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.     

Synthesis of the anionic fluororeceptors based on thiourea and amide groups and recognition property for α,ω-dicarboxylate

Three new neutral receptors (1, 2 and 3) containing thiourea and amide groups were synthesized by simple steps in good yields. The binding properties for anions of 1, 2 and 3 were examined by UV-vis, fluorescence, and ¹H NMR spectroscopy. Receptors 1, 2 and 3 all had a better adipate anion selectivity by comparison with other dicarboxylate anions. The association constants of 1, 2 and 3 with adipate were higher as compared to other anions (malonate, succinate, glutarate). In particular, a distinct color change was observed from light yellow to orange-red upon addition of adipate to the solution of 1 in DMSO. The UV-vis and fluorescence data indicate that a 1:1 stoichiometry complex is formed between compound 1, 2 or 3 and dicarboxylate anions through hydrogen bonding interactions.     

Columnar/smectic metallomesogens derived from heterocyclic benzoxazoles

The synthesis, mesomorphic behavior, and optical properties of two new series of metal complexes 1a,b-M (M=Pd, Cu, Zn) derived from benzoxazoles 2a,b are reported. The crystal and molecular structures of mesogenic 5-decyloxy-2-(6-decyloxybenzooxazol-2-yl)phenol and nonmesogenic bis[5-octyloxy-2-(6-octyloxybenzooxazol-2-yl) phenol]Pd(II) were determined by means of X-ray structural analysis. Two benzoxazoles 2a exhibited monotropic SmA phases, and all benzoxazoles 2b were nonmesogenic. On the other hand, metal complexes 1a-M exhibited distinctly different mesomorphism from complexes 1b-M. Complexes 1a-Pd formed SmC phases; complexes 1a-Cu and 1a-Zn formed crystal phases. In contrast, complexes 1b-Zn exhibited columnar phases, and complexes 1b-Cu and 1b-Pd were nonmesogenic. The difference of the mesomorphism in 1a-M and 1b-M was probably attributed to the geometry and/or the overall molecular shape created by 2a and 2b. The electronic configuration of metal ion might play an important role in forming the mesophases. The fluorescent properties of these compounds were also examined.     

Pheromone synthesis. Part 255: Synthesis and GC–MS analysis of pheromonal triacylglycerols of male Drosophila fruit flies

Pheromonal triacylglycerols and their analogs, 1A, 1B, 2A, 2B, 3A, 3B, and 3C, of male Drosophila fruit flies were synthesized and analyzed by GC–MS. Their GC retention times were found to be a reliable measure to analyze and identify these triacylglycerols with acetyl, oleoyl and tigloyl groups, although the stereo- and regioisomers of 1 (1A and 1B), 2 (2A and 2B), and 3 (3A, 3B, and 3C) could not be distinguished from each other by MS alone.     

Photoinduced cycloadditions of N-methyl-1,8-naphthalenedicarboximides with alkynes

Photoinduced cycloadditions of N-methyl-1,8-naphthalenedicarboximide 1 with phenylacetylenes 2a-2c, cyclopropylacetylene 2d, diphenylacetylenes 2e-2f and 1-phenylpropyne 2g were investigated. In the case of phenylacetylenes 2a, 2b and cyclopropylacetylene 2c, photoreaction with 1 takes place at the naphthalene C(1)C(2) bond to give the cyclobutene products. For 4-methoxyphenylacetylene 1c, the cyclobutene 3c is obtained together with the 4-benzo[a]thebenidinone 4c derived from a primary oxetene product formed by [2+2] addition of the imide carbonyl with the alkyne. Similar to 2c, photocycloaddition of 1 with 2e and 2f gave the cyclobutenes 7e, 7f, 8f and the 4-benzo[a]thebenidinone products 9e, 9f and 10f, respectively, derived from the corresponding oxetenes. Photoreaction of 1 with 2g gave cyclobutene 7g and benzo[a]thebenidinone 9g. Sensitization experiment and internal heavy atom effect study showed that these reactions proceed from the ππ* singlet excited state of 1. Estimation of the free energy change for electron transfer between ¹1* and the alkynes and the calculation of charge and spin density distribution in the anion radical of 1 and the cation radical of the alkynes suggested that the cyclobutene products are formed by direct [2+2] cycloaddition of ¹1* with the alkyne, while the formation of the oxetene products is the result of electron transfer interaction between ¹1* and the alkyne. The regioselectivity in the oxetene formation is accounted for by charge and spin density distribution in the anion radical of 1 and the cation radical of the alkyne.     

