17α-Konfigurierte 20-methylpregnan-derivate

A mixture of 1a+1b (17α), obtained by C-17-epimerization of pregnenolone (1a) was converted into 3a+3b by Wittig-reaction. 3a+3b were acetylated to a mixture of 4a+4b, from which 4b was isolated by cristallization of 3a and following AgNO₃-chromatography of the mother-liquors. Δ²⁰⁽²²⁾ → Δ¹⁷-doublebond-isomerization occurs by hydrogenation (Pd/C) of 3a (17β) to give 5. Hydrogenation (Pt-catalyst) of 4b (17α) leads to 8b, which was converted into the 20-methylpregnane-derivatives 7b, 9b–13b. By comparison with the 17β epimers 1a–4a, 7a–13a a spectroscopic determination of the relative configuration on C-17 of 17-alkylsubstituted steroids was possible.     

One-pot synthesis of multisubstituted quaterphenyls and cyclopropanes

An efficient one-step synthetic route toward multifunctionalized quaterphenyls 3 or cyclopropanes 4 is developed from substituted chalcones 1 and sulfones 2 in good yields via a regioselective [3C+3C] or [1C+2C] annulation. The reaction features mild conditions, multisubstitution, and functional groups tolerance and is transition metal catalyst-free. The protocol provides a novel alternative to the conventional methodologies for the synthesis of quaterphenyls or cyclopropanes.     

Total synthesis and stereochemistry of 13-hydroxy-α-eudesmol

The first total synthesis of both C-11 epimers of 13-hydroxy-α-eudesmol 1a and 1b by the use, as a key reaction, of the Sharpless asymmetric dihydroxylation of alkene 7 is presented. The absolute configuration of natural 13-hydroxy-α-eudesmol is established through comparison of the ¹H NMR spectrum of natural diol and synthetic diols. In our synthesis another natural product (+)-α-selinene 2 has also been accomplished.     

Enantioselective total syntheses of kudtriol, 5-epi-kudtriol and their C-11 epimers

Two approaches for the enantioselective syntheses of naturally occurring kudtriol 2a and 5-epi-kudtriol 3a as well as their C-11 epimers are presented, both using the Sharpless asymmetric dihydroxylation as the key reaction. Through comparison of the spectral data of natural triols and synthetic samples, we could confirm the absolute configuration of the natural triols.     

Novel thiosemicarbazone derivatives containing benzimidazole moiety: Green synthesis and anti-malarial activity

A series of (E)-2-[5-chloro-1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (7a–7t) and (E)-2-[1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (8a–8t) were prepared via the synthesis of 1-(substituted-1H-benzimidazol-2-yl) ethanol (3a–3b) which was synthesized by the condensation of substituted o-phenylenediamine (2a–2b) with dl-lactic acid (1) followed by oxidation with sodium hypochlorite in mild acidic condition to form the corresponding ketones 4a–4b. Final compounds were formed by condensation of 4a–4b with different thiosemicarbazides 6a–6t. A total of 40 compounds were synthesized and characterized by FT-IR, ¹H NMR, ¹³C NMR, Mass spectral technique and elemental analysis, in addition they were evaluated for anti-malarial properties. Among the compounds tested 7o, 7p, 7q, 7r, 7s, 8e and 8h exhibited good antimalarial activity in vitro.     

Synthesis and application of an efficient calix[4]arene-based anion receptor bearing imidazole groups for Cr(VI) anionic species

We synthesized the new calix[4]arene amines bearing two and four imidazole or tert-butylamine moieties (9a,b/10a,b) by the reaction of di- or tetra-tosylated calix[4]arene derivatives (7 and 8, respectively) with 1-(3-aminopropyl)imidazole and/or tert-butylamine, respectively. After the characterization of 9a,b/10a,b their extraction abilities toward Cr(VI) anionic species (CAS) was evaluated and compared by the liquid–liquid extraction method. The extraction results revealed that calix[4]arene amine having four imidazole groups (10a) was an efficient anion receptor for CAS. Moreover, the extraction of CAS by 10a in the presence of other anions such as Cl^?, NO₃^?, and PO₄^3? showed that 10a could be a selective anion receptor for CAS in the presence of those anions.     

Structures des virescenosides F et G,nouveaux metabolites de Oospora virescens (Link) Wallr.

