Steroids dehydration

D-Mevalonic acid is the fundamental intermediate in the biosynthesis of the terpenoids and steroids, together classed as poly-isoprenoids. The biogenetic isoprene unit is isopentenyl pyrophosphate which arises by enzymic decarboxylation-dehydration of mevalonic acid pyrophosphate. D-Mevalonic acid is almost quantitatively incorporated into cholesterol synthesized by rat liver homogenates. 

The most difflcult pharmaceutically relevant oxidation of steroids is the introduction of a 14 -hydroxyl group. This functional group is found in heart-active steroids (cardenolides) such as digitoxigenin, which also contain a 17/J-butenolide substituent. The 14/ -hydroxyl group is easily cleaved off by dehydration and must therefore not be treated with Lewis or... 

When used at room temperature in the presence of an active platinum catalyst in an inert solvent, e.g., acetone or ethyl acetate, oxygen will oxidize nonhindered, saturated hydroxyl groups and exposed allylic alcohols. This reagent has found extensive use in sugar chemistry and is particularly suited for the selective oxidation of either 3a- or 3j -alcohols of steroids. Other hydroxyl groups on the steroid skeleton are much less sensitive to oxidation. As a result, this reaction has been used extensively in research on polyhydroxy cardiac-active principles, e.g., the cardenolides and bufadienolides, where the 3-hydroxyl group is easily oxidized without extensive oxidation or dehydration of other hydroxyl groups. The ordinarily difficult selective oxidation of the... 

If homolytic reaction conditions (heat and nonpolar solvents) can be avoided and if the reaction is conducted in the presence of a weak base, lead tetraacetate is an efficient oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. The yield of product is in many cases better than that obtained by oxidation with chromium trioxide. The reaction in pyridine is moderately slow the intial red pyridine complex turns to a yellow solution as the reaction progresses, the color change thus serving as an indicator. The method is surprisingly mild and free of side reactions. Thus 17a-ethinyl-17jS-hydroxy steroids are not attacked and 5a-hydroxy-3-ket-ones are not dehydrated. 

In the early days of steroid chemistry, dehydrations were usually carried out under rather drastic conditions, frequently in the presence of strong acids (see, for example, ref. 176, 181, 182). Such conditions have been replaced by milder and more selective methods, except in those instances when either the product is stable e.g. ref. 183, 184) or rearrangement is desired. The importance of stereochemical factors in rearrangements is widely recognized for instance, the Westphalen rearrangement of 5a-alcohols (92) cf. ref. 185,... 

Acetonides are quite stable to base, and to oxidation, dehydration and acylation reactions carried out in pyridine. They are cleaved by acid hydrolysis. The 17,21-acetonides of 17a,21-dihydroxy-20-keto steroids and related acetals are split by very mild acid conditions. ... 

Extension of this reaction to other substrates, however, revealed that it is more complex, and that side products are formed depending on (1) the nature of the substrate, (2) the reaction conditions, e.g. temperature and solvent,and (3) the method of work-up." Thus, in addition to the desired substitution products, primary and secondary hydroxy steroids generally yield esters and ethers and undergo simple dehydration as well as dehydration accompanied by rearrangement. 

Under mild conditions and in a variety of solvents, tertiary steroid alcohols are inert to the fluoroamine. At elevated temperatures, however, they afford exclusively, and in high yield, products resulting from dehydration with or without rearrangement. Thus, 17a-methyltestosterone (10) furnishes in 42% yield the 18-norsteroid (11). 

High vacuum sublimation of the 3-monobenzoate of (32) or tosylchloride dehydration gives 3/ -benzoyloxy-7-methylenecholest-5-ene (33). The configuration of (32) is probably as shown since 7a-hydroxy steroids dehydrate readily to yield homoannular dienes. In an analogous reaction ethyl and iso-butyl Grignard reagents give alkylidene compounds as the only isolated products. 

The stereochemistry of the product resulting from the reaction of a 17-keto steroid with ethylidenetriphenylphosphorane is different from that of the 17-ethylidene steroids obtained by dehydration of 17a-ethyl-17/ -hydroxy compounds, Wolff-Kishner reduction of A -20-keto steroids or by sodium-alcohol or sodium-ammonia " reductions of 17-ethynyl carbinols. These latter products have generally been assumed to possess the trans configuration (C-21 methyl away from the bulk of the ring system) because of anticipated greater stability. The cis configuration for... 

