Diketo Compounds Research Articles

Polymer‐Supported Phosphoric‐Acid Catalysed Enantioselective Pictet‐Spengler Cyclisation for the Synthesis of Quaternary Tryptolines in Batch/Continuous Flow

AbstractThe enantioselective Pictet‐Spenlger reaction of tryptamines and diketo compounds catalyzed by a polymer‐supported phosphoric acid (TRIP) has been accomplished for the first time in continuous flow. Using this approach, a diverse library of quaternary tryptolines has been synthesized in 36–95% yield with 39–99% enantiomeric excess. The scalability of the reaction has been demonstrated in continuous flow, with a residence time of only 24 minutes. The robust immobilized catalyst has been recycled and reused multiple times in batch and flow. The synthesis of the chiral precursors of Tadalafil, the Iboga‐type alkaloid (+)‐Tabertinggine and antimalarial spiroindolinones has been achieved in batch and continuous‐flow.magnified image

Expanding the Diversity of Pyridines Through Annulation of Keto and Diketo Compounds

AbstractAn efficient gold [Au]‐catalyzed one‐pot synthesis has been developed for the construction of biologically interesting mono‐ and bipyridines by utilizing the commercially available cyclic ketones and propargylamine in a sealed tube. The formation of bipyridine derivative 21 a indicates that annulation followed by retro‐Diels–Alder reaction is occurring with norbornene system. However, keto‐derivatives containing bicyclo[2.2.2]octene system 25 indicate that retro‐Diels–Alder reaction is not facile. Compounds 32 a and 33 a were subjected to ring opening cross‐ metathesis to generate diversity and further functionalization of pyridine derivatives.

Synthesis of cis-Oriented Vicinal Diphenylethylenes through a Lewis Acid-Promoted Annulation of Oxotriphenylhexanoates.

This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoates. The reaction is a BBr3-promoted cyclization of 1,6-ketoesters (1) to five-membered diketo compounds (2). The synthesis is interesting as it constitutes one of the few examples of modular stereoselective synthesis of structures with a cis-oriented vicinal diphenylethylene. The core structure of 2 can be smoothly derivatized, which makes it a promising synthetic building block for further stereoselective synthetic applications.

Metal- and Base-Free Combinatorial Reaction for C-Acylation of 1,3-Diketo Compounds in Vegetable Oil: The Effect of Natural Oil

C-acylation of 1,3-diketo compounds has been done successfully employing 1,3 diketo compounds, oxalyl chloride, and phenol derivatives through metal, base, and toxic solvent-free protocol. Dioxinon...

Mutational Analysis of the Binding Pockets of the Diketo Acid Inhibitor L-742,001 in the Influenza Virus PA Endonuclease

The influenza virus PA endonuclease, which cleaves capped host pre-mRNAs to initiate synthesis of viral mRNA, is a prime target for antiviral therapy. The diketo acid compound L-742,001 was previously identified as a potent inhibitor of the influenza virus endonuclease reaction, but information on its precise binding mode to PA or potential resistance profile is limited. Computer-assisted docking of L-742,001 into the crystal structure of inhibitor-free N-terminal PA (PA-Nter) indicated a binding orientation distinct from that seen in a recent crystallographic study with L-742,001-bound PA-Nter (R. M. DuBois et al., PLoS Pathog. 8:e1002830, 2012). A comprehensive mutational analysis was performed to determine which amino acid changes within the catalytic center of PA or its surrounding hydrophobic pockets alter the antiviral sensitivity to L-742,001 in cell culture. Marked (up to 20-fold) resistance to L-742,001 was observed for the H41A, I120T, and G81F/V/T mutant forms of PA. Two- to 3-fold resistance was seen for the T20A, L42T, and V122T mutants, and the R124Q and Y130A mutants were 3-fold more sensitive to L-742,001. Several mutations situated at noncatalytic sites in PA had no or only marginal impact on the enzymatic functionality of viral ribonucleoprotein complexes reconstituted in cell culture, consistent with the less conserved nature of these PA residues. Our data provide relevant insights into the binding mode of L-742,001 in the PA endonuclease active site. In addition, we predict some potential resistance sites that should be taken into account during optimization of PA endonuclease inhibitors toward tight binding in any of the hydrophobic pockets surrounding the catalytic center of the enzyme.