Several glycosides (virescenosides) have been isolated from Oospora virescens (Link) Wallr. Virescenosides A, 1a, B, 1b and C, 1c, are β-D-altropyranosides of virescenol A, 2a, B, 2b and C, 2c. Here we describe the isolation of two metabolites, virescenosides F (3a), C₂₆H₄₀O₉, and G (3b), C₂₆H₄₀O₈. They are the first natural glycosides of altruronic acid. Virescenosides F and G readily undergo lactonisation. Two types of lactones have been isolated for which structures 5a, 5b and 7a, 7c are proposed.     

Synthesis of chiral 1- and 2-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-dienes and their behaviour in Diels–Alder cycloadditions

The synthesis of (±)-(E)-1-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 1 and (S_S)-2-(p-tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 2 and their reactions with cyclic dienophiles are described. Cycloaddition of diene 1 with N-methylmaleimide 10 was performed under pressure affording a complex reaction mixture from which two epimers at C-3′, (±)-11a and (±)-11b [2,3,3a,4,5,7a-hexahydro-2-methyl-7a-(1-methylsuccinimide-3-yl)-1H-isoindole-1,3,5-triones], were isolated in equal amounts. Diene (±)-1 cycloadded to the more reactive 4-methyl-1,2,4-triazoline-3,5-dione 14 at atmospheric pressure and room temperature. However, nothing can be said about the stereochemical outcome of this addition since the loss of the chiral auxiliary via the sulfoxide–sulfenate rearrangement gave the bicyclic α,β-unsaturated ketone 17 (2-methyl-2,3,5,6-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1,3,6-trione). Diels–Alder cycloaddition of enantiopure diene 2 with 10 occurred under pressure leading to a diastereomeric mixture of adducts where the trimethylsilyl enol ether moiety spontaneously evolved to the ketone function. The major enantiopure product 18a [(3aS,6S,7aR,R_S)-2-methyl-6-(p-tolylsulfinyl)perhydroisoindole-1,3,5-trione] was isolated and characterized. Cycloadditions of both dienes to dienophile 10 appear highly stereoselective.     

Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.     

Reactions of dispiro[2.0.2.2]oct-7-ene. Electrophilic and free radical additions

Dispiro[2.0.2.2]oct-7-ene 1 was synthesized by debrominatioa of cis- and trans-7,8-dibromodispiro[2.0.2.2]octane 3a with LAH and by dechlorination of cis- and trans-7,8-dichlorodispiro[2.0.2.2]octane 3b with magnesium. Stepwise electrophilic additions to 1 of HBr, HI, Br₂ and Cl₂ were studied. The major products (and yields) from these reactions were: 7-bromodispiro[2.0.2.2]octane 2a (43%), 4-iodo-4,5-ethanospiro[2,3]hexane 4b (ca. 50%); trans-3a (40%); and cis-3b (20%). Free-radical addition of hydrogen bromide to 1 gave an 80% yield of 7-bromodispiro[2.0.2.2]octane 2a. At ?10°, hydroboration-oxidation of 1 was found to give mainly 7-hydroxydispiro[2.0.2.2]octane 2a in ca. 90% yield; at 25°, near equal amounts of 2c and 4-(2-hydroxyethyl) spiro[2.3]hex-4-ene 14 were obtained.     

One-pot synthesis of multifunctionalized cyclopropanes

A facile one-step synthetic protocol toward multifunctionalized cyclopropanes 4 is developed from substituted chalcones 1 and sulfones 2 in good yields via a [2C+1C] annulation.     

Synthesis and circular dichroism of optically active 1,3-disubstituted isochromans of dopamine D4 antagonist activity

The C-1 epimers of the 3-methyl-6,7-dimethoxy analogues of the D₄ antagonist sonepiprazole 1b and 5-HT_1D agonist PNU-109291 1a containing both the isochroman and p-methoxyphenylpiperazine chromophores were prepared in order to study the applicability of circular dichroism for the assignment of the configuration of 1,3-disubstituted isochromans and test their dopamine D₄ antagonist activity.     