The reaction of 17-keto steroids with hydrogen cyanide (or acetone cyanohydrin) to form a mixture of the 17-cyano-17-hydroxy compounds, followed by dehydration and reaction with methyl Grignard reagent, is one of the earliest methods for the conversion of androstanes to pregnanes. 

A method of fixing the position of the double bond involves first condensing the 20-ketopregnane with benzaldehyde at C-21, then reducing the ketone to hydroxyl and dehydrating.Alternatively, the 20-keto-21-benzylidene steroid can be converted to the A ° -enol chloride prior to ozonolysis. 

A rather special procedure for the preparation of 21-hydroxy-20-ketopreg-nanes starts with the 17a-ethoxyethynyl-17 -hydroxy steroids described earlier. Free radical addition of ethanethiol to the triple bond, followed by acid-catalyzed hydrolysis and dehydration gives the 20-thioenol ether 21-aldehyde. This can be reduced with lithium aluminum hydride to the C-21 alcohol and then hydrolyzed to the C-20 ketone in the presence of mercuric chloride. The overall yield, without isolation of intermediates, is in the order of 50% ... 

In the case of 18,20-cyclo-20-hydroxy steroids this is achieved by dehydration and oxidative cleavage. ... 

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-... 

Dehydration to olefins, which sometimes accompanies the reaction of alcohols with DAST [95, 108], is seldom as extensive as with a-fluoroamines (FAR and 1,1,2,3,3,3 hexafluoropropyldiethylamine) but occurs in a few cases to the exclusion of fluonnation, thus, 9a-fluoro-11-hydroxysteroids give 9a fluoro-A -steroids [127, 128] Dehydration accompanied by Wagner-Meerwein rearrangement occurs during the fluonnation of testosterone [129] Intermolecular dehydration to form ethers in addition to fluorides is observed in the reaction of benzhydryl alcohols [104] (Table 6)... 

Steroidal a,j8-unsaturated ketones such as /l -3-ketones undergo a facile reaction with pyrrolidine to give the corresponding, d - -dienamines (111) (40,53). The reaction is much slower with morpholine and piperidine, which is undoubtedly due to the generation of the double bond exocyclic to the six-membered hetero rings in the step involving the dehydration of the intermediate carbinolamine (112) to the corresponding iminium ion (113). 

Dehydration of 221 affords the corresponding 9,11 olefin, 223. When this compound is subjected to the series of reactions for introduction of the 9,11 fluorohydrin, there is obtained the antiinflammatory steroid flumethasone (224).° As might be expected from the incorporation of a group in almost every posi-tion known to increase potency 224 is an extremely active agent. 

Testosterone is one of the most important male steroid hormones. When testosterone is dehydrated by treatment with acid, rearrangement occurs to yield the product shown. Propose a mechanism to account for this reaction. 

Almost all types of cell can be used to convert an added compound into another compound, involving many forms of enzymatic reaction including dehydration, oxidation, hydroxyla-tion, animation, isomerisation, etc. These types of conversion have advantages over chemical processes in that the reaction can be very specific, and produced at moderate temperatures. Examples of transformations using enzymes include the production of steroids, conversion of antibiotics and prostaglandins. Industrial transformation requires the production of large quantities of enzyme, but the half-life of enzymes can be improved by immobilisation and extraction simplified by the use of whole cells. 

The steric bulk of steroid structures prevents their use as the only organic side group present. However, mixed-substituent polymers that contain both steroidal side groups and amino acid ester or other cosubstituent units can be readily synthesized. If a saturated A ring is present in the steroid, linkage to the polymer chain is complicated by side reactions that result from dehydration of the steroid (chlorophosphazenes are powerful dehydrating agents). 

Albumin 18-20 Maintains plasma oncotic pressure transports small molecules Dehydration, anabolic steroids, insulin, infection Overhydration, edema, kidney insufficiency, nephrotic syndrome, poor dietary intake, impaired digestion, burns, congestive heart failure, cirrhosis, thyro id/adrena / pitu itary hormones, trauma, sepsis... 

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