Steroid 17a-hydroxylation

A 17a-methyl in the product of ring D homo-annulation of 17-hydroxy-20-keto steroids may limit the general synthetic utility of the reaction. On the other hand, the 17a-hydroxyl group gives additional flexibility in planning further transformations. Moreover, by adjusting reaction conditions, the stereochemistry of the products can be changed. 

Betamethasone is the steroid represented by this structure. It is composed of a 3-keto group on ring A, an 11 p-hydroxyl group and a 17a-hydroxyl group on ring C and D respectively. 

At one time the microbial introduction of a hydroxy group into the tertiary 17a-position of steroids was considered to have potential importance as a stage in the preparation of adreno-corticosteroids. In this connection, 17a-hydroxylation of 21-hydroxyprogesterone (1) was undertaken with Trichothecium roseum 289 and Cephalotheeium roseum 290. 

CMorination of steroids (4, 264-265 5, 352-353 6, 298-299). Breslow s method for chlorination of steroids at C91- has been developed into a useful method for conversion of 17a-hydroxyprogesterone (1) into the triene (4), a useful intermediate to highly active corticoids.2 The hindered 17a-hydroxyl group is esterified with m-iodobenzoic anhydride and 4-dimethylaminopyridine. Irradiation of the ester (2) with C6H5IC12 in the presence of NaOAc (HC1 scavenger) affords 3 in quantitative... 

Bernstein s group used the methoximino group to protect 20-ketosteroids, and Eardley and Long found that treatment with thionyl chloride in pyridine causes elimination of the 17a-hydroxyl group from 17a,21-dihydroxy-20-methoximino-steroids (1) to give A < -derivatives (2). 

The valve that allows entry of 17-OH pregnenolone into the sex steroid pathway is the 17,20-lyase component of CYP17, the SER enzyme that catalyzes the 17a-hydroxylation of steroids. As noted above, the lyase component of the enzyme is active in certain tissues for reasons that are not currently clear. Both A" and steroids are known to feed into the sex steroid pathways although the absence of 3/6HSD precludes the former. It should be emphasized that the formation of androgenic steroids is necessary before estrogen formation is possible therefore, the initial reaction in the sex steroid pathway invariably produces an androgenic steroid. 

FIGURE 58-1 Pathway of synthesis of testosterone in the Leydig cells of the testes. Leydig cells express steroid 17a-hydroxylase (CYP17), which carries out sequential 17-hydroxylation and C17-20 lyase reactions in the biosynthetic pathway to produce androgens. Bold arrows indicate favored pathways. 

Kremers P. Progesterone and pregnenolone 17a-hydroxylase substrate specificity and selective inhibition by 17a-hydroxylated products. J Steroid Biochem 1976 7 571-575. 

In the next reaction steps, the enzymes 3)S-hydroxy-A -steroid dehydrogenase, steroid A-isomerase and steroid 17a-hydroxylase are involved. Oxidation at C-3 and double bond migration leads to progesterone, the hormone of the corpus luteum. Afterwards, the C-17 position is hydroxylated to give 17 -hydroxyprogesterone. The reverse reaction sequence is also known and... 

A soln. of 3a,23-diacetoxy-16,16-dimethyl-21-normethyl-17(20)-oxido-11-0X0-22-choleno-24 (20)-lactone in tetrahydrofuran treated with ethylenediamine, and allowed to stand 20-24 hrs. at room temp. 3a-acetoxy-17a-hydroxy-16,16-di-methylpregnane-ll,20-dione. Y 98.5%.—The use of ethylenediamine prevents D-homoannulation. This is the last step of the glyoxylate process for the introduction of 17a-hydroxyl into steroids according to J. A. Hogg and A. H. Nathan, USP 2 740 782. F. e. s. R. D. Hoffsommer et al., J. Org. Chem. 27, 353 (1962) glyoxylate process s. a. M. Sletzinger and S. Karady, J. Org. Chem. 27, 368 (1962). 

Another P450 from steroid metabolism, namely CYP17A1, possesses two activities 17a-hydroxylase and 17,20-lyase activity. First, itcatalyzes the 17a-hydroxylation... 

In a 250 ml Erlenmeyer flask covered with aluminum foil, 14.3 g (0.0381 mole) of 17a-acetoxy-3j5-hydroxypregn-5-en-20-one is mixed with 50 ml of tetra-hydrofuran, 7 ml ca. 0.076 mole) of dihydropyran, and 0.15 g of p-toluene-sulfonic acid monohydrate. The mixture is warmed to 40 + 5° where upon the steroid dissolves rapidly. The mixture is kept for 45 min and 1 ml of tetra-methylguanidine is added to neutralize the catalyst. Water (100 ml) is added and the organic solvent is removed using a rotary vacuum evaporator. The solid is taken up in ether, the solution is washed with water and saturated salt solution, dried over sodium sulfate, and then treated with Darco and filtered. Removal of the solvent followed by drying at 0.2 mm for 1 hr affords 18.4 g (theory is 17.5 g) of solid having an odor of dihydropyran. The infrared spectrum contains no hydroxyl bands and the crude material is not further purified. This compound has not been described in the literature. 

While 17a-hydroxy-20-keto steroids do not react, those without the 17-hydroxyl group give good yields of 17/ -acetylamino steroids, and the presence of a 16a- or 16j8-methyl group does not interfere. 

Generally, the successful conversion of 20-ketopregnanes to 17-hydroxy-androstanes with peracids requires the protection of other ketones, with the exception of those at C-11, and possibly C-12 e.g., as ketals or cyanohydrins ) and isolated double bonds e.g., as dibromides). Unprotected hydroxyl groups do not interfere, except, as expected, a 17a-hydroxy-20-keto steroid is oxidized to the 17-ketone. The use of nitrate esters to protect... 

Diketo steroids have been prepared by air oxidation of 3-keto-5i5-steroids in potassium /-butoxide-t-butanoF or by hydrolysis of 4,5-epoxy-3-ketones followed by dehydration. However, the most general synthesis is that used by Camerino et al. to prepare Vketo-A-norandrostanes and pregnanes. Hydroxylation of 17a,20.20,21-bismethylenedioxypregn-... 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

Joannou GE (1981) Identification of 15/5-hydroxylated C21 Steroids in the neo-natal period the role of 3a,15/),17a-trihydroxy-5/ -pregnan-20-one in the perinatal diagnosis of congenital adrenal hyperplasia (CAH) due to a 21-hydroxylase deficiency. J Steroid Biochem 14 901-912... 

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