Cytotoxic cembranoids from the Red Sea soft coral, Sarcophyton auritum

Chemical investigation of the Red Sea soft coral Sarcophyton auritum led to the isolation and structure elucidation of two new diterpene cembranoids; 2-epi-sarcophine (2) and (1R,2E,4S,6E,8R,11R,12R)-2,6-cembradiene-4,8,11,12-tetrol (4), as well as two known diterpene cembranoids, reported for the first time from this species, namely sarcophine (1) and (+)-7α,8β-dihydroxydeepoxysarcophine (3). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The isolated cembranoids were found to display high cytotoxicity against HepG2 (liver cancer cell line) and MCF-7 (breast cancer cell line).     

Analysis of European oak bark beetle (Scolytus intricatus) extracts using hyphenated and chiral chromatography techniques

Two bioactive compounds, viz. 4-methylheptan-3-ol (I) and 4-methylheptan-3-one (II) have been identified in European oak bark beetle (Scolytus intricatus) extracts by gas chromatography coupled with mass spectrometric and electroantennographic detector systems. Further examination of these compounds using gas chromatography on chiral stationary phases, as well as a comparison with optically active standards proved the absolute configuration of the identified compounds to be (3R,4S)-I and (S)-II. The discovery of (3R,4S)-I and (S)-II as insect-produced compounds in both sexes of S. intricatus constitutes the first reported occurrence in this species.     

Regioselective Baeyer-Villiger lactonization of 2-substituted pyrrolidin-4-one. Synthesis of statine

Nine 2-substituted pyrrolidin-4-ones 4a-i were obtained via a series of functional group transformation of known prolinol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a-i was constructed in the regioselective Baeyer-Villiger lactonization of ketones 4a-i and reduction of the resulting 4-substituted tetrahydro-1,3-oxazin-6-ones 3a-i. A new and straightforward synthesis of (3S,4S)-statine (6) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).     

Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (−)-trolline, (+)-crispin A, (+)-oleracein E

Tetrahydroisoquinoline alkaloids, (S)-(−)-trolline, (R)-(+)-crispin A, and (R)-(+)-oleracein E, have been synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The key step in the synthesis include a stereoselective Bi(OTf)₃-catalyzed intramolecular 1,3-chirality transfer reaction of chiral non-racemic amino allylic alcohols (S)-6 and (R)-6 to construct both enantiomers of (E)-1-propenyl tetrahydroisoquinoline 4.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

The stereoselective synthesis of (E)-octafluoro-1,3,5-hexatriene and (3E,5E,7E)-dodecafluoro-1,3,5,7,9-decapentaene

(E)-(1,2-Difluoro-1,2-ethenediyl)bis[tributylstannane], 3, readily undergoes a Pd(PPh₃)₄/CuI-catalyzed cross-coupling reaction with iodotrifluoroethene to yield (E)-octafluoro-1,3,5-hexatriene, 4, in high isomeric purity. (1Z,3E,5Z)-(1,2,3,4,5,6-Hexafluoro-1,3,5-hexenetriyl)bis[tributylstannane], 7, was sequentially prepared from (1Z,3E,5Z)-(1,2,3,4,5,6-hexafluoro-1,3,5-hexenetriyl)bis[triethylsilane], 5, which was prepared via a Pd(PPh₃)₄/CuI-catalyzed cross-coupling reaction of 3 with (E)-1,2-difluoro-1-iodo-2-triethylsilylethene, 6. Pd(PPh₃)₄/CuI cross-coupling of 7 with iodotrifluoroethene gave (3E,5E,7E)-dodecafluoro-1,3,5,7,9-decapentaene, 8.     

Dioxadispiroketal Compounds and a Potential Acyclic Precursor from Amomum aculeatum

Four new compounds having an unusual 1,7-dioxadispiro[5.1.5.2]-12-ene-11-one tricyclic ring system (1-4), their potential precursor, 5R-hydroxy-1-(4-hydroxyphenyl)-eicosan-3-one (5), and two known compounds, aculeatins A (6) and B (7), have been isolated from Amomum aculeatum. All compounds were characterized by spectroscopic methods and the configurations were established by 2D NOE correlations. Compounds 1-4, 6, and 7 showed cytotoxic activity against several human cancer cell lines.     

