Synthesis of ‘thianthrene dimer’ by the coupling reaction of stannylthianthrenes in the presence of copper catalysts

The coupling reaction of 1-tributylstannylthianthrene (5) and 2-tributylstannylthianthrene (7) in the presence of copper catalysts at rt afforded the thianthrene dimer 1,1′-bithianthrene (3), 2,2′-bithianthrene (8), and 1,2′-dithianthrene (9) in high yields. Also we obtained thianthrene oxide dimer (R,R) (S,S)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (12) and (R,S) (S,R)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (13) from 1-tributylstannyl-10-S-monoxythianthrene (10) under the same reaction condition. The final structural conformation of 3, 8, 9, and 12 was performed by X-ray crystallographic analysis. Further, the solvent effects in the coupling reactions were also examined.     

Highly efficient, multigram and enantiopure synthesis of (S)-2-(2,4′-bithiazol-2-yl)pyrrolidine

(S)-2-(4-Bromo-2,4′-bithiazole)-1-(tert-butoxycarbonyl)pyrrolidine ((S)-1) was obtained as a single enantiomer and in high yield by means of a two-step modified Hantzsch thiazole synthesis reaction when bromoketone 3 and thioamide (S)-4 were used. Further conversion of (S)-1 into trimethyltin derivative (S)-2 broadens the scope for further cross-coupling reactions.     

Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives

A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido[3,2,1-de]acridines were synthesized for antitumor evaluation. These agents can be considered as analogues of glyfoline or (±)1,2-dihydroxyacronycine derivatives. The key intermediates, 3,7-dioxopyrido[3,2,1-de]acridines (15a,b or 24a,b), for constructing the target compounds were synthesized either from 3-(N,N-diphenylamino)propionic acid (14a,b) by treating with Eaton’s reagent (P₂O₅/MsOH) (Method 1) or from (9-oxo-9H-acridin-10-yl)propionic acid (23a-c) via ring cyclization under the same reaction conditions (Method 2). Compounds 15a,b and 24a,b were converted into (±)3-hydroxy derivatives (25a-d), which were then further transformed into pyrido[3,2,1-de]acridin-7-one (28a-d) by treating with methanesulfonic anhydride in pyridine via dehydration. 1,2-Dihydroxylation of 28a-d afforded (±)cis-2,3-dihydroxy-7-oxopyrido[3,2,1-de]acridine (29a-d). Derivatives of (±)3-hydroxy (25a,b) and (±)cis-2,3-dihydroxy (29a-d) were further converted into their O-acetyl congeners 26a,b and 30a-d, respectively. We also synthesized 2,3-cyclic carbonate (31, 32, and 33) from 29a-c. The anti-proliferative study revealed that these agents exhibited low cytotoxicity in inhibiting human lymphoblastic leukemia CCRF-CEM cell growth in culture.     

Cyclopalladation of enantiopure oxazolines having the prochiral CMe2 moiety at position 2 of the heterocycle

(R)-4-Ethyl-2-(1,1-dimethylpropyl)-2-oxazoline (1) and (S)-4-tert-butyl-2-(1,1-dimethylbutyl)-2-oxazoline (2) were synthesized in two steps from the corresponding enantiopure amino alcohols and acid chlorides in a total yield of 95% and 72%, respectively. (S)-2-(1-Adamantyl-1-methylethyl)-4-isobutyl-2-oxazoline (3) was obtained from adamantyl bromide and l-leucinol in five steps in a total yield of 82%. Reactions of oxazolines 1–3 with Pd(OAc)₂ in AcOH or CH₂Cl₂ followed by treatment with LiCl afforded the corresponding μ-Cl dimeric cyclopalladated complexes 15, 17, and 20 in good yield. Compounds 15, 17, and 20 reacted with PPh₃ to furnish the corresponding mononuclear complexes 16, 19, and 21. The ³¹P NMR spectra of trans(N,P) adducts 16, 19, and 21 contained signals of two diastereomers in a ratio of ca. 1.3:1.     

