Novel ecdysteroid analogs with oxygen-containing heterocycles in the steroid skeleton

Abstract

The reaction of ecdysteroids (20-hydroxyecdysone and its acetonides) with lithium in liquid ammonia gave novel analogs with an oxetane 9α,14α-oxacycle in the steroid skeleton. In aqueous alcohol solution the 9,14-oxa analogs rearrange to the more stable 9α,13α−oxa analogs through a 1,2-migration of the 18-Me group from the C-13 to the C-14 atom.Although widely used in the chemistry of steroids [1, 2] for the selective reduction of a double bond in conjugated enones, a reaction with alkali metals in liquid ammonia has been little studied amongst the series of ecdysteroids. It is only known that the reaction of 20-hydroxyecdysone diacetonide with lithium in liquid ammonia solution gives a 14α-hydroperoxy derivative rather than the corresponding 7,8-dihydro analog [3].We have found that the action of a solution of lithium in liquid ammonia on the ecdysteroids 20-hydroxyecdysone (1), its 2,3:20,22 diacetonide (2), and the 20,22-acetonide (3) and 2,3-acetonide (4) and subsequent treatment of the reaction mixture with NH 4 Cl gives the corresponding 14α-hydroperoxides 5-8 together with the previously unknown 9α,14α-oxa derivatives 9-12 which are analogs of ecdysteroids with an oxetane ring in the steroid skeleton (Scheme 1). In the case of compound 1 the corresponding oxetane 9 and 14α-hydroperoxide 5 are formed in approximately equimolar amounts while the acetonides 2 and 3 are primarily converted to the corresponding oxetanes 10 and 11. For the 2,3-acetonide 4 the oxetane formed 12 is less stable than oxetanes 9-11 and elution of reaction products (SiO 2 , MeOH/CHCl 3 , 1:50) gave a mixture of the oxetane 12 and its isomerization product 19 as well as a mixture of the 14α-hydroperoxide 12 and starting material 4. Repeated chromatography (SiO 2 , MeOH/CHCl 3 ) of a mixture of compounds 12 and 19 gave the individual forms of the transformation products of oxetane 12, i.e. compounds 15 and 19.

Stereospecific formation of 7,8β-dihydroanalogs at the reduction of ponasterone acetonide with lithium in liquid ammonia

“…At the same time as was previously reported under the same conditions the 20-hydroxyecdysone and its acetonides instead of the corresponding 7,8-dihydroanalogs gave the oxidation products of ecdysteroids, 14α-hydroperoxides VI [12][13][14] or 9α,14α-epoxy-14α-deoxyspiro derivatives (oxetanes) VII [13,14].…”

Synthesis of ecdysteroids with migrated group H3C 18

“…The 1 H NMR spectrum of compound IV is in many respects similar to the spectrum of compound II [3]. In the 13 C NMR spectum of compound IV the signals of atoms C 9 and C 13 are observed at δ 87.12 and 98.30 ppm respectively confi rming the presence of an oxygen bridge between atoms C 9 and C 13 .…”

“…This compound in aqueous ethanol slowly rearranged giving a mixture of diacetonides of 20-hydroxy-14-deoxy-13-demethyl-14β-methyl-9α,13α-epoxyecdysone (II) and 9α-hydroxystachysterone C (III) [3].…”

9α-hydroxylation of 25-fluoroponasterone a diacetonide in lithium-ammonia solution

“…Analogous reactions with ecdysteroids have been poorly studied; however, it is known [3,4] that the reaction of 20-hydroxyecdysone and its acetonides with lithium in liquid ammonia and subsequent treatment with ammonium chloride and evaporation of ammonia on exposure to air gives ecdysteroids with an ether bridge in the C ring instead of expected 7,8-dihydro derivatives. For instance, 20-hydroxyecdysone diacetonide I is thus converted into oxetane II and 14α-hydroperoxide III [3] (Scheme 1).…”