The preparation of several new estrane, androstane, and 19-norpregnane derivatives with unnatural configuration is discussed. A synthesis of both enantiomers (166) and (18) from estrone is described. The structure and configuration of the compounds reported are established on the basis of their physical properties.Canadian Journal of Chemistry, 46, 349 (1968) When reporting the multistage transformation of the cardiac aglycone strophanthidin (1) to 14p,17a-19-norprogesterone (2a), Ehrenstein (2) opened the field of steroid chemistry to new horizons. The bis-iso-19-norprogesterone (2a) resembled the natural hormone progesterone (3) but lacked the angular methyl grouping at position-10, and the stereocliemistry at C-14, as well as at C-17 was different. Because the 14p,17a-19-norprogesterone (2a) was shown to exhibit higher biological activity (3) than progesterone (3), several research groups decided to undertake the synthesis of steroids with abnormal configuration (4). Hence, since Ehrenstein's early observation, numerous similar steroids, among which the 14p,17a-progesterone (26) and 19-iiorsteroids (4, 5), have been prepared. Related work was also undertaken in tlie Syntex Labora--, ---tories (4d, 6). In the present study the preparation of several other llew steroids unnatural with acid, the a,p-unsaturated ketone (60) affords configuration, belonging to the estrane, andro-a mixture of three isomeric compounds separable stane, and 19-norpregnane series is reported.by column cllromatogra~h~. The first substance Treatment of the enol acetate (5) (7, 8) of is the 14p-is0mer (6b) (71, ~haracterized by its estrone methyl ether (4a) with bromine affords nuclear magnetic resonance (n.m.r.1 spectrum the 160i-bromo derivative, (4b) (7), as the main wl~icli sliows olefinic resonance as a doublet at compound. The 16a-configuration2 is assigned 374 c.p.s. (J15,16 = 6 c.P.s.) (C-16H) and a to the bromine atom on the basis of the optical further doublets (J15.16 = 5 C.P.S.; properties exhibited by this compound (4b), J14.15 = c.P.s.) at 427 C.P.S. (C-15H). Its ultrasince the Cotton effect associated the 17-violet (uav.) absorption spectrum and the positive keto c~lromop~lore is less intense than in 4a, in Cotton effect for the n-T" transition of the a,bagreement with the octant rule (10). Conversion unsaturated at ca. 340 m p are of the bromo-ketone (4b) into its cycloethylene cl'aracteristic of compound (6b). The second ketal followed by dehydrobromjnation (7, 11) isO"er is the p,? ' -et1lylenic ketone ( 6~) (7). and mild acid ~lydrolysis provides the known Althougli the U.V. spectrum of this conipound is a15-17-ketone ((ja) (7, 111, typified by a ,legafi,,e reminiscent of (but less intense than) that ofcomCotton effect in the 350 mp region. on treatment pound (6b), its n.m.r. spectrum is characteristic in having only one olefiilic proton (338 c.p.s.). Moreover, compound (6c) exhibits a relatively For personal use only.
In vorangehenden Arbeiten3) hatten wir die UV.-Bestrahlungen von d5-ungesattigten sowie gesattigten 5a-und 5/3-11 -0xo-pregnan-Verbindungen beschrieben, die vorwiegend unter Angriff an der angularen Methylgruppe 19 zur Ausbildung von t-Cyclobutanol-Derivaten fuhrten (vgl. z. €3. 23 -+ 24 und 25 + 26; Abschnitt 3 ) . Es hatte sich dabei gezeigt, dass das Ausmass dieser Ringschluss-Reaktion stark von der Konstitution bzw. Konfiguration des Kohlenstoffatoms 5 im Ausgangsketon abhangt, dagegen die Selektivitiit beziiglich des Angriffs an C-19 dadurch nicht wesentlich beeinflusst wird. Als Ursache fur die Abnahme der Cyclisationsgeschwindigkeit in der Reihenfolge 5a > A5 $ 5 8 waren sterische Wechselwirkungen in Retracht gezogen worden3')), die miiglicherweise den Reaktionsverlauf massgeblich begunstigen bzw. hemmen.Mit den im folgenden heschriebenen Versuchen wurde ein Reitrag zur Abklarung dieser Problemstellung angestrebt. Zu diesem Zweck bestrahlte man die 4,4-Dimethyl-11-0x0-pregnane 5 und 7, in welchen die axiale Methylgruppe 19 eine zusatzliche sterische 1,3-Wechselwirkung mit der ebenfalls axial angeordneten 4fl-Metliylgruppe erfahrt (vgl. Partialformeln a und b, Abschnitt 3). Herstellung von 3,20-Di-athylendioxy-11-0~0-4,4-dimethyl-d6-pregnen (5) und 3,20-Di-athylendioxy-l1 -oxo-4,4-dimethyl-5cL-pregnan (7). -Behandlung von llcr-Hydro-xy-progesteron (1) 4) mit einem tfberschuss an Kalium-t-butylat und Methyljodid in t-Butanol bei Zimmertempcratur5) lieferte glatt das d5-ungesattigte 4,4-T)imcthyl-Uerivat 2, das auch als Acetat 3 charaktcrisiert wurclc. Das ungesattigte Keto-dikctal 5 war aus 2 durch Oxyrlation tlesselbcn zum Triketon 4 und anschliessende Ketalisierung zuganglich. Die gcsattigte Verbindung 7 wurtie durch Ketalisierung des Triketons 6 erhalten, das seinerseits bei der Hydrierung von 2 mit Platinkatalysator in Eisessig uad anschliessencler Oxylation dcr angefallenen, in rciner lTorm nicht isolierten 3,11,20-Trihydroxy-Verbindung cntstrtnd.Zur Sicherstcllung der t~ans-~4nordnung der Ringe A und B des gesattigten Iceto-diketsls 7 xvurde dieses iiber das Diketon 10 mit dcr Verbindung 14 verkniipft, deren Scr-Konfiguration aus dem Vergleich ihrer Rotationsdispersions-I(urvc rnegativcr C O T T O N -E f f e k t bci 305 mp, molxre l ) 21. Mitt.: Proc. chem.
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