A synthesis of 11-homo-aldosterone

A synthesis of 11-homo-aldosterone acetate (1a) is described. 3β-Acetoxy-11-methylene-5α,25D-spirostan (3) was converted in 4 steps into 3β-acetoxy-11β-acetoxymethyl-5α-pregnan-20-one (9, Chart I), which was photocyclized to 20a, saponified regioselectively, and oxidized to 3-oxo-11β-acetoxymethyl-18,20-cyclopregnan-20α-ol-3-one (22, Chart II). Introduction of the 1,4-diene in 22 followed by a selective reduction of the 1-ene afforded 11β-acetoxymethyl-18,20-cyclopregn-4-en-20α-ol-3-one (26). Finally, the 18,20-cyclo ring of 26 was manipulated through 30, 31, 32, 33 to produce 1a. The bulky 11β-acetoxymethyl group distorted the steroid molecule to such an extent that the routine photochemical functionalization of the angular Me-18 via a nitrite or a hypoiodite became inoperative, and routine procedures for introduction of a 4-ene into 5α-3-one via a 1,4-dien-3-one were unsuccessful. Two new methods for the introduction of a 4-ene into steroidal 5α-3-ones were investigated using 5α-cholestanone and 5α-dihydrotestosterone as models. The first route, which was applicable to the synthesis of 1a, was the stepwise introduction of a 1-ene and a 4-ene utilizing Sharpless's acidic phenylselenyl chloride procedure, followed by a selective reduction of the 1-ene. The second route, which appeared equally promising, was protection of the C-2 site with N-methylanilinomethylene followed by introduction of the 4-ene and subsequent deprotection of the C-2.     

Synthesis of calix[4]arene(amido)monocrowns and their photoresponsive derivatives

A series of new calix[4]arene(amido)mono-crown compounds have been synthesized through aminolysis of calix[4]arene esters and intramolecular cyclization of the intermediates. The title compounds were converted into their nitro and azo substituted derivatives to provide novel photoresponsive molecular receptors for transition metal ions. Single crystal X-ray analysis of calix[4]arene(ethyleneamido)mono-crown (2a) revealed that the compound is present in a cone conformation with an amido loop that caps the lower rim of calix[4]arene cavity to result in stacking along axis a and axis c to provide supramolecular aggregates in the solid state. Evaluation of synthesized macrocycles in the solution phase for recognition of transition metal cations (Cr³⁺, Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺, Ag⁺, Cd²⁺, Pb²⁺, Hg⁺, Hg²⁺, Pd²⁺, and Pt²⁺) by UV-visible spectroscopy revealed that p-tert-butyl-calix[4]arene mono-(amidocrown) 1c selectively shows a blue shift at 38 nm on interaction with Hg⁺ ions.     

Solid-state and solution photocycloadditions of 4-acyloxy-2-pyrones with maleimide

Solid-state photosensitized reactions of 4-acyloxy-2-pyrones (1b,c) with maleimide (2) afforded endo-endo double-[4+2] cycloadducts (3b,c) with high stereoselectivity. Sensitized photoreactions of 1a-d with 2 in solution gave exo-endo double-[4+2] cycloadducts (4a-d). 2-Pyrones 1a-d were photolyzed to give carboxylic acids (5a-d) via their valence isomerization in the solid state and in solution. Such kinds of photoreaction of the 4-acyloxy-2-pyrones were dramatically different from regio- and stereoselective [2+2] cycloadditions of 4-alkyloxy-2-pyrones. The photoreaction mechanisms of 1 with 2 and 1 itself were analyzed by powder X-ray diffraction analysis and MO calculations.     

Palladium catalysed enantioselective asymmetric allylic alkylations using the Berens’ DIOP analogue

Berens’ DIOP analogue 1a was evaluated in a series of Pd(0) catalysed asymmetric allylic alkylations of both acyclic and cyclic substrates using both C- and N-nucleophiles. The reaction conditions were exhaustively analysed and a maximum ee of 60% was obtained using rac-1,3-diphenylpropenyl acetate 3 and malonate as the nucleophile. rac-3-Acetoxycyclohexene 5 gave inferior ee’s. Various solvents were applied including [bmim]PF₆. The results using benzylamine were comparable to those obtained using malonate. For 3, in all cases the reaction exclusively gave the branched alkylated product 4 and allylic amine 8, with no trace of their linear regioisomers. The [allylPd-1a]BF₄ complex 7 was prepared, characterised and screened in the asymmetric allylic alkylation of rac-1,3-diphenylpropenyl acetate 3. It was also immobilised on montmorillonite K-10 support and preliminary solid phase reactions were conducted with 3.     

