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2017 Volume 37 Issue 9
2017, 37(9): 2175-2186
doi: 10.6023/cjoc201705001
Abstract:
Monofluoroalkenes have found applications in many areas of research, including the design and development new materials and drug. The highly stereoselective synthesis of this privileged structural motif has attracted great synthetic attention. This review summarizes recent progresses in highly stereoselective synthesis of monofluoroalkenes from aldehydes, ketones and diazo compounds, other substrates such as alkynes, alkenyl metallic species and alkenes are also included. The advantages and disadvantages of different methods are discussed.
Monofluoroalkenes have found applications in many areas of research, including the design and development new materials and drug. The highly stereoselective synthesis of this privileged structural motif has attracted great synthetic attention. This review summarizes recent progresses in highly stereoselective synthesis of monofluoroalkenes from aldehydes, ketones and diazo compounds, other substrates such as alkynes, alkenyl metallic species and alkenes are also included. The advantages and disadvantages of different methods are discussed.
2017, 37(9): 2187-2202
doi: 10.6023/cjoc201703002
Abstract:
Lewis acid-transition metal (LA-TM) complexes, with the LA site functions as an electron acceptor and the TM center functions as an electron donor, have been emerging as a new type of bifunctional catalysts lately, different from traditional transition metal bifunctional catalysts. Due to their rapid developments recently, the boron-based LA-TM complexes, which are divided into three major types, the sp3, sp2, and sp boron-based complexes, are reviewed in this paper according to their binding features. Reactions promoted by this new type of LA-TM bifunctional catalysts have been surveyed, including migration reactions, activation of H-H/E-H/E-E bonds, hydrogenations, hydrosilylations, and transfer dehydrogenation reactions etc. This overview of boron-based LA-TM complexes could provide valuable information to explore the new horizon in LA-TM bifunctional catalysis.
Lewis acid-transition metal (LA-TM) complexes, with the LA site functions as an electron acceptor and the TM center functions as an electron donor, have been emerging as a new type of bifunctional catalysts lately, different from traditional transition metal bifunctional catalysts. Due to their rapid developments recently, the boron-based LA-TM complexes, which are divided into three major types, the sp3, sp2, and sp boron-based complexes, are reviewed in this paper according to their binding features. Reactions promoted by this new type of LA-TM bifunctional catalysts have been surveyed, including migration reactions, activation of H-H/E-H/E-E bonds, hydrogenations, hydrosilylations, and transfer dehydrogenation reactions etc. This overview of boron-based LA-TM complexes could provide valuable information to explore the new horizon in LA-TM bifunctional catalysis.
2017, 37(9): 2203-2210
doi: 10.6023/cjoc201704030
Abstract:
Many organometallic reactions involve three elementary steps including oxidative addition, transamination, and reductive elimination. But sometimes very high barrier exists for this approach, leading to the failure of the reactions. The key development in recent reports is the implementation of visible-light photocatalysts as a means to induce the desired redox processes in a mild and selective manner. In this context, organometallic reactions mediated by photoredox catalysts could give rise to novel reactivity, thus this area has drawn much attention in organic chemistry community. In this review, prominent examples from the recent literatures are organized on the basis of the elementary transformation enabled by photoredox catalysis.
Many organometallic reactions involve three elementary steps including oxidative addition, transamination, and reductive elimination. But sometimes very high barrier exists for this approach, leading to the failure of the reactions. The key development in recent reports is the implementation of visible-light photocatalysts as a means to induce the desired redox processes in a mild and selective manner. In this context, organometallic reactions mediated by photoredox catalysts could give rise to novel reactivity, thus this area has drawn much attention in organic chemistry community. In this review, prominent examples from the recent literatures are organized on the basis of the elementary transformation enabled by photoredox catalysis.
2017, 37(9): 2211-2220
doi: 10.6023/cjoc201703038
Abstract:
The construction of C-S bond is the fundamental of organic synthesis, which plays an important role in the synthesis of natural products, biomolecules and functional materials. Thus, it has been received much attention. Base on the different C-S bonding method, the C-H bond activation, decarboxylation coupling reaction and Ullmann reaction are introduced. The ligands of Ullmann C-S coupling are also summarized.
The construction of C-S bond is the fundamental of organic synthesis, which plays an important role in the synthesis of natural products, biomolecules and functional materials. Thus, it has been received much attention. Base on the different C-S bonding method, the C-H bond activation, decarboxylation coupling reaction and Ullmann reaction are introduced. The ligands of Ullmann C-S coupling are also summarized.
2017, 37(9): 2221-2236
doi: 10.6023/cjoc201703041
Abstract:
Benzothiazole group is of characteristic fluorescence, and each also contains two heteroatoms (N and S). Hence, benzothiazole group is always viewed as fluorophore and recognition moiety in structure of fluorescent probes, playing an essential role on provision of fluorescence signal and binding sites. Recently, utilizing these properties of benzothiazole moiety to design and synthesize better fluorescent probes has gradually become one of focuses in fluorescent detection research. Classifying benzothiazole-based fluorescent probes into four main categories according to different analytes, such as metal cations, anions, sulfur-containing compounds and other species, the design, synthesis, detecting mechanism and relevant application of these probes are reviewed. And their development tendency in the future is prospected.
