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Hybrid molecules consisting of geraniol and butenolide were designed and synthesized by the late-stage divergent strategy. In the synthetic route, ring-closing metathesis was utilized for the construction of a butenolide moiety. A biological evaluation of the eight synthetic hybrid compounds revealed that these molecules exhibit antifouling activity against the cypris larvae of the barnacle Balanus (Amphibalanus) amphitrite with EC 50 values of 0.30-1.31 μg mL -1 . These results show that hybridization of the geraniol and butenolide structural motifs resulted in the enhancement of the antifouling activity.

A collective synthesis of a γ-butyrolactone class of paraconic acids such as (+)-methylenolactocin, (+)-phaseolinic acid, (+)-nephrosteranic acid, (+)-nephrosterinic acid, (+)-rocellaric acid and (+)-protolichesterinic acid is described. The strategy adopted is protecting-group-free based on efficient Pd-catalyzed Suzuki-Miyaura coupling and Ru-catalyzed Sharpless oxidation to construct the core β-CO 2 H-γ-butyrolactone unit to accomplish the synthesis of various paraconic acids.

The asymmetric total syntheses of hedyosumin E aglycon, 7,10-epoxyhedyosminolide and ent-zedolactone A were realized, with the first two being achieved for the first time.

Phosphorylated cyclopropanes, generated via the Rh(ii)-catalysed intramolecular cyclopropanation of α-(diethoxyphosphoryl)acetates, have been found to be useful precursors in the synthesis of α-alkylidene-γ-butyrolactones. These cyclopropyl intermediates undergo regioselective reductive ring-opening and subsequent Horner-Wadsworth-Emmons olefination to complete the synthesis. Total syntheses of (±)-savinin and (±)-gadain, as well as the first total synthesis of (±)-peperomin E, are all described using this method.

Gamma-butyrolactones (GBLs) are signalling molecules that control antibiotic production in Streptomyces bacteria. The genetically engineered strain S. coelicolor M1152 was found to overproduce GBLs SCB1-3 as well as five novel GBLs named SCB4-8. Incorporation experiments using isotopically-labelled precursors confirmed the chemical structures of SCB1-3 and established those of SCB4-8.

A regio- and stereoselective one-pot C-H insertion/olefination protocol has been developed for the late stage installation of α-methylene-γ-butyrolactones into conformationally restricted cyclohexanol-derivatives. The method has been successfully applied in the total synthesis of eudesmanolide natural product frameworks, including α-cyclocostunolide.

The first total synthesis of the marine prostanoids clavulolactones II and III is presented from an easily accessible chiral, non-racemic cyclopentenone intermediate. Key steps involve selective TBDMS deprotection, selective reduction of the β-side chain and aldol condensation. Clavulolactones II and III were successfully prepared from (S)-4-((tert-butyldimethylsilyl)oxy) cyclopent-2-en-1-one over nine steps, in overall yields of 21 and 7% respectively.

Triazolinylidenes promote γ-selective C-carboxylation (up to 99 : 1 regioselectivity) in the O- to C-carboxyl transfer of furanyl carbonates in contrast to DMAP that promotes preferential α-C-carboxylation with moderate regiocontrol (typically 60 : 40 regioselectivity). The generality of this process is described and a simple mechanistic and kinetic model postulated to account for the observed regioselectivity.

This communication reports a significant breakthrough on the novel catalytic amide allylation to the acyclic α-ketoester systems, achieving satisfactorily high yields and extremely high levels of the asymmetric induction to allow for highly enantioselective synthesis of ester functionalised α-methylene-γ-butyrolactones.

A method for the selective transamidation of the 3-oxo sub-family of N-acyl homoserine lactones (3-oxo-AHLs) under physiologically relevant conditions has been developed. The reaction has the potential to serve as a strategy for selective knockdown of key autoinducers in a multicellular environment.

The first stereoselective total synthesis of gonytolide C, which is a monomeric unit of an innate immune promoter gonytolide A, has been accomplished from the aldol reaction between acetophenone derived from orcinol and butyrolactone containing α-keto ester followed by the excellent diastereoselective intramolecular cyclization. The first total synthesis of gonytolide G has been achieved by the oxidation of benzylic methyl in gonytolide C. Additionally, total synthesis of lachnone C and a formal synthesis of blennolide C and diversonol have been achieved by this synthetic method.

A series of structurally related analogues of the natural product paracaseolide A were synthesized and identified as potent PTP1B inhibitors. Among these analogues, compound 10 in particular showed improved PTP1B enzyme inhibitory activity, high selectivity for PTP1B over TC-PTP, and improved cellular effects.

