Steroide und Sexualhormone. 261. Mitteilung. Quassinoide Bitterstoffe II. Partialsynthetischer Zugang zu Quassin: Überführung von Testosteron in eine Schlüsselverbindung mit angulärer 8β-Methylgruppe

Partial Synthesis of Quassin: Synthesis of a Key Intermediate with an Angular 8β-Methyl Group from Testosterone A key intermediate in the partial synthesis of quassin ( 1 ) was synthesized in 28 steps starting from testosterone ( 9 ) (Scheme 3). The key features are: (i) The conversion of testosterone ( 9 ) into the 1α, 2β, 3β-O-substituted 4α-methylandrostane 19 (Scheme 3) and its transformation into an intermediate 26 with the ring A partial structure of quassin (Scheme 4). (ii) The conversion of 19 to the vinylogous α-hydroxyketone 5 (Scheme 6 and 7). (iii) The photochemically induced [2+2]-cycloaddition of allene to hydroxyenone 5 , affording the 8β, 14β-cyclobutano-derivative 6 (Scheme 2 and 8). (iv) The conversion of 6 into the key compound 7 . In connection with this last transformation a new method for the degradation of phenylselenoesters of carboxylic acids to the corresponding nor-alkanes was developed (see Scheme 8). Details of this reaction will be published elsewhere [18].     

Transamidation reactions. Part 11. N-substituted 3-aminopropanenitriles and 2-aminoacetonitriles as Schiff-base equivalents

In presence of a strong base, the 13-membered cyclic compound 3 yielded, by loss of acetonitrile or its equivalent, the bicyclic product 5 instead of the 17-membered compound 4 as expected (Scheme 2). Investigation of model compounds (Scheme 4) and of model reactions (Schemes 5 and 6) led to the conclusion that the reaction proceeds via an intermediate formaldehyde imine; a Schiff base, e.g. 3b (Scheme 5), which reacts intra- and intermolecularly with a nucleophile to form a Mannich-type product. It seems to be a general principle that N-substituted 3-aminopropanenitrile and 2-aminoacetonitrile derivatives behave in the presence of a strong base as Schiff -base equivalents (Schemes 5 and 6).     

The Chemistry of Thujone. Part XIV.. Synthesis of biologically active aryl terpenoid analogues

Employing thujone-derived intermediates, a series of achiral ( 9a–d ; Scheme 1) and chiral ( 11b and 11d; Scheme 2) terpene analogues related to the biologically active ‘terpenoid’ hybrids have been prepared. The stereochemistry of the key epoxidation reaction was established by correlation of the product 11b with the previously reported alcohol (R)- 20 of known absolute configuration (Scheme 3).     

Experiments on the total synthesis of Lysolipin I. Part III. Preparation and transformations of substituted 1,2,3,4-Tetrahydrodibenzofuran-1-ones

1,2,3,4-Tetrahydrodibenzofuran-1-ones were obtained by Michael addition of 1,3-cyclohexadione ( 2 ) to o-benzoquinone ( 3 ) and to p-benzoquinones 8 and 11 (Scheme 2). In addition to the expected 7,8-disubstituted adduct 14 , the ZnCl₂-catalyzed reaction of dione 2 with methoxy-p-benzoquinone ( 11 ) afforded a small amount of the 6,8-disubstituted regio-isomer 13 (Scheme 2). The projected cleavage of these dibenzofuranones to 3-methoxy-2-phenyl-2-cyclohexenone 22 could be effected by treatment with NaOH followed by methylation (Scheme 3). Attempted acetalization of such dibenzofuranones resulted in a retro-Claisen-type cleavage, giving the benzofuryl-butyrate 16 . Other transformations include reduction of the ketone, of the C(4a)=C(9b) bond, and alkylation with Li-ethoxyacetylide (Scheme 3). Oxidation of 8-hydroxy-7-mehoxydibenzofuran derivatives led to o-quinones instead of the desired ring cleavage to p-quinones (Scheme 4).     

