Steroids utilizing

Breslow s template-directed remote oxidation of steroids utilizes an aryl iodide as a template to direct the oxidation of steroid tertiary carbons by the radical relay mechanism, in which a chlorine radical is transferred from a [9-1-2] [PhICl] radical to the iodine atom of the template and then relayed to a geometrically accessible hydrogen atom. This method allows a highly regioselective functionalization of nonactivated carbon atoms of steroids [Eq. (78)] [137,138]. 

The use of the Pathfinder descriptor for QSAR is exemplified here through application to two datasets taken from the literature (i) 31 steroids utilized in the original CoMFA study [3], since considered a benchmark for evaluating QSAR methods [4] (ii) 55 inhibitors of HIV-1 reverse transcriptase proposed by Chan and coworkers [5], interestingly this series could only be successfully correlated by means of a structure-based approach [6]. 

In addition to the steroid hormones, the steroids utilized for pharmaceutical applications can be selectively determined using appropriate immobilized enzymes in an IMER. Use of a-, p-, and/or stereoespecific dehydrogenases permits one to enhance the selective... 

It has become increasingly evident that considerable variability in steroid utilization and metabolism exists among phytophagous species of insects. In recent years, we have discovered several phytophagous species that are unable to convert C28 or C29 phytosterols to cholesterol. This Includes one species that dealkylates the C-24 substituent of the side chain but produces mostly saturated sterols and several species that totally lack the ability to dealkylate the sterol side chain. Certain members of this latter group are of particular interest because they have adapted to utilizing a Cos sterol as an ecdysteroid precursor and makisterone A (C28) has been identified as the major ecdysteroid of certain developmental stages of these species. 

We will discuss some of our comparative sterol metabolism studies and provide specific examples to illustrate some of these unusual variations in steroid utilization and metabolism in insects, and to show how this information is useful in predicting differences in ecdysteroid biosynthesis in certain species. We will also point out instances in which these variations in neutral sterol metabolism can be related to phylogenetic relationships between species. 

Paper Chromatography - Johnson and Fowler give Rf data for dexamethasone and related steroids utilizing the following system ... 

Danishevsky and co-workers devised an ingenious synthesis of estrone (and other 19-nor-steroids) utilizing 6-substituted a-picolines as ring A synthons in a variant of the Robinson annulation process. The synthesis was initially applied to ( )-D-homoestrone and an improved version was developed for (-I-)-estrone and related (-l-)-19-norandrostenones. 

In the following decades, chemists tried to utilize more and more the knowledge on reactions which had already been gained. A number of landmark syntheses represent the change to modern chemistry, such as the synthesis of the estrogenic steroid equilenin (W. Bachmann, 1939), of pyridoxine (K. Folkers, 1939), and of quinine (R.B. Woodward, W. von E. Doering, 1944) [23]. 

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

Diene carboxylates can be prepared by the reaction of alkenyl halides with acrylates[34]. For example, pellitorine (30) is prepared by the reaction of I-heptenyl iodide (29) with an acrylate[35]. Enol triflates are reactive pseudo-halides derived from carbonyl compounds, and are utilized extensively for novel transformations. The 3,5-dien-3-ol triflate 31 derived from a 4,5-unsaturated 3-keto steroid is converted into the triene 32 by the reaction of methyl acrylate[36]. 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

Spironolactone is the most clinically usehil steroidal aldosterone antagonist, and unlike GR antagonists, this compound is utilized much more frequendy than aldosterone agonists. Interfering with reabsorption and secretion in the late distal segment, this compound is predominantiy used with other diuretics. Canrenone, an olefinic metaboHte of spironolactone, and potassium canrenoate, in which the C-17 lactone has been hydrolyzed open, are also potent mineralocorticoid antagonists. 

The area of nonsteroidal antiestrogens along with other classes of nonsteroidal antagonists of sex-steroid hormone action has been reviewed to 1986, and these compounds have been grouped by chemical stmcture as a basis of classification rather than any biochemical or biological test system utilized to assess antagonist activity (46). 

