Totalsynthese optisch aktiver Steroide, IIITotalsynthese von optisch aktiven 13‐Äthyl‐gonan‐Derivaten

Abstract

1) laRt sich mikrobiologisch zum optisch aktiven 13-~thyl-3-methoxy-8.14-seco-gona-l.3.5(10).9-tetraen-17~-ol-14-on (12) reduzieren. Diese Substanz ermoglicht die Herstellung von naturlichen 13-khylgonan-Derivaten. Natiirliches 13-Athyl-17a-athiny1-gon-4-en-17~-01-3-on (11) wird synthetisiert.Durch Steroid-Totalsynthesen ist es moglich, die 13-Methylgruppe durch andere Alkyl-und Arylsubstituenten zu ersetzenl-6). Von den bisher untersuchten 13-Alkylbzw. Aryl-gonan-Derivaten sind die 13-Athylderivate von Interesse, da sie einige ausgezeichnete pharmakologische Eigenschaftenl. 2) besitzen. -Schliisselsubstanz der Synthese istanalog zur 13-Methylreihedas 13-Athyl-3-methoxy-8.14-secogona-1.3.5(10).9-tetraen-14.17-dionl. 2) ( l ) , eine Verbindung, die noch kein Asymmetriezentrum enthalt.Erst die anschlieflende Kondensation zum racem. 13-~thyl-3-rnethoxy-gona-1.3.5(10).8.14pentaen-17-on (racem. 2) fuhrt zur Ausbildung eines asymmetrischen Kohlenstoffatoms (Cl,) und damit zur Racematbildung. Die folgenden Stufen, die Hydrierung zu racem. 3 und die anschlieRende Reduktion zu racem. 5 (oder erst Reduktion zu racem. 4 und dann Hydrierung zu racem. 5), sowie die Birch-Reduktion zum racem. 13-Athyl-3-methoxy-gona-1.3.5(lO)-trien-17p-01 (racem.6) 1 J ) verlaufen wie in der 13-Methylreihe jedoch nahezu stereospezifisch und *) 11. Mitteilung: C. Rufer, E. Schroder und H. Gibian, Liebigs Ann. Chem. 701, 206 (1967). * * ) Wenn nicht durch ,,racem." gekennzeichnet, handelt es sich bei allen im Text beschrie-1) H. Smith und Mitarbeiter, J. chem. SOC. [London] 1964, 4472.

Hormones

“…Compound 35 is optically active and belongs to the normal series; i.e., C-13 and C-17 have the same configuration as in natural steroid compounds. Because subsequent reactions are stereospecific, the final product (d-norgestrel) retains the optical activity and normal configuration introduced by microbiological reduction [161] (see figure on previous page). Acidic cyclization of 35 produces 36, which has a double bond between C-14 and C-15.…”

“…The naturally occurring estrogens, estrone (10), estradiol (47), and estriol (48), as well as the estrogens from mare urine, equilin (49), equilenin (50), and their 17-dihydro compounds, are of considerable importance in the treatment of menopausal symptoms (for structures, see Table 5) [161]. However, very high oral doses are required to elicit responses because these compounds are rapidly metabolized and inactivated in the liver.…”

“…The double bond at the 5,6-positions of the starting compound, 16α-methylpregnenolone 3-acetate (159), is converted stereospecifically with perbenzoic acid to the 5,6α-oxide (160). Compound 160 is then cleaved with boron trifluoride to give the 6β-fluoro-5α-hydrin (161). After insertion of the 17α-and 21-hydroxyl groups, oxidation with chromium trioxide, and dehydration to the 3-keto-4,5-dehydro system (162), the 6β-fluoro group is isomerized to the 6α-fluoro group by treatment with acid.…”

“…[6533-00-2] (38), the gestagenic component of the contraceptives Neogynon and Stedirild, is produced by total synthesis [159][160][161]. 6-Methoxy-1-tetralone is converted to the vinyl alcohol (33) with vinylmagnesium chloride.…”

Hormones

“…Oppenauer oxidation produces the keto-function at C-17; ethynylation and hydrolysis of the methyl ether finally give (D)-levonorgestrel. [57] Due to the lack of a good understanding of dose/response relations, the "first-generation" oral contraceptives contained relatively high-dosed oestro-…”