Synthese und Reaktionen 8-gliedriger Heterocyclen aus 3-Dimethylamino-2,2-dimethyl-2H-azirin und Saccharin bzw. Phthalimid

Synthesis and Reactions of 8-membered Heterocycles from 3-Dimethylamino-2,2-dimethyl-2H-azirine and Saccharin or Phthalimide 3-Dimethylamino-2,2-dimethyl-2H-azirine ( 1 ) reacts at 0-20° with the NH-acidic compounds saccharin ( 2 ) and phthalimide ( 8 ) to give the 8-membered heterocycles 3-dimethylamino-4,4-dimethyl-5,6-dihydro-4 H-1,2,5-benzothiadiazocin-6-one-1,1-dioxide ( 3a ) and 4-dimethylamino-3,3-dimethyl-1,2,3,6-tetrahydro-2,5-benzodiazocin-1,6-dione ( 9 ), respectively. The structure of 3a has been established by X-ray (chap. 2). A possible mechanism for the formation of 3a and 9 is given in Schemes 1 and 4. Reduction of 3a with sodium borohydride yields the 2-sulfamoylbenzamide derivative 4 (Scheme 2); in methanolic solution 3a undergoes a rearrangement to give the methyl 2-sulfamoyl-benzoate 5 . The mechanism for this reaction as suggested in Scheme 2 involves a ring contraction/ring opening sequence. Again a ring contraction is postulated to explain the formation of the 4H-imidazole derivative 7 during thermolysis of 3a at 180° (Scheme 3). The 2,5-benzodiazocine derivative 9 rearranges in alcoholic solvents to 2-(5′-dimethylamino-4′,4′-dimethyl-4′H-imidazol-2′-yl) benzoates ( 10 , 11 ), in water to the corresponding benzoic acid 12 , and in alcoholic solutions containing dimethylamine or pyrrolidine to the benzamides 13 and 14 , respectively (Scheme 5). The reaction with amines takes place only in very polar solvents like alcohols or formamide, but not in acetonitrile. Possible mechanisms of these rearrangements are given in Scheme 5. Sodium borohydride reduction of 9 in 2-propanol yields 2-(5′-dimethylamino-4′,4′-dimethyl-4′H-imidazol-2′-yl)benzyl alcohol ( 15 , Scheme 6) which is easily converted to the O-acetate 16 . Hydrolysis of 15 with 3N HCl at 50° leads to an imidazolinone derivative 17a or 17b , whereas hydrolysis with 1N NaOH yields a mixture of phthalide ( 18 ) and 2-hydroxymethyl-benzoic acid ( 19 , Scheme 6). The zwitterionic compound 20 (Scheme 7) results from the hydrolysis of the phthalimide-adduct 9 or the esters 11 and 12 . Interestingly, compound 9 is thermally converted to the amide 13 and N-(1′-carbamoyl-1′-methylethyl)phthalimide ( 21 , Scheme 7) whose structure has been established by an independent synthesis starting with phthalic anhydride and 2-amino-isobutyric acid. However, the reaction mechanism is not clear at this stage.     

Photochemische Reaktionen. 93. Mitteilung. Zur Photochemie konjugierter Epoxy-inone: Die UV.-Bestrahlung von 5,6-Epoxy-5-isopropyl-6-methyl-hept-3-in-2-on

The Photochemistry of Conjugated Epoxy-Inones: Photolysis of 5,6-Epoxy-5-isopropyl-6-methyl-hept-3-in-2-on This paper continues the series of investigations of the photochemistry of α,β-unsaturated γ,δ-epoxyketones by examining the hitherto unknown photochemical behaviour of α,β-acetylenic-γ,δ-epoxy-ketones. As model compound, the aliphatic epoxy-ynone 7 (thermally stable at 180°) was synthesized (Scheme 1). It can be converted with BF₃O (C₂H₅)₂ in good yields to the 1,5-diketone 8 , the yne-1,4-diketone 49 and in small amounts to the fluorhydrine 50 (Scheme 1). On n,π*- or π, π*-excitation, 7 shows mainly cleavage of the C (γ)-O-bond to give a diradical a (Scheme 11), whose ultimate fate is strongly solvent dependent. In acetonitrile a mainly rearranges to the 1,5-diketone 8 and, to a smaller extent, shows fragmentation to acetone and formation of polymers. Except for small amounts of the dimeric products 9A,9B and biphenyl, the same compounds are obtained in benzene. In cyclopentane, however, a gives only little of 8 , and mainly a plethora of compounds formed by a radical process like H-abstraction from solvent, incorporation of cyclopentylradicals, dimerization and fragmentation reactions (9A, 9B, 11–20) (Scheme 3). Irradiation of 7 in propan-2-ol or in dioxane yields products of analogous radical processes as well of photoreduction (Scheme 4). However, the analogous epoxyenone 32 gives mainly products of photoisomerizations without interference by the solvent [6]. On photochemical excitation in acetonitrile, the 1,5-diketone 8 shows unspecific decomposition, but in cyclopentane it yields the reduction products 12, 26A, 26B, 27, 28 plus cyclopentylcyclopentane (15) (Scheme 6).     