The primary quorum sensing system in the opportunistic pathogen Pseudomonas aeruginosa is regulated through the synthesis and secretion of N-3-oxo-dodecanoyl-L-homoserine lactone (C12) which binds the transcriptional activator LasR. In this study we report the design, synthesis and biological evaluation of new analogs of C12. Analysis of the autoinducer binding site cavity of LasR revealed a positively charged cavity near the center of bound C12. Accordingly, we synthesized two piperidine-C12 diastereoisomers and tested their biological activity. Both analogs proved to be strong LasR agonists that showed a synergistic effect when presented together with the natural ligand. Moreover, binding of the analogs resulted in phenotypic changes characteristic of QS controlled receptor activation.

A general synthesis of γ-trifluoromethyl α,β-unsaturated γ-butyrolactones is described. The fluoride-catalyzed nucleophilic addition of a trifluoromethyl (CF3) group generated from (trifluoromethyl)trimethylsilane (CF3SiMe3, Ruppert-Prakash reagent) to a masked maleic anhydride 1 (cyclopentadiene-maleic anhydride adduct) provides the corresponding adducts 2 with high stereoselectivity. The γ-trifluoromethyl α,β-unsaturated γ-butyrolactones 4 were obtained after treatment of the adducts 2 with Grignard reagents, followed by flash-vacuum pyrolysis.

The HKR of racemic anti- or syn-3-substituted epoxy esters catalyzed by a Co(III)salen complex provides ready access to the corresponding enantioenriched 3,4-disubstituted γ-butyrolactones and 3-substituted epoxy esters. This strategy has been successfully employed in the formal synthesis of biologically active 3,4-disubstituted piperidine derivatives, (-)-paroxetine and Ro 67-8867 and a natural product, (+)-eldanolide.

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.

Pseudomonas aeruginosa is a notorious human pathogen associated with a range of life-threatening nosocomial infections. There is an increasing problem of antibiotic resistance in P. aeruginosa, highlighted by the emergence of multi-drug resistant strains. Thus the exploration of new strategies for the treatment of P. aeruginosa infections is clearly warranted. P. aeruginosa is known to produce a range of virulence factors that enhance its ability to damage the host tissue and cause disease. One of the most important virulence factors is pyocyanin. P. aeruginosa regulates pyocyanin production using an intercellular communication mechanism called quorum sensing, which is mediated by small signalling molecules termed autoinducers. One native autoinducer is N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). Herein we report the synthesis of a collection of abiotic OdDHL-mimics. A number of novel compounds capable of competing with the endogenous OdDHL and consequently, inhibiting the production of pyocyanin in cultures of wild type P. aeruginosa were identified. We present evidence suggesting that compounds of this general structural type act as direct antagonists of quorum sensing in P. aeruginosa and as such may find value as molecular tools for the study and manipulation of this signalling pathway. A direct quantitative comparison of the pyocyanin suppressive activities of the most active OdDHL-mimics with some previously-reported inhibitors (based around different general structural frameworks) of quorum sensing from the literature, was also made.

We report a concise synthesis of A-factor, the prototypical γ-butyrolactone signalling compound of Streptomyces bacteria. In analogy to enzymatic reactions in A-factor biosynthesis, our synthesis features a tandem esterification-Knoevenagel condensation yielding a 2-acyl butenolide and a surprising, chemoselective conjugate reduction of this α,β-unsaturated carbonyl compound using sodium cyanoborohydride.

A highly efficient catalytic asymmetric vinylogous Mukaiyama-Michael reaction of the 2-silyloxyfuran with chalcone derivatives, catalyzed by a chiral N,N'-dioxide-scandium(III) complex, has been accomplished which tolerates a wide range of substrates. The reaction proceeds with complete regioselectivities, excellent diastereoselectivities (up to >99 : 1 dr) and good to excellent enantioselectivities (up to 94% ee) under mild conditions, delivering highly functionalized enantiomerically enriched anti-γ-substituted butenolides. The process is air-tolerant and easily manipulated with available reagents. In order to illustrate the synthetic potential of this reaction, the gram-scale synthesis and the elaboration of the butenolides have been explored. On the basis of the experimental results, a possible catalytic cycle and favorable stereorecognition model have been proposed.

Titanium chelate addition of aryl nucleophiles to cyclopropyl aldehyde 6 followed by a tin-catalyzed one-pot retro-aldol, acetalisation and lactonisation sequence afforded cis and trans γ-aryllactone acetals. A γ-furyllactone derived by this approach was further transformed in two steps to model compounds for the oxidised northeastern sectors of selected Pseudopterogorgia diterpenoids.

cis-Reticulatacin-10-ones A and B were synthesised as a predefined mixture of diastereoisomers (dr ∼ 1 : 9) in nine steps from the acid chloride 8, and without the use of hydroxyl protecting groups. Comparison of the chiral HPLC chromatogram of the synthetic sample with that of the natural product isolated from the roots of the tropical fruit tree Annona muricata L. showed the natural product to be a mixture of A and B diastereoisomers (dr ∼ 1 : 1).