Structural Analysis of Specific Metal Chelating Inhibitor Binding to the Endonuclease Domain of Influenza pH1N1 (2009) Polymerase

It is generally recognised that novel antiviral drugs, less prone to resistance, would be a desirable alternative to current drug options in order to be able to treat potentially serious influenza infections. The viral polymerase, which performs transcription and replication of the RNA genome, is an attractive target for antiviral drugs since potent polymerase inhibitors could directly stop viral replication at an early stage. Recent structural studies on functional domains of the heterotrimeric polymerase, which comprises subunits PA, PB1 and PB2, open the way to a structure based approach to optimise inhibitors of viral replication. In particular, the unique cap-snatching mechanism of viral transcription can be inhibited by targeting either the PB2 cap-binding or PA endonuclease domains. Here we describe high resolution X-ray co-crystal structures of the 2009 pandemic H1N1 (pH1N1) PA endonuclease domain with a series of specific inhibitors, including four diketo compounds and a green tea catechin, all of which chelate the two critical manganese ions in the active site of the enzyme. Comparison of the binding mode of the different compounds and that of a mononucleotide phosphate highlights, firstly, how different substituent groups on the basic metal binding scaffold can be orientated to bind in distinct sub-pockets within the active site cavity, and secondly, the plasticity of certain structural elements of the active site cavity, which result in induced fit binding. These results will be important in optimising the design of more potent inhibitors targeting the cap-snatching endonuclease activity of influenza virus polymerase.

Synthesis, biological evaluation and molecular modeling studies of quinolonyl diketo acid derivatives: New structural insight into the HIV-1 integrase inhibition

New quinolonyl diketo acid compounds bearing various substituents at position 6 of the quinolone scaffold were designed and synthesized as potential HIV-1 integrase inhibitors. These new compounds were evaluated for their antiviral and anti-integrase activity and showed inhibitory potency similar to that of 6-bromide analog 2. Molecular modeling and docking studies were performed to rationalize these data and to provide a detailed understanding of the mechanism of inhibition for this class of compounds.

Properties of homo- and heteronuclear mixed biscarbene complexes with conjugated bithiophene units

Abstract The syntheses and structures of homo- and heteronuclear biscarbene complexes with bithiophene spacers were investigated. The complexes were synthesized by lithiation of bithiophene followed by metallation using combinations of the metal precursors MnMeCp(CO)3, W(CO)6, Mo(CO)6 and Cr(CO)6, after which the reaction was quenched with triethyloxonium tetrafluoroborate. This classical Fischer method yielded monocarbene complexes, [MLnC(OEt)C4H2S–C4H3S], ([MLn] = Cr(CO)5 1a, W(CO)5 2a or MnMeCp(CO)2 3a), homonuclear biscarbene complexes, [MLnC(OEt)C4H2S–C4H2SC(OEt)MLn], ([MLn] = Cr(CO)5 1b, W(CO)5 2b or MnMeCp(CO)2 3b) and heteronuclear biscarbene complexes, [MLnC(OEt)C4H2S–C4H2SC(OEt)M′Ln] (1d: [MLn] = Cr(CO)5 and [M′Ln] = W(CO)5; 1e: [MLn] = MnMeCp(CO)2 and [M′Ln] = Cr(CO)5; 1f: [MLn] = Cr(CO)5 and [M′] = Mo(CO)5); 2d: [MLn] = MnMeCp(CO)2 and [M′Ln] = W(CO)5; 3c: [MLn] = MnMeCp(CO)2 and [M′Ln] = Mo(CO)5). Electron density calculations with the gaussian 03 software package of 1e revealed a polar rod with the negative pole towards the chromium carbene side, whereas the biscarbenes 1d and 1b showed very little polarity. By-products resulting from activation of the carbene moieties in homonuclear biscarbene complexes included (i) ester-type complexes of the form [MLnC(OEt)C4H2S–C4H2SC(O)OEt], ([MLn] = Cr(CO)5 1c or W(CO)5 2c), formed in situ in the reaction of 1b and 2b, (ii) the organic bis-ester compound [EtOC(O)C4H2S–C4H2SC(O)OEt] 4, where both metal moieties had been substituted by oxygen and (iii) the carbon–carbon coupled dimeric bithienyl compound [C4H3S–C4H2SC(O)C(O)C4H2S–C4H3S] 5. By-products obtained from heteronuclear biscarbene reactions contain the former diketo compound (or a derivative) as spacer between two metal carbonyl fragments and have the general formula [MLnC(OEt)C4H2S–C4H2SCR–CR′C4H2S–C4H2SC(OEt)MLn] (5a: [M] = Cr(CO)5, R = OH, R′ = OEt; 5b: [M] = W(CO)5, R = R′ = O; 5c: [M] = Mo(CO)5, R = R′ = O). Reaction of 1d, 1e and 1f with hex-3-yne resulted in the formation of benzannulated products 6a, 6b and 6c. All novel complexes were fully characterized using various spectroscopic techniques. The crystal structures of 1b, 2a and 5 are reported.