New phlegmarane-type, cernuane-type, and quinolizidine alkaloids from two species of Lycopodium

Two new phlegmarane-type alkaloids, cermizines A (1) and B (2), three new quinolizidine alkaloids, cermizine C (3) and senepodines G (4) and H (5), and a new C₁₆N₂ type alkaloid consisting of a quinolizidine and a piperidine ring, cermizine D (6), as well as two new cernuane-type alkaloids, cernuine N-oxide (7) and lycocernuine N-oxide (8), have been isolated together with cernuine (9) and lycocernuine (10) from the club moss Lycopodium cernuum and L. chinense. The relative stereochemistry of 1-4 and 6, and the absolute stereochemistry of 5, 7, and 8 were elucidated by combination of NOESY correlations, modified Mosher's method, chemical transformations, and computational methods. Cermizine D (6) might be a biosynthetic intermediate of cernuane-type alkaloids such as 7-10.     

Molecular structures and ab initio molecular orbital calculations of the optically active derivatives of 1-aminocyclopropane-1-carboxylic acid

The novel optically active derivatives of 2,2′-disubstituted-1-aminocyclopropane-1-carboxylic acid (−)-2 and (+)-3 were synthesised from the spiro-azlactone (+)-1. Oxidation of the diol moiety of (+)-3 gave by ring enlargement the racemic mixture of 2,3-dihydrofuran derivative (±)-6. This conversion is explained by stepwise rearrangement of the initially formed tetrasubstituted cyclopropanecarbaldehyde 4 through zwitterionic's reactive intermediate 5. The formation of (±)-6 is preferred energetically as established by ab initio calculations of the ground states and possible intermediates for that rearrangement. The crystal structure and absolute configuration of the compounds (+)-1, (−)-2, (+)-3 and (−)-7 were determined by single-crystal X-ray diffraction method. All four compounds possess Z-configuration of the cyclopropane ring. The dioxolane ring in the structures (+)-1 and (−)-2 adopts half-chair conformation, while the cyclopropane ring and geminally substituted groups in the structures (−)-2, (+)-3 and (−)-7 possess the anticlinal conformation. The molecules of the compound (+)-1 are connected by very weak intermolecular hydrogen bond of C-H?O type. In the compounds (−)-2, (+)-3 and (−)-7inter- and intramolecular hydrogen bonds of N-H?O type were observed. The spiro-compound (+)-1 exhibited a more pronounced inhibitory activity against the proliferation of murine leukemia and human T-lymphocytes cells than other type of tumor cell lines and normal human fibroblast cells.     

Photochemical isomerisation studies of rubifolide and bipinnatin J. Unravelling some of the biosynthesis interrelationships between macrocyclic and polycyclic cembranoids found in corals

Irradiation of natural rubifolide (1) and bipinnatin J (2) for short periods of time using a 400 W sunlamp results in photochemical Z- to E-isomerisations to their corresponding E-isomers 10 and 16, respectively, neither of which has yet been discovered in Nature. Prolonged irradiation of rubifolide (1) produces the ring-contracted compound kallolide B (11a), and photooxidation of E-rubifolide (10) leads to epilophodione (12); both 11a and 12 are found in corals. The photoisomerisation studies provide an insight into the most likely origins of more complex cembranoids, for example, 4, 5, 18 and 19 from the archetypal cembranoids 1, 2, and 3 in vivo. The studies also suggest a likely route to the unusually rearranged cembranoid sarcofuranocembrenolide B (23) via a cascade of photo-initiated radical cyclisations and rearrangements from the biradical intermediate 24 produced from cembranoid 22.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Rapid syntheses of (±)-pterocarpans and isoflavones via the gold-catalyzed annulation of aldehydes and alkynes

(±)-Pterocarpan and analogues (4a-c) have been synthesized efficiently via the annulation of salicylaldehydes (1a, 1b and 1c) and o-methoxymethoxylphenylacetylene (2a), followed by a one-pot reduction and acidic cyclization of the ketones (3a-c). In addition, isoflavone derivatives (5a-c) have been synthesized rapidly, in two steps, via the annulation of salicylaldehyde (1a) and arylacetylenes (2b, 2c and 2d), followed by IBX/DMSO oxidation of the isoflavanones (3d, 3e and 3f).     

Efficient and regioselective chromium(0)-catalyzed reaction of 2-substituted furans with diazo compounds: stereoselective synthesis of (2E,4Z)-2-aryl-hexadienedioic acid diesters

Pentacarbonyl(η²-cis-cyclooctene)chromium(0) (1) catalyzes efficiently reactions of diazo compounds with electron-rich furans. The reaction of 2-methoxyfuran (2) with alkyl α-diazoarylacetate (3a-g) furnishes the (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g) in excellent yields. These reactions are highly regioselective. The cyclopropanation intermediates formed from 1 and diazo compounds 3a-g always arise from a carbene addition to the less substituted CC bond of 2. The resulting cyclopropanation product undergoes a ring opening reaction to form the corresponding (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g). The pentacarbonylchromium(0)-catalyzed reactions of 2-alkylfuran (5a-b) with ethyl α-diazophenylacetate (3a) and 9-diazo-9H-fluorene (3h) produce the 1(E),3(E)-butadienes (6a-d) in very good yields.     

