Hydantoins,thiohydantoins, glycocyamidines—36: 1,5,5- and 3,5,5-triphenyl derivatives

In contrast to the α-chloroamides 1a-c which, when reacted with potassium N-cyanoanilide, furnish anomalous substitution products (2a-c), the related nitrile and ester yields normal substitution products (3a and b) under the same conditions. 1,5,5-Triphenylhydantoin (4a) and a series (5a-8a, 13 and 14) of its derivatives have been prepared starting with 3a and b. Acid hydrolysis of 3a yields, in addition to the normal products (4a and 5a) considerable quantities of the rearranged product 4b. An authentic sample of the latter, as well as a series of its derivatives (5b-8b and 11) have been prepared starting with α,α-diphenylglycinonitrile and 2-methylthio-1,4,4-triphenyl-2-imidazolin-5-one (9). When reacted with ammonia and ammonium iodide, 9 gave, in addition to the normal ammonolysis product 7b, the Dimroth rearrangement product 16, as well as 5,5-diphenylglycocyamidine, by apparent dephenylation of 16. The mass spectra of the imidazole derivatives 4–8, a and b, 9, 11, 13 and 14 are discussed.     

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.     

Pd-catalyzed asymmetric synthesis of allylic tert-butyl sulfones and sulfides: Kinetic resolution of the allylic substrate by a chiral Pd-complex

The acyclic and cyclic allylic tert-butyl sulfones 3, ent-3, 11a, 11b and 15a–c of 89–98% ee were synthesized in 40–92% yield by a Pd-catalyzed reaction of the respective allylic acetates and carbonates rac-1a, rac-1b, rac-10a, rac-10b and rac-14a–c with LiO₂St-Bu in the presence of the chiral ligands 2a, ent-2b and 12. Formation of the n-butyl sulfones 13a and 13b of 95% ee was observed. Reactions of rac-1a and 1b/ent-1b with LiO₂St-Bu in the presence of 2a and ent-2b, respectively, in THF under heterogeneous conditions were accompanied by a kinetic resolution of the allylic substrates. The faster reacting allylic substrate and the preferentially formed sulfone had the same absolute configuration. The allylic tert-butyl sulfide 17 of 92% ee was obtained in 63% yield by the Pd-catalyzed reaction of rac-1b with Me₃SiSt-Bu in the presence of ent-2b.     

Further applications of endocyclic enamine-enone annulations : The total syntheses of rac-Sceletium alkaloid A4 and 3'-demethoxy sceletium alkaloid A4

The total synthesis of rac-sceletium alkaloid A₄1a and of its 3'-demethoxy analogue 1b via the annulation of endocyclic enamines 4a–b is presented. The Michael acceptor 5a is a useful synthon for the two-step synthesis of 2,3-disubstituted pyridines from Δ²-pyrrolines.     

The total synthesis and anti-fertility activity of 6-silasteroids

4,4-Dimethyl-6-methoxy-4-sila-1-tetralone (2) was prepared by a modified literature procedure and converted to 3-methoxy-6,6-dimethyl-6-silaestra-1,3,5(10),8,14-pentaen-17β-yl acetate (5c). Catalytic hydrogenation of 5c gave 3-methoxy-6,6-dimethyl-6-silaestra-1,3,5(10),8-tetraen-17β-yl acetate (6b), and its 14-iso- and Δ^{1,3,5(10),8(14)} isomers, the proportions varying with the catalyst and solvent. Reduction of 6b with lithium-liquid ammonia, and O-demethylation, gave 6,6-dimethyl-6-silaestradiol (8b). Reduction of the 3-methyl ether of 8b with lithium-liquid ammonia-t-butanol and hydrolysis afforded 3-keto-6,6-dimethyl-6-silaestr-1(10)-en-17β-ol (15), which was catalytically reduced to its 1,10α-dihydro derivative 17. The 5,6 SiC bond of 8b, 15 and their derivatives was cleaved by boron tribromide, aq. ethanolic hydrogen fluoride, and other reagents, providing a series of 5,6-seco-6,6-dimethyl-6-silasteroids. X-ray crystallographic analysis of 17 and the 17α-ethynyl derivative of 15 confirmed the stereochemical assignments. None of the compounds which were subjected to uterotropic, anti-uterotropic, or post-coital assays, showed significant activity. A partially completed synthesis of 6-silaestradiol (21a) is described.     

