1,5-Hydride shift in Wolff-Kishner reduction of (20R)-3beta,20, 26-trihydroxy-27-norcholest-5-en-22-one: synthetic, quantum chemical, and NMR studies.
Heating (20R)-3beta,20,26-trihydroxy-27-norcholest-5-en-22-one (1) with hydrazine and KOH at 160 degrees C completely converted the steroid to a diastereoisomeric mixture of the new (20R,22RS)-27-norcholest-5-ene-3beta,20,22-triols (2). Exclusive formation of 2 suggests that the expected Wolff-Kishner reduction to a methylene group at the C-22 ketone in 1 was diverted to the C-26 position by a 1,5-hydride shift. All attempts under acid conditions failed to produce a C-22 phenyl hydrazone from 1. However, reaction of 1 was reacted with phenylhydrazine in hot KOH, gave the C-26 phenylhydrazone 4 as the sole product. Evidently, under alkaline conditions, first a hydride ion undergoes an intramolecular transfer from the C-26 CH(2)OH group to the C-22 ketone in 1, and then the phenylhydrazine traps the newly formed aldehyde. To examine this hypothesis, we constructed computer-simulated transition state models from quantum chemical calculations and then compared data from these models with NMR measurements of the reaction mixtures containing 2. The NMR data showed that the C-22 diastereoisomers of 2 are formed in a nearly 1:1 ratio exactly as predicted from the energy-optimized transition states, which were calculated for intramolecular 1,5-hydride shifts that produced each of the two C-22 diastereoisomers. Accordingly, these results support the hypothesis that an intramolecular 1,5-hydride shift mechanism promotes complete conversion of 1 to 2 under classical Wolff-Kishner reduction conditions.
Szendi
Zsuzsanna
Z
Department of Organic Chemistry, University of Szeged, H-6720 Szeged Dóm tér 8, Hungary. szendi@chem.u-szeged.hu
Forgó
Péter
P
Tasi
Gyula
G
Böcskei
Zsolt
Z
Nyerges
Levente
L
Sweet
Frederick
F
D000447:Aldehydes / Q000737:chemistry; D002778:Cholestanones / Q000737:chemistry* / Q000378:metabolism; D002783:Cholestenones / Q000737:chemistry*; D006358:Hot Temperature; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical
C450846:(20R)-3beta,20,26-trihydroxy-27-norcholest-5-en-22-one; D000447:Aldehydes; D002778:Cholestanones; D002783:Cholestenones