Benzothiazole group is of characteristic fluorescence, and each also contains two heteroatoms (N and S). Hence, benzothiazole group is always viewed as fluorophore and recognition moiety in structure of fluorescent probes, playing an essential role on provision of fluorescence signal and binding sites. Recently, utilizing these properties of benzothiazole moiety to design and synthesize better fluorescent probes has gradually become one of focuses in fluorescent detection research. Classifying benzothiazole-based fluorescent probes into four main categories according to different analytes, such as metal cations, anions, sulfur-containing compounds and other species, the design, synthesis, detecting mechanism and relevant application of these probes are reviewed. And their development tendency in the future is prospected.
2017, 37(9): 2237-2249
doi: 10.6023/cjoc201704026
Abstract:
Ugi reaction is an effective and atom-economical multicomponent reaction. The sequences of Ugi multicomponent reactions and following various postcondensation transformations constitute an extremely powerful synthetic method for heterocyclic compounds with elaborate substitution patterns. Herein, the development in this field is summarized.
Ugi reaction is an effective and atom-economical multicomponent reaction. The sequences of Ugi multicomponent reactions and following various postcondensation transformations constitute an extremely powerful synthetic method for heterocyclic compounds with elaborate substitution patterns. Herein, the development in this field is summarized.
2017, 37(9): 2250-2262
doi: 10.6023/cjoc201704031
Abstract:
The 1, 2-difunctionalization of conjugated dienes is an important homogeneous catalytic reaction. The obtained products through 1, 2-difunctionalization are widely existed in natural products and bioactive compounds, and are also sources of important organic intermediates, in addition, the preserved double bond in the difunctionalized product can be further transformed to give the desired structures or be functionalized sequentially to achieve multi-functionalization. The main difficulties focus on the encountered complex selectivities, including the regioselectivity, chemoselectivity and stereoselectivity in reactions. In recent years, with the development of organometallic chemistry, metal palladium, copper, iron or silver catalyzed 1, 2-difunctionalizations of conjugated dienes have been reported in succession. In some cases the enantioselective 1, 2-difunctionalizations of conjugated dienes were achieved via the introduction of chiral ligands. This review mainly focus on the recent metal catalyzed 1, 2-difunctionalizations of conjugated dienes.
The 1, 2-difunctionalization of conjugated dienes is an important homogeneous catalytic reaction. The obtained products through 1, 2-difunctionalization are widely existed in natural products and bioactive compounds, and are also sources of important organic intermediates, in addition, the preserved double bond in the difunctionalized product can be further transformed to give the desired structures or be functionalized sequentially to achieve multi-functionalization. The main difficulties focus on the encountered complex selectivities, including the regioselectivity, chemoselectivity and stereoselectivity in reactions. In recent years, with the development of organometallic chemistry, metal palladium, copper, iron or silver catalyzed 1, 2-difunctionalizations of conjugated dienes have been reported in succession. In some cases the enantioselective 1, 2-difunctionalizations of conjugated dienes were achieved via the introduction of chiral ligands. This review mainly focus on the recent metal catalyzed 1, 2-difunctionalizations of conjugated dienes.
2017, 37(9): 2263-2274
doi: 10.6023/cjoc201703008
Abstract:
Organic second-order nonlinear optical (NLO) chromophores are the main constituent part of nonlinear optical material. Scientists are dedicated to researching on the synthesis of novel chromophores with excellent performance by the facile design and modification of organic second-order NLO chromophores for decades. However, the researches on NLO chromophores in order to achieve the efficient translation of molecular microscopic nonlinearity (hyperpolarizability β) into macroscopic electro-optic (EO) coefficients r33 is still a challenging task. In recent years, a large number of essays report the novel NLO chromophores by adding isolation groups which can change the shape of chromophores and decrease the electrostatic interaction aimed to achieve the bigger EO coefficients. In this review, the recent processes of novel NLO chromophores modified by isolation groups are reviewed systematically and comprehensively.
Organic second-order nonlinear optical (NLO) chromophores are the main constituent part of nonlinear optical material. Scientists are dedicated to researching on the synthesis of novel chromophores with excellent performance by the facile design and modification of organic second-order NLO chromophores for decades. However, the researches on NLO chromophores in order to achieve the efficient translation of molecular microscopic nonlinearity (hyperpolarizability β) into macroscopic electro-optic (EO) coefficients r33 is still a challenging task. In recent years, a large number of essays report the novel NLO chromophores by adding isolation groups which can change the shape of chromophores and decrease the electrostatic interaction aimed to achieve the bigger EO coefficients. In this review, the recent processes of novel NLO chromophores modified by isolation groups are reviewed systematically and comprehensively.