Synthesis, conformation and PKC isozyme surrogate binding of indolinelactam-Vs, new conformationally restricted analogues of (−)-indolactam-V

New conformationally restricted analogues of tumor promoter (−)-indolactam-V (1), indolinelactam-Vs (8, 11) and their hexyl derivatives at position 1 or 7 (9, 10, 12, 13), were synthesized from 1. (3R)-Indolinelactam-V (8) adopted a conformation similar to the twist form of 1 with a cis amide, while the conformation of (3S)-indolinelactam-V (11) was close to that of the sofa form of 1 with a trans amide. 7-Hexyl derivatives of 8 and 11 (10, 13) showed binding affinities for C1 domains of protein kinase C (PKC) isozymes compared to 1, but exhibited little selectivity among these PKC isozymes. However, introduction of the hexyl group at position 1 of 8 and 11 significantly enhanced their binding selectivity for novel PKC isozymes. The best selectivity for novel PKC isozymes was observed in (3S)-1-hexylindolinelactam-V (12) with a sofa-like conformation. These results suggest that a sofa-restricted analogue of 1 with a hydrophobic chain at an appropriate position would be a promising lead for designing agents with a high selectivity for novel PKC isozymes.     

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.     

Anti-Pseudomonas aeruginosa xanthones from the resin and green fruits of Cratoxylum cochinchinense

Cochinchinones I-L (1-3 and 13) along with 11 known xanthones (4-12, 14, and 15) were isolated from the resin and green fruits of Cratoxylum cochinchinense. In addition, four new acetylated compounds (16-19) were derivatized from 7-geranyloxy-1,3-dihydroxyxanthone (14) and 3-geranyloxy-1,7-dihydroxyxanthone (15). All compounds were characterized on the basis of spectroscopic analyses. The structures of cochinchinone I (1), a monoacetate (18) and a dibrosylate (20), were also confirmed by X-ray diffraction analysis. The antibacterial and antifungal activities of selected compounds were evaluated as well.     

The biomimetic synthesis of SNF4435C and SNF4435D, and the total synthesis of the polyene metabolites aureothin, N-acetyl-aureothamine and spectinabilin

Full details of the biomimetic conversion of polyene metabolite spectinabilin (5) into the isomeric natural products SNF4435C (1) and SNF4435D (2) by a cascade of E/Z-isomerizations and electrocyclizations are reported. Additionally, short total syntheses of the related natural products (±)-aureothin (3), (±)-N-acetyl-aureothamine (4) and (±)-spectinabilin (5) are presented. The key steps in the synthesis of (±)-3, (±)-4 and (±)-5 are the construction of the tetrahydrofuran motif using a palladium-catalyzed cycloaddition and the ruthenium-catalyzed cross metathesis of alkene 17 to form the common intermediate, boronic ester 24, which was further transformed using a trans-selective Suzuki coupling with a dibromide and a stereospecific Negishi-type methylation.     

Photobehaviour of 2- and 3-heteroaryl substituted o-divinylbenzenes; formation of fused 2,3- and 3,2-heteroareno-benzobicyclo[3.2.1]octadienes and 3-heteroaryl benzobicyclo[2.1.1]hexenes

New β-3-thienyl (8) and β-3-furyl derivatives of o-divinylbenzene (9) have been synthesised and their photochemical behaviour compared with 2-thienyl (7) and 2-furyl derivatives (2). Whereas the β-(2-heteroaryl) substituted o-divinylbenzenes (7 or 2) give only bicyclo[3.2.1]octadiene structure (14 or 1) by 1,6-ring closure of the biradical intermediate, β-(3-heteroaryl) substituted o-divinylbenzenes (8 or 9) give bicyclo[3.2.1]octadiene structure (23 or 24) and bicyclo[2.1.1]hexene structure (25 or 26) by 1,6- and 1,4-ring closure, respectively. This photochemical approach provides a simple method to 2,3- and 3,2-fused thiophene and furan polycyclic compounds.     