Glyconothio-O-lactones Part II. Cycloaddition to Dienes,Diazomethane, and Carbenoids

The addition of dienes, diazomethane, and carbenoids to the manno- and ribo-configurated thio-γ-O-lactones 1 and 2 was investigated. Thus, 1 (Scheme 1) reacted with 2,3-dimethylbutadiene (→ 4 , 73%), cyclopentadiene (→ 5a/b 1:1, 70%), cyclohexa- 1,3-diene (→ 9a/b 2:3, 92%), and the electron-rich butadiene 6 (→ 7a/b 3:1, 82%). Wheras 5a/b was separated by flash chromatography, 7a/b was desilylated leading to the thiapyranone 8 . Selective hydrolysis of one isopropylidene group of 9a/b and flash chromatography gave 10a and 10b . The structures of the adducts were elucidated by X-ray analysis ( 4 ), by NOE experiments ( 4 , 5a , 5b , 7a/b , 10a , and 10b ), and on the basis of a homoallylic coupling ( 7a/b ). The additions occurred selectively from the ‘exo’ -side of 1 . Only a weak preference for the ‘endo’-adducts was observed. Hydrogenation of 9a/b with Raney-Ni (EtOH, room temperature) gave the thiabicyclo [2.2.2]octane 11 . Under harsher conditions (dioxane, 110°), 9a/b was reduced to the cyclohexyl ß-D C-glycoside 12 which was deprotected to 13 . X-Ray analysis of 13 proved that the desulfuration occurred with inversion of the anomeric configuration. The regioselective addition of the dihydropyridine 14 to 1 (Scheme 2) and the methanolysis of the crude adduct 15 gave the lactams 16a (32%) and 16b (38%). Desilylation of 15 with Bu₄NF · 3H₂O, however, gave the unsaturated piperidinedione 17 (92%) which was deprotected to the tetrol 18 (65%). Similarly, 2 was transformed via 19 (62%) into the triol 20 (74%). The cycloaddition of 1 with CH₂N₂ (Scheme 3) gave a 35:65 mixture of the 2,5-dihydro- 1,3,4-triazole 21 and the crystalline 4,5-dihydro 1,2,3-triazole 22 . Treatment of 21 and 22 with base gave the hydroxytriazoles 23 and 24 , respectively. The structure of 24 was established by X-ray analysis. The triazole mixture 21/22 was separated by prep. HPLC at 5°. At room temperature, 21 already decomposed (half-life 21.6 h) leading in CDCI₃ solution to a complex mixture (containing ca. 20–25% of the spirothiirane 27 and ca. 7–10% of its anomer) and in MeOH solution exclusively to the O,O,S-ortholactone 26 . Crystals of 22 proved be stable at 105°. Upon heating in petroleum ether at 100°, 22 was transformed into a ca. 1:1 mixture of 27 and the enol ether 28 . The reaction of 1 with ethyl diazoacetate (Scheme 4) in the presence of Rh₂(OAc)₄. 2H₂O gave the unsaturated esters 29 (33%) and 30 (26%), whereas the analogous reaction with diethyl diazomalonate afforded the spirothiirane 31 (68%) and the enol ether 32 (29%). Complete transformation of 31 into 32 was achieved by the treatment with P(NEt₂)₃. Similary, 33 (69%) was prepared from 2 .     

