Photooxidative dehydrogenation of Δ8-drimen-and Δ8-11-homodrimen-7-ones into α,α ′-dienones

An efficient two-step procedure for photooxidative dehydrogenation of drimane and 11-homodrimane compounds containing an 8-en-7-one structural unit into α,α′-dienones was elaborated. The method is based on the transformation of ketones into the respective enol acetates followed by photosensitized oxygenation. Methyl 7-oxo-11-homodrima-5,8-dien-12-oate, 5,6-dehydro-7-ketoisodrimenine, 11-acetoxydrima-5,8-dien-7-one and 11,12-diacetoxydrima-5,8-dien-7-one were prepared in high yields starting from methyl 7-oxo-11-homodrim-8-en-12-oate, 7-oxoisodrimenine, 11-hydroxydrim-8-en-7-one and 11,12-diacetoxydrim-8-en-7-one, respectively. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 678–682, April, 2006.     

Convenient Access to 2,3-Disubstituted-cyclobut-2-en-1-ones under Suzuki Conditions and Their Synthetic Utility

A regioselective synthesis of general applicability has been designed for the one-pot preparation of 2,3-disubstituted-cyclobutenones from iodoalkynes through cyclobutenylation, Suzuki CC coupling, and ketone formation. This one-pot methodology has been applied to the selective synthesis of an orally active cyclooxygenase II inhibitor. Furthermore, the obtained cyclobut-2-en-1-ones were used as synthons in several transformations, such as, the preparation of β-lactams, phthalazines, cyclohexa-2,5-dien-1-ones, and cyclopent-3-en-1-ones.     

Synthesis of 5-amino-1,5-diarylpenta-2,4-dien-1-ones

Nucleophilic addition of morpholine and piperidine to 1,5-diarylpent-2-en-4-yn-1-ones involves the triple bond in the latter, regardless of the substituents in the aryl rings, to produce the corresponding (E,E)-5-(morpholin-4-yl or piperidin-1-yl)-1,5-diarylpenta-2,4-dien-1-ones in up to 93% yield. According to the X-ray diffraction data, the synthesized compounds in crystal have s-cis and s-trans conformations of the enone and dienone fragments, respectively.     

Noncommunicating photoreaction paths in some pregna-1,4-diene-3,20-diones.

The photochemistry of three pregna-1,4-diene-3,20-diones bearing a hydroxy or alkoxy group at C(17) (4-6) has been examined. Irradiation at 254 or 366 nm, where absorption by the cross-conjugated ketone moiety in ring A is predominant or exclusive, causes the 'lumiketone' rearrangement of this chromophore in low to medium quantum yield (Phi(r) 0.05 to 0.31). On the contrary, irradiation at 310 nm, where the isolated ketone at C(20) absorbs a large portion of light causes Norrish-I fragmentation of that chromophore with a higher Phi(r) (0.11-0.83). This leads to end-products arising from the conversion of the C(17) alkyl radical, in a way depending on the structure and the medium (reduction by hydrogen donating solvent, addition of oxygen when present). No intramolecular T-T energy transfer between the separated chromophores occurs. The 'lumiketone' rearrangement occurs independently from the irradiation wavelength (Phi(r) 0.06-0.18) with the strictly related androsta-1,4-dien-3-one 8 lacking the C(20) ketone function.     

Identification de stérols à chaînes latérales courtes dans l′éponge Damiriana hawaiiana