Cannabinoid rearrangements: Synthesis of Δ5-tetrahydrocannabinol

1β,6β-Epoxy-hexahydrocannabinol acetate (1) in the presence of borontrifluoride rearranged to 6-oxo-hexahydrocannabinol acetate (3b) and to the aldehyde (4). Hydroboration of Δ⁶-THC gave the 6-hydroxy hexahydrocannabinols 5a and 8a. The latter was converted into Δ⁵-THC (11). This THC isomer shows no cannabis-type activity in rhesus monkeys.     

Photochemistry of benzene and quinoxaline fused Δ-1,2,3-triazolines and their trapping products

The benzene and quinoxaline fused Δ²-1,2,3-triazolines 1a and 1b were synthesized in good yields using Knoevenagel condensation and intramolecular 1,3-dipolar cycloaddition as two of the key reactions. Photolysis (254 nm) of Δ²-1,2,3-triazoline 1a or 1b in acetonitrile led to the homolytic cleavage of nitrogen that generated diethyl diazomalonate 7, highly reactive intermediates aziridines 8a,b, and isoindoles B. The latter two species subsequently underwent rearrangement to give the nitrogen extrusion products 9a,b, and polymers. Furthermore, the reactive intermediates were trapped by dienophiles to give the corresponding cycloadducts. Subsequent rearrangement of the N-bridged cycloadducts gave N-substituted pyrrolo[3,4-b]quinoxalines 12b and 15b in 6% and 9% yields, respectively. Irradiation of 1a in the presence of fumaronitrile led to the isolation of cycloadduct 16a with retention of stereochemistry. Thermal reaction of 1b gave more nitrogen extruded product 9b (58-63% yield) than that by photolysis (5-23% yield), which implied that zwitterionic intermediate might be involved in the former.     

Studies on the α-acetylation of δ-valerolactone and ε-caprolactone

The synthetic approach to α-acetylated δ-valero- (7a) and ε-caprolactone (7b) is reported. While 7a was isolated in 21% yield from the respective iodoester 5a by an alkylation sequence involving transesterification and Finkelstein reaction, 7b was not obtained from 5b but the dimer 8. Also transesterification and olefin ring closing metathesis (RCM) failed to prepare 7b. RCM resulted in the dimeric lactone 10, showing that the formation of 14-membered rings is favored over that of seven-membered rings. A Mukaiyama-type Claisen reaction finally gave α-acetyl lactones 7a and 7b in practically useful quantity of about 10 g (62% yield): starting lactones 13a,b were converted to silylenolethers 14a,b, which were acetylated with acetic anhydride in presence of the Lewis acid catalyst TiCl₄. However, acetylation depends on the addition sequence of starting materials: if the mixture of Ac₂O/TiCl₄ is added to 14b, lactone 7b can be further converted to give bis-oxepanonyl ethanols 15a,b. Both compounds 15 were characterized by X-ray crystallography and NMR.     

Oxidative behaviour of 3-aryl-2H-1,4-benzoxazines

Autoxidation of 3 - phenyl - 2H - 1,4-benzoxazine 8 gives 2 - hydroxy -3 - phenyl - 2H - 1,4-benzoxazine 13, 3 - phenyl - 2H - 1,4-benzoxazin - 2 - one 11, and 2 - phenylbenzoxazole 10 according to the conditions. Oxidation of 8 with DDQ in the presence of air gave mainly the bisacetal 17 but in the absence of air the major product was trans-Δ^2,2′-bi-(3-phenyl-2H-1,4-benzoxazine) 21a. Corresponding dimers were obtained from the 3-p-bromophenylbenzoxazine 9. The trans-isomers 21a and 22a are photochromic and change into their cis-isomers on exposure in solution to direct sunlight.     

A synthesis of rhodotorulic acid

A comparative study of the catalytic hydrogenation of benzyloxyamine hydrochloride (2a·HCl), benzyl benzohydroxamate (2b), and benzohydroxamic acid (3b) using PdC as a catalyst has disclosed that 2a·HCl smoothly undergoes the hydrogenolytic cleavage at both the benzyl—O and NO bonds, whereas 2b almost selectively suffers benzyl—O cleavage. The use of the benzyl group for protecting a hydroxamic acid function, suggested by the hydrogenolysis study, was embodied in the synthesis of rhodotorulic acid (1) starting with the reaction of 2a with bromide 5 to give 8. The key intermediate l-9 was conveniently prepared by the selective, asymmetric deacetylation of 8 using Taka-diastase. Conversion of l-9 into amino ester l-13 through the N^α-protected amino acid (l-11) and ester l-12 and coupling of l-11 with l-13 yielded dipeptide ll-14. Removal of the tert-butoxycarbonyl group from ll-14 and cyclization of the resulting amino ester produced the penultimate benzyl hydroxamate (ll-15), which was debenzylated selectively with PdC and hydrogen to furnish 1.     