2017, 37(9): 2275-2286
doi: 10.6023/cjoc201703021
Abstract:
Hydrogenation of oxalates is one of the important organic reactions, which has an ultimate use for the industrial production of ethylene glycol. The studies on the ruthenium complexes-based homogeneous catalytic reaction systems are herein summarized. With the focus on the catalytic reaction systems, the important factors with significant influences on the oxalate transformation efficiency as well as the product selectivity are discussed, including temperature, H2 pressure, catalyst concentration, reaction duration, additives, and so on. The catalytic reaction mechanisms are also discussed in detail, where the mechanism for the H2-heterolysis promoted under the metal-ligand cooperation for the oxalate hydrogenation to ethylene glycol is enhanced. This study would be useful for designing the new catalyst applicable in industry.
Hydrogenation of oxalates is one of the important organic reactions, which has an ultimate use for the industrial production of ethylene glycol. The studies on the ruthenium complexes-based homogeneous catalytic reaction systems are herein summarized. With the focus on the catalytic reaction systems, the important factors with significant influences on the oxalate transformation efficiency as well as the product selectivity are discussed, including temperature, H2 pressure, catalyst concentration, reaction duration, additives, and so on. The catalytic reaction mechanisms are also discussed in detail, where the mechanism for the H2-heterolysis promoted under the metal-ligand cooperation for the oxalate hydrogenation to ethylene glycol is enhanced. This study would be useful for designing the new catalyst applicable in industry.
2017, 37(9): 2287-2302
doi: 10.6023/cjoc201703036
Abstract:
Transition metal-catalyzed C-H activation is one of the most important areas in organic synthesis. Directed C-H activation can obviate the prefunctionalization of substrate, therefore providing a highly efficient and concise strategy for C-C formation. The cross-coupling of transition metal-activated C-H bond with organic electrophilic reagents has been proven effective for construction of various C-C bonds. Meanwhile, the oxidative coupling between the corresponding intermediates with organometallic reagents has become the focus for chemists due to their high reactivity, and notable achievements have been made in recent years. Here the oxidative couplings of C-H bond and organometallic reagents have been discussed and summarized according to the hybridization of substrate and organometallic reagents.
Transition metal-catalyzed C-H activation is one of the most important areas in organic synthesis. Directed C-H activation can obviate the prefunctionalization of substrate, therefore providing a highly efficient and concise strategy for C-C formation. The cross-coupling of transition metal-activated C-H bond with organic electrophilic reagents has been proven effective for construction of various C-C bonds. Meanwhile, the oxidative coupling between the corresponding intermediates with organometallic reagents has become the focus for chemists due to their high reactivity, and notable achievements have been made in recent years. Here the oxidative couplings of C-H bond and organometallic reagents have been discussed and summarized according to the hybridization of substrate and organometallic reagents.
2017, 37(9): 2303-2314
doi: 10.6023/cjoc201704038
Abstract:
The flexible naphthyltriazolylmethane-bearing uric acid transporter 1 (URAT1) inhibitor 1 is a novel, highly potent drug candidate for the treatment of hyperuricemia and gout. In order to understand the effect of substituents at the CH2 linker between naphthalene and triazole rings on the bioactivity, 7 highly congested compounds 2a~2g were designed and synthesized. All the synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS, and their in vitro URAT1 inhibitory assay was studied. The results showed that the bioactivity decreased dramatically after the introduction of substituents to the CH2 linker, and among the synthesized compounds the bioactivity dropped as the flexibility of the molecules decreased, strongly indicating that any substituents at the CH2 linker were intolerable. The structure-activity relationship discovered here will be valuable to the design of URAT1 inhibitors.
The flexible naphthyltriazolylmethane-bearing uric acid transporter 1 (URAT1) inhibitor 1 is a novel, highly potent drug candidate for the treatment of hyperuricemia and gout. In order to understand the effect of substituents at the CH2 linker between naphthalene and triazole rings on the bioactivity, 7 highly congested compounds 2a~2g were designed and synthesized. All the synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS, and their in vitro URAT1 inhibitory assay was studied. The results showed that the bioactivity decreased dramatically after the introduction of substituents to the CH2 linker, and among the synthesized compounds the bioactivity dropped as the flexibility of the molecules decreased, strongly indicating that any substituents at the CH2 linker were intolerable. The structure-activity relationship discovered here will be valuable to the design of URAT1 inhibitors.