Identification of short side chain sterols in the sponge Damiriana hawaiiana The steroidal composition of the sponge Damiriana hawaiiana is examined. Twenty-seven components are identified. In addition to the C₂₆-C₂₉, Δ⁵-mono and diunsaturated sterols, the sponge contains sterols without side-chain: androsta-5, 16-dien-3β-ol( 1 ), androst-5-en-3β-ol( 2 ); sterols with a non-functionalized side-chain consisting of two, three, four, five and six carbon atoms: pregna-5, 20-dien-3β-ol( 5 ), pregn-5-en-3β-ol( 6 ), 23, 24-bisnor-chola-5, 20-dien-3β-ol( 7 ), 23, 24-bisnor-chol-5-en-3β-ol( 8 ), 24-nor-chol-5-en-3β-ol( 10 ), chol-5-en-3β-ol( 11 ), 26, 27-bisnor-cholest-5-en-3β-ol( 12 ), and sterols possessing a short oxygenated side-chain such as 3β-hydroxy-androst-5-en-17-one( 3 ), androst-5-en-3β, 17β-diol( 4 ) and 3β-hydroxy-26, 27-bisnor-22-trans-cholesta-5, 22-dien-24-one( 14 ). The probable biological or dietary origin rather than artifact production of these hitherto undescribed components from marine sources is supported by their relatively high concentration and their relative proportions, both very different from those expected for autoxidation.     

Steroidal analogues of unnatural configuration—VII : Total synthesis of 17β-hydroxy-9-methyl-9β, 10α-oestr-4-en-3-one,a novel retrotestosterone isomer

Conjugate methylation of 17β-hydroxy-des-a-oestr-9-en-5-one (1) and the derived 4,5-seco-steroid (6b) afforded the respective 9β-methyl compounds. Base-catalysed alkylation of 17β-hydroxy-9-methyl-des-a-9/gb-oestran-5-one (3a) resulted in attack at C(6); this result was used to prepare the anthrasteroid (5). Ring closure of the 9β-methyl-4,5-seco-steroid (8) derived from 6b afforded 17β-hydroxy-9-methyl-9β,10α-oestr-4-en-3-one (9a). Conjugate methylation of 17β-hydroxyoestra-4,9-dien-3-one (11) resulted in 1,4-addition to the dienone system.     

A simple synthesis of 4-amino-6-methyl-1,1,1-trifluoro(trichloro)hepta-3,5-dien-2-ones and 2,2-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyridone

Treatment of 2,2-dimethyl-6-trifluoro(trichloro)methyl-2,3-dihydro-4-pyrones with ammonia gives 4-amino-1,1,1-trifluoro(trichloro)-6-methylhepta-3,5-dien-2-ones. Under similar conditions 1,1,1-trifluoro-2-hydroxy-6-methylhepta-2,5-dien-4-one and 6-chloro-1, 1,1-trifluoro-2-hydroxy-6-methylhept-2-en-4-one cyclize into 2,2-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyridone. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2263–2265, December, 1997.     

General patterns in the photochemistry of pregna-1,4-dien-3,20-diones

The photochemistry of six pregna-1,4-dien-3,20-diones has been compared and found to involve both the cyclohexadienone moiety in ring A and the isolated ketone at C-20. The two reactions take place proportionally to the fraction of light absorbed by each chromophore. The cross-conjugated ketone absorbs predominantly or exclusively at both 254 and 366 nm and undergoes the "lumi" rearrangement to bicyclo[3.1.0]hex-3-en-2-one. The quantum yield of the reaction diminished somewhat with increasing lambda(exc), e.g., for prednisolone Phi(254) (nm) = 0.42, Phi(366) (nm) = 0.3. A much stronger lowering is caused by halogen substitution in position 9 (by a factor of 3 for F, >50 for Cl), apparently due to a shortened triplet lifetime caused by heavy atom effect. At 310 nm, both chromophores absorb to a comparable degree and both may react. The reaction at C(20) ketone involves either quite efficient alpha-cleavage (C(17)-C(20)) for compounds bearing an acetal or hydroxyl function at C(17) or less effective (by a factor of ca. 10) hydrogen abstraction from the 18-methyl group in the other cases (finally resulting in Norrish II fragmentation or Yang cyclization). The results allow generalizing how the substitution pattern surrounding each chromophore affects the photoreactivity at that site and the competition between the two modes, allowing predicting the photochemistry of this family of antiinflammatory drugs.     

