Effective and selective transformations of ecdysteroids into 7,8-dihydro analogs via catalytic hydrogenation under alkaline conditions

Abstract

SHORT COMMUNICATIONSHydrogenation of the double C=C bond in the B ring of ecdysteroids leads to their 7,8-dihydro analogs which are structurally related to brassinosteroids [1]. Attempts to obtain 7,8-dihydro analogs from 20-hydroxyecdysone and its derivatives by reaction with alkali metals in liquid ammonia [2], which is widely used for selective reduction of double bonds in conjugated ketones of the steroid series were unsuccessful [3,4]. Better results were obtained with the use of lithium tetrahydridoaluminate, but the reduction of the C 7 =C 8 double bond was accompanied by reduction of the 6-oxo group [5].Catalytic hydrogenation of ecydisteroids over 10% Pd/C in ethanol was not selective, and the reaction mixtures contained a number of products, including unreacted initial compounds, instead of the desired 7,8-dihydro derivatives [6]. Suksamrarn et al. [7] recently reported on stereoselective catalytic hydrogenation of ∆ 7 -6-oxo steroids in the presence of sodium nitrite [7]; however, 7,8-dihydro analogs of 20-hydroxyecdysone and its derivatives could not be obtained according to this procedure [5].We found that addition of excess metallic sodium to a solution of 20-hydroxyecdysone (I) in methanol and subsequent hydrogenation over 10% Pd/C at room temperature under atmospheric pressure (reaction time ~3 h) gives 20-hydroxy-7,8-dihydroecdysone (II) as the only product which was isolated in ~90% yield by column chromatography on silica gel. Likewise, 2,3:20,22-di-O-isopropylidene-20-hydroxyecdysone (III) and 2,3 : 20,22-di-O-isopropylideneponasterone A (IV) were converted under the same conditions into the corresponding dihydro analogs V and VI (Scheme 1).It is necessary to follow the above operation sequence to obtain 7,8-dihydro analogs of ecdysteroids. When ecdysteroid was added to a preliminarily prepared solution of sodium methoxide in methanol and the catalyst was then added, no hydrogenation of the C 7 =C 8 bond occurred. It was also necessary to bubble hydrogen through the reaction mixture contain-I, II, R 1 = R 2 = R 3 = R 4 = H; III-VI, R 1 R 2 = R 3 R 4 = Me 2 C; I, II, III, V, R 5 = OH; IV, VI, R 5 = H.

In vitro adjuvant antitumor activity of various classes of semi-synthetic poststerone derivatives

“…Hydrogenation of cholestane and pregnane type ecdysteroids with 10% Pd-C as a catalyst in the presence of sodium nitrite in ethanol was earlier reported [24]. We developed an efficient method of alkaline hydrogenation of the Δ7-bond of the conjugated keto group (MeONa, H 2 , 10% Pd-C), which provides the target 7,8α-dihydro ecdysteroid derivatives in high yields [25]. In this work using the alkaline hydrogenation, we prepared for the first time 7,8α-dihydro poststerone acetonide 4, the structure of which was proved by 1D and 2D NMR spectroscopy.…”

Synthesis of ecdysteroids with migrated group H3C 18

“…from the 20-hydroxyecdysone in the lithium-ammonia solution [2] unexpectedly were converted under the hydrogenation conditions [4] also into compound IV. The formation of compound IV from the hydroperoxide VII is the more curious since in the lithium-ammonia solution it turns only into the 20-hydroxyecdysone [2].…”

“…We recently reported on a new hydrogenation method of the Δ 7 -bond of ecdysteroids under the catalysis with Pd/C in methanol containing sodium methylate [4]. Under these conditions oxetane I was converted into 20-hydroxy-14-deoxy-13-demethyl-14β-methyl-9α,13α-epoxy-7,8α-dihydroecdysone (2,3:20,22)-diacetonide (IV).…”

“…The comparison of the 13 C NMR spectra of 9α-hydroxystachysterone C (III) and its 7,8α-dihydroanalog VI confi rms the similar character of their structures, and the lack in the spectrum of compound VI of signals at 121.1 and 152.3 ppm proves the hydrogenation of the Δ 7 -bond shown also by the downfi eld shift of the signal of saturated ketone (δ 212.97 ppm). α-Confi guration of the chiral center C 8 formed in compounds IV and VI at the hydrogenation corresponds to the established stereochemistry in the hydrogenation of the Δ 7 -bond under the conditions described in [4].…”

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

“…However the reduction of the sterically diffi cultly accessible Δ 7 -bond in ecdysteroids failed to be selective under common conditions of the catalytic hydrogenation due to numerous side reactions [1][2][3]. Recently a stereoselective catalytic hydrogenation of Δ 7 -6-ketosteroids was reported on palladium in the presence of sodium nitrite [4] or sodium methylate [5] providing the availability of ecdysteroids 7,8α-analogs.…”