Reaktion von 3-Amino-2H-azirinen mit Diphenylcyclopropenthion. Vorläufige Mitteilung

Reaction of 3-Amino-2H-azirines with Diphenylcyclopropenethione 3-Dimethylamino-2H-azirines ( 4a , 4b ) react with diphenylcyclopropenethione ( 8 ) to give 4(3 H)-pyridinethione derivatives of type 10 (Scheme 3). The reaction mechanism for the formation of 10 is given in Scheme 3 by analogy with a previous reported one [4] [5]. Hydrolysis of the 4(3 H)-pyridinethione 10a yields 2-oxo-2, 3-dihydro-4(1 H)-pyridinethione ( 11 ) and reduction of 10a with sodium borohydride leads to the 2, 3-dihydro-4 (1 H)-pyridinethione 12 (Scheme 4). The results of the reaction of 4a , 4b and the thione 8 demonstrate the similarity to the reaction of 4a , 4b and 2 [5] (cf. Scheme 1). In contrast, the reactions of imines of type 7a with 2 and 8 , respectively, lead to different products (cf. [1] [6]).     

7‐Halogenated 7‐Deazapurine 2′‐Deoxyribonucleosides Related to 2′‐Deoxyadenosine, 2′‐Deoxyxanthosine,and 2′‐Deoxyisoguanosine: Syntheses and Properties

A series of 7‐fluorinated 7‐deazapurine 2′‐deoxyribonucleosides related to 2′‐deoxyadenosine, 2′‐deoxyxanthosine, and 2′‐deoxyisoguanosine as well as intermediates 4b – 7b, 8, 9b, 10b , and 17b were synthesized. The 7‐fluoro substituent was introduced in 2,6‐dichloro‐7‐deaza‐9H‐purine ( 11a ) with Selectfluor (Scheme 1). Apart from 2,6‐dichloro‐7‐fluoro‐7‐deaza‐9H‐purine ( 11b ), the 7‐chloro compound 11c was formed as by‐product. The mixture 11b / 11c was used for the glycosylation reaction; the separation of the 7‐fluoro from the 7‐chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N‐halogenosuccinimides ( 11a → 11c – 11e ). Nucleobase‐anion glycosylation afforded the nucleoside intermediates 13a – 13e (Scheme 2). The 7‐fluoro‐ and the 7‐chloro‐7‐deaza‐2′‐deoxyxanthosines, 5b and 5c , respectively, were obtained from the corresponding MeO compounds 17b and 17c , or 18 (Scheme 6). The 2′‐deoxyisoguanosine derivative 4b was prepared from 2‐chloro‐7‐fluoro‐7‐deaza‐2′‐deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pK_a values of the halogenated nucleosides were determined (Table 3). ¹³C‐NMR Chemical‐shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7‐halogen substituents (Fig. 3). In aqueous solution, 7‐halogenated 2′‐deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).     

Synthesis and Structure of Carbonyliron Complexes of Allenecarboxylates and Allenic Lactones

On irradiation in the presence of Fe(CO)₅, the allenecarboxylates 1 afforded binuclear carbonyliron complexex 6 (Scheme 3), whereas the allenic lactone 7 under similar conditions gave a mixture of one binuclear and two mononuclear carbonyliron complexes ( 9 , 8 , and 10 ; Scheme 4). The structure of the complexes has been elucidated by X-ray crystallography. The structure of the binuclear complex 9 corresponds to that of 6 , while 8 has been shown to be a 1,3-butadiene(tricabonyl)iron complex. The unique structure of the 10 represents a new type of allenic complex. A stepwise formation of the complexes via intermediate allene(tetracarbonyl) iron complexes type 11 and 13 is suggested. Treatment of the binuclear complex 6b with FeCl₃ led to the formation of the free ligand and a mixture of mononuclear complexes 13 and 14 (Scheme 5). On heating, the 1,3-diene complex 8 yielded the free ligand 15 , the prouduct of a (1,3) H shift in the allene 7 ; the complex 10 on the other hand liberates 7 on treatment with ethylenetracarbonitrile (TCNE) (Scheme 6).     