Biotransformation of (+)-androst-4-ene-3,17-dione

Fermentation of (+)-androst-4-ene-3,17-dione (1) with Curvularia lunata for 10 days yielded five oxidative and reductive metabolites, androsta-1,4-diene-3,17-dione (2), 17beta-hydroxyandrosta-1,4-dien-3-one (3), 11alpha-hydroxyandrost-4-ene-3,17-dione (4), 11alpha,17beta-dihydroxyandrost-4-en-3-one (5) and 15alpha-hydroxyandrosta-1,4-dien-17-one (6). The structures of these metabolites were elucidated on the basis of spectroscopic techniques. These microbially transformed products were assayed against the clinically important enzymes, tyrosinase and prolyl endopeptidase.     

Photochemistry of some steroidal bicyclo[3.1.0]hexenones

The photochemistry of five 11-hydroxy-1,5-cyclopregn-3-en-2-ones (‘lumi’ products from the corresponding pregna-1,4-dien-3-ones) has been investigated. In all cases the photoproducts were 1,11-oxy derivatives, resulting from intramolecular attack of the hydroxyl group to the incipient positive charge at C-1. When a fluorine atom was present at C-6, HF elimination took place concurrently with the nucleophilic addition and led to linearly conjugated dienones, rather than the enones obtained in the other cases. Quantum yields were in the range 0.06-0.2, the lower values applying when a fluorine atom was present in position 6 (not in position 9). The results add new evidence on the role of zwitterionic intermediates in the photochemistry of cross-conjugated dienones and the corresponding lumi photoproducts.     

Nucleophilic sulfanylation of 1,5-disubstituted pent-2-en-4-yn-1-ones

Regioselectivity of nucleophilic addition of benzenethiols and phenylmethanethiol to 1,5-diarylpent-2-en-4-yn-1-ones in ethanol in the presence of triethylamine at 0–30°C is determined by the nucleophile nature. Phenylmethanethiol adds to the double bond, whereas benzenethiols add to the triple bond. The addition products, 1,5-diaryl-3-benzylsulfanylpent-4-yn-1-ones and 1,5-diaryl-5-(4-arylsulfanyl)penta-2,4-dien-1-ones, respectively, were isolated in 43–89% yield. Substituents in the aryl rings of the substrates did not affect the reaction direction.     

Stereoselective synthesis of cyclohexa-2,4-dien-1-ones and cyclohex-2-en-1-ones from phenols

A convenient synthetic method for the synthesis of substituted cyclohex-2-en-1-ones by the direct alkylation of phenols has been developed. Furthermore, enantiomerically enriched 2,6-dimethyl-6-(3-methylbut-2-enyl)-cyclohexa-2,4-dienone was prepared by the deprotonation of 2,6-dimethylphenol with a sparteine–lithium complex followed by alkylation with 1-chloro-3-methylbut-2-ene. 2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone was prepared from the corresponding cyclohexa-2,4-dien-1-one by selective hydrogenation of the 4,5-double bond. The method was extended to 2-methyl-naphthalen-1-ol and 1-methyl-naphthalen-2-ol resulting in 2-(R)-methyl-2-(3-methylbut-2-enyl)-2H-naphthalen-1-one and 1-(S)-methyl-1-(3-methylbut-2-enyl)-1H-naphthalen-2-one, respectively.     

Megastigma-5,8-dien-4-on,ein Aromastoff der gelben Passionsfrucht und des Virginia-Tabaks

Megastigma-5,8-dien-4-one, an aroma constituent of the yellow passion fruit and Virginia tobacco Preparative gas chromatography allowed isolation of megastigma-5, 8 (E)-dien-4-one ( 3 ) from small subfractions of both yellow passion fruit and Virginia tobacco condensates. Along with 3 , the Z-isomer 4 occurs in the aroma of the yellow passion fruit. Both these novel flavor compounds were synthesized by a two-step, non-biomimetic route starting from 2, 6, 6-trimethylcyclohex-2-en-1-one. The E-isomer 3 was also formed by acid-catalyzed dehydration/rearrangements of ionol- and damascol monoepoxides 5, 6, 7, 8 and hydroxy-ionols and -damascol 9, 10 and 11 . Such a biomimetic conversion indirectly supports the assumption that 3 and 4 might originate from the oxidative degradation of carotenoid precursors possibly related to canthaxanthine.     