Singlet oxygen addition to homoallylic substrates in solution and microemulsion: novel secondary reactions

The photooxygenation of three homoallylic substrates, the γ,δ-unsaturated ketone 1a, nitrile 2a, and the γ,δ-unsaturated ester 3a was investigated in homogeneous solution and in microemulsion (for 1a). Two secondary reaction pathways were detected for the allylic hydroperoxides of type b and c, respectively. The cyclization reactions of 1b and 2b to the 1,2-dioxanes 1d and 2d followed well-known reaction patterns, whereas the base-catalyzed epoxide (1e-3e) formation from the tertiary allylic hydroperoxides 1c-3c is a unprecedented reaction type.     

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron-rich 2-azadienes

tert-Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2H-azirine 3 leading to Diels-Alder cycloadducts in moderate yields. The reactions are endo- and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b, 4b. There are two isomers (4 and 5) from 1a, 1c and 1d. A different result was obtained with the diene 1e. Diene 1e formed products 4e and 8. Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7. Compound 8 gave aziridine 9.     

The regioselectivity of the formation of 2-pyrazolylthiazoles and their precursors from the reaction of 2-hydrazinothiazoles with 4,4,4-trifluoro-1-hetaryl-1,3-butanediones

Reaction of 2-hydrazinothiazoles 1 with 1-thienyl- and 1-furyl-1,3-butanediones 2a,b in methanol in the presence of hydrochloric acid mainly leads to a mixture of pyrazoles 3 and pyrazolines 4 or pyrazoles 3 and 5 in strong acidic conditions. Isomeric hydrazones 6 and pyrazolines 4 were formed and isolated in these reactions in the absence of hydrochloric acid. It has been shown that the regioselectivity in the reaction of diketones 2 with hydrazine 1 is governed by both the concentration of acid and the nature of substituents in the 1,3-diketones 2. Cyclization of hydrazones 6 is shown to occur under milder conditions than dehydration for pyrazolines 4. The new heterocyclic compounds were prepared and fully characterized by NMR spectra and by X-ray analysis for 3c.     

Synthesis and dynamics of atropisomeric (S)-N-(α-phenylethyl)benzamides

The synthesis of atropisomeric 2-substituted benzamides 2a-e, 3a-e, and 4a-e, and characterization by X-ray structure analysis of 2d, 2e, 3c, 3e, 4c, and 4e are reported. Dynamic ¹H NMR spectroscopic studies of benzamides 2b-d, 3b-d, and 4b-d indicate that only two of the four possible rotamers are present in solution, with population ratios ranging between 1.5:1 and 4.1:1. The measured free energy of activation to interconversion of the rotamers ranged from 12.4 to 18.9 kcal mol⁻¹. Benzamides ArCON[(S)-phenethyl]₂ (2e, 3e, and 4e), exhibited atropisomer ratios between 1.7:1 and 1:1, and free energies of interconversion of the rotamers ranged from 11.5 to 17.6 kcal mol⁻¹. The highest rotation barriers were observed for the ortho-nitro derivatives 2a-e. Molecular calculations at the semiempirical level (PM3MM) gave free energies of activation for benzamides 2e and 3e of 23.6 and 12.4 kcal mol⁻¹, respectively, which are comparable to the experimental values.     

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).     

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a-h, 6a,b, 8a-n, 10a-g, and 16a,b, and (pyrimidin-4-yl)acetonitriles 13a-g has been delineated by base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 1a-h, 5, 7, and 15 by formamidine acetate 2a, acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-1-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.     

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.     

