THF Moiety Research Articles

Targeting Carbohydrate Mimetics of Tetrahydrofuran-Containing Acetogenins to Prostate Cancer.

The high potency of the tetrahydrofuran-containing acetogenins (THF-ACGs) against a broad range of human cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-ACG mimetics in which the THF and butenolide moieties of a mono-THF-ACG were replaced with carbohydrate and thiophene residues, respectively. In the present study, towards the targeting of these carbohydrate analogues to prostate cancer (PCa), we synthesized prodrugs in which a parent thiophene or butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA), a highly specific ligand for prostate-specific membrane antigen (PSMA), which is overexpressed on prostate tumors. Both prodrugs were found to be more active against receptor positive LNCaP than receptor-negative PC-3 cells, with 2.5 and 12 times greater selectivity for the more potent thiophene analog and the less active butenolide congener, respectively. This selectivity for LNCaP over PC-3 contrasted with the behavior of the parent drugs, which showed similar or significantly higher activity for PC-3 compared to LNCaP. These data support the notion that higher activity of these DUPA-derived prodrugs against LNCaP cells is connected to their binding to PSMA and suggest that the conjugation of PSMA ligands to this family of cytotoxic agents may be effective for targeting them to PCa.

Synthesis of carbohydrate analogues of the THF-acetogenin 4-deoxyannomontacin and their cytotoxicity against human prostate cancer cell lines

The THF containing acetogenin 4-deoxyannonmontacin (4-DAN) has attracted interest for its potent cytotoxicity against a broad range of human tumor cell lines, and relatively simple structure. Herein is described the synthesis and cytotoxicity of C-10 epimers of 4-DAN and analogues thereof comprising carbohydrate and thiophene substitutes for the THF and butenolide moieties respectively. The key synthetic ploy was the union of THF and butenolide segments or their substitutes, via an alkene cross metathesis. The different analogues showed cytotoxicity in the low micromolar to nanomolar range against the human prostate cancer cell lines LNCaP and PC3. A relatively simple mannose-linked thiophene analog was found to be similar in activity to 4-DAN.

Synthesis and Olfactory Properties of Seco-Analogues of Lilac Aldehydes.

Lilac aldehydes are considered as principal olfactory molecules of lilac flowers. We have designed, prepared, and evaluated a set of racemic seco-analogues of such natural products. The synthesis employs commercially available α-chloroketones as substrates that are transformed in four steps to target compounds. Their qualitative olfactory analysis revealed that the opening of the tetrahydrofuran ring leads to a vanishing of original flowery scent with the emergence of spicy aroma accompanied by green notes, and/or fruity aspects of novel seco-analogues. These results suggest the important osmophoric role of THF moiety for the generation of the typical flowery aroma associated with lilac aldehydes.

The distinctively singular self-assembly of a “molecular stair”: observation of a quadrilateral C–H⋯O hydrogen bonding cycle in the crystal structure of a tetracyclic oligo-tetrahydrofuran

A comparative analysis of the crystal structures of three structurally related molecular stairs has identified a rare C–H⋯O H-bonding motif and revealed the significant role played by the peripheral THF moieties in their modes of self-assembly.

Total synthesis of (-)-bucidarasin a starting from an original chiral building block.

The highly stereoselective total synthesis of (-)-bucidarasin A, which also elucidated the absolute structure of its natural form, is described. The total synthesis features effective use of the original chiral building block prepared by us and a series of highly stereoselective reactions, i.e., hydroxy-directed hydrogenation, [4 + 2] cycloaddition of a sterically hindered dienophile, reduction of ketones, formation of the C9 side-chain diene, and formation of the THF moiety bearing two acetyloxy groups.

Diastereoselective one-pot Wittig olefination–Michael addition and olefin cross metathesis strategy for total synthesis of cytotoxic natural product (+)-varitriol and its higher analogues

A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a-j) of this molecule. The key features of the synthetic strategy include one-pot Wittig olefination followed by a highly diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous analogues of the title natural product for drug development.

Synthesis of the gymnodimine tetrahydrofuran core through a Ueno–Stork radical cyclization

A straightforward access to the C10-C20 skeleton of gymnodimine, incorporating a tetrahydrofuran fragment, is described. The elaboration of the THF moiety is based on a stereocontrolled Ueno-Stork cyclization. A Lewis-acid mediated allylation of the resulting acetal at C13 and a Horner-Wadsworth-Emmons olefination on the ketone at C17 complete the synthesis.