Convenient synthesis of 3-fluoro-4,5-diphenylfuran-2(5H)-one from benzoin ethers : Novel and efficient Z-E isomerisation and cyclisation of 2-fluoroalkenoate precursors, substitution of vinylic fluorine

Mixtures of ethyl (E)- and (Z)-4-alkoxy-2-fluoro-3,4-diphenylbut-2-enoates (6-8) prepared from benzoin ethers and ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate were transformed in high yields to the target 3-fluoro-4,5-diphenylfuran-2(5H)-one (14) using bromine in tetrachloromethane at room temperature. The non-cyclisable Z-isomers 6b-8b were gradually isomerised to the cyclisable E-isomers 6a-8a during the process. The reaction of the (E)-butenoates 6a-8a with boron trifluoride led to furanone 14, while in Z-isomers 6b-8b both alkoxy group and vinylic fluorine were substituted with bromine during the reaction. Mechanisms for both complex reactions have been proposed. Furanone 14 was transformed to 2-[tert-butyl(dimethyl)silyloxy]-3-fluoro-4,5-diphenylfuran (18) as a novel building block.     

Synthesis and characterization of polybinaphthalene incorporating chiral (R) or (S)-1,1′-binaphthalene and oxadiazole units by Heck reaction

Chiral conjugated polymers P-1 and P-2 were synthesized by the polymerization of (R)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((R)-M-1) and (S)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((S)-M-1) with 2,5-bis(4-vinylphenyl)-1,3,4-oxadiazole (M-2) under Pd-catalyzed Heck coupling reaction, respectively. Both monomers and polymers were analysed by NMR, MS, FT-IR, UV, DSC-TG, fluorescent spectroscopy, GPC and CD spectra. The chiral conjugated polymers exhibit strong Cotton effect in their circular dichroism (CD) spectra indicating a high rigidity of polymer backbone. CD spectra of polymers P-1 and P-2 are almost identical and have opposite signs for their position. These polymers have strong blue fluorescence.     

Chemistry of xanthorrhizol: synthesis of several bisabolane sesquiterpenoids from xanthorrhizol

(−)-Xanthorrhizol (1) isolated from the rhizomes of Curcuma xanthorrhiza has been transformed to several bisabolane-type sesquiterpenoids, in a stereoselective manner. 10R- and 10S-10,11-dihydro-10,11-dihydroxyxanthorrhizols (2, 3), (−)-curcuquinone (4), (−)-curcuhydroquinone (5), helibisabonol A (7) and allylic alcohol 8 have been prepared from xanthorrhizol in optically active forms. All the routes involved a Sharpless AD to introduce the stereogenic centre at C-10.     

Synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone

Radical-mediated opening of a chiral trisubstituted epoxy alcohol using cp₂TiCl furnished the ‘2-methyl-1,3-diol’ moiety with the desired stereochemistry, which led to a total synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone 1.     

Optically active cyclopentadienyl and indenyl ligands obtained from lactic acid esters

Asymmetric cyclopentadienes and indenes are easily prepared by nucleophilic attack of LiCp or LiInd on tosylate or triflate of ethyl (S)-(−) lactate. The selectivity of the reaction depends on the nature of the leaving group. This is particularly true in the case of the reaction of LiCp with sulfonates of ethyl (S)-(−) lactate. Indeed, only the monosubstituted cyclopentadiene lactate 2 is obtained from the triflate 6, whereas from the tosylate 1, besides 2 (20%) a 1,3-disubstituted cyclopentadiene lactate 3 is isolated (16.5%). From cyclopentadiene and indene lactate 2 and 7, optically active β-hydroxycyclopentadiene 10 and β-hydroxyindene 11 are obtained by reduction with LiAlH₄. Two rhodium(I) complexes 14 and 15 have been synthesized from (R,S)-2-(cyclopentadienyl)N,N-dimethylpropanamide 12 and (S)-2-(cyclopentadiene)propan-1-ol 10, respectively. The molecular structure of these complexes has been determined. Analytical and preparative chiral HPLC have been used to determine the optical purity of the ligands and to isolate enantiopure cyclopentadienyl complexes from racemic or enantiomerically enriched rhodium(I) complexes.     

Determination of the absolute structure of albaconol

The concise synthesis of (8aR)-(−)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison of the sign of specific rotation of between synthetic (8aR)-(−)-albaconol (1) and natural (+)-albaconol (1), the absolute structure of natural (+)-1 was determined to be 1R,2R,4aS,8aS configuration.     

