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In the search for aldosterone antagonists with an optimal activity profile, twelve 9α, 11-epoxy-steroids were prepared and compared with their 9α, 11α -unsubstituted analogues in terms of steroid receptor binding in vitro and electrolyte excretion in vivo. Substitution of the parent structures by an epoxy group at positions 9α, 11 resulted in marginal effects on mineralocorticoid receptor binding and electrolyte excretion, but greatly reduced androgen and gestagen receptor binding. This finding is reflected in the largely lacking unwanted anti-androgenic and gestagenic side effects in animal models of the three most interesting 9α, 11 -epoxy-spirolactones 4(CGP 33033), 18(CGP 29245), and 25 (CGP 30083).

A Simple Route to 3-Amino-nocardicinic Acid Starting from nocardicin A (1), a novel and efficient procedure for the preparation of 3-amino-nocardicinic acid (4) and its protected derivatives 6 and 8–11 is described.

As a first step toward total synthesis of histrionicotoxin and its congeners, the preparation of (±)-cis-Azaspiro[5.5]undecan-8-ol (11) is described.

Irradiation at 254 nm of 19-dimethoxyandrost-4-en-17 β-ol-3-one acetate (8) afforded the epimeric cyclization products 9 (yield 20%) and 10 (4%). Similar transformations were also achieved with the analogous dimethoxy-enone 24 ( 25, 65%), and-dienone 30 ( 31, 72%), and with the methoxy-enone 33 ( 34, 30%), and-dienone 35 ( 36, 17%).

A 18-step transformation of dehydroabietic acid (1) into ketone 40, convenient starting material for the prparation of 14α-methylsteroids, is described.

The UV.-isomerisation of 11-oxo-14β,17α-pregnane 9 to the 11,19-cyclo-derivative 11 is described. In addition the Pb(OAc)4-fragmentation of photoproduct 11 was investigated. 11 yielded besides the expected 11-oxo-19-hydroxy-pregnane 18 the novel 9,11-seco-11,19-cyclosteroid 19. The structure of 19 was established by chemical transformations and subsequently confirmed by X-ray analysis [2].

UV. Irradiation of N-Phenacylformamides UV. irradiation of suitable N-phenacylformamides (e.g.2) leads under transfer of the formyl H-atom to the corresponding β-lactams (e.g.3). Scope and structural limitations of the novel reaction are discussed.

On UV.-irradiation in i-octane the α,β-unsaturated ketone 14 is transformed into a mixture of 15 and 16.

1 In analogy to the previously described photochemical isomerisation of 3,20-diethylenedioxy-11-oxo-5 α-pregnane (I II) the UV.-irradiation of the Δ5- and 5β-11-oxo-steroids III and XXII gives rise to the 11 α-hydroxy-11, 19-cyclo derivatives IV and XXIII, respectively. The observed yields of these tertiary cyclobutanol products decrease in the order II > IV > XXIII. The possible significance of these structure-dependent rate differences is discussed.

1. A new two-step process for the functionalisation of the non-activated methyl group 19 of 5α-steroids is described. In the first step UV.-irradiation of the 11-oxo-5α-pregnane derivate I in ethanol gives rise to a preferential attack of the photochemically excited carbonyl on methyl group 19, leading to the formation of the tertiary cyclobutanol compound II in high yield. The latter, upon treatment with lead tetraacetate in benzene solution, undergoes selective fragmentation of the photochemically formed C-11β-C-19 bond furnishing the 19-hydroxy-11-oxo-5α- pregnane compound V.

The photochemical transformation of 3-oxo-17β-acetoxy-Δ1;5-androstadiene (2) and its 10α-diastereoisomer 7 has been investigated. With low conversion of 2, an isomer was produced for which structure 8 (6β-H) is proposed. After longer photolysis times, both compounds, 2 and 8, were consumed, and the four stereoisomeric photoproducts 9–12 were obtained. Products 9 and 10 on one hand, and 11 and 12 on the other, are photochemically interconvertible. Dienone 7 yielded a very similar product mixture from which ketones 10 and 12 could be isolated. Further, the presence of a dienone isomer was demonstrated to which structure 8 (6α-H) is assigned.

3-Oxo-4,5-oxido-10β-steroids have previously been shown to rearrange photolytically to the corresponding 3,5-dioxo-10(5 4)-abeo compounds (cf. a, b c). According to the present findings, the 10α-testosterone oxide 4 gives specifically the l0α-product 5 and the stereoisomeric 4-methyl-testosterone oxides 8 and 10 undergo stereospecific rearrangements to the products 11 and 12 respectively.

Results previously reported on the fragmentation of monohydric alcohols with lead tetraacetate are extended and correlated on the basis of new experimental evidence.

Irradiation of ethanolic solutions of the 20-keto-pregnane derivatives I, XIII and XX leads to the formation of their respective stereoisomeric 20-hydroxy-18,20-cyclo-pregnane compounds, whose structures and configurations have been fully determined. Known fragmentation reactions are simultaneously observed.

The α,β-unsaturated γ,δ-epoxyketone 7 is isomerized almost exclusively to the δ-diketone 9 both upon irradiation in the n π* absorption band with light of wavelengths above 310 nm (in anhydrous dioxane or benzene solutions) and upon triplet sensitization using acetophenone in benzene. The reaction may be formulated by the cleavage of the CγO oxide bond and the shift of the δ-hydrogen to the γ-position, and thus bears a formal “double bond homology” to the photochemical α,β-epoxyketone rearrangement. Excitation in the π π* absorption band of 7 with light of wavelength 253,7 nm (in anhydrous dioxane solution) leads to the formation of product 10 as well as to the triplet rearrangement to 9. With this result a novel partial synthesis of O-acetyl-B-nortestosterone has been accomplished, which has the advantages of fewer steps and higher product yield (7 10: ∼30% yield) than previously published syntheses. On the basis of the presently available experiments, the mechanism of the transformation 7 10, which constitutes one of the still few examples of enone photoreactions induced selectively from the π,π* excited singlet, remains unknown.