Synthesis of Esters of 3-(2-Aminoethyl)-1H-indole-2-acetic Acid and 3-(2-aminoethyl)-1H-indole-2-malonic acid (= 2-[3-(2-aminoethyl)-1H-indol-2-yl]propanedioic acid) 4th communication on indoles,indolenines, and indolines

Alkyl 3-(2-aminoethyl)-1H-indole-2-acetates 6a and 6b are synthesized starting from methyl 1H-indole-2-acetate (2) via methyl 3-(2-nitroethenyl)-1H-indole-2-acetate (4) and the alkyl 3-(2-nitroethyl)-1H-indole-2-acetates 5a and (Scheme 1). Analogously, diisopropyl 3-(2-aminoethyl)-1H-indole-2-malonate 20b is obtained from diisopropyl 1H-indole-2-malonate 11c (Scheme 4). An alternative synthesis of 20a and 20b follows a route via 15–18 and the dialkyl 3-(2-azidoethyl)-1H-indole-2-malonates 19a and 19b , respectively (Scheme 3). The aminoethyl compounds 6a and 20a are easily transformed into lactams 7 and 21 , respectively. Procedures for the preparation of the indoles 2 and 11a and of the alkylating agent 14 are described. A tautomer 12 of 11a is isolated.     

Photocyclisierungen von 1, 1'-Polymethylen-di-2-pyridonen. 46. Mitteilung über Photoreaktionen

Photocyclization of 1, 1′-Polymethylene-di-2-pyridones . Benzophenone sensitized irradiation of the four dipyridones 1-4 gave the internal photocyclization products 6 (64%, Scheme 4), 7 (60%, Scheme 5), 8 (Scheme 6), and 11 (26%, Scheme 7), respectively. The decamethylene compound 5 yielded only polymeric material. The primary [2+2] photoproduct 8 from dipyridone 3 (Scheme 6) is relatively unstable. Further irradiation or heating to 65° induced a Cope rearrangement to give compound 9 which, on heating to 137°, was converted into the isomeric compound 10 . This product, as well as the other photoproducts mentioned, are rearranged back to their respective starting materials upon direct irradiation with 254 nm light or by heating to higher temperatures. The various possibilities for cycloadditions of pyridones are discussed as well as the possible factors which are responsible for the highly regioselective photoreactions of the dipyridones 1–4 .     

Nucleotides. Part LXXVIII

Several N(‐hydroxyalkyl)‐2,4‐dinitroanilines were transformed into their phosphoramidites (see 5 and 6 in Scheme 1) in view of their use as fluorescence quenchers, and modified 2‐aminobenzamides (see 9, 10, 18 , and 19 in Scheme 1) were applied in model reactions as fluorophors to determine the relative fluorescence quantum yields of the 3′‐Aba and 5′‐Dnp‐3′‐Aba conjugates (Aba=aminobenzamide, Dnp=dinitroaniline). Thymidine was alkylated with N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to give 25 which was further modified to the building blocks 27 and 28 (Scheme 3). The 2‐amino group in 29 was transformed by diazotation into the 2‐fluoroinosine derivative 30 used as starting material for several reactions at the pyrimidine nucleus (→ 31, 33 , and 35 ; Scheme 4). The 3′,5′‐di‐O‐acetyl‐2′‐deoxy‐N²‐[(dimethylamino)methylene]guanosine ( 37 ) was alkylated with methyl and ethyl iodide preferentially at N(1) to 43 and 44 , and similarly reacted N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to 38 and the N‐(2‐iodoethyl)‐N‐methyl analog 50 to 53 (Scheme 5). The 2′‐deoxyguanosine derivative 53 was transformed into 3′,5′‐di‐O‐acetyl‐2‐fluoro‐1‐{2‐[(2,4‐dinitrophenyl)methylamino]ethyl}inosine ( 54 ; Scheme 5) which reacted with 2,2′‐[ethane‐1,2‐diylbis(oxy)]bis[ethanamine] to modify the 2‐position with an amino spacer resulting in 56 (Scheme 6). Attachment of the fluorescein moiety 55 at 56 via a urea linkage led to the doubly labeled 2′‐deoxyguanosine derivative 57 (Scheme 6). Dimethoxytritylation to 58 and further reaction to the 3′‐succinate 59 and 3′‐phosphoramidite 60 afforded the common building blocks for the oligonucleotide synthesis (Scheme 6). Similarly, 30 reacted with N‐(2‐aminoethyl)‐2,4‐dinitroaniline ( 61 ) thus attaching the quencher at the 2‐position to yield 62 (Scheme 7). The amino spacer was again attached at the same site via a urea bridge to form 64 . The labeling of 64 with the fluorescein derivative 55 was straigthforward giving 65 . and dimethoxytritylation to 66 and further phosphitylation to 67 followed known procedures (Scheme 7). Several oligo‐2′‐deoxynucleotides containing the doubly labeled 2′‐deoxyguanosines at various positions of the chain were formed in a DNA synthesizer, and their fluorescence properties and the T_ms in comparison to their parent duplexes were measured (Tables 1–5).     

