-droxy derivative 2 by the action of Colletotrichium Uni. During formation of the acetal (3), inversion takes place on C-7. Acidic cleavage of 3 results in the triol, 4, which can also be produced by direct acidic catalysis from 2 [12,13]. After selective protection to the 3/l,15a-dipivalate (5), the 15/1,16/1-methylene compound, 6, can be synthetized, and then stereoselectively transformed to the 5/ ,6/ -epoxide, 7. This reacts with triphenylphosphine and tetrachloromethane in pyridine to produce the 7a-chloro derivative, 8. On treatment with zinc and acetic acid, 8 can be converted to the key compound 9, which has a 5/i-hydroxy-6-ene structure. Compound 9 can then be methylenated stereoselectively in the 6/1,7/1 position by the Simmons-Smith method. The last three steps - 10 —> 11 —> 12 — drospirenone -include the build-up of the spironolactone ring, after which water is lost from the molecule and oxidation affords drospirenone. 

This experimental observation is illustrated in Figure 8.66 by the tandem mass spectra of two bile acids of the A4-3-oxo class the taurine conjugates oI 7a-hydroxy-3-oxochol-4-cn-24-oic acid and 7a, 12a-dihydro-3-oxochol-4-en-24-oic acid. [311] Similar spectra were obtained for the A4-3-hydroxy derivatives. The general fragmentation diagram deduced from these spectra is shown in Figure 8.67. 

A -Androsten-3,17-dione (S-22), la-cyano-A -androsten-3,17-dione (S-37), ljS-acetylthio-A -androstene-3,17-dione (S-38), 7a-methyl-A -androstene-3,17-dione (S-23), A -androstene-3,l 1,17-trione (S-43), 11/3-hydroxy-A -androstene-3,17-dione (S-44), 3a -hydroxyandrostane-17-one (D-27), 3/3-hydroxyandrostane-I7-one (D-161), and androstane-3,17-dione (D-30) compared to the corresponding 17/3-hydroxy derivatives exhibit much smaller androgenic and anabolic activities with unfavorable anabolic-androgenic ratios (with the exception of S-23, which has a favorable ratio). 

Bile-acid formation in rats involves hydroxylation to give 7a- and 6j8-hydroxy-derivatives. In many cases, no isotope effect was observed on hydroxylation of the appropriate labelled sterol. These examples involve cytochrome P-450 in the oxidation. However, oxidation of [7a- H,24- C]deoxycholic acid or tauro-deoxycholic acid to the corresponding cholic acid showed an isotope effect of 3.8 on examination of recovered starting material. 

Ozone on silica gel introduces a 25-hydroxy-substituent into suitable compounds with a cholestane side-chain. By using the la,3/8-diacetoxy-6/8,7a-dibromo-derivative (383), prepared from the known 6-ene, the 25-hydroxylated compound was obtained as the only product (11% conversion). Trifluoroacetylation followed by dehydrobromination afforded the 5,7-diene (385), which was transformed into la,25-dihydroxy-vitamin D3 by the usual method. 

New tirucallane triterpenoids are adenophorate (70) (T-ray analysis) from Adenophora triphylla (Campanulaceae),32 and the ring a seco derivatives (71) and (72) from Guarea cedrata (Meliaceae).52 Treatment of the 7a-hydroxy- or 7-keto-apotirucall-14-enes (73)—(75) with monoperphthalic acid affords the corresponding 14a,15a-epoxides.53... 

Deoxycholic acid, oxygenated in the presence of Fe sulphate and ascorbic acid in a phosphate buffer, afforded the 15a-hydroxy-derivative in low yield. 7a-Hydroxylation under similar conditions has been reported previously. ... 

In the 5a series allochenodeoxycholate is 12a-hydroxylated to allocholate in the bile fistula rat [131] or with a hepatic microsomal preparation from rat, rabbit or human liver fortified with NADPH [152,153]. Kallner [133] noted that small amounts of more polar derivatives were present in rat bile, with largely unchanged allochenodeoxycholate. AUohyocholate was identified as a minor metabolite [154]. With rabbit liver microsomal preparations, allochenodeoxycholate is a competitive inhibitor for 12a-hydroxylation of 7a-hydroxy-cholest-4-en-3-one and 5a-choles-tane-3a,7a-diol, precursor of cholic and allocholic acids, respectively [155]. Allo-cholic acid has also been characterized as a metabolite of 3 8,7a-dihydroxy-5-cholenic acid after intraperitoneal injection into carp [156]. 

In the commonly occurring 5a-hydroxy-6a,7a-epoxy derivatives, C-5 appears around 73.0 where the ring junction A/B is trans and 5-hydroxyl is a-axial. With 58-hydroxyl with A/B cis... 

The full paper on the synthesis of 32-functionalized lanostanes has appeared. The 32-norlanosterol derivative (34), prepared from 3jS-acetoxy-7a-hydroxy-lanostano-32-nitrile, was found to have the unnatural 14-jS-H configuration. 

Alkoxy-radicals in ring b, generated from hydroxy-derivatives of B-homo-cholestanes with Pb(OAc)4, attack suitably placed C—H bonds to form trans-annular ether bridges. The main reactions are illustrated in Scheme 16. The 7a/ -alcohol gave only a little of the 7a, 19-oxide, the main product being an unsaturated aldehyde of uncertain structure. All the reactions in Scheme 16 occur through favourable conformations of the seven-membered ring. ... 

---