A sterically controlled transformation of 3-oxo-17β-acetoxy-Δ1−-α-androstene (2) into 1β,4β-oxido-3-aza-17β-hydroxy-A-homo-5α-androstane (16) is described. With the exception of two conversions [1415 (60%); 15 16 (50%)], the yields of the remaining seven steps are higher than 75% each. The reaction sequence will serve as a model for an analogous partial synthesis of samandarine (1).

The photorearrangement previously described [3] of saturated and Δ1-unsaturated 3-oxo-4,5-epoxy-10β-steroids to 3,5-dioxo-10(5 4)-abeo compounds proceeds most likely via a radical 1,2-alkyl shift (Chart 1). The similar rearrangements of the related 10α-epoxyketone 10 and the 4-methyl-epoxyketones 13, 15, 16, 20 and 21 to the corresponding 3,5-diketones occurred without epimerization at the migrating carbon atom (C-10) and the site of substitution (C-4) (Chart 3). The stereochemical control of the rearrangement is in agreement with the earlier proposed mechanism of a concerted alkyl radical shift in these alicyclic systems.

11-Oxygenated 18,20-cyclo-steroids have been prepared by two methods : 1. Irradiation of 3β, 11β-diacetoxy-20-oxo-5α-pregnane and of 3-ethylenedioxy-11 α-acetoxy-20-oxo-Δ5-pregnene with ultraviolet light gave the corresponding (20S)-20-hydroxy-18,20-cyclo-pregnane derivatives as major products. 2. Incubation of (20 S)-3-oxo-20-hydroxy-Δ4-18, 20-cyclo-pregnene with an Aspergillus ochraceus WILHELM culture furnished the corresponding 11 α-hydroxy derivative.

The synthesis of the two stereoisomeric diepoxyketones 9 and 22, and of the tetrols 7 and 20 is described. Compound 7 contains the ring-A-triol partial structure characterising some naturally occurring cardiac glycosides.

A partial synthesis of dihydroanhydrohirundigenin (4), a hydrogenation product of naturally occurring anhydrohirundigenin (2) is described. Furthermore 4 is transformed into the formal dihydroderivative 14 of hirundigenin (1).

Irradiation of 3,3-ethylenedioxy-20-keto-21-acetoxy-Δ5-pregnene (I) in ethanolic solution leads to the formation of 3,3-ethylenedioxy-18,20-oxido-20ξ-hydroxy-21-acetoxy-Δ5-pregnene (II) and 3, 3-ethylenedioxy-20ξ-hydroxy-21-acetoxy-Δ5-18,20-cyclo-pregnene (IV).

The irradiation of 3-oxo-10β-hydroxy-17β-acetoxy-Δ1;4-estradiene (2) in dioxane solution with predominantly monochromatic light (2537 A) yields a mixture of 17-O-acetyl-estradiol (3) and the diketone 4. The latter ist structurally related to products previously obtained by irradiation of O-acetyl-1-dehydro-testosterone.

UV. -irradiation of the 11-oxo-δ14-5α-pregnene derivate 16 gives rise to a novel photochemical reaction. The preferential attack of the photochemically excited carbonyl on CH-8 furnishes the tertiary cyclopropanol compound 18 in high yield.

It is shown that irradiation of the 20-keto-pregnane derivatives I, XI and XVI leads predominantly to cyclisation between the carbon atoms 18 and 20 with formation of the novel pentacyclic steroid compounds II, XII and XVII. Simultaneously fragmentation reactions occur yielding products of type XIX and XX.

On UV. irradiation in i-octane or t-butyl alcohol the α,β-unsaturated δ-hydroxy ketone 2 undergoes fragmentation to the novel 14,15-seco-steroid 3.

10α-Testosterone and its 1-dehydro derivative have been synthesised in 7 and 8 steps, respectively, from O-acetyl-1-dehydro-testosterone. The key step, which is described in a preceding paper, was the selective inversion of configuration at C-10 of the starting material, effected through a photochemical reaction.

Irradiation of 3,19-dioxo-17β-acetoxy-Δ4-androstene (2) at room temperature in either of its two absorption bands centered at about 245 and 315 nm, respectively, led to products 21, 22, and 23 (Chart 3). Compounds 21 and 22 result from rearrangements involving intramolecular formal 1,2- (21) and 1,3-shifts (22) of the angular formyl group, and the formation of compound 23 proceeds through the elimination of the formyl radical and the incorporation of a hydrogen from the medium. Evidence favors the latter process to be a secondary radical reaction rather than a primary photochemical step.

A synthesis of the four stereoisomeric 1,4-oxido-3-oxa-A-homo-androstane-derivatives 3, 9, 13, and 19 is described, starting from the lactones 1, 11, and 15.

Zusammenfassung. Im Rahmen der vorliegenden Mitteilung berichten wir uber den partial-synthetischen Aufbau von 3-Oxo-17 β-acetoxy-14α-methyl-Δ4-8α, 9β, 10α, 13α-ostren (12), dessen Struktur anschliessend mittels dreidimensionaler Rontgenanalyse [2] sichergestellt worden ist. Als Ausgangsmaterial der Synthese diente die tricyclische Verbindung 2, die, zusammen mit 3, von uns (s. vorhergehende Mitt. [1]), aus Dehydroabietinsaure (1) dargestellt worden ist.

UV.-irradiation of 10α-testosterone (1) in t-butanol with a high-pressure mercury lamp yields the Δ5-isomer (2).