Epoxide‐Hydrolase‐Initiated Hydrolysis/Rearrangement Cascade of a Methylene‐Interrupted Bis‐Epoxide Yields Chiral THF Moieties without Involvement of a “Cyclase”

In contrast with electrophilic enzyme-catalysed cyclisations in terpenoid biosynthesis, cyclisations of tetrahydrofuran moieties found in several groups of natural products, such as annonaceous acetogenins, neurofurans and phytooxylipins, appear to proceed through a nucleophilic cascade mechanism starting from bis-epoxy fatty acid precursors. This hypothesis was verified by epoxide-hydrolase-catalysed hydrolytic ring-opening/cyclisation cascades starting from a methylene-interrupted meso-bis-epoxide model substrate, which furnished the corresponding THF products with excellent de and ee values. Molecular modelling showed that the points of enzyme attack were consistent with the stereospecificities of the enzymes, whereas the stereochemical courses of the cyclisation were solely governed by Baldwin's rules and did not invoke the involvements of a "cyclase".

Anti-Oligoannelated THF Moieties: Synthesis via Push−Pull-Substituted Cyclopropanes

The first synthesis of anti-fused oligoannelated THF moieties is reported. The key transformation of the synthetic sequence, consisting of cyclopropanation, reduction and oxidation, is the expansion of a push-pull-substituted three-membered ring into a five-membered enol ether system. A repetition of the sequence allows the creation of oligoacetals up to a nonacyclic system.

Synthesis and structures of some new types of lithium β-diketiminates

The tetracyclic dilithio-Si,Si'-oxo-bridged bis(N,N'-methylsilyl-beta-diketiminates) 2 and 3, having an outer LiNCCCNLiNCCCN macrocycle, were prepared from [Li{CH(SiMe(3))SiMe(OMe)(2)}](infinity) and 2 PhCN. They differ in that the substituent at the beta-C atom of each diketiminato ligand is either SiMe(3) (2) or H (3). Each of and has (i) a central Si-O-Si unit, (ii) an Si(Me) fragment N,N'-intramolecularly bridging each beta-diketiminate, and (iii) an Li(thf)(2) moiety N,N'-intermolecularly bridging the two beta-diketiminates (thf = tetrahydrofuran). Treatment of [Li{CH(SiMe(3))(SiMe(2)OMe)}](8) with 2Me(2)C(CN)(2) yielded the amorphous [Li{Si(Me)(2)((NCR)(2)CH)}](n) [R = C(Me)(2)CN] (4). From [Li{N(SiMe(3))C(Bu(t))C(H)SiMe(3)}](2) (A) and 1,3- or 1,4-C(6)H(4)(CN)(2), with no apparent synergy between the two CN groups, the product was the appropriate (mu-C(6)H(4))-bis(lithium beta-diketiminate) 6 or 7. Reaction of [Li{N(SiMe(3))C(Ph)=C(H)SiMe(3)}(tmeda)] and 1,3-C(6)H(4)(CN)(2) afforded 1,3-C(6)H(4)(X)X' (X =CC(Ph)N(SiMe3)Li(tmeda)N(SiMe3)CH; X' = CN(SiMe3)Li(tmeda)NC(Ph)=C(H)SiMe3)(9). Interaction of A and 2[1,2-C(6)H(4)(CN)(2)] gave the bis(lithio-isoindoline) derivative [C6H4C(=NH)N{Li(OEt2)}C=C(SiMe3)C(Bu(t))=N(SiMe3)]2 (5). The X-ray structures of 2, 3, 5 and 9 are presented, and reaction pathways for each reaction are suggested.

Synthesis, characterization, and reactivity of the first hafnium alkyl complex stabilized by amidate ligands

A photo and thermally stable bis(amidate)–dibenzyl complex of Hf ([DMP(NO)Ph]2Hf(CH2Ph)2(THF) (2a) was formed as a monosolvated THF adduct in near quantitative yield from Hf(CH2Ph)4 and N-2,6-dimethylphenyl(phenyl)amide (1). Isomerization between the THF-bound product and the THF-free product can be observed visually by the conversion from a red-orange product at low temperatures to a pale yellow product at high temperatures. Solid-state crystallographic characterization of the orange product confirmed its constitution as a monosolvated species. Kinetic parameters for the exchange of the THF moiety were determined from variable-temperature NMR experiments. The product of the hydrolysis of the Hf dibenzyl species by water was characterized by X-ray crystallography, and was found to be a rare tetrametallic Hf oxo cluster species (3).Key words: hafnium, protonolysis, amidate, coordination chemistry, organometallic chemistry, exchange processes.

