Bufadienolides of plant and animal origin

Cycloalkenes by intramolecular wittig reaction

Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.

Certain chemical entities, compositions and methods

1,3‐Dipolare Cycloadditionen, 72. Reaktionen der Knallsäure mit ungesättigten Verbindungen

It has been said that the active components in the Digitalis extracts have been “the most ingested drugs in medicine”.1 These substances, usually called cardenolides, differ from ordinary steroids in three major respects: the C/D ring system is cis rather than trans fused, there is a tertiary hydroxyl at C-14, and the substituent at C-17 (a butenolide) is in the thermodynamically less stable â orientation.2 As might be expected, many partial syntheses of cardenolides have been described starting with readily available steroids.3,4 We now report the total synthesis of natural (+)-digitoxigenin (1), the biologically active cardenolide which, as its trisaccharide derivative digitoxin, is one of the most frequently used of the active principles isolated from Digitalis species. We divided the synthesis, which we carried out both to racemic and to natural (+)-digitoxigenin, in three parts: synthesis of the tricyclic enone 2; elaboration of the fused 5-membered ring D to produce a tetracyclic system bearing both a 14-â-hydroxy substituent and a substituent at C-17 capable of further transformation; and, finally, elaboration of that substituent to the â-oriented butenolide system. We chose to approach the construction of the tricyclic enone 2 via an intramolecular [4 + 2] cycloaddition, as schematized in Figure 1. We initiated the synthesis from the monoketal (-)-3, prepared by applying to the readily available (S)-enantiomer of the Wieland Miescher ketone,5 the sequence previously described6 using its racemate. Ozonolysis of the trimethylsilyl enol ether of 3 gave, in a not unprecedented reaction,7 a mixture of R-hydroxy ketones which was reduced (NaBH4) to the corresponding glycols, followed by cleavage with periodate to the dialdehyde 4 (71% overall yield from 3). The two aldehyde groups in 4 now had to be differentially elaborated.

The total synthesis of a natural cardenolide: (+)-digitoxigenin

Ausgehend von 20-Ketimino-Steroiden ist es moglich, sowohl gesattigte wie ungesattigte 17α-Oxy-20-ketone herzustellen. Hierzu werden Ketimine (VII), die aus 20-Aminen leicht zuganglich sind, mit Acetanhydrid acetyliert, wobei sie unter Umlagerung in 17(20)-En-20-monoacetylamine (VIII) oder unter energischeren Bedingungen in 17 (20)-En-20-diacetylamine (IX) ubergehen. An die Monoacetylamine last sich mit Benzopersaure Sauerstoff addieren. Die so erhaltenen 17.20-Oxido-20-acetylamine (X) ergeben bei alkalischer Hydrolyse 17α-Oxy-20-ketone (XI).



Enacetylamine mit einer Δ5-3-Acetoxy-, Δ5-3-Oxy- oder einer Δ4-3-Keto-Gruppierung konnen partiell an der semicyclischen Doppelbindung mit Benzopersaure umgesetzt werden. 20-Acetamino-pregnadien-(5.17 (20))-ol-(3β) (XVII) und sein 3-Acetat (XII) sowie 20-Acetamino-pregnadien-(4.17 (20))-on-(3) (XIX) reagieren so mit einem aquivalent Benzopersaure unter Bildung der 17.20-Oxyde (XIV, XVIII, XX). Ihre alkalische Verseifung ergibt 17α-Oxypregnen-(5)-ol-(3β)-on-(20) (XV) bzw. 17α-Oxy-progesteron (XXI). Die Unterschiede im reaktiven Verhalten von 17 (20)-En-20-ol-acetaten und 17 (20)-En-20-acetylaminen werden diskutiert.

über die Herstellung von 17α-Oxy-20-keto-Steroiden aus 17(20)-En-20-acetamino-Steroiden†

Herstellung von ungesättigten Lactonen der Steroid-Reihe, II

Herstellung von ungesättigten Lactonen der Steroid-Reihe, III1,2) Partialsynthese von Digitoxigenin

Compounds of formula I ##STR1## wherein R1 and R1' are identical or different and represent hydrogen, an alkyl radical or alkoxy radical having 1-4 carbon atoms, the allyl group, a halogen atom or the nitro group, R2 represents an acrylic acid radical or an acrylic acid nitrile radical of the formulae ##STR2## wherein R5 represents hydrogen, an alkyl radical having 1-5 carbon atoms, an aryl radical or aryl-lower alkyl radical either unsubstituted or substituted by lower alkyl or alkoxy, R6 represents hydrogen or an alkyl radical having 1-8 carbon atoms, R7 represents hydrogen, a lower alkyl radical or an aryl-lower alkyl radical, R3 and R4 represent together with the nitrogen atom a heterocyclic ring with 5-7 members being optionally substituted by C1 -C4 alkyl, in which ring one carbon atom may be replaced by one oxygen atom, sulfur atom or one further nitrogen atom, the latter may be substituted, or wherein R3 represents hydrogen and R4 represents a phenyl-alkylene or phenyl-alkylidene radical of the formula ##STR3## in which Alk is alkyl having 1 to 3 carbon atoms, and n is a figure from 1-3, and R8 and R9 are identical or different and represent hydrogen, an alkoxy radical having 1-3 carbon atoms or the benzoyl radical or R8 and R9 represent together the bismethylene dioxy radical, as well as the physiologically compatible acid addition salts and a process for preparing these compounds.

Werner Fritsch

Papers

über die Herstellung von 17α-Oxy-20-keto-Steroiden aus 17(20)-En-20-acetamino-Steroiden†

Herstellung von ungesättigten Lactonen der Steroid-Reihe, II

Herstellung von ungesättigten Lactonen der Steroid-Reihe, III1,2) Partialsynthese von Digitoxigenin

1-Aryloxy-2-hydroxy-3-aminopropanes

Herstellung von ungesättigten Lactonen der Steroidreihe, VII. Synthese von 4(5)-Dehydro-bufadienoliden