Aldosterone acetate

Among the numerous applications of this reaction reported over four decades, some typical examples of the functionalization are outlined in Schemes 3 to 10. Thus, Scheme 3 outlines the well-known Barton transformation of corticosterone acetate nitrite into aldosterone acetate oxime which, with nitrous acid, gives aldosterone 12-acetate [4]. The yield of 18-oxime is, however, rather low (21 %), since attack by the 11/3-alkoxyl radical on C-19 competes with the desired attack on C-18. Incorporation of the 1,2-double bond into the nitrite prevented undesired C-19 attack by the radical and a far better yield (47 %) of 18-oxime was achieved [5] (Scheme 4). This example may indicate that the Barton reaction is sensitive to... 

In reality, it required only a few weeks to convert 3 into aldosterone acetate lb.5-7 The acetate is a biological equivalent to aldosterone and easier to handle and store. The overall yield of crystalline acetate was about 15%. However, this was satisfactory for the preparation of 60 g of aldosterone acetate... 

The importance of conformation in selective attack of the 1 l/ -alkoxy radical on C18 and C19 was nicely illustrated by the photolysis of the nitrite 18 derived from the dienone 19. This afforded only C18 attack.7 Treatment of the derived oxime with nitrous acid gave 1-dehydro-aldosterone acetate 20. This is a convenient precursor for labelled aldosterone acetate since selective hydrogenation with tritium gives 1,2-ditritiated aldosterone acetate. 

An improved synthesis7 of aldosterone acetate lb was based on the readily available dienone 30. Conversion to the nitrite and photolysis affords the oxime 31 with no attack on C19. On warming in iso-propyl alcohol this oxime 31, cyclized smoothly to the nitrone 32 with the loss of water. This nitrone is at the right oxidation level to rearrange to the 21-acetoxyimine. The overall yield of nitrone from 30 was 55%. 

Barton reaction In the Barton reaction " a methyl group in the 7 -position to an OH group is converted into an oxime group. For example, corticosterone acetate (2.45) on reaction with nitrosyl chloride (NOCl) in pyridine forms its 1 l -nitrite 2.46, which on photolysis in toluene gives aldosterone acetate oxime (2.47) in 21% yield. Treatment of 2.47 with nitrous acid (HNO2) gives aldosterone acetate (2.48) (Scheme 2.40). 

Remote Oxidation.—Remote oxidation reactions generally involve intramolecular hydrogen abstraction. The best known example is the Barton reaction (photolysis of nitrite esters). "- One of the most important applications of this reaction was to the synthesis of aldosterone acetate. The yield of this reaction has been substantially improved (55%) by irradiating the dienone nitrite ester (172) in which the extended conjugation ensures that sufficient separation between C-19 and the 11/3-oxygen atom exists to suppress functionalization at C-19 in favour of attack at C-18. Another recent application of the Barton reaction occurred in the synthesis of perhydrohistrionicotoxin (175), where the key step was the stereoselective formation of the oxime (174) from the nitrite ester (173). °... 

Functionalization of lOP- and 13P-Me of steroids from the lOP-ol nitrite synthesis of aldosterone acetate (Schemes 13 and 14)... 

These examples are the most weU-known applications of the reaction found by Barton as well as by his colleagues. The irradiation of corticosterone acetate nitrite affords aldosterone acetate oxime, which with nitrous acid gives aldosterone 12-acetate (Scheme 13). The overall yield, however, is rather low (15%) because an attack by the lip-alkoxyl radical on C19 competes with the desired attack on CIS. The incorporation of the 1,2-double bond into the nitrite could avoid an undesired C19 attack by the radical a far better yield (47%) of 19-oxime was achieved, as shown in Scheme 14. These examples of the functionalization may indicate that the Barton reaction is sensitive to structural changes and that the distance and conformation requirements between the alkoxyl radical and the methyl group, which are in a 1,3-diaxial relationship, is rather strict (Scheme 14). 