Inhibitors of Strand Transfer That Prevent Integration and Inhibit Human T-Cell Leukemia Virus Type 1 Early Replication

The replication of the retrovirus human T-cell leukemia virus type 1 (HTLV-1) is linked to the development of lymphoid malignancies and inflammatory diseases. Data from in vitro, ex vivo, and in vivo studies have revealed that no specific treatment can prevent or block HTLV-1 replication and therefore that there is no therapy for the prevention and/or treatment of HTLV-1-associated diseases in infected individuals. HTLV-1 and human immunodeficiency virus type 1 (HIV-1) integrases, the enzymes that specifically catalyze the integration of these retroviruses in host cell DNA, share important structural properties, suggesting that compounds that inhibit HIV-1 integration could also inhibit HTLV-1 integration. We developed quantitative assays to test, in vitro and ex vivo, the efficiencies of styrylquinolines and diketo acids, the two main classes of HIV-1 integrase inhibitors. The compounds were tested in vitro in an HTLV-1 strand-transfer reaction and ex vivo by infection of fresh peripheral blood lymphocytes with lethally irradiated HTLV-1-positive cells. In vitro, four styrylquinoline compounds and two diketo acid compounds significantly inhibited HTLV-1 integration in a dose-dependent manner. All compounds active in vitro decreased cell proliferation ex vivo, although at low concentrations; they also dramatically decreased both normalized proviral loads and the number of integration events during experimental ex vivo primary infection. Accordingly, diketo acids and styrylquinolines are the first drugs that produce a specific negative effect on HTLV-1 replication in vitro and ex vivo, suggesting their potential efficiency for the prevention and treatment of HTLV-1-associated diseases.

A heterogeneous strong basic Mg/La mixed oxide catalyst for efficient synthesis of polyfunctionalized pyrans

An efficient synthesis of polyfunctionalized 4H-pyrans is carried out in one pot through condensation of an aldehyde, malononitrile, and an active methylenic diketo compound using a heterogeneous strong basic Mg/La mixed oxide catalyst. The protocol offers advantages in terms of higher yields, short reaction times, and mild reaction conditions, with reusability of the catalyst.

“Inhibition” of the Enzyme Model TpPh,MeZn–OH by Diketo Compounds

AbstractIn order to gain a structural understanding of zinc enzyme inhibition, the model complex TpPh,MeZn–OH was treated with various diketo compounds. α‐Keto carboxylic acids were attached to the zinc ion as anionic O,O‐chelate ligands, of which benzoylformate was oxidatively decarboxylated in air to form the benzoate complex. Two functionalized β‐diketones did not use their functionality in forming the β‐diketonate complexes. Of the α‐diketones, 2,3‐pentanedione formed the α‐keto enolate complex, while 1‐phenyl‐1,2‐propanedione underwent oxidative C–C coupling resulting in a red dinuclear bis(α‐keto enolato) complex. Of the diaryl‐α‐diketones, benzil did not react, but pyridil underwent hydrolytic cleavage to pyridine‐2‐carbaldehyde and picolinate, of which the latter was bound to the zinc ion as an N,O‐chelate ligand.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Macrocycles via Doebner Reaction Followed by Macrolactonization

The synthesis of 14 different macrocycles is reported. Upon reacting different formylphenoxyacetic acid derivatives with 5-aminopentanol and a diketo compound, eight different Doebner product intermediates were obtained. These intermediates were then subjected to cyclization by using polymer-bound carbodiimide to give macrolactones. Both the monomers and the dimers could be isolated and characterized. In some cases trimers could be seen from the HPLC-MS. The ratios and distribution of the different-sized rings are discussed.