2017, 37(9): 2315-2321
doi: 10.6023/cjoc201703010
Abstract:
The N-tetrahydrofurfuryl diphoshinoamine (PNP) ligand (E) was synthesized by means of two-step salt elimination reactions where separation of the two kinds of the aminyl lithium salts for the respective reactions is necessary for obtaining a high yield of E. The ligand reacted with CrCl3(THF)3 and Cr(CO)6 to give P, P-chelation complexes[{Ph2PN(CH2OC4H7)-PPh2}CrCl2(μ-Cl)]2 (1) and[Ph2PN(CH2OC4H7)PPh2]Cr(CO)4 (2), respectively. Complexes E, 1 and 2 were characterized by spectroscopy and elemental analysis, of which complex 2 was further confirmed by X-ray crystallography. Upon activation with methylaluminoxane (MAO) or AlEt3, the catalyst systems including 1, 2, E/CrCl3(THF)3, E/Cr(acac)3 and E/CrCl2(THF)2 were investigated. The best catalytic activity was achieved by 15.9 kg (product)/g (Cr)·h in which a selectivity of 63.6% for 1-C8 was obtained.
The N-tetrahydrofurfuryl diphoshinoamine (PNP) ligand (E) was synthesized by means of two-step salt elimination reactions where separation of the two kinds of the aminyl lithium salts for the respective reactions is necessary for obtaining a high yield of E. The ligand reacted with CrCl3(THF)3 and Cr(CO)6 to give P, P-chelation complexes[{Ph2PN(CH2OC4H7)-PPh2}CrCl2(μ-Cl)]2 (1) and[Ph2PN(CH2OC4H7)PPh2]Cr(CO)4 (2), respectively. Complexes E, 1 and 2 were characterized by spectroscopy and elemental analysis, of which complex 2 was further confirmed by X-ray crystallography. Upon activation with methylaluminoxane (MAO) or AlEt3, the catalyst systems including 1, 2, E/CrCl3(THF)3, E/Cr(acac)3 and E/CrCl2(THF)2 were investigated. The best catalytic activity was achieved by 15.9 kg (product)/g (Cr)·h in which a selectivity of 63.6% for 1-C8 was obtained.
2017, 37(9): 2322-2327
doi: 10.6023/cjoc201703019
Abstract:
Four series of derivatives, 6-substituted-1, 2, 4-triazolo[3, 4-a] phthalazine derivatives and 6-substituted tetrazolo[5, 1-a]phthalazine derivatives have been synthesized. The structures of compounds are confirmed by 1H NMR, 13C NMR, IR and HRMS. The anticonvulsant effects of the compounds are evaluated with maximal electroshock test by intraperitoneally injected in mice. The experimental results show that N-(4-bromophenyl)tetrazolo[5, 1-a]phthalazin-6-amine (7a) was the most potent compound, with a median effective dose of 5.89 mg·kg-1. Its anticonvulsant effect is better than the reference drug, carbamazepine.
Four series of derivatives, 6-substituted-1, 2, 4-triazolo[3, 4-a] phthalazine derivatives and 6-substituted tetrazolo[5, 1-a]phthalazine derivatives have been synthesized. The structures of compounds are confirmed by 1H NMR, 13C NMR, IR and HRMS. The anticonvulsant effects of the compounds are evaluated with maximal electroshock test by intraperitoneally injected in mice. The experimental results show that N-(4-bromophenyl)tetrazolo[5, 1-a]phthalazin-6-amine (7a) was the most potent compound, with a median effective dose of 5.89 mg·kg-1. Its anticonvulsant effect is better than the reference drug, carbamazepine.
2017, 37(9): 2328-2335
doi: 10.6023/cjoc201703049
Abstract:
A series of mono-and 1, 1'-disubstituted 1, 2, 3-triazolylferrocene derivatives have been synthesized and characterized. In UV-Vis spectroscopy, 1, 1'-disubstituted compounds have the larger molar absorption coefficient than those of monosubstituted compounds. The fluorescence intensity weakened with increasing the number of alkoxy chain and further weakened after introduction of the highly electronegative chlorine atom. All new compounds showed quasireversible redox process. The potentials for 1, 1'-disubstituted 1, 2, 3-triazolylferrocene derivatives anodically shifted about 150 mV compared with those of monosubstituted compounds, indicating harder oxidation by loss of an electron for the former. These compounds started to decompose at about 285~305℃. The 1, 2, 3-triazolylferrocene derivative with one terminal alkoxy chain had high melting point, and suffered from degradation reaction before changing into isotropic liquid, and those with multiterminal alkoxy chains showed either simple melting and freezing process or crystal polymorphic phase to isotropic liquid phase transitions in the heating and cooling cycles.
A series of mono-and 1, 1'-disubstituted 1, 2, 3-triazolylferrocene derivatives have been synthesized and characterized. In UV-Vis spectroscopy, 1, 1'-disubstituted compounds have the larger molar absorption coefficient than those of monosubstituted compounds. The fluorescence intensity weakened with increasing the number of alkoxy chain and further weakened after introduction of the highly electronegative chlorine atom. All new compounds showed quasireversible redox process. The potentials for 1, 1'-disubstituted 1, 2, 3-triazolylferrocene derivatives anodically shifted about 150 mV compared with those of monosubstituted compounds, indicating harder oxidation by loss of an electron for the former. These compounds started to decompose at about 285~305℃. The 1, 2, 3-triazolylferrocene derivative with one terminal alkoxy chain had high melting point, and suffered from degradation reaction before changing into isotropic liquid, and those with multiterminal alkoxy chains showed either simple melting and freezing process or crystal polymorphic phase to isotropic liquid phase transitions in the heating and cooling cycles.