Peridinin is a light-harvesting carotenoid found in oceanic photosynthetic organisms. It possesses a unique gamma-ylidenbutenolide function and engages in energy transfer to chlorophyll a with very high (>90%) efficiency. In order to examine the relationship between the unique structure of peridinin and its facility in carrying out energy transfer, we have synthesized two different ylidenbutenolide-modified derivatives of peridinin. In this communication, the details of the syntheses are described as are the stereochemical and spectral characteristics of the derivatives; the novel ylidenbutenolide functional group stabilizes the molecule and maintains the conjugated pi-electron system in an all-trans configuration.

Different from the reaction of 2,3-allenoic acids with Selectfluor, 4-fluoro-2(5H)-furanones and (E)-3-fluoro-4-oxo-2-alkenoates were highly selectively generated from 2,4-disubstituted 2,3-allenoates with Selectfluor under different conditions in moderate yields. The reaction of 2,4,4-trisubstituted 2,3-allenoates afforded the corresponding 4-fluoro-2(5H)-furanones highly selectively with up to 95% yield under different conditions. The scope of the substrates has been carefully explored. Due to the more readily availability of 2,3-allenoates as compared to 2,3-allenoic acids, new 4-fluoro-2(5H)-furanones were prepared. Based on the isolation and characterization of the minor fluorohydroxylation product E-5m, a mechanism has been proposed.

The enantioselective synthesis of Anomala osakana pheromone and Janus integer pheromone has been achieved without using any protecting groups. The synthesis involved using an asymmetric alkynylation to obtain gamma-hydroxy-alpha,beta-acetylenic esters with high ee (84%) and yields ( approximately 80%), followed by selective hydrogenation and lactonization in high overall yields (87% and 89%).

A Diels-Alder cycloaddition approach to the sweroside aglycone intermediate of iridoids was explored using silylated butenolides and levoglucosenone as dienophiles under both Lewis acid and thermal conditions. Results of this study reveal no evidence that using less sterically demanding derivatives compromise the diastereofacial selectivity of the cycloaddition using silylated butenolides. Further chemistry performed on cycloadducts concentrated on the identification and management of methodologies suitable for its conversion into sweroside aglycone. During the course of these studies, a dehydrative cyclisation onto a preformed tetrahydrofuran ring to a bis-tetrahydrofuranoid moiety was unravelled. In addition studies on levoglucosenone-derived cycloadducts provide extensive insight into the conformational behaviour and reactivity. Further, the X-ray crystal structure of an alcohol intermediate from one-carbon homologation studies provided the first structural evidence confirming the diastereoselectivity of the cycloaddition procedure.

Chiral alpha,beta-unsaturated esters, containing a single, gamma-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(alpha-methylbenzyl)amide to the homochiral alpha,beta-unsaturated esters display "matching" and "mismatching" effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding beta-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant beta-amino adducts gives access to the corresponding beta-amino-gamma-substituted-gamma-butyrolactones in good yield and high de.

Thapsigargin is a densely oxygenated guaianolide which displays potent sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) binding affinities. The total syntheses of designed unnatural analogues of this important natural product are described. This article constitutes the chemical synthesis behind an ongoing project. Rational modifications have been made to the lactone region of thapsigargin in order to obtain derivatives for future structure-activity relationship studies.

In this paper, a novel route to gamma-alkylidenebutenolides (gamma-AIBs) by way of stereoselective vinylogous aldol reaction of the unactivated butenolide in simple and general conditions is reported.

Parallel solution-phase synthesis of sulfide AHL analogues (10a-s) by one-pot or a sequential approach is reported. The corresponding sulfoxides 13a-e and sulfones 14a-e were prepared to expand the diversity of the 19-member array of sulfides . Likewise, dithianes 12a-c were prepared with similarity both to sulfides 10a-s and to bioactive structures from garlic. Design and biological screening of all compounds presented in this work targeted inhibition of quorum-sensing comprising competitive inhibition of transcriptional regulators LuxR and LasR. The design was based on critical interactions within the binding-site and structural motifs in molecular components isolated from garlic, 7 and 8, shown to be quorum-sensing inhibitors but not antibiotics. A potent quorum-sensing inhibitor N-(heptylsulfanylacetyl)-l-homoserine lactone (10c) was identified. Together with data collected for the other analogues, the resulting structure-activity relationship led to a hypothesis in which competitive binding was assumed.

The human pathogen Pseudomonas aeruginosa uses N-butyryl-L-homoserine lactone (BHL) and N-(3-oxododecanyl)-L-homoserine lactone (OdDHL) as small molecule intercellular signals in a phenomenon known as quorum sensing (QS). QS modulators are effective at attenuating P. aeruginosa virulence; therefore, they are a potential new class of antibacterial agent. The lactone in BHL and OdDHL is hydrolysed under physiological conditions. The