Zur Photochemie von 2, 1-Benzisoxazolen (Anthranilen) und thermischen und photochemischen Umsetzungen von 2-Azido-acylbenzolen in stark saurer Lösung

On the Photochemistry of 2, 1-Benzisoxazoles (Anthraniles) and on the Thermal and Photochemical Decomposition of 2-Azido-acylbenzenes in Strongly Acidic Solution Anthranils 6 (Scheme 3), when irradiated with a mercury high-pressure lamp, in 96% sulfuric acid yielded, after work-up, 2-amino-5-hydroxy-acylbenzenes 8 and as side products 2-amino-3-hydroxy-acylbenzenes 9 (cf. Schemes 5–7 and Table 1). When C(5) of the anthranils 6 carries a methyl group a more complex reaction mixture is found after irradiation in 96% sulfuric acid (cf. Schemes 8 and 9): 3, 5-dimethyl-anthranil ( 6d ) yielded (after irradiation and acetylation) 2-acetyl- amino-5-methyl-acetophenone ( 15 ), 2-acetylamino-5-acetoxymethyl-acetophenone ( 18d ) and 2-acetylamino-5-acetoxy-6-methyl-acetophenone ( 12c ). The latter product was also formed after irradiation of 3, 4-dimethylanthranil ( 6c ) in 96% sulfuric acid. 3, 5, 7-Trimethyl-anthranil ( 6f ) formed under the same conditions 2-acetylamino-3, 5-dimethyl-acetophenone ( 15f ) and 2-acetylamino-5-acetoxymethyl-3-methyl-acetophenone ( 18f ). Since qualitatively the same product patterns were observed when the corresponding 2-azido-acetophenones 7 were decomposed in 96% sulfuric acid it is concluded that anthranilium ions (cf. 6b -H⊕, Scheme 11) on irradiation are transformed by cleavage of the N, O-bond into 2-acyl-phenylnitrenium ions (cf. 25b -H⊕) in the singlet ground state. The nitrenium ions are trapped directly by nucleophiles ( HSO ?₄ in 96% sulfuric acid), thus, yielding the hydroxy-acetophenones 8 and 9 (Scheme 11). If C(5) is blocked by a methyl group a [1, 2]-rearrangement of the methyl group may occur (cf. Scheme 13) or loss of sulfuric acid can lead to quinomethane iminium ions (cf. 32-H⊕ , Scheme 13) which will react with HSO ?₄ ions to yield, after hydrolysis and acetylation, the 5-acetoxymethyl substituted acetophenones 18d and 18f . It is assumed that the reduction products (2-acetylamino-acetophenones 15 ) are formed from the corresponding nitrenium ions in the triplet ground state.     

Thermal and Photochemical Reactions of 1,2-Annelated Barrelenes and Hydrobarrelenes in the presence of transition-metal carbonyls

The [Co₂(CO)₈]-mediated retro-Diels-Alder reaction of the annelated barrelenes 1 afforded the 1H-indol-2(3H)-one derivatives 3 (Scheme 1), while the hydrobarrelene 4a , under the same conditions, was converted to the anilide 6 (Scheme 2); 4b remained unaffected. The direct irradiation of 1 led to the annelated cyclooctatetraenes 7 (Scheme 3). On irradiation in the presence of excess of [Fe(CO)₅], 1a , 1b , and 4a gave the tricarbonyliron complexes 8 , 9 , and 11 , respectively (Schemes 3 and 4); under these conditions, 4b was inert.     