NAD and NADP are required as redox coen2ymes by a large number of enzymes and ia particular dehydrogenases (Fig. 6). NAD" is utilized ia the catabohe oxidations of carbohydrates, proteins, and fats, whereas NADPH2 is the coenzyme for anaboHc reactions and is used ia fats and steroid biosynthesis. NADP+ is also used ia the cataboHsm of carbohydrates (2). 

Lithium-ammonia reductions of most steroidal enones of interest create one or two new asymmetric centers. Such reductions are found to be highly stereoselective and this stereoselectivity constitutes the great utility of the reaction. For conjugated enones of the normal steroid series, the thermodynamically most stable products are formed predominantly and perhaps exclusively. Thus the following configurations are favored 5a, 8/ , 9a, and in certain cases 14a (see page 35). Starr has listed numerous examples illustrating these facts and Smith " and Barton have tabulated similar data. 

Catalytic hydrogenation has been utilized extensively in steroid research, and the method has been found to be of great value for the selective and stereospecific reduction of various functional groups. A number of empirical correlations concerning selectivity and product stereochemistry compiled for steroid hydrogenations has been listed in a previous review. ... 

Since the stereochemical course of a catalytic hydrogenation is dependent on several factors, " an understanding of the mechanism of the reaction can help in the selection of optimal reaction conditions more reliably than mere copying of a published recipe . In the first section the factors which can influence the product stereochemistry will be discussed from a mechanistic viewpoint. In subsequent sections the hydrogenation of various functional groups in the steroid ring system will be considered. In these sections both mechanistic and empirical correlations will be utilized with the primary emphasis being placed on selective and stereospecific reactions. 

While the foregoing concepts have been utilized to rationalize the product distribution obtained on hydrogenation of a number of monocyclic olefins, it should be noted that the effect of pressure on the stereochemistry of hydrogenation of steroidal double bonds has not been critically evaluated. 

While no examples were encountered in the steroid field which utilize this technique, it is well documented in the case of diterpenes. Ferruginol-3-one (79), for example, gives a hexadeuterio product (80) which after back... 

A recent modification of this technique utilizes A,A-d2-propylamine as the solvent for the lithium reduction, thereby eliminating the inconveniences associated with the preparation and handling of liquid deuterioammonia. Under these conditions the reaction can be carried out at room temperature and less overreduction of the carbonyl group is observed. For example, the reduction of A" -3-keto steroids (159) under these conditions, followed by back exchange in protic media, leads to the corresponding 5a-di-3-ketones (160) which exhibit good isotopic purity. ... 

An example is the preparation of 18-trideuterio 5a-steroids bearing a side chain at C-17. Labeling of this position with three deuteriums was accomplished by utilizing the Johnson procedure for steroid total synthesis. This synthesis involves, in part, introduction of the 18-angular methyl group by methylation of the D-homo-17a-keto-17-furfurylidene intermediate (243). By substituting d3-methyl iodide in this step, the C/D cis- and ra/J5-18,18,18-d3 labeled ketones [(244) and (245)] are obtained. Conversion of the C/D tra 5-methylation product (245) into 18,18,18-d3-d /-3)8-hydroxy-5a-androstan-17-one (246) provides an intermediate which can be converted into a wide variety of C-18 labeled compounds of high (98%) isotopic... 

Extensions of this concept have utilized enamine hydrolysis (171, X = R N) and the quenching of the enolate anion (171, X = O ) e.g. ref. 353). a,(i-Un-saturated ketones are usually more stable than their p,y counterparts, but there are notable exceptions to this, and in such cases the deconjugated ketone may be isolated from the equilibrated system. For example, retro steroids (9, 10a) have a large proportion of A -3-ketone at equilibrium, and 17-ketones yield the more stable A -system on treatment with acid. ... 

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