Palladium(0) catalyzed enantioselective rearrangement of O-allylic thiocarbamates to S-allylic thiocarbamates: asymmetric synthesis of allylic thiols

The Pd(0) catalyzed rearrangement of the O-allylic thiocarbamates rac-2a, rac-2b and rac-4 in the presence of the chiral bisphosphane 5 proceeded quantitatively and gave the S-allylic thiocarbamates 6a, 6b and 7, respectively, with 91, 92 and 97% ee, respectively, in high yields. Saponification of the S-allylic thiocarbamate 7 furnished the allylic thiol 9 with 97% ee.     

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.     

Methylene-2-ethynylcyclopropanes: synthesis and biological activity of (Z)- and (E)-9-{[2-ethynyl-2-(hydroxymethyl)cyclopropylidene]methyl}adenine and -guanine

Synthesis of methylene-2-ethynylcyclopropane analogues of nucleosides 12a, 12b, 13a, and 13b is described. Ethyl methylenecyclopropane carboxylate 14 was hydroxymethylated to give alcohol 15, which was reduced to diol 16. Selective protection with tert-butyldimethylsilyl group gave derivative 17, which was oxidized to aldehyde 18. Wittig reaction with CBr₄ gave dibromoalkene 19. Elimination of both bromine atoms afforded methylene-2-ethynylcyclopropane 20. Bromoselenenylation using N-bromosuccinimide and diphenyldiselenide gave intermediate 21. Alkylation of adenine and 2-amino-6-chloropurine with 21 provided the Z,E-isomeric mixtures 22a and 22c. Oxidation afforded selenoxides 23a and 23c. Mild thermolysis furnished methylenecyclopropanes Z-24a, E-24a, and 24c. Deprotection and separation of Z,E-isomers gave adenine analogues 12a and 13a, and 2-amino-6-chloropurine intermediates 12c and 13c. Hydrolytic dechlorination of 12c and 13c afforded guanine analogues 12b and 13b. Adenine Z-isomer 12a inhibits replication of Epstein-Barr virus through its cytotoxicity. The E-isomer 13a is a substrate for adenosine deaminase.     

Synthesis of labda-8(17),13(14)-diene-15,16-olide and 15,16-epoxy-labda-8(17),13(16)-14-triene and their rearrangement to clerodane derivatives

The title compounds 1b and 1c were synthesized from manool. On treatment with either trifluoroacetic acid or formic acid 1b provided in nearly 100% yield 4a with a rearranged labdane skeleton. With sulfuric acid, however, 1b gave solely Δ^8,9-isomer 5. Reduction of 4a with lithium diisobutylaluminum hydride afforded 4b. On treatment with sulfuric acid 4a reverted to 5. Rearrangement of the epoxide 6 with boron trifluoride- etherate led to a complex product mixture from which no pure substance was obtained.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

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.     

Dimerisation des polyphenyl-allenes—III : Formation baso-catalysee de dimeres polycycliques du triphenyl-allene

Thermal opening of the 3trans dimer of triphenylallene 1 is conrotatory, and generates the diradical 2Z,Z. This intermediate, through ortho reclosures involving the two types of substituing phenyl groups (modes a or b), can lead to the bicyclic compounds 4a and 4b. The existence of an equilibrium between the 3trans dimer and its less stable isomers 4a and 4b is substantiated by the formation of naphthalenic derivatives 9a and 9b when the reaction is carried out in the presence of strong bases, which give rise to irreversible prototropic shifts 4 → 9. A weak base such as quinoline allows only a less complete isomerization of polyenes 4a and 4b, leading to their isomers 8a and 8b. The latter then thermally cyclize, in a classical way, and lead respectively to the tetracyclic compounds 12cis and 11b. The occurrence of such an equilibrium between 3trans and 4a,b accounts for the previously reported obtention of the dihydronaphthacene 14, in the precise instance of triphenyl-allene 1 dimerization, and more generally corroborates the recently proposed mechanism of naphthacenic compounds production from chlorinated polyphenyl-allenes.     