Synthesis of Selenophenes

The preparation of selenophenes is here reviewed. Although it does not include the synthesis of fused rings systems with selenophenes, the entire range of reactions is covered: from acetylenes, olefins, β- diketo compounds, furan, imine, amide, cycle contraction using sodium selenide, cycloaddition, radical cyclisation and much more. Keywords: selenophenes, heterocycles, selenium, ring closure, selenide, cyclisation

Sepiapterin reductases from Chlorobium tepidum and Chlorobium limicola catalyze the synthesis of l-threo-tetrahydrobiopterin from 6-pyruvoyltetrahydropterin

The ORF sequences of the gene encoding sepiapterin reductase were cloned from the genomic DNAs of Chlorobium tepidum and Chlorobium limicola, which are known to produce l-threo- and l-erythro-tetrahydrobiopterin (BH4)- N-acetylglucosamine, respectively. The deduced amino acid sequence of C. limicola consists of 241 residues, while C. tepidum SR has three residues more at the C-terminal. The overall protein sequence identity was 87.7%. Both recombinant proteins generated from Escherichia coli were identified to catalyze reduction of diketo compound 6-pyruvoyltetrahydropterin to l-threo-BH4. This result suggests that C. limicola needs an additional enzyme for l-erythro-BH4 synthesis to yield its glycoside. The catalytic activity of Chlorobium SRs also supports the previously proposed mechanism of two consecutive reductions of C1′ carbonyl group of 6-pyruvoyltetrahydropterin via isomerization reaction.

Design and synthesis of novel indole beta-diketo acid derivatives as HIV-1 integrase inhibitors.

Diketo acids such as S-1360 (1A) and L-731,988 (2) are potent and selective inhibitors of HIV-1 integrase (IN). A plethora of diketo acid-containing compounds have been claimed in patent literature without disclosing much biological activities and synthetic details (reviewed in Neamati, N. Exp. Opin. Ther. Pat. 2002, 12, 709-724). To establish a coherent structure-activity relationship among the substituted indole nucleus bearing a beta-diketo acid moiety, a series of substituted indole-beta-diketo acids (4a-f and 5a-e) were synthesized. All compounds tested showed anti-IN activity at low micromolar concentrations with varied selectivity against the strand transfer process. Three compounds, the indole-3-beta-diketo acids 5a and 5c, and the parent ester 9c, have shown an antiviral activity in cell-based assays. We further confirmed a keto-enolic structure in the 2,3-position of the diketo acid moiety of a representative compound (4c) using NMR and X-ray crystallographic analysis. Using this structure as a lead for all of our computational studies, we found that the title compounds extensively interact with the essential amino acids on the active site of IN.

Metabolism and toxicological detection of the new designer drug 3′,4′-methylenedioxy-α-pyrrolidinopropiophenone studied in urine using gas chromatography–mass spectrometry

R, S-3′,4′-Methylenedioxy-α-pyrrolidinopropiophenone (MDPPP) is a new designer drug with assumed amphetamine-like effects, which has appeared on the illicit drug market. The aim of this study was to identify the MDPPP metabolites using solid-phase extraction, ethylation or acetylation as well as to develop a toxicological detection procedure in urine using solid-phase extraction, trimethylsilylation and GC–MS. Analysis of urine samples of rats treated with MDPPP revealed that MDPPP was completely metabolized by demethylenation of the methylenedioxy group followed by partial 3′-methylation of the resulting catechol, oxidative desamination to the corresponding diketo compounds and/or hydroxylation of the pyrrolidine ring with subsequent dehydrogenation to the corresponding lactam. The hydroxy groups were found to be partly conjugated. Based on these data, MDPPP could be detected in urine via its metabolites by full-scan GC–MS using mass chromatography for screening and library search for identification by comparison of the spectra with reference spectra.

Metabolism and toxicological detection of the new designer drug 4′-methoxy-α-pyrrolidinopropiophenone studied in rat urine using gas chromatography–mass spectrometry

R, S-4′-Methoxy-α-pyrrolidinopropiophenone (MOPPP) is a new designer drug with assumed amphetamine-like effects, which has appeared on the illicit drug market. The aim of this study was to identify the MOPPP metabolites using solid-phase extraction, ethylation or acetylation as well as to develop a toxicological detection procedure in urine using solid-phase extraction, trimethylsilylation and GC–MS. Analysis of urine samples of rats treated with MOPPP revealed that MOPPP [limit of detection ( S/ N 3) was 100 ng/ml] was completely metabolized by demethylation of the methoxy group, hydroxylation of the pyrrolidine ring with subsequent dehydrogenation to the corresponding lactam and/or oxidative desamination to the corresponding diketo compounds. To some extent, the demethylated MOPPP metabolites were hydroxylated with partial subsequent methylation in position 3′. The hydroxy groups were found to be partly conjugated. Based on these data, MOPPP could be detected in urine via its metabolites by full-scan GC–MS using MS for screening and library search for identification by comparison of the spectra with reference spectra.