Chiroptical switching system based on the host-guest interaction between metal cations and poly(phenylacetylene)s bearing polycarbohydrate ionophore

Polycarbohydrate macromonomers with different degrees of polymerization (DP), that is, end-functionalized (1 → 6)-2,5-anhydro-3,4-di-O-ethyl-d-glucitols with 4-ethynylbenzoyl groups (macromonomer 2: DP = 6.6, and macromonomer 3: DP = 9.5) were synthesized. The copolymerizations of these macromonomers and phenylactylene (PA) were carried out in various molar ratios to give poly(phenylacetylene)s bearing a polycarbohydrate ionophore as the graft chain with various grafting rates, poly-(2_x-co-PA_y) and poly-(3_x-co-PA_y). These polymers showed split-type circular dichroism (CD) spectra in the long absorption region of the conjugated polymer backbones (280-500 nm). This indicated that poly-(2_x-co-PA_y) and poly-(3_x-co-PA_y) had predominantly one-handed helical conformations in the backbones. The CD spectral patterns of these polymers were inverted in the presence of metal cationic guest molecules. On the other hand, control experiments using poly(phenylacetylene)s bearing a monocarbohydrate (poly-(4_x-co-PA_y)) and metal cations did not show such a CD spectral inversion. These results clearly indicated that the chiroptical switching of the poly(phenylacetylene)s bearing polycarbohydrate ionophore was attributable to the host-guest complexation of the polycarbohydrate ionophore with metal cations.     

Pd(0) catalyzed three-five-component C-2-arylallylation of active methylene heterocycles: pyrazolones, oxazolones, isoxazolones and N,N′-dimethylbarbituric acid

A Pd(0) catalyzed three-five-component cascade involving an aryl iodide, allene and a heterocyclic pronucleophile is used to prepare 2-arylallyl derivatives (10-12 and 16-24) from 3-phenyl-5-isoxazolone (6) and 1-phenyl-3-methylpyrazolin-5-one (7) in moderate yield. Similar cascade allylation of masked amino acids 4-methyl-2-phenyl-4H-oxazol-5-one (8a), 4-benzyl-2-phenyl-4H-oxazol-5-one (8b) and 4-isopropyl-2-phenyl-4H-oxazol-5-one (8c) gave analogous products (25-37) in good yield. N,N-Dimethylbarbiturates (38-49) are similarly prepared from N,N-dimethylbarbituric acid (9) in excellent yield.     

[4+2] Cycloaddition of 1-phosphono-1,3-butadiene with azo- and nitroso-heterodienophiles

Under microwave activation, diethyl 1-phosphono-1,3-butadiene (1) reacted with t-butyl azodicarboxylate (2) and o-nitrosotoluene (5) to furnish quantitatively [4+2] cycloadducts, 3-phosphono-3,6-dihydro-1,2-pyridazine (3) and 6-phosphono-3,6-dihydro-1,2-oxazine (6), respectively. Selective oxidation and/or reduction of 6 led to functionalized δ-aminophosphonic derivatives in cyclic (7, 8) and aliphatic series (9, 10). Intermediate 10 may be cyclized into 2-phosphono-2,5-dihydro-1-pyrrole (12).     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Stereoisomeric bis(phenylglycinol)malonamide gelators: rare examples of gelling meso-compounds

Gelation of malonamides was investigated for the first time. Bis(phenylglycinol)malonamide 1, and methyl-, dimethyl-, ethyl-, diethyl- and isopropylmalonamides 2, 3, 4, 5 and 6, respectively, exhibited profoundly different gelling properties. Monoalkyl malonamides are efficient organogelators, and their gelling properties strongly depend on their stereochemistry. In contrast, symmetrically substituted dialkymalonamides, that is, (R,R)-dimethylmalonamide 3 and (R,R)-diethylmalonamide 5 as well as the unsubstituted 1 lack any gelation ability. Methyl derivative (R,R)-2 is an excellent, and its ethyl analogue (R,R)-4 a moderate gelator of toluene, p-xylene and tetralin while the isopropyl derivative (R,R)-6 shows only very weak gelation of tetralin and some more polar solvents. Meso diastereoisomers (R,r,S)-2 and (R,s,S)-2, as well as (R,r,S)-4 and (R,s,S)-4), each possessing a pseudoasymmetric centre represent very rare examples of gelling meso-compounds. The racemate 4 (rac-4) showed more efficient gelation of some solvents than the pure enantiomer (R,R)-4, while rac-2 failed to gel any of the solvents which were efficiently gelled by (R,R)-2.