Structural Characterization of an Etheno-2‘-deoxyguanosine Adduct Modified by Tetrahydrofuran

The reaction of 2'-deoxyguanosine with the alpha,beta-unsaturated aldehydes trans-2-octenal, trans-2-nonenal, trans-2-decenal, trans,trans-2,4-nonadienal, and trans,trans-2,4-decadienal in THF gives rise to three novel adducts: 3-(2'-deoxy-beta-D-erythro-pentafuranosyl)-7-[3-hydroxy-1-(3-(2'-deoxy-beta-D-erythro-pentafuranosyl)-3,5-dihydro-imidazo[1,2-a]purin-9-one-7-yl)-propyl]-3,5-dihydro-imidazo[1,2-a]purin-9-one (A7) and 3-(2'-deoxy-beta-D-erythro-pentafuranosyl)-7-(tetrahydrofuran-2-yl)-3,5-dihydro-imidazo[1,2-a]purin-9-one (A8 and A9), which are not observed in the absence of THF. These adducts were isolated from in vitro reactions by reversed-phase HPLC and fully characterized on the basis of spectroscopic measurements. Adduct A7 consists of two 1,N2-etheno-2'-deoxyguanosine (1,N2-epsilon dGuo) residues linked to a hydroxy-carbon side chain; adducts A8 and A9 are interconvertible 1,N2-epsilon dGuo derivatives bearing a THF moiety. The proposed reaction mechanism involves the electrophilic attack on 1,N2-epsilon dGuo by the carbonyl of 4-hydroxy-butanal, generated via ring opening of alpha-hydroxy-THF (THF-OH), yielding adducts A8 and A9. A further combination of these adducts with another 1,N2-epsilon dGuo produces the double adduct A7. These findings demonstrate that reactions of unsaturated aldehydes in the presence of THF produce novel condensation 1,N2-epsilon dGuo-THF adducts. Further studies would indicate the relevance of these adducts in THF toxicity.

Heterodicarba-nido-hexaboranes from Hydroborations of Exocyclic Unsaturated Heterodiborolanes

The hydroboration of 1-aza-2,5-diduryl-3,4-diisopropylidene- and 2,5-diduryl-1-thia-3,4-diisopropylidene-2,5-diborolanes (1b, 2b) with equimolar amounts of BH3·thf leads to the corresponding 2-aza-4,5-dicarba- and 4,5-dicarba-2-thia-nido-hexaboranes 3c and 4e. When an excess of BH3·thf reacts with the azadiborolane 1b the azadiborole derivative 5 is obtained as the main product. This surprising result is explained by the addition of three BH3·thf moieties and the subsequent loss of B3H7·thf. The reaction of the sterically less hindered tert-butylazadiborolane 1c with BH3·thf yields two 2-aza-4,5-dicarba-nido-hexaboranes (3d,e), both of which carry a tBu group in the apical position. A possible reaction pathway is suggested. The new heterocarboranes 3c,d,e and 4e are identified by multinuclear NMR spectroscopy and mass spectrometry. X-ray crystallographic studies of 3c and 4e confirm the nido-arrangement of the cluster atoms.

Synthesis of an aprotic polar polymer with tetrahydrofuran moiety: Copolymer composition control in radical copolymerization with styrene using suspension system

A method to control the copolymer composition in suspension polymerizations of monomers with different polarity was studied: the copolymerization of a styrene-type monomer having THF moiety (1) with styrene (feed ratio 1 : 1) was carried out at 85 °C using benzoyl peroxide (BPO) in a suspension system consisting of water and monochlorobenzene. The copolymerization was greatly affected by a mixture ratio of suspension system, and when the H2O : PhCl ratio was 7 : 1 (v/v), 1 and St were consumed almost at the same rate, which suggested the formation of a random copolymer with uniform composition. The copolymer was proven to have an identical structure as expected, and a composition ratio of 1 : 1 by 1H NMR analysis and elemental analysis. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 453–458, 2001

