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

Abstract

The reduction of ponasterone А diacetonide with lithium in liquid ammonia stereospecifi cally led to 7,8β-dihydroanalogs of 5α-and 5β-epimers of ponasterone А and 7,8β-dihydro-6α-hydroxy derivative. 7,8β-Dihydroponasterone А, phytoecdysteroid from the needles of Japanise yew Taxus cuspidata, and its 5α-epimer were synthesized.The reduction of the double bond in the B ring of ecdysteroids resulting in their 7,8-dihydroanalogs provide a possibility to obtain compounds with a new biological action [1]. 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.In natural sterines the hydrogen atom at the chiral С 8 carbon has a β-confi guration, and the B and C rings exist in the trans-junction. The conjugated steroid 8-enones are known to react with lithium in liquid ammonia (under Birch reaction conditions) with a high selectivity to be reduced into the corresponding saturated ketones with the formation of a 8β-chiral center [6].We established that ponasterone А diacetonide (I) in the reaction with lithium in liquid ammonia was converted into a mixture of 5β-(IIа) and 5α-(IIb) epimeric ketones and 5βН,8βН,6α-alcohol III, the product of further reduction of saturated ketone IIa (see the scheme).The structure of alcohol III was established from the analysis of the 1D and 2D 1 Н and 13 С NMR spectra. Compared to the spectrum of the initial compound I where the signal of atom С 6 appears in the region 203.0 ppm, the С 6 signal of alcohol III is shifted to the region of 67.6 ppm. The reduction of the Δ 7(8) -double bond is indicated by the shift of signals of atoms С 7 and С 8 from the weak fi eld to the region 39.8 and 34.0 ppm. In the HSQC spectrum they correlate with the signals of protons Н 2 С 7 (δ 1.34 and 1.74 ppm) and НС 8 (1.55 ppm). The correlation in the NOESY spectrum between the protons of the group Н 3 С 19 (δ 0.99 ppm) and НС 5 (δ 1.89 ppm) confi rms the β-orientation of the proton at the atom С 5 , the correlation between the protons НС 5 and НС 6 (δ 4.20 ppm) indicates the β-orientation of the latter. The proton НС 6 is coupled also with protons Н 3 С 19 and НС 8 (HMBS spectrum). The β-orientation of the proton НС 8 corresponds to its correlation with the protons Н 3 С 18 (δ 0.91 ppm).Thus compound III is a 6α-alcohol where the proton at the newly formed chiral center С 8 has the β-confi gurqation, and the proton at С 5 conserves the β-confi guration of the initial ecdysteroid.We failed to separate the mixture of diacetonides of 5β/α-epimeric ketones IIa, IIb, but their 20,22-monoacetonides IVa, IVb were isolated by the column chromatography on silica gel. The structure of compounds IVa, IVb was established applying 1D and 2D 1 Н and 13 С N...