Palladium(II) and palladium(0)-cocatalyzed ring opening and oxidation reactions of 2-(arylmethylene)cyclopropylcarbinols

In the presence of Pd(II) acetate and triethylamine as well as triphenylphosphine, 2-(arylmethylene)cyclopropylcarbinols 1 underwent ring opening and oxidation reactions smoothly to deliver (2E,4E)-5-arylpenta-2,4-dienals 2 in toluene at 60 °C in moderate to good yields under ambient atmosphere. Mechanisms involved with an in situ generated Pd(0) species from Pd(II) and Et₃N or PPh₃ catalyzed isomerization of 1 to provide (E,E)-5-arylpenta-2,4-dien-1-ols 3 and following a Pd(II) catalyzed aerobic oxidation of 3 have been proposed on the basis of control and deuterium labeling experiments.     

Biomimetically inspired total synthesis of (12S)-12-hydroxymonocerin and (12R)-12-hydroxymonocerin

A concise asymmetric total synthesis of (12S)-12-hydroxymonocerin (1) and (12R)-12-hydroxymonocerin (2) were efficiently achieved from the known 4-bromo-2,6-dimethoxyphenol. The synthetic approach was inspired by our biomimetic synthesis of (+)-monocerin (3) and 7-O-demethylmonocerin (4). The cis-fused furobenzopyranones of 1 and 2 was efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of compound 10 using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).     

Synthesis of l-azaisotryptophan and its analogs: a general access to new 2-substituted azaindoles

l-(N-Cbz)-7-azaisotryptophan, l-(N-Cbz)-1a, a new isostere of tryptophan, was synthesized by reacting Li₂-(N-Boc)-2-amino-3-picoline, Li₂-(N-Boc)-2a, with appropriately protected l-aspartic acid followed by simple functional group manipulation. This synthetic success led us to access a set of analogs of azaisotryptophan (4a–c; 6a–c) as well as a new class of chiral amines (7a–c; 8a–c) for future application in asymmetric synthesis and design of homochiral ligands. Further, we have generalized the method substantiating a variety of new azaindol-2-yl derivatives (10aa–10lc) with functionalized substituents. In a preliminary luminescence characterization, l-(N-Cbz)-1a has exhibited about 30 nm bathochromic shifted fluorescence emission compared to tryptophan and (N-Cbz)-tryptophan.     

Facile and clean synthesis of α-alkenoyl ketene-(S,S)-acetals via the aldol condensation reactions in water

The aldol condensation reactions of α,α-diacetyl ketene-(S,S)-acetals, 1a and 1b, with aromatic aldehydes 2 in the presence of NaOH in water have been investigated. At room temperature, the base-mediated condensations proceed smoothly to afford the corresponding mono-condensed products, α-alkenoyl ketene-(S,S)-acetals 3, in high yields. At reflux temperature, the reactions produce high yields of symmetric double condensed α,α-dialkenoyl ketene-(S,S)-acetals 4 when 2 equiv of aldehyde are employed. Moreover, compounds 3 can condense with a different aldehyde to give unsymmetric double condensed α,α-dialkenoyl ketene-(S,S)-acetals 5.     

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.     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

Chiral self-assembly of triorganotin complexes: Syntheses, characterization, crystal structures and antitumor activity of organotin(IV) complexes containing (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid ligands

Six new chiral triorganotin(IV) complexes, {(R₃Sn)₂[C₃H₆(COO)₂]}_n (R = Me: 1; Bu: 2), {(R₃Sn)₂[C₄H₈(COO)₂]}_n (R = Me: 3; Bu: 4), and {(R₃Sn)₂[C₂H₄O(COO)₂]}_n (R = Me: 5; Bu: 6) have been prepared by treatment of (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid, with the corresponding R₃SnCl (R = Me, Bu) and sodium ethoxide in methanol. All the complexes were characterized by elemental analysis, FT-IR, NMR (¹H, ¹³C, ¹¹⁹Sn) spectroscopy and TGA. Except for 3, all of the complexes were also characterized by X-ray crystallography. The structural analyses reveal that complexes 1 and 5 have 2D network structures in which (R)-(+)-methylsuccinic acid and l-(−)-malic acid act as tetradentate ligands coordinated to trimethyltin(IV) ions. Complexes 2 and 4 have 3D metal-organic framework structures in which the deprotoned acids serve as tetradentate ligands. Complex 6 adopts a 1D zigzag chain structure and forms a 2D supramolecular framework through intermolecular C-H?O interactions. In addition, the antitumor activities of complexes 1-6 have been studied. We also have measured the specific rotation of the chiral dicarboxylic acids and the organotin derivatives.