2017, 37(9): 2336-2342
doi: 10.6023/cjoc201703004
Abstract:
Phenanthridines are important core structures found in a variety of natural products and other biologically important molecules with a wide range of biological activities and applications, including antibacterial and anticancer agents. A practical and efficient domino method for the preparation of dihydrophenanthridines from diynes and aryl halides is developed via palladium-catalyzed[2+2+2] cycloaddition reactions. All new products were fully characterized by IR, 1H NMR, 13C NMR and high-resolution mass spectrometry. The molecular structure of 1-(7, 12-diphenyl-5-tosyl-5, 6-dihydrobenzo[j]-phenanthridin-10-yl)ethan-1-one (3b) was confirmed by using single-crystal X-ray analyses.
Phenanthridines are important core structures found in a variety of natural products and other biologically important molecules with a wide range of biological activities and applications, including antibacterial and anticancer agents. A practical and efficient domino method for the preparation of dihydrophenanthridines from diynes and aryl halides is developed via palladium-catalyzed[2+2+2] cycloaddition reactions. All new products were fully characterized by IR, 1H NMR, 13C NMR and high-resolution mass spectrometry. The molecular structure of 1-(7, 12-diphenyl-5-tosyl-5, 6-dihydrobenzo[j]-phenanthridin-10-yl)ethan-1-one (3b) was confirmed by using single-crystal X-ray analyses.
2017, 37(9): 2343-2351
doi: 10.6023/cjoc201703022
Abstract:
In order to explore novel leading compound with good nematicidal activity, a series of 1, 3, 4-oxadiazole (thiadiazole) thioether derivatives containing a trifluorobuten group were designed and synthesized, and their structures were identified by IR, 1H NMR, 13C NMR spectra, ESI-MS and elemental Anal. ysis. The results of nematicidal activity assays revealed that compounds 5a and 6b possessed excellent nematicidal activity agaist Caenorhabditis elegans in vitro after 48 h, with LC50 values of 21.92 and 44.94 μg/mL, respectively, which were superior than that of fosthiazate (72.52 μg/mL) and fluensulfone (72.96 μg/mL). Furthermore, most of compounds exhibited moderate activity against Tylenchus semipenetranss at 100 μg/mL, compound 5b showed better nematicidal activity than fosthiazate and fluensulfone after 48 h and 72 h with the values of 79.9% and 96.7%.
In order to explore novel leading compound with good nematicidal activity, a series of 1, 3, 4-oxadiazole (thiadiazole) thioether derivatives containing a trifluorobuten group were designed and synthesized, and their structures were identified by IR, 1H NMR, 13C NMR spectra, ESI-MS and elemental Anal. ysis. The results of nematicidal activity assays revealed that compounds 5a and 6b possessed excellent nematicidal activity agaist Caenorhabditis elegans in vitro after 48 h, with LC50 values of 21.92 and 44.94 μg/mL, respectively, which were superior than that of fosthiazate (72.52 μg/mL) and fluensulfone (72.96 μg/mL). Furthermore, most of compounds exhibited moderate activity against Tylenchus semipenetranss at 100 μg/mL, compound 5b showed better nematicidal activity than fosthiazate and fluensulfone after 48 h and 72 h with the values of 79.9% and 96.7%.
2017, 37(9): 2352-2360
doi: 10.6023/cjoc201703048
Abstract:
From the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus WH1-2216-6, a new 5, 5, 6-polycyclic tetramate macrolactam (PTM) named 16-hydroxymaltophilin (1) was isolated and identified along with five known analouges, dihydromaltophilin (2), 4-deoxydihydromaltophilin (3), maltophilin (4), xanthobaccin C (5) and FI-2 (6), by means of UV-guided isolation as well as the spectroscopic identification. The cytotoxicities of compounds 1~5 were tested against the human normal hepatic cell line (L-02) and the seven human cancer cell lines, A549, MCF-7, Jurkat, BXPC-3, HCT-116, PANC-1 and K562. The results showed that compounds 1~5 were active against the above human cancer cell lines with the IC50 values of 0.1~9.7 μmol·L-1, among which the new compound 1 was the lowest toxic to L-02 cell and the most selective to Jurkat, HCT-116 and BXPC-3 cells with the selection index (SI) of 31.5, 41.4 and 52.4, respectively. The antifungal activities of 1~6 against Aspergillus fumigatus AF293 were also tested by two-fold dilution method. Compounds 2 and 4 were active against A. fumigatus AF293 with the minimum inhibitory concentration (MIC) values of 3.04 and 6.12 μmol·L-1, respectively. To the best of our knowledge, this is the first time to report the antifungal activity of 5, 5, 6-PTMs against A. fumigatus AF293. Apart from the cytotoxicity of compounds 2 and 3 against A549 and MCF-7 tumor cells lines, the other cytotoxicities were reported here for the first time, indicating the potential use of PTMs as the antitumor and antifungal lead compounds against A. fumigatus.