Über die Stereoselektivität der α-Alkylierung von (1R, 2S) (+)-cis-2-hydroxy-cyclohexancarbonsäureäthylester

The Stereoselectivity of the α-Alkylation of (+)-(1R, 2S)-cis-Ethyl-2-hydroxy-cyclohexanecarboxylate In continuation of our work on the stereoselectivity of the α-alkylation of β-hydroxyesters [1] [2], we studied this reaction with the title compound (+)- 2 . The latter was prepared through reduction of 1 with baker's yeast. Alkylation of the dianion of (+)- 2 furnished (?)- 4 in 72% chemical yield (Scheme 1) and with a stereoselectivity of 95%. Analogously, (?)- 7 was prepared with similar yields. Oxidation of (?)- 4 and (?)- 7 respectively furnished the ketones (?)- 6 (Scheme 3) and (?)- 8 (Scheme 4) respectively, each with about 76% enantiomeric excess (NMR.). It is noteworthy that yeast reduction of rac- 6 (Scheme 3) is completely enantioselective with respect to substrate and product and gives optically pure (?)- 4 in 10% yield, which was converted into optically pure (?)- 6 (Scheme 3). The alkylation of the dianionic intermediate shows a higher stereoselectivity (95%) from the pseudoequatorial side than that of 1-acetyl- or 1-cyano-4-t-butyl-cyclohexane (71% and 85%) [9] or that of ethyl 2-methyl-cyclohexanecarboxylate (82%). The stereochemical outcome of the above alkylation is comparable with that found in open chain examples [1] [2]. Finally (+)-(1R, 2S)- 2 was also alkylated with Wichterle's reagent to give (?)-(1S, 2S)- 9 in 64% yield. The latter was transformed into (?)-(S)- 10 and further into (?)-(S)- 11 (Scheme 5). (?)-(S)- 10 and (?)-(S)- 11 showed an e.e. of 76–78% (see also [11]). Comparison of these results with those in [11] confirmed our former stereochemical assignment concerning the alkylation step.     

Stereoselektive Synthesen von (Z)-(10-Methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yliden)essigsäure

Stereoselective Syntheses of (Z)-(10-Methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)acetic Acid Two stereoselective syntheses for the antiinflammatory compound 1 ((Z)-isomer) are described. In the first approach (Strategy A, Scheme 1) the stereoselective synthesis of 1 was realized via the bicyclic compound 11 under thermodynamic conditions, followed by a thiophene annelation with retention of the double-bond geometry (Schemes 2–4). Optimized conditions were necessary to avoid (E/Z)-isomerization during annelation. In the second approach (Strategy B, Scheme 1), diastereoisomer 17b was obtained selectively from a mixture of the diastereoisomers 17b and 18b by combining thermodynamic epimerization and solubility differences (Scheme 5). Diastereoisomer 17b was converted into the tricyclic compound 23 using a novel thiophene annelation method which we described recently (Scheme 6). In a final step, a stereospecific ‘syn’-elimination transformed the sulfoxide 24 into the target compound 1 (Scheme 7). To avoid (E/Z)-isomerization, it was necessary to trap the sulfenic acid liberated during the reaction. The key reactions of both approaches are highly stereoselective (> 97:3).     

Nucleophilic Addition to C,C Double Bonds. Proximity and homoconjugative effects. Preliminary communication

Proximity effects alone as well as in combination with electronic effects are responsible for the observed phenomenon of base-catalyzed ether formation initiated by nucleophilic attack on a C, C double bond of the tricyclic olefin alcohols 1–10 (Scheme 1, Table 1). With compounds 1–4 , bearing a keto group, formation of the ethers 11–14 proceeds through a corresponding homoenolate b (Scheme 2) as an intermediate. In one case such a species could be trapped as the methyl ether 21 (Scheme 3). Special attention is given to the stereochemical course of the homoketonization. Ring opening in 21 under acidic conditions occurs regioselectively, however non-stereoselectively (Scheme 3). Full regio- and stereoselectivity (retention) is observed under basic conditions starting from the unsaturated keto alcohols 1 and 2 (Scheme 4) as well as from the keto ethers 11 and 12 (Scheme 5, Table 2).     