Synthesis,antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles: 1st Cancer Update

A series of 1-(N-methyl 2a–c and N-benzenesulphonyl-1H-indol-3-yl)-3-aryl-prop-2-ene-1-ones 3a–c were prepared and allowed to react with urea, thiourea or guanidine and gave the pyrimidine derivatives 4a–c to 9a–c. Base catalyzed reaction of 2a–c or 3a–c with ethyl acetoacetate gave cyclohexanone derivatives 10a–c and 11a–c, respectively. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 12a–c and 13a–c, respectively. On the other hand, condensation of 2c or 3c with some hydrazine derivatives namely, hydrazine hydrate, acetyl hydrazine, phenyl hydrazine and benzyl hydrazine hydrochloride gave pyrazole derivatives 14a,b-17a,b, respectively. Moreover, reaction of 2c or 3c with hydroxyl amine hydrochloride gave isoxazole derivatives 18a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that, compounds 14a, 14b, 15a and 15b were found to be the most active ones of all the tested compounds toward Salmonella typhimurium (ATCC 14,028) compared to the reference drug chloramphenicol. Eighteen new compounds namely, pyrimidin-2(1H)-ones 4a–c and 5a–c, pyrimidin-2(1H)-thiones 6a–c and 7a–c and pyrimidin-2-amines 8a–c and 9a–c were tested for their in vitro cytotoxicity against human liver carcinoma (HEPG2), human breast cancer (MCF7) and human colon cancer (HCT-116) cell lines and showed that, compounds 4c, 5c, 6c, 8c and 9c were found to be the highly active compounds compared to the reference drug doxorubicin.     

Synthese totale de la (±) negamycine

A total synthesis of (±) negamycine 1 has been achieved in 14 steps from the acrolein dimer 6, which possesses the same carbon skeleton as the key intermediate lactone 4. Treatment of 2-acetoxymethyl 3,4-dihydro[2H]pyran 8, obtained from 6, with lead tetracetate gave the allylic hemiketal 15, which was converted into the corresponding anomeric methyl ethers 23. Hydroxylation of the double bond of 23 with mercuric acetate, occurred selectively at the γ-position and the resulting isomeric alcohols 24 were isolated as their dimesylates 25a and 25b. Condensation of sodium azide with the (trans-derivative 25a resulted in the formation of the cis-diazide 26a by inversion of configuration at C₃. Hydrogenation of 26a followed by acetylation of the intermediate diamine gave the cis-diamide 28 having the required stereochemistry. Oxidation of the corresponding hemiketal 29 by means of silver silicate yielded the diacetamido-lactone 4, which was then hydrolysed into (±) δ-hydroxy β-lysine 2 by refluxing aqueous HCl. Under the conditions required to protect the amino-groups as benzylcarbamates, the lactone 30 was produced. However, 30 gave directly the hydrazine 36 by condensation with benzyl N-methyl-hydrazinoacetate in refluxing acetonitrile m the presence of SiO₂. Finally (±) negamycine was obtained by hydrogenolysis of the protecting groups of 36. The antibacterial activities of the racemic antibiotic have been compared, in vitro and in vivo, with those of the natural product and with gentamicine C.     

Arylid-OX and Arylid-BOX derived catalysts: applications in catalytic asymmetric cyclopropanation

A novel family of chiral non-racemic monodentate oxazoline ligands known as Arylid-OXs 1a and 1b was prepared in good overall yields. These ligands were screened in bench-mark Cu(I)-catalyzed cyclopropanations and gave ees as high as 58%. Both ¹H NMR and computational studies using 1a indicated that the active catalyst was most likely to be the di-coordinated complex, Cu(I)-1a₂(MeCN)₂. Two novel ortho-substituted Arylid-BOX ligands 2a and 2b were also synthesized in very good yields. These ligands were tested in the same reaction as for 1a and 1b and, although excellent yields could be obtained with 2b, which is assumed to be due to an electron-donating effect from the ortho-methoxy group, a best ee of only 56% was obtained with 2a. In fact, both the enantioselectivities and diastereoselectivities obtained with these ortho-substituted ligands were in line with those previously obtained with the para-substituted series.