Synthesis of new chiral calix[4]arene diamide derivatives for liquid phase extraction of α-amino acid methylesters

The synthesis of chiral diamide derivatives of calix[4]arene from the reaction of p-tert-butylcalix[4]arene diester 1a and calix[4]arene diester 1b with various amino alcohols were reported. The ¹H and ¹³C NMR, data showed that the compounds synthesized exist in the cone conformation. The extraction study properties of these new compounds 3a,b–4a,b towards some selected α-amino acid methylesters are also reported.     

Reactions of some anellated 2-aminothiophenes with electron poor acetylenes

The reactivity of 2-aminothiophenes in two different anellations: (a) [b]-anellation to a saturated carbocycle and (b) [3,4-c]-anellation to benzopyrans, towards typical acetylenic dienophiles has been investigated. Because of the absence of conjugation, the thiophenes of type (a) do not undergo [4+2]-cycloaddition with acetylenic dienophiles. Instead, the N-vinylated products 2 and 3 were obtained with dimethyl acetylene dicarboxylate (DMAD). Electron poor alkynes react with the thiophenes of type (b) in three main ways: DMAD reacts in a [4+2]-mode in dioxane to give the products 7, 8 and 14; a Michael addition type reaction also takes place at the doubly vinylene homologous carbon atoms (C-1 in the starting materials 4, 9 and 10) in dioxane, methanol or ethanol. Methyl propiolate reacts in a similar way. The doubly N-vinylated product 26 was obtained from 10 in toluene and the C-1 vinylated products 24B and 27 were obtained from 9 in dioxane and 10 in methanol. The reaction of 10 with phenyl ethyl propiolate in dimethylformamide gave no addition product, instead a dimer of the acetylenic reagent was the isolated product. The accuracy of the assigned structures 5, 12 and 13a could be achieved on the basis of a single-crystal X-ray structure analysis of compound 13a. The reaction mechanism and the nature of the isolated products are dependent on the nature of the solvent. No addition reaction was observed between 17 and DMAD. The influence of the N-substitution on the nature of the addition (Michael or Diels-Alder) could be settled through the reactions of 18 and 21 with DMAD, which gave 19 and 14 (via 22), respectively as the only isolable products.     

Rearrangements of 3-heterobicyclo[3.2.0]hept-6-enes

Studies directed at a synthesis of dihydrothiepin 1b have resulted in the elucidation of several factors which effect cyclobutene ring opening in the 3-heterobicyclo[3.2.0]hept-6-ene ring system. We report the unexpected rearrangement of 4a, 4b, 13b and 13c to the synthetically useful a-vinyl-2,5-dihydrothiophenes 7a, 7b, 15a and 15b, respectively. Conversion of 4a to 6 is suggested to occur by a 1,3-rearrangement of 4a to isomeric 3-thiabicyclo[3.2.0]hept-6-ene 19 followed by cyclobutene ring opening in 19.     

Synthesis of silicon-functionalized 7-silanorbornadienes and their thermolysis and photolysis

A series of 7-silanorbornadienes were prepared and characterized by X-ray crystallographic analysis. 2,3-Benzo-7-mesityl-1,4,5,6-tetraphenyl-7-silanorbornadiene (1a) was prepared by the [4+2] cycloaddition reaction of 1-mesityl-2,3,4,5-tetraphenyl-1-sila-2,4-cyclopentadiene (4) with benzyne. 7-Hydro 1a was converted into 7-chloro-substituted silanorbornadiene 1b. Treatment of 1b with lithium phenylamide and lithium phenylthiolate gave 7-phenylamino-substituted silanorbornadiene 1c and 7-phenylthio-substituted silanorbornadiene 1d, respectively. Reductive lithiation of 1b with lithium naphthalenide afforded 7-lithiated silanorbornadiene 1f, which reacted with chlorotrimethylsilane to give 7-trimethylsilyl-substituted silanorbornadiene 1e. Stereochemistry at the bridging silicon during these transformations was determined by X-ray crystallographic analysis. Thermolysis of 1 produced corresponding silylenes 5, which were trapped with triethylsilane to give disilanes 6. Photolysis of 1 except 1c also afforded corresponding silylenes 5. Theoretical calculation of the models of silanorbornadienes was performed at the MP2/6-31+G(d, p) level.