Cytotoxic diterpenoids from Vietnamese medicinal plant Croton tonkinensis GAGNEP

Six new ent-kaurane-type diterpenoids were isolated from the leaves of the endemic Vietnamese medicinal plant Croton tonkinensis GAGNEP. (Euphorbiaceae) together with three known ent-11alpha-acetoxy-7beta,14alpha-dihydroxykaur-16-en-15-one (1), ent-kaur-16-en-15-one 18-oic acid (5) and ent-18-hydroxykaur-16-ene (7). Their structures were determined by spectroscopic analyses to be ent-7beta-acetoxy-11alpha-hydroxykaur-16-en-15-one (2), ent-18-acetoxy-11alpha-hydroxykaur-16-en-15-one (3), ent-11alpha-acetoxykaur-16-en-18-oic acid (4), ent-15alpha,18-dihydroxykaur-16-ene (6), ent-11alpha,18-diacetoxy-7beta-hydroxykaur-16-en-15-one (8), and ent-(16S)-1alpha,14alpha-diacetoxy-7beta-hydroxy-17-methoxykauran-15-one (14). ent-Kaurane-type diterpenoids from Croton tonkinensis 2-4, 6, and 9-13, were tested for toxicity in the brine shrimp lethality assay. Compounds 9, 10, and 12 demonstrated significant activity, compounds 2, 3, 6, and 11 showed weak activity, and compounds 4 and 13 were inactive.     

Säurekatalysierte Umlagerung von 4-Allyl-cyclohex-2-en-1-olen; Beispiele für ladungskontrollierte [3s, 4s]-Umlagerungen von cyclischen Allylkationen

The acid-catalysed rearrangement of the cyclohex-2-en-1-ols 15 , d₃- 15 , 16 , 17 and 19 , the cyclohexa-2,5-dien-1-ols 20 and 21 , and also the allyl alcohols 22 and 23 (Scheme 3), using 98-percent sulfuric acid/acetic anhydride 1:99 at room temperature, was investigated. From the rearrangement of 4-allyl-4-phenyl-cyclohex-2-en-1-ol ( 15 ), with reaction times greater than 2 hours a single product is obtained, 4-allyl-biphenyl ( 50 ) in 33% yield (Scheme 9). With reaction times below 2 hours the acetate 53 from 15 was isolated, and this could be converted into 50 . The reaction of 2′,3′,3′-d₃-15 in Ac₂O/H₂SO₄ lead to 1′,1′,2′-d₃-50 (Scheme 11). The rearrangement of 4-allyl-4-methyl-cyclohex-2-en-1-ol (16) (Scheme 14) yielded 39% of the corresponding acetate 60 and 30% of 4-allyl-toluene ( 6 ), which also resulted by a rearrangement of 60 under the reaction conditions. These rearrangements are all [3s,4s]-sigmatropic reactions, which proceed via the cyclohexenyl cation a (Scheme 12, R = C₆H₅, CH₃). In Ac₂O/H₂SO₄ the allyl-cyclohexadienes primarely formed subsequently undergo dehydrogenation to yield the benzene derivatives 6 , 50 and d₃- 50 . From the rearrangement of 4,4-diphenyl-cyclohex-2-en-1-ol ( 19 ) at 0° a reaction mixture is obtained which consists of the acetate 55 , 2,3-diphenyl-cyclohexa-1,4-diene ( 57 ) and o-terphenyl ( 56 ) (Scheme 10). Both 55 and 57 are converted under the reaction conditions to o-terphenyl ( 56 ). No 4-(1′-methylallyl)-biphenyl is obtained from the rearrangement of 4-crotyl-4-phenyl-cyclohex-2-en-1-ol ( 17 ). In this case, apart from the corresponding acetate 64 , a single product 5-(1′-acetoxyethyl)-1-phenyl-bicyclo[2.2.2]oct-2-ene ( 65 ) (Scheme 16) was obtained; under the reaction conditions the acetate 64 rearranges to 65 . The rearrangement of 4-allyl-4-phenyl-cyclohexa-2,5-dien-1-ol ( 20 ) gives, as expected, not only 4-allyl-biphenyl ( 50 ) but also 2- and 3-allyl-biphenyl ( 51 and 52 ) and biphenyl (Scheme 13). 4-Benzyl-4-methyl-cyclohexa-2,5-dien-1-ol (syn- and anti- 21 ) gave in Ac₂O/H₂SO₄ at 10° as rearrangement products 93% of 2-benzyltoluene ( 97 ) and 7% of 4-benzyl-toluene ( 98 ) (Scheme 21). Hence [1,4]-rearrangements in cyclohexadienyl cations, seems to occur only to a limited extent. The alicyclic alcohols 22 and 23 (Scheme 18) gave, in Ac₂O/H₂SO₄, as main product the corresponding acetates 73 and 75 , as well as small amounts of olefins 74 and 76 formed by dehydration i.e. [3,4]-rearrangements occur in these systems. Also no [3,4]-rearrangements were observed in solvents reactions of either 4,4-dimethyl-hepta-1, 6-dien-3-yl tosulate (79; see Scheme 19) or its corresponding alcohol 24.     