Inter- and intra-molecular hydrogen-bonded trifluoromethylated alcohols: X-ray crystal structures of 2,5-bis(trifluoromethyl)hexane-2,5-diol, 1,1,1,4,4,4-hexafluoro-2-(3,4-methylenedioxyphenyl)butane-2,3-diol, and 1,1,1-trifluoro-2-oxo-3-(3,4-methylenedioxyphenyl)propane-2-ol

Trifluoromethylated alcohols, 2,5-bis(trifluoromethyl)hexane-2,5-diol ( 1), 1,1,1,4,4,4-hexafluoro-2-(3,4-methylenedioxyphenyl)butane 2,3-diol ( 2), and 1,1,1-trifluoro-2-oxo-3-(3,4-methylenedioxyphenyl)propane-2-ol ( 3) were prepared by direct nucleophilic trifluoromethylation of the corresponding diketo compounds, acetonylacetone and 3,4-methylenedioxyphenylglyoxal, respectively, with (trifluoromethyl)trimethylsilane. Their structures were confirmed by single crystal X-ray analyses. The presence of inter-molecular hydrogen bonding is observed in 1 and 3, and a greater range of interactions, both inter- and intra-molecular, are seen in 2.

Nucleophilic di- and tetrafluorination of dicarbonyl compounds.

Reactions of various diketo compounds with Deoxofluor [(CH(3)OCH(2)CH(2))(2)NSF(3)] have been investigated. When reacted with Deoxofluor, alpha-diketones, R(1)COCOR(2) (R(1) = R(2) = Ph; R(1) = R(2) = 4-Me-C(6)H(4); R(1) = Ph, R(2) = Me; R(1) = Me, R(2) = Et) (1a-d) formed difluoro derivatives (2a-d) in the presence of a catalytic amount of HF and/or tetrafluoro (3a-d) products depending on the reaction conditions and stoichiometry used. Reactions of beta-diketones, R(3)COCH(2)COR(4) (R(3) = R(4) = Ph; R(3) = R(4) = Me; R(3) = Me, R(4) = Ph) (4e-g), with Deoxofluor in the presence of a catalytic amount of HF led to the formation of difluoroalkenones as a mixture of E (5e-g) and Z (6e-g) isomers in good yield. Reaction of other diones, R(5)CO-X-COR(6) (R(5) = R(6) = Ph, X = -CH=CH-; R(5) = R(6) = Me, X = -C(6)H(4)C(6)H(4)-; R(5) = R(6) = Ph, X = -CH(2)CH(2)CH(2)-; R(5) = R(6) = Me, X = -CH(2)CH(2)-) (7h-k) with Deoxofluor produced mainly difluoro products (8h-k) with low yields of tertrafluoro derivatives (9h-k). Acyclic alpha-keto amides react poorly to give the corresponding difluoro derivatives, whereas cyclic alpha-keto amides (10l-p) react smoothly under very mild conditions to produce the corresponding difluoro products (11l-p) in >88% isolated yield.

Diketo compounds with (trifluoromethyl)trimethylsilane: double nucleophilic trifluoromethylation reactions.

Reactions of various diketo compounds with (trifluoromethyl)trimethylsilane (Me3SiCF3) in the presence of catalytic amounts of cesium fluoride have been studied. gamma-Ketoesters, CH3COCH2CH2CO2R (R = Et, Bu), were reacted with 2 equiv of Me3SiCF3 at room temperature to give CH3C(OH)(CF3)CH2CH2COCF3 in good yield after hydrolysis. alpha-Diketones, R1COCOR2 (R1 = R2 = Ph; R1 = Ph, R2 = Me; R1 = R2 = Me; R1 = Me, R2 = Et), when reacted with Me3SiCF3, formed 1:1 or 1:2 addition products depending on the reaction conditions and stoichiometry used. Reactions of diones CH3COXCOCH3 (X = -CH2CH2-, -C6H4C6H4-, -CH2-) with Me3SiCF3 also led to the formation of the mono- or diaddition products depending on reaction conditions. With various kinds of substituted arylglyoxals, 2 equiv of Me3SiCF3 produced monoaddition products in 70-75% yield and diaddition products in 5-10% yield. One of the monoalcohols and two of the diols have been characterized by single-crystal X-ray analysis, and the presence of inter- and intramolecular hydrogen bonding has been confirmed.