Revisiting diterpene lactones of Suregada multiflora

Phytochemical investigations on the organic extracts of the leaves of Suregada multiflora have led to the isolation of ten tetracyclic diterpene lactones 1-10, members of a rare class of abiatene diterpene lactones. Compounds 1-5 were found to be new. The structures of gelomulides F (11), D (12) and E (13) were revised on the basis of 2D NMR and X-ray diffraction evidences. Compounds 1 and 2 contain an epoxy linkage between C-8 and C-14, whereas compounds 3-5 were identified as 8,14-dihydroxy analogues of diterpene lactones. The stereochemical assignments in new compound 1 are based on X-ray diffraction analysis. Compounds 6 and 7 were identified as the known gelomulides A, G. The structures of compounds 7-9 were unambiguously confirmed by X-ray diffraction analyses.     

A novel synthesis of 2-arylhydrazono-6-amino-4-arylbenzene-1,3-dicarbonitriles and their conversion into phthalazines

Compounds 1a-d react with benzylidenemalononitrile 2 to yield dihydroaminopyridazines 3a-d and, in contrast, compounds 1e,f react with 2 under the same conditions to yield aminobenzenedicarbonitriles 8e,f compound 8e underwent intramolecular cyclization to phthalazine 9e. Compound 10e reacted with 2a to yield 11e.     

Functionalized esters as bis-electrophiles in a silicon-induced domino synthesis of annulated carbocycles

The reaction of silyl-substituted carbanion 1b with arene-1,2-dicarboxylates 6, 15 yields indenone derivatives 11, 16 in a domino process involving silyl C→O migration and elimination. However, in a competing pathway, the initial addition of 1b leads to lactone formation (8, 17). Substrates 26, 38 containing an ester group and a bromine substituent react with 1b under substitution of the halogen not allowing silyl migration. But desilylation with TBAF gives reactive carbanions providing benzo-annulated cycloalkanones 29, 40.     

Spontaneous proton-transfer copolymerization of 2-methyl-2-oxazoline with itaconic acid

Copolymerization of two monomers, 2-methyl-2-oxazoline (1) and itaconic acid (2) was carried out. The copolymerization proceeded spontaneously in 1:1 monomer feed ratio to give 2:1 copolymer 3. The mechanism for the production of such a 2:1 copolymer was explained by the in situ formation of monomer 5 from 1 and 2. Then, the propagation proceeded between 5 and 1 via zwitterionic intermediates. When the ratio of 1 in the feed was higher, the homopropagation of 1 took place.     

Synthesis of polyfunctionalized furans from 3-acetyl-1-aryl-2-pentene-1,4-diones

The BF₃-catalyzed cyclization of 3-acetyl-1-aryl-2-pentene-1,4-diones 1a-e in the presence of water in boiling tetrahydrofuran gave bis(3-acetyl-5-aryl-2-furyl)methanes 2a-e in 26-79% yields along with a small amount of 3-acetyl-5-aryl-2-methylfurans 3a-e. The exact structure of 2a was determined by X-ray crystallography. The use of a half volume of the solvent for the reaction of 1a resulted in the formation of 2,4-bis(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-phenylfuran (4) together with 2a and 3a. A similar reaction of 1a was carried out in the presence of 3-acetyl-5-(4-methylphenyl)-2-methylfuran (3d) to afford 4-(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-(4-methylphenyl)-2-methylfuran (5) in 49% yield. The BF₃-catalyzed reaction of 1a with 2,4-pentanedione in dry tetrahydrofuran at 23°C gave 3-(3-acetyl-5-phenyl-2-furfuryl)-4-hydroxy-3-penten-2-one (6a) and 3-(3-acetyl-2-methyl-4-phenyl-5-furyl)-4-hydroxy-3-penten-2-one (7a) in 66 and 24% yields, respectively. The product distribution depended on the reaction temperature. A similar reaction of 1b-e also yielded the corresponding trisubstituted furans 6b-e and tetrasubstituted furans 7b-e in good yields. These results suggested the presence of the furfuryl carbocation intermediate A during the reaction. The one-pot synthesis of 6a and 7a was also achieved by a similar reaction using phenylglyoxal. The deoxygenation of 1a with triphenylphosphine gave 3a in 88% yield, while 1a was treated with concentrated hydrochloric acid to yield 3-acetyl-2-chloromethyl-5-phenylfuran (8) which was quantitatively transformed in ethanol into 3-acetyl-2-ethoxymethyl-5-phenylfuran (9) and in water into 3-acetyl-5-phenylfurfuryl alcohol (10), respectively. In addition, the Diels-Alder reaction of cyclopantadiene with 1a gave the corresponding [4+2] cycloaddition products 11 and 12.     

Formation of bis- and tris[2]catenanes via the cross-catenation of Pd(II)- and Pt(II)-linked coordination rings

We have demonstrated the self-assembly of linear oligo[2]catenanes via selective cross-catenation. A Pd(II)-linked double looped molecule 1 was transformed into the cyclic trimer c-(1)₃ through the catenation. When 1 was treated with a kinetically inert Pt(II)-linked single looped molecule 2a in aqueous media (1:1.2 DMSO/H₂O) at room temperature, linear oligo[2]catenanes of 2a-(1)_n-2a (n=1 and 2) were selectively obtained, because the kinetically inert Pt(II)-linked ring 2a is allowed to thread on only kinetically labile Pd(II)-linked ring of 1. The distribution of the oligomers depends on the monomer ratio of 1 to 2a. When the ratio of 1 to 2a was 1:2, bis[2]catenane 3a (2a-1-2a) was quantitatively assembled. When the ratio of 1 to 2a was 1:1, not only 3a but also tris[2]catenane 4 (2a-1-1-2a) was assembled. The ratio of 3a to 4 was carefully determined to be 1:1 by NMR. The lengths of 3a and 4 in an extended conformation were estimated by MD/MM2 simulation to be 3.6 and 5.4 nm, respectively.     

Synthesis and reactivity of new functionalized Pd(II) cyclometallated complexes with boronic esters

Treatment of the functionalized Schiff base ligands with boronic esters 1a, 1b, 1c and 1d with palladium (II) acetate in toluene gave the polynuclear cyclometallated complexes 2a, 2b, 2c and 2d, respectively, as air-stable solids, with the ligand as a terdentate [C,N,O] moiety after deprotonation of the -OH group. Reaction of 1j with palladium (II) acetate in toluene gave the dinuclear cyclometallated complex 5j. Reaction of the cyclometallated complexes with triphenylphosphine gave the mononuclear species 3a, 3b, 3c, 3d and 6j with cleavage of the polynuclear structure. Treatment of 2c with the diphosphine Ph₂PC₅H₄FeC₅H₄PPh₂ (dppf) in 1:2 molar ratio gave the dinuclear cyclometallated complex 4c as an air-stable solid.Deprotection of the boronic ester can be easily achieved; thus, by stirring the cyclometallated complex 3a in a mixture of acetone/water, 3e is obtained in good yield. Reaction of the tetrameric complex 2a with cis-1,2-cyclopentanediol in chloroform gave complex 2c after a transesterification reaction. Under similar conditions complexes 3a and 3d behaved similarly: with cis-1,2-cyclopentanediol, pinacol or diethanolamine complexes 3c, 3b, 3g and 3f, were obtained. The pinacol derivatives 3b and 3g experiment the Petasis reaction with glyoxylic acid and morpholine in dichloromethane to give complexes 3h, and 3i, respectively.     

Exceptional molecular architectures via cycloadditions to pyrenequinones

The thermal reaction of phencyclone (2) with a 1:1 mixture of 1,8-pyrenequinone (4) and 1,6-pyrenequinone (5) yields 2:1 adducts only of compounds 2 and 4. The observed polycyclic aromatic hydrocarbon 8 is formed via double Diels-Alder addition of 2 to 4, and the polycyclic ketone 9 arises from a combination of Diels-Alder and hetero-Diels-Alder reactions of 2 and 4. In contrast, Lewis acid-catalyzed reactions of 2, 4, and 5 give 2:1 adducts only of 2 and 5. The chief product, polycyclic diketone 10, is derived from a double hetero-Diels-Alder addition of 2 to 5. X-ray analysis of compound 8 shows it to be an exceptionally large polycyclic aromatic arch, and the X-ray structure of 10 reveals it to be a chiral molecular tweezer.