Synthesis of dansyl-labeled probe of thiophene analogue of annonaceous acetogenins for visualization of cell distribution and growth inhibitory activity toward human cancer cell lines.

The convergent synthesis of the dansyl-labeled probe of the thiophene-3-carboxamide analogue of annonaceous acetogenins, which shows potent antitumor activity, was accomplished by two asymmetric alkynylations of the 2,5-diformyl THF equivalent with an alkyne having a thiophene moiety and another alkyne tagged with a dansyl group. The growth inhibitory profiles toward 39 human cancer cell lines revealed that the probe retained the biological function of its mother compound, and would be useful for studying cellular activity.

Thiophene-3-carboxamide analogue of annonaceous acetogenins as antitumor drug lead.

Five novel acetogenin analogues with a furan, thiophene, or thiazole ring were synthesized, and their inhibitory activities toward human cancer cell lines were evaluated. The analogues showed more potent activities than natural acetogenin. One of them, the thiophene-3-carboxamide analogue, strongly inhibited the growth of human lung cancer cell line NCI-H23 in the xenograft mouse assay without critical toxicity.

Structure-activity relationships of hybrid annonaceous acetogenins: powerful growth inhibitory effects of their connecting groups between heterocycle and hydrophobic carbon chain bearing THF ring on human cancer cell lines.

Five novel hybrid molecules of annonaceous acetogenins and insecticides targeting mitochondrial complex I were synthesized and their growth inhibitory activities against 39 human cancer cell lines were investigated. It was revealed that the connecting group between the N-methylpyrazole part and the hydrophobic alkyl chain bearing the THF ring influenced their biological activities significantly. Amide-connected analog 2, in particular, showed selective and very potent activity (<10 nM) against some cancer cell lines.

Critical role of a methyl group on the γ-lactone ring of annonaceous acetogenins in the potent inhibition of mitochondrial complex I.

C34-epi and C34-epi-C35-trifluoro analogues of solamin, a mono-THF annonaceous acetogenin, were synthesized. Their inhibitory activity, along with previously synthesized analogues (C35-fluoro, C35-difluoro, and C35-trifluorosolamins), against bovine mitochondrial NADH-ubiquinone oxidoreductase (complex I) was determined. The present study revealed that the methyl group on the γ-lactone moiety is critical to the potent inhibition of complex I by natural acetogenins.

Dichlorination of olefins with NCS/Ph(3)P.

A 2 : 1 mixture of NCS and Ph(3)P successfully promoted the anti-dichlorination of olefins to provide corresponding dichlorides, serving as a molecular chlorine surrogate generated in situ.

Stereoconvergent route to chiral cyclohexenone building blocks: formal synthesis of (-)-dysidiolide.

A stereoconvergent access to chiral carbocyclic building blocks is reported. 6-(3'-Hydroxy-4'-methylpent-4'-enyl)-3-methoxy cyclohex-2-enone () that consists of four stereoisomers, i.e., racemic ca. 1 : 1 diastereomers, is converted to enantiomerically pure carbocycles through a combination of regioselective catalytic asymmetric reduction and alkylative remote stereoinduction. The present stereoconvergent strategy has allowed the formal synthesis of bioactive (-)-dysidiolide.

Double C-H functionalization in sequential order: direct synthesis of polycyclic compounds by a palladium-catalyzed C-H alkenylation-arylation cascade.

Palladium-catalyzed cascade C-H alkenylation and arylation provides convenient access to polycyclic aromatic compounds. Treatment of 3-bromoaniline derivatives bearing a bromocinnamyl group on the nitrogen atom with a catalytic amount of [Pd(OAc)(2)] and PCy(3)·HBF(4) in the presence of Cs(2)CO(3) in dioxane affords naphthalene-fused indole derivatives in good yields. This double cyclization reaction is also applicable to heterocyclic substrates, giving fused indoles containing a heteroaromatic ring such as dibenzofuran, dibenzothiophene, carbazole, indole, or benzofuran through heterocyclic C-H arylation. When using a 2,6-unsubstituted aniline derivative, the first C-H arylation preferentially proceeds at the more hindered position of the aniline ring.

Intramolecular iron(II)-catalyzed aminobromination of allyl N-tosyloxycarbamates.

Allyl N-tosyloxycarbamates are found to be catalytically transformed into ß-brominated oxazolidinones with FeBr(2)/n-Bu(4)NBr in t-BuOH.

Stereoselective α-quaternization of 3-methoxycycloalk-2-enones via 1,4-diastereoinduction of alkoxy dienolates.

The alkylation of dienolates generated from 3-methoxycycloalk-2-enones having a 3'-hydroxyl alkenyl chain provides the corresponding quaternized cycloalkenones in a highly diastereoselective manner. The high degree of stereocontrol in the α-quaternization possibly implies intervention of a rigid chelating transition state that allows an efficient 1,4-asymmetric induction to take place.

Design and synthesis of C35-fluorinated solamins and their growth inhibitory activities against human cancer cell lines.

The convergent synthesis of C35-fluorinated analogues of solamin, a mono-THF Annonaceous acetogenin, has been achieved by the Sonogashira coupling of the THF ring fragment and the fluorinated γ-lactone fragment. It was revealed that the number of fluorine atoms on the γ-lactone moiety affects the growth inhibitory activities against human cancer cell lines.

Total synthesis of (±)-platencin.

