Use Of Natural Sterol Resources

Since the androst-4-ene-3,17-dione(4-AD)and the androsta-1,4-diene-3,17-dione (ADD) were obtained from the degradation of natural sterols by microorganisms in good yield, using 4-AD and ADD as the starting materials to synthesize various steroidal drugs, has attracted the attention of many organic synthetic chemists.Now there are many studies on synthesizing steroidal drugs that contain a 4-en-3-one or 1,4-dien-3-one mority with 4-AD and ADD as starting material. However, due to the lack of effective and high stereoselective reducing 4-ene method in the conjugated enone, synthesizing steroidal drugs with saturated A ring from AD and ADD is still a chasing target. Therefore, the dissertation is focused on regio-and stereoselective reduction A4-3-keto moiety of certain steroids with Na2S2O4/NaHCO3 and CuCl/NaBH4, respectively. To both reducing agents, the 17-substituents in the D ring obviously influenced the stereoselective reduction of 4-ene in the A ring by a so-called conformational transmission effect. Plus, our study explored the synthetic route of Epiandrosterone and Metenolone with 4-AD as stalling material. What have been accomplished are as follows:1. Na2S2O4/NaHCO3 was explored to regio-and stereoselectively reduce 4-en-3-one steroids to 5α- and 5β-isomers, not pure 5a-isomer as the literature reported. The ratio and yields of isomers formed by stereoselectivite reaction at 5-position of A ring were related with the spatial conjoint styles of 17-substituents in D ring. This remote phenomenon should be resulted from so-called conformational transmission effect. Furthermore, Epiandrosterone, a key intermediate for synthesizing a number of steroidal drugs, was synthesized from 4-AD in four steps via 17-hydrocyanation, acylation, reduction of 4-ene with sodium dithionite and 17-deprotection with an overall yield of 45%. The configurations of corresponding isomers produced by 7b and 4-AD respectively were identified by X-ray diffraction.2. CuCl/NaBH4 was explored to regio- and stereoselectively reduce 4-en-3-one steroids. The 17-substituents in D ring also had obvious conformational transmission effect, which showed that when 17-one was substituented by acyclic group gave 3β-OH-5a-H as main isomer; 3α-OH-5β-H isomer was observed as main isomer with Δ4-3-keto conjugated reduction of 17-spirocyclic ethyleneketal protected androst-4-en-3-one derivatives. Considering the scaffold configuration of 3a-hydroxy-5p-H moiety coincided with that of bile acid analogs, this selective reduction could also be an alternate way on the synthetic study of bile acids using 4-AD and its derivates. which from the microorganism degradation of natural sterols, as the potential materials. Meanwhile, configurations of the reductive compounds 54e was identified by X-ray diffraction.3. The study showed that though there’s similar H NMR spectrum of 5α-and 5β-isomer, the chemical shift of H-9 was observed to present at 0.63～0.94 with a clear multiplet signal in all of the 5a-isomers whereas there was not any corresponding chemical shift signals in 1H NMR of all 5β isomers. The detail could provide a reference for the configuration determination.4. A synthetic route of Metenolone with 13 steps was completed in a total yield of 18%. All compounds were confirmed by spectrum and the aim product was identified by X-ray diffraction.