Synthesis of an aprotic polar polymer with tetrahydrofuran moiety: Copolymer composition control in radical copolymerization with styrene using suspension system

A method to control the copolymer composition in suspension polymerizations of monomers with different polarity was studied: the copolymerization of a styrene-type monomer having THF moiety (1) with styrene (feed ratio 1 : 1) was carried out at 85 °C using benzoyl peroxide (BPO) in a suspension system consisting of water and monochlorobenzene. The copolymerization was greatly affected by a mixture ratio of suspension system, and when the H2O : PhCl ratio was 7 : 1 (v/v), 1 and St were consumed almost at the same rate, which suggested the formation of a random copolymer with uniform composition. The copolymer was proven to have an identical structure as expected, and a composition ratio of 1 : 1 by 1H NMR analysis and elemental analysis. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 453–458, 2001

Synthesis and cytotoxic activity of acetogenin analogues

A set of 16 new simplified analogues of acetogenins has been designed based on: (i) the replacement of the bis THF moiety of these natural products by an ethylene glycol bis ether unit; (ii) the introduction of different lipophilic side chains (alkyl, aryl, dialkylamino, O-cholesteryl); (iii) the presence of the same terminal isolactone. In vitro cytotoxic activity against L1210 leukemia is reported.

Utilization of Transition-Metal Properties To Control Polyborane Formation. Synthesis of thearachno-Diiridahexaborane(12) 2,5-{Cp*IrH}2B4H8and Its Conversion to thenido-Diiridahexaborane(10) 1,2-{Cp*Ir}2(μ-H)B4H7(Cp* = η5-C5Me5)

Metal-assisted borane condensation is demonstrated by the formation of the hexaborane(12) analogue arachno-2,5-{Cp*IrH}2B4H8 (3) by the reaction of two BH3·THF moieties with the metal centers of the tetraborane(10) analogue {Cp*IrH}2(μ-H)B2H5 (1). Mild thermolysis of 3, which contains separated B2H4 fragments, results in H2 elimination and the formation of the hexaborane(10) analogue nido-1,2-{Cp*Ir}2(μ-H)B4H7 (2), containing a contiguous B4H7 fragment.

Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I

The annonaceous acetogenins are the most potent of the known inhibitors of bovine heart mitochondrial complex I. These inhibitors act, at the terminal electron transfer step of the enzyme, in a similar way to the usual complex I inhibitors, such as piericidin A and rotenone; however, structural similarities are not apparent between the acetogenins and these known complex I inhibitors. A systematic set of isolated natural acetogenins was prepared and examined for their inhibitory actions with bovine heart mitochondrial complex I to identify the essential structural factors of these inhibitors for the exhibition of potent activity. Despite their very potent activity, the structural requirements of the acetogenins are not particularly rigid and remain somewhat ambiguous. The most common structural units, such as adjacent bis-tetrahydrofuran (THF) rings and hydroxyl groups in the 4- and/or 10-positions, were not essential for exhibiting potent activity. The stereochemistry surrounding the THF rings, surprisingly, seemed to be unimportant, which was corroborated by an exhaustive conformational space search analysis, indicating that the model compounds, with different stereochemical arrangements around the THF moieties, were in fairly good superimposition. Proper length and flexibility of the alkyl spacer moiety, which links the THF and the α,β-unsaturated γ-lactone ring moieties, were essential for the potent activity. This probably results from some sort of specific conformation of the spacer moiety which regulates the two ring moieties to locate into an optimal spatial position on the enzyme. It is, therefore, suggested that the structural specificity of the acetogenins, required for optimum inhibition, differs significantly from that of the common complex I inhibitors in which essential structural units are compactly arranged and conveniently defined. The structure–activity profile for complex I inhibition is discussed in comparison with those for other biological activities.

ChemInform Abstract: Synthesis of the THF Moiety of Annonacin Based on Aldolization and Baeyer‐Villiger Oxidation.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of the THF moiety of annonacin based on aldolisation and Baeyer-Villiger oxidation

Anti aldolisation of cyclohexanone with an E or Z γ,δ-unsaturated aldehyde followed by epoxidation-cyclisation and stereoselective Baeyer-Villiger oxidation affords key THF synthons of annonaceous acetogenins related to the annonacin type. Erythro (or threo)-trans (or cis)-threo diastereoisomers are thus obtained in only 6 steps.