Microbial transformation of cortisol and prolyl endopeptidase inhibitory activity of its transformed products

Incubation of cortisol (1) with Gibberella fujikuruoi for 12 days yielded an oxidatively cleaved product, 11beta-hydroxyandrost-4-en-3,17-dione (2), while incubation with Bacillus subtilis and Rhizopus stolonifer yielded the reduced product, 11beta, 17alpha,20,21-tetrahydroxy-(20S)-pregn-4-en-3-one (3). Other reduced products, 11beta, 17alpha, 21-trihydroxy-5alpha-pregnan-3, 20-dione (4) and 3beta, 11beta, 17alpha, 21-tetrahydroxy-5alpha-pregnan-20-one (5) were obtained by incubation of compound 1 with Bacillus cerus. The inhibitory activity of compounds 1-5 against prolyl endopeptidase enzyme (PEP) was also assayed. Compounds 2 (IC50 162.8 microM) and 4 (IC50 157 microM) have shown significant inhibitory activity against PEP.     

N-methyl-N-alkylsilyltrifluoroacetamide-I2 as a new derivatization reagent for anabolic steroid control.

Analytical methods for the control of growth promoters have to be specific and sensitive. At low concentration levels, it is difficult to identify some molecules unambiguously even with the improved performance of analytical methods. GC-MS analysis of 17 beta-trenbolone and its major metabolite, 17 alpha-trenbolone, is a good example. A new derivatization agent has been developed which is based on silylation of the 3- and 17-oxygenated functions and nucleophilic substitution in the 4-position. The structure of the derivatized products was demonstrated using a simple model, cyclohex-2-en-1-one, by NMR and MS spectrometry. In contrast to data found in the literature, this derivative permitted specific mass spectra for trenbolone, sensitive signals for high mass ions and reproducible gas chromatograms to be obtained. The addition of an N(CH3)COCF3 radical to the steroid nucles allowed highly specific detection in GC-high resolution MS even following extraction from complex matrices; sensitive responses were also observed in the negative chemical ionization mode. Moreover, there are significant differences in the electron ionization mass spectra of the two stereoisomers, 17 alpha- and 17 beta-trenbolone. These preliminary results and those obtained for androsta-1,4-dien-3-one and pregna-4,6-dien-3-one indicate useful advances for the determination of steroids and potential applications for metabolism studies on such compounds.     

Novel Enone-benzene Rearrangement of 4,4-Dialkylcholest-5-en-3-ones to Ring-B Aromatic Steroidal Hydrocarbons Catalysed by p-Toluenesulfonic acid

Under acidic conditions, α,α-dimethyl-β,γ-unsaturated cyclohexanones undergoes an enone-benzene rearrangement leading to aromatic derivatives^1-4. We recently run an enone-benzene rearrangement of 4,4-dimethyl-cholest-5-en-3-one (1a) catalysed by montmorillonite K-10 to give 1,3,4-trimethyl-19-norcholesta-1,3,5(10)-triene (2a) in moderate yield accompanying intractable mixture of hydrocarbons as by products⁵. Repetition of this reaction by employing TsOH as a catalyst, 2a was obtained in 65% yield and a new product, 6-methyl-3-isopropyl-A,19-dinorcholesta-6,8,10(5)-triene (3a), was also isolated in 25% yield. The formation of 3a has not been reported in earlier studies^1-5. Herein we report the novel enone-benzene rearrangement of 4,4-dialkylcholest-5-en-3-ones (1a~d) leading to ring-B aromatic steroidal hydrocarbons (3a~d) catalysed by TsOH (Scheme 1).     

