Synthesis of 20-hydroxyecdysone 25-acetate

Abstract

A scheme has been developed for the selective conjugation of 20-hydroxyecdysone (20E) at the 25-position, with the synthesis of 20E 25-acetate as an example. The proposed scheme also permits the selective synthesis of 20E 22-esters from both lower and higher fatty acids, which opens up prospects for the creation from them of drugs with a prolonged action.The ecdysteroids are a group of Iiatural compounds possessing a broad spectrtun of biological activity. In insects they are molting hormones [1]. In mammals and man these compounds possess a pronounced tonic action. Prospects have been shown for their use as components of drugs with an adaptogenic, cardiotonic, antiatherosclerotic, antiulcer, and wound-healing action [2].In addition to the free ecdysteroids, conjugates of them have been detected in natural materials of both plant and animal origin. The most widespread class of ecdysteroid conjugates is formed by monoesters of o~-ecdysone and 20-hydroxyecdysone (20E), namely their 2-, 3-, and 25-acetates and their 22-esters with higher carboxylic acids [3][4][5][6]. Their physiological fimctions have not yet been elucidated in detail. So far as concerns invertebrates, they are regarded as inactive, reserve, forms of the hormones [7]. In view of what has been said above, the synthesis of monoesters of ecdysteroids and the creation from them of a new type of ecdysteroid-containing drugs with a prolonged action is a promising direction.The task of our investigation was the development of a scheme for the selective conjugation of 20E at the 25-position, using as an example the synthesis of 20E 25-acetate (20E25Ac).Structurally, 20E (1) is a polyhydroxy compound. Since the capacity for the esterification of the hydroxy groups of 20E decreases in the sequence C-2 > C-22 > C-3 > > C-2fi [6], the synthesis of its 25-esters is possible only if the diol groups are protected. A method is known for obtaining 20E25Ac by the preliminary protection of the diol groups in the form of a diacetonide [3]. However, hydrolysis of the product of the acylation of 20E diacetonide gave 20E25Ac with a yield of less than 0.3%. The main hydrolysis product was 20E25Ac 20,22-monoacetonide, which shows the resistance of 20E 20,22-monoacetonide to hydrolysis. Our attention was then attracted to a paper on the synthesis of an ecdysteroid with a long sidechain from eyasterone by Ourisson et al. [8], who succeeded in selectively protecting the 20,22-diol group in the form of the phenylboronate and the 2,3-diol group in the form of the acetonide.We have used this method of protecting the diol groups in developing a scheme for the selective conjugation of 20E at C-25 for the exemplary case of the synthesis of 20E 25-acetate. The 2,3-acetonide of 20E 20,22-phenylboronate (3) proved to be stable under the conditions of esterification. The resulting 2,3-acetonide of the 25-acetate (5) was stable under the conditions for the hydrolysis of the phenylboronate (with an aqueous solution of hydrogen peroxide). The acetonide protection was readily eliminated i...

Steroids: reactions and partial synthesis

“…183 A number of syntheses of ecdysone analogues including some variations in the side chain possessing a tetrahydrofuran ring, have been reported. [184][185][186] The synthesis of 5-epiaragusterol A 80 from deoxycholic acid, has been achieved. 187 This sterol shows antiproliferative activity against KB cells.…”