A novel route to (±)-platencin is reported, in which the highly stereoselective alkylative quaternization of a cyclohexenone scaffold via 1,4-diastereoinduction and two radical carbon-carbon bond-forming reactions that involve titanium(III)-mediated cyclization and stannyl-radical-mediated skeletal rearrangement are utilized.

Asymmetric alkynylation of aldehydes with propiolates without high reagent loading and any additives.

The asymmetric alkynylation of aliphatic and aromatic aldehydes with propiolates was mediated by dialkylzinc and a novel prolinol catalyst without high reagent loading and any additives, such as Ti(Oi-Pr)(4), to give the corresponding γ-hydroxy-α,ß-acetylenic esters with high enantiomeric excess of up to 95%.

Total synthesis of (±)-kainic acid: a photochemical C-H carbamoylation approach.

A novel photochemical C-H carbamoylation of an octahydroisoindole derivative with PhNCO has allowed the authors to provide a unique access to a highly functionalized proline motif from which total synthesis of (±)-kainic acid, a bioactive marine alkaloid, has been accomplished.

Asymmetric total synthesis of (+)-danicalipin A.

A convergent asymmetric total synthesis of (+)-danicalipin A is accomplished, in which two chlorinated fragments are stereoselectively joined by 1,3-dipolar coupling, leading to the confirmation of the absolute configuration of the natural product.

Convergent synthesis of fluorescence-labeled probes of Annonaceous acetogenins and visualization of their cell distribution.

The convergent synthesis of fluorescence-labeled solamin, an antitumor Annonaceous acetogenin, was accomplished by two asymmetric alkynylations of 2,5-diformyl tetrahydrofuran with an alkyne tagged with fluorescent groups and another alkyne with an α,ß-unsaturated γ-lactone. Assay for the growth inhibitory activity against human cancer cell lines revealed that the probe with the fluorescent groups at the end of the hydrocarbon chain may have the same mode of action as natural acetogenins. The merged fluorescence of dansyl-labeled solamin and MitoTracker Red suggests that Annonaceous acetogenins localize in the mitochondria.

Synthesis of fused and linked bicyclic nitrogen heterocycles by palladium-catalyzed domino cyclization of propargyl bromides.

The palladium(0)-catalyzed direct construction of bicyclic heterocycles is described. Treatment of propargyl bromides that have nucleophilic functional groups connected by two or three carbon atoms with catalytic [Pd(PPh(3))(4)] affords bis-cyclization products in good yields. The desired bicyclic heterocycles can be obtained selectively when using substrates with appropriate nucleophilic groups. We also describe the reaction of a 2-alkynylazetidine derivative with a catalytic amount of [Pd(PPh(3))(4)] under base-free conditions, which affords the same fused heterocycles as the corresponding propargyl bromides.

Asymmetric total synthesis of (+)-hexachlorosulfolipid, a cytotoxin isolated from Adriatic mussels.

The enantioselective total synthesis of (+)-hexachlorosulfolipid, a cytotoxin found in the Adriatic mussel Mytilus galloprovincialis, is described. The unique chlorinated hydrocarbon motif of the lipid is successfully furnished by a series of dichlorination reactions of chiral epoxides with chlorophosphonium reagent generated in situ from Ph(3)P/NCS. The present total synthesis has allowed the confirmation of the absolute configuration of the natural cytotoxic (+)-hexachlorosulfolipid originally proposed by Fattorusso, Ciminiello, and co-workers.

Construction of linked nitrogen heterocycles by palladium(0)-catalyzed intramolecular domino cyclization of 2-alkynylaziridines bearing a 2-aminoethyl group via ring expansion with isocyanate.

A novel palladium(0)-catalyzed domino cyclization of 2-alkynylaziridines with isocyanates through ring expansion is described. Treatment of N-protected 2-(4-aminobut-1-ynyl)aziridine derivatives with a catalytic amount of Pd(PPh(3))(4) and aryl isocyanates in THF at room temperature affords 4-(4,5-dihydropyrrol-2-yl)imidazolidin-2-one derivatives in good yields. Interestingly, bis-adducts were selectively obtained by use of excess isocyanate (5 equiv) at lower reaction temperature.

Medicinal chemistry of Annonaceous acetogenins: design, synthesis, and biological evaluation of novel analogues.

Most Annonaceous acetogenins are characterized by between one and three THF ring(s) with one or two flanking hydroxyl group(s) in the center of a C32/34 fatty acid, and the terminal carboxylic acid is combined with a 2-propanol unit to form an alpha,beta-unsaturated gamma-lactone. While many studies have addressed the properties and synthesis of natural acetogenins due to their attractive biological activities and unique structural features, a number of analogues have also been described. This review covers the design, synthesis, and biological evaluation of acetogenin analogues.

Total synthesis of the beta-catenin inhibitor, (-)-agelastatin A: a second-generation approach based on radical aminobromination.

The second-generation approach to (-)-agelastatin A has been established. The present strategy features the FeBr(2)-mediated radical cyclization of 2-cyclopentenyloxycarbonyl azide that allows for the stereoselective installation of a cis-vicinal aminobromo functionality suitable for producing the BCD-ring system of agelastatin A. The aminobromination method streamlines access to oxazolidinone, a key intermediate in the previously reported synthesis, thereby culminating in the new total synthesis of (-)-agelastatin A.