Pteridines. Part CXVII

A series of side chain reactions starting from the 6‐ and 7‐styryl‐substituted 1,3‐dimethyllumazines 1 and 21 as well as from the 6‐ and 7‐[2‐(methoxycarbonyl)ethenyl]‐substituted 1,3‐dimethyllumazine 2 and 22 were performed first by addition of Br₂ to the C?C bond forming the 1′,2′‐dibromo derivatives 3, 4, 24 , and 26 in high yields (Schemes 1 and 3) (lumazine=pteridine‐2,4(1H,3H)‐dione). Treatment of 3 with various nucleophiles gave rise to an unexpected tele‐substitution in 7‐position and elimination of the Br‐atoms generating 7‐alkoxy‐ (see 5 and 6 ), 7‐hydroxy‐ (see 7 ) and 7‐amino‐6‐styryl‐1,3‐dimethyllumazines (see 8 – 11 ) (Scheme 1). On the other hand, 4 underwent, with dilute DBU (1,8‐diazabicyclo[5.4.0]undec‐2‐ene), a normal HBr elimination in the side chain leading to 18 , whereas treatment with MeONa afforded a more severe structural change to 19 . Similarly, 24 and 26 reacted to 27, 32 , and 33 under mild conditions, whereas in boiling NaOMe/MeOH, 24 gave 7‐(2‐dimethoxy‐2‐phenylethyl)‐1,3‐dimethyllumazine ( 30 ) which was hydrolyzed to give 31 (Scheme 3). From the reactions of 4 and 24 with DBU resulted the dark violet substance 20 and 25 , respectively, in which DBU was added to the side chain (Scheme 2). The styryl derivatives 1 and 21 could be converted, by a Sharpless dihydroxylation reaction, into the corresponding stereoisomeric 6‐ and 7‐(1,2‐dihydroxy‐2‐phenylethyl)‐1,3‐dimethyllumazines 34 – 37 (Scheme 4). The dihydroxy compounds 34 and 35 were also acetylated to 38 and 39 which, on catalytic reduction followed by formylation, yielded the diastereoisomer mixtures 40 and 41 . Deacetylation to 42 and 45 allowed the chromatographic separation of the diastereoisomers resulting in the isolation of 43 and 44 as well as 46 and 47 , respectively. Introduction of a 6‐ or 7‐ethynyl side chains proceeded well by a Sonogashira reaction with 6‐ ( 48 ) or 7‐chloro‐1,3‐dimethyllumazine ( 55 ) yielding 49 – 51 and 56 – 58 (Scheme 5). The direction of H₂O addition to the triple bond is depending on the substituents since the 6‐ ( 49 ) and 7‐(phenylethynyl)‐1,3‐dimethyllumazine ( 56 ) showed attack at the 2′‐position yielding 53 and 60 , in contrast to the 6‐ ( 51 ) and 7‐ethynyl‐1,3‐dimethyllumazine ( 58 ) favoring attack at C(1′) and formation of 6‐ ( 52 ) and 7‐acetyl‐1,3‐dimethyllumazine ( 59 ).     

Synthese von Trifluoromethyl-substituierten Schwefel-Heterocyclen unter Verwendung von 3,3,3-Trifluorobrenztraubensäure-Derivaten

Synthesis of Trifluoromethyl-Substituted Sulfur Heterocycles Using 3,3,3-Trifluoropyruvic-Acid Derivatives The reaction of methyl 3,3,3-trifluoropyruvate ( 1 ) with 2,5-dihydro-1,3,4-thiadiazoles 4a, b in benzene at 45° yielded the corresponding methyl 5-(trifluoromethyl)-1,3-oxathiolane-5-carboxylates 5a, b (Scheme 1) via a regioselective 1,3-dipolar cycloaddition of an intermediate ‘thiocarbonyl ylide’ of type 3 . With methyl pyruvate, 4a reacted similarly to give 6 in good yield. Methyl 2-diazo-3,3,3-trifluoropropanoate ( 2 ) and thiobenzophenone ( 7a ) in toluene underwent a reaction at 50°; the only product detected in the reaction mixture was thiirane 8a (Scheme 2). With the less reactive thiocarbonyl compounds 9H-xanthene-9-thione ( 7b ) and 9H-thioxanthene-9-thione ( 7c ) as well as with 1,3-thiazole-5(4H)-thione 12 , diazo compound 2 reacted only in the presence of catalytic amounts of Rh₂(OAc)₄. In the cases of 7a and 7b , thiiranes 8b and 8c , respectively, were the sole products (Scheme 3). The crystal struture of 8c has been established by X-ray crystallography (Fig.). In the reaction with 12 , desulfurization of the primarily formed thiirane 14 gave the methyl 3,3,3-trifluoro-2-(4,5-dihydro-1,3-thiazol-5-ylidene)propanoates (E)-and (Z)- 15 (Scheme 4). A mechanism of the Rh-catalyzed reaction via a carbene addition to the thiocarbonyl S-atom is proposed in Scheme 5.