A photochemical partial synthesis of aldosterone (19) made the hormone available on an industrial scale for the first time (114). Corticosterone acetate (51 acetate) is treated with nitrosyl chloride in pyridine at 20°C to yield the 11-nitrite (115). Irradiation of (115) leads to rearrangement with formation of the C g-oxime (116). Removal of the oxime residue with nitrous acid furnishes aldosterone (19) in excellent yield. 

Aldosterone Aldosterone, llj3,21-dihydroxypregn-4-en-2,18,20-trione (27.2.4), is synthesized from 21-0-acetylcorticosterone, which when reacted with nitrosyl chloride in pyridine gives the nitrite 27.2.1. When photochemically irradiated, this compound is transformed to the oxime 27.2.2, which is hydrolyzed by nitrous acid and forms the semiacetal 27.2.3, which is an acetate of the desired aldosterone. Alkaline hydrolysis of the acetyl group of this compound leads to the desired aldosterone (27.2.4) [33]. 

Fig. 4.3. Example of a tissue-specific hormone inactivation. Cortisol is enzymatically converted to an keto compound at the Cll position. The modified cortisol compound can no longer bind and activate the aldosterone receptor. Aldosterone can not be turned over by 11-P-dehydroge-nase because the OH group at position 11 forms a half-acetal with the formyl group (C18).

Addition to 1-atkenes (8, 25). The critical steps in a recent synthesis of aldosterone (4) involve anli-Markovnikov addition of C6H5SeBr to I, oxidation to the allylic bromide, and acetate displacement to give 2. The corresponding 21-monoacctate was converted to the triol 3 (0s04, N-mcthylmorpholine N-oxide). The final steps to 4 involved periodate cleavage and saponification.2... 

Thus, in patients with Addison s disease or other forms of adrenal insufficiency, continuing oral administration of cortisone acetate or fludrocortisone acetate enables salt balance to be restored. Other corticosteriods and analogues that have been used in the hormonal control of sodium levels include aldosterone and deoxycortone acetate. Individual corticosteroids vary in the extent to which they possess the various hormonal activities so that combination therapy is usually required if, for example, mineral balances are to be maintained when corticosteroids are administered for their anti-inflammatory, antirheumatic or anti-allergic properties. 

In contrast to patients with secondary aldosteronism (see below), these patients have low (suppressed) levels of plasma renin activity and angiotensin II. When treated with deoxycorticosterone acetate (20 mg/d intramuscularly for 3 days—no longer available in the USA) or fludrocortisone (0.2 mg twice daily orally for 3 days), they fail to retain sodium and their secretion of aldosterone is not significantly reduced. When the disorder is mild, it may escape detection when serum potassium levels are used for screening. However, it may be detected by an increased ratio of plasma aldosterone to renin. Patients are generally improved when treated with spironolactone, and the response to this agent is of diagnostic and therapeutic value. 

Further, acetic acid lip-hydroxy-3,18,20-trione-pregn-4-ene lip,18-lactone 17-oxoethyl ether has been converted to lip-hydroxy-18-one-pregn-4-ene lip,18-lactone-3,20-bis-ethylenketal 17-oxoethyl ether, which was reduced with lithium-aluminum hydride to 3,20-bis-ethylenketal aldosterone. Then by hydrolisation of 3,20-bis-ethylenketal aldosterone with FICI04 aldosterone can be obtained. 

In 1957, Celia and Kagawa [5] reported about the preparation of two steroidal 17-spirolactones, which were capable of blocking the urinary sodium/potassium action of aldosterone and desoxycorticosterone-acetate in adrenalectomized rats. These compounds were closely related in structure to aldosterone and were assigned the code names SC 5233 and SC 8109, respectively. Structures of these three compounds are shown in Figure 1. 

Scheme 3. Transformation of corticosterone acetate nitrite into aldosterone 21-acetate.

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