3-Alkyl-1-benzoxepin-5-on-Derivate und 2-Alkyl-1, 4-naphthochinone aus 2-Acylaryl-propargyläthern

3-Alkyl-1-benzoxepin-5-one derivatives and 2-alkyl-1,4-naphtoquinones from 2-acylaryl propargyl ethers. It was found that 3-alkyl-1-benzoxepin-5(2H)-ones of type B can be synthesized by treating 2-acylaryl propargyl ethers of type A with sodium methylsulfinyl methide (NaMSM, dimesyl sodium) (Scheme 13). Oxepinone derivatives of type B undergo ring contraction with base (also NaMSM) to yield the quinol derivatives C which, oxidize (during work-up), if R² = H, to the 1,4-naphthoquinones D (Scheme 13). The propargyl ethers used are listed in Scheme 1. The naphthalene derivatives 1 and 3 give oxepinones (E- 9 and a mixture of 14/15 respectively), whereas the expected oxepinone from 2 is transformed directly into the quinone 11 (Scheme 2, 3 and 5). Isomerizations of 2-acetylphenyl propargyl ethers ( 4, 5 and 6 ) (Schemes 6, 7 and 8) are less successful because of side reactions. If however the acetyl group is replaced by a propionyl or substituted propionyl group (as in ethers 7 and 8 ) oxepinones are obtained again in good yield (Scheme 9). The mechanistic pathway for the transformation of naphthyl propargyl ethers (and phenyl derivatives) under influence of NaMSM is shown in Scheme 10. The base-catalysed conversion of 4-phenyl-l-benzoxepin-5(2H)-one,benzo[f]furo[2,3-c](10 H)-oxepin-4-oncsand 3-methoxy-G,11- dihydro-dibenzo[b, e]loxepin-11-oneinto thc corresponding quinones has been reported [13] [20] [21]. The conversion of 2-acylaryl propargyl others via the isolable benzoxepin-5-one derivativcs or directly into the specifically substituted 1,4-naphthoquinone derivatives is of synthetic interest.     

Structurally characterized hetero-oligopolyphenylenes: synthetic advances toward next-generation heterosuperbenzenes

The successful Diels-Alder [2+4] cycloaddition of dipyrimidyl acetylene and suitably substituted 2,3,4,5-tetraarylcyclopenta-2,4-dien-1-ones (3-7) generates a series of selectively functionalized hexaarylbenzenes. Each has two pairs of peripheral functional groups (R' and R=tert-butyl 8 and R=methyl 9, methoxy 10, bromo 11, triisopropylsilylethynyl 12) and four ortho-imine nitrogen atoms. The dibromo derivative 11 is a useful precursor for the formation of a mono ethynyl 13 and diethynyl 14 substituted polyphenylene. Changing the dienophile to di(2-thienyl)acetylene gives an S-heteroatom polyphenylene 15. The compounds were fully characterized by using (1)H, (13)C and a range of 2 D NMR spectroscopic techniques, elemental analysis, and mass spectrometry. Oxidative cyclodehydrogenation of dimethoxy hexaphenylbenzene 10 by using iron(III) chloride results in the formation of a spirocyclic dienone 16, which in a separate reaction undergoes dienone/phenol rearrangement to give the first 4-fused-ring, N-heterosuperbenzene (HSB) 17. Six single crystal molecular structures reveal the commonality of unidirectional twisting of the external aromatic rings in these heteroatom polyphenylenes. The twist angles and any H-bonding or interdigitation in these structures are discussed.