From the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus WH1-2216-6, a new 5, 5, 6-polycyclic tetramate macrolactam (PTM) named 16-hydroxymaltophilin (1) was isolated and identified along with five known analouges, dihydromaltophilin (2), 4-deoxydihydromaltophilin (3), maltophilin (4), xanthobaccin C (5) and FI-2 (6), by means of UV-guided isolation as well as the spectroscopic identification. The cytotoxicities of compounds 1~5 were tested against the human normal hepatic cell line (L-02) and the seven human cancer cell lines, A549, MCF-7, Jurkat, BXPC-3, HCT-116, PANC-1 and K562. The results showed that compounds 1~5 were active against the above human cancer cell lines with the IC50 values of 0.1~9.7 μmol·L-1, among which the new compound 1 was the lowest toxic to L-02 cell and the most selective to Jurkat, HCT-116 and BXPC-3 cells with the selection index (SI) of 31.5, 41.4 and 52.4, respectively. The antifungal activities of 1~6 against Aspergillus fumigatus AF293 were also tested by two-fold dilution method. Compounds 2 and 4 were active against A. fumigatus AF293 with the minimum inhibitory concentration (MIC) values of 3.04 and 6.12 μmol·L-1, respectively. To the best of our knowledge, this is the first time to report the antifungal activity of 5, 5, 6-PTMs against A. fumigatus AF293. Apart from the cytotoxicity of compounds 2 and 3 against A549 and MCF-7 tumor cells lines, the other cytotoxicities were reported here for the first time, indicating the potential use of PTMs as the antitumor and antifungal lead compounds against A. fumigatus.
2017, 37(9): 2361-2368
doi: 10.6023/cjoc201704002
Abstract:
Enterovirus 71 (EV71) is the main pathogen caused Human Hand, Foot and Mouth Disease (HFMD) in China. It not only caused mild case, but also serious case. However, no effective commercialize drugs for the treatment of HFMD were available nowadays. TJAB1099 is an effective EV71 inhibitor which was designed based on the capsid protein VP1 of EV71. The preclinical study has revealed that it owns excellent druggability. Here an practical synthesis of TJAB1099, initiated with 2-amino-4-bromide pyridine is reported. The total synthetic steps are six and its total yield is 12%. The purity of TJAB1099 is more than 99%, and silic gel chromatography is not required in the whole process. This synthetic method has been examined by hectogram level starting feeding for several times, and the total yield and the content of impurities are stable. This method could meet the need of the inhibitor amount for the preclinical study, and it could lay the foundation of further large scale synthesis.
Enterovirus 71 (EV71) is the main pathogen caused Human Hand, Foot and Mouth Disease (HFMD) in China. It not only caused mild case, but also serious case. However, no effective commercialize drugs for the treatment of HFMD were available nowadays. TJAB1099 is an effective EV71 inhibitor which was designed based on the capsid protein VP1 of EV71. The preclinical study has revealed that it owns excellent druggability. Here an practical synthesis of TJAB1099, initiated with 2-amino-4-bromide pyridine is reported. The total synthetic steps are six and its total yield is 12%. The purity of TJAB1099 is more than 99%, and silic gel chromatography is not required in the whole process. This synthetic method has been examined by hectogram level starting feeding for several times, and the total yield and the content of impurities are stable. This method could meet the need of the inhibitor amount for the preclinical study, and it could lay the foundation of further large scale synthesis.
2017, 37(9): 2369-2376
doi: 10.6023/cjoc201702016
Abstract:
The preparation of gem-diamine derivatives of phosphonates from α-carbamatemethylphosphonates is reported. In our earlier work, the reaction of sulfone with dialkylphosphonate gave α-carbamatemethylphosphonate as the major product. However, gem-diamine derivative of phosphonate was unexpectedly formed as a side product when decreasing the amount of dialkylphosphonate. Although few reports exist on the synthesis of this unique structure, gem-diamine derivatives have shown potential biological activity as an anti-cancer reagent. After optimization, a methodology for the synthesis of gem-diamine derivatives of α-carbamatemethylphosphonate is provided. The reaction of α-carbamatemethylsulfone with α-carbamatemethylphosphonate using LiOH as a base and commercial petroleum ether as solvent provided gem-diamine derivatives in good to excellent yields. This simple protocol runs under very mild conditions, and has a broad substrate scope.
The preparation of gem-diamine derivatives of phosphonates from α-carbamatemethylphosphonates is reported. In our earlier work, the reaction of sulfone with dialkylphosphonate gave α-carbamatemethylphosphonate as the major product. However, gem-diamine derivative of phosphonate was unexpectedly formed as a side product when decreasing the amount of dialkylphosphonate. Although few reports exist on the synthesis of this unique structure, gem-diamine derivatives have shown potential biological activity as an anti-cancer reagent. After optimization, a methodology for the synthesis of gem-diamine derivatives of α-carbamatemethylphosphonate is provided. The reaction of α-carbamatemethylsulfone with α-carbamatemethylphosphonate using LiOH as a base and commercial petroleum ether as solvent provided gem-diamine derivatives in good to excellent yields. This simple protocol runs under very mild conditions, and has a broad substrate scope.
2017, 37(9): 2385-2391
doi: 10.6023/cjoc201701049
Abstract:
A series of novel octahydro-1H-pyrrolo[3, 2-c]pyridine derivatives were designed and synthesized as C-C chemokine receptor type 5 (CCR5) antagonists, and their biological activity of anti-human immunodeficiency virus type 1 (HIV-1) is evaluated. A majority of these compounds showed anti-HIV-1 activities. Octahydro-1H-pyrrolo[3, 2-c]pyridine derivative 19c exhibited potency against HIV-1 replication less than 1 μmol·L-1. Function assay was employed and the result showed that there were other drug targets for HIV-1 inhibition besides CCR5. In addition, the preliminary structure-activity relationship (SAR) of these compounds was rationalized by docking studies.
A series of novel octahydro-1H-pyrrolo[3, 2-c]pyridine derivatives were designed and synthesized as C-C chemokine receptor type 5 (CCR5) antagonists, and their biological activity of anti-human immunodeficiency virus type 1 (HIV-1) is evaluated. A majority of these compounds showed anti-HIV-1 activities. Octahydro-1H-pyrrolo[3, 2-c]pyridine derivative 19c exhibited potency against HIV-1 replication less than 1 μmol·L-1. Function assay was employed and the result showed that there were other drug targets for HIV-1 inhibition besides CCR5. In addition, the preliminary structure-activity relationship (SAR) of these compounds was rationalized by docking studies.
2017, 37(9): 2392-2398
doi: 10.6023/cjoc201702032
Abstract:
A series of functionalized coumarino[4, 3-d]pyrazolo[3, 4-b]pyridine derivatives 3a~3h were synthesized by the addition and cyclization of 3-acetoacetylcoumarin with 5-aminopyrazole catalyzed by CuSO4. Some of the synthesized compounds had high fluorescence quantum yields. The properties of the compounds with cations such as Ag+, Cr3+, Co2+, Cu2+, Pb2+, Sn4+, Fe3+ and Zn2+ were examined by fluorescence spectroscopy. The results showed that compounds 3a and 3b have selective recognition for Zn2+.
A series of functionalized coumarino[4, 3-d]pyrazolo[3, 4-b]pyridine derivatives 3a~3h were synthesized by the addition and cyclization of 3-acetoacetylcoumarin with 5-aminopyrazole catalyzed by CuSO4. Some of the synthesized compounds had high fluorescence quantum yields. The properties of the compounds with cations such as Ag+, Cr3+, Co2+, Cu2+, Pb2+, Sn4+, Fe3+ and Zn2+ were examined by fluorescence spectroscopy. The results showed that compounds 3a and 3b have selective recognition for Zn2+.
2017, 37(9): 2399-2408
doi: 10.6023/cjoc201702026
Abstract:
Due to isoxazole derivatives possess a wide range of herbicidal, insecticidal and pharmacological activitives, the synthetic methodologies for preparation of isoxazole derivatives have drawn much attention in recent years. Herein, 3, 4-diaryl-5-aryloxymethyl isoxazole derivatives were effectively synthesized from 3-aryl-5-(bromomethyl)isoxazole via consecutive bromination, etherification, followed by Suzuki coupling reaction catalyzed by Pd(PPh3)2Cl2. Preliminary bioassay data showed that some of the title compounds exhibited certain insecticidal activities against Oriental armyworm.
Due to isoxazole derivatives possess a wide range of herbicidal, insecticidal and pharmacological activitives, the synthetic methodologies for preparation of isoxazole derivatives have drawn much attention in recent years. Herein, 3, 4-diaryl-5-aryloxymethyl isoxazole derivatives were effectively synthesized from 3-aryl-5-(bromomethyl)isoxazole via consecutive bromination, etherification, followed by Suzuki coupling reaction catalyzed by Pd(PPh3)2Cl2. Preliminary bioassay data showed that some of the title compounds exhibited certain insecticidal activities against Oriental armyworm.
2017, 37(9): 2377-2384
doi: 10.6023/cjoc201704023
Abstract:
A series of novel 2-amino-4-phenylthiazole derivatives containing amide moiety were designed and synthesized based on the structural features of sorafenib. The structures of synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS. Both the anticancer and antibacterial activities of all the target compounds were evaluated. Most of the compounds showed potent activities, especially N-(3-(2-acetamidothiazol-4-yl)phenyl)-3-fluorobenzamide (4n) exhibited a remarkable antitumor effect against human colon cancer cell line (HT29) and human lung epithelial cells (A549) cells with IC50 values of 6.31 and 7.98 μmol·L-1, respectively. Further mechanistic study revealed that 4n can influence the Raf/MEK/ERK pathway. In addition, N-(3-(2-acetamidothiazol-4-yl)phenyl)-3, 4-dichlorobenzamide (4h), N-(3-(2-acetamidothiazol-4-yl)phenyl)-3-chlorobenzamide (4i) and N-(3-(2-acetamidothiazol-4-yl)phenyl)-2, 4-dichlorobenzamide (4o) exhibit moderate antibacterial activity against the tested bacteria.
A series of novel 2-amino-4-phenylthiazole derivatives containing amide moiety were designed and synthesized based on the structural features of sorafenib. The structures of synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS. Both the anticancer and antibacterial activities of all the target compounds were evaluated. Most of the compounds showed potent activities, especially N-(3-(2-acetamidothiazol-4-yl)phenyl)-3-fluorobenzamide (4n) exhibited a remarkable antitumor effect against human colon cancer cell line (HT29) and human lung epithelial cells (A549) cells with IC50 values of 6.31 and 7.98 μmol·L-1, respectively. Further mechanistic study revealed that 4n can influence the Raf/MEK/ERK pathway. In addition, N-(3-(2-acetamidothiazol-4-yl)phenyl)-3, 4-dichlorobenzamide (4h), N-(3-(2-acetamidothiazol-4-yl)phenyl)-3-chlorobenzamide (4i) and N-(3-(2-acetamidothiazol-4-yl)phenyl)-2, 4-dichlorobenzamide (4o) exhibit moderate antibacterial activity against the tested bacteria.
2017, 37(9): 2409-2415
doi: 10.6023/cjoc201704020
Abstract:
Six linear precursors of linaclotide containing different protected cysteine residues were synthesized by Fmoc solid-phase methods. Wang resin was used in the peptide syntheses. The protective groups of cysteine thiol were trityl (Trt) and acetamidomethyl (Acm) in the different positions. The six linear precursors of linaclotide include three[4 Trt+2 Acm] and three[2 Trt+4 Acm] ones. The linaclotide with three disulfide bonds was prepared from these linear precursors by semiregioselective strategy. Firstly, linear peptides were cleaved from Wang resins by TFA-TIS-H2O. At the same time, the Trt groups were removed to give free thiol groups, whereas Acm groups were still remained in the peptides. Secondly, the free thiol groups were oxidized by 20% hemin/DIEA system to from disulfide bond(s). Finally, cysteines containing Acm groups were deprotected by CH3SiCl3/PhS(O)Ph/TFA coaktail and disulfide bond(s) were formed simultaneously. The precursors of peptides[4 Trt(2, 5, 10, 13)+2 Acm(1, 6)], [2 Trt(1, 6)+4 Acm(2, 5, 10, 13)] and[2 Trt(5, 13)+2 Acm(1, 2, 6, 10)] give linaclotide at the conversion ratios of 71.9%, 31.5%, and 81.4% respectively. Other three peptides failed in the conversion or were found to be less suitable to prepare linaclotide. Our results indicated that the order of disulfide bond formation is very important to prepare linaclotide by using semiregioselective or regioselective strategies. The Cys5-Cys13 disulfide bond is the most privileged and should be formed firstly among the three disulfide bonds in linaclotide.
Six linear precursors of linaclotide containing different protected cysteine residues were synthesized by Fmoc solid-phase methods. Wang resin was used in the peptide syntheses. The protective groups of cysteine thiol were trityl (Trt) and acetamidomethyl (Acm) in the different positions. The six linear precursors of linaclotide include three[4 Trt+2 Acm] and three[2 Trt+4 Acm] ones. The linaclotide with three disulfide bonds was prepared from these linear precursors by semiregioselective strategy. Firstly, linear peptides were cleaved from Wang resins by TFA-TIS-H2O. At the same time, the Trt groups were removed to give free thiol groups, whereas Acm groups were still remained in the peptides. Secondly, the free thiol groups were oxidized by 20% hemin/DIEA system to from disulfide bond(s). Finally, cysteines containing Acm groups were deprotected by CH3SiCl3/PhS(O)Ph/TFA coaktail and disulfide bond(s) were formed simultaneously. The precursors of peptides[4 Trt(2, 5, 10, 13)+2 Acm(1, 6)], [2 Trt(1, 6)+4 Acm(2, 5, 10, 13)] and[2 Trt(5, 13)+2 Acm(1, 2, 6, 10)] give linaclotide at the conversion ratios of 71.9%, 31.5%, and 81.4% respectively. Other three peptides failed in the conversion or were found to be less suitable to prepare linaclotide. Our results indicated that the order of disulfide bond formation is very important to prepare linaclotide by using semiregioselective or regioselective strategies. The Cys5-Cys13 disulfide bond is the most privileged and should be formed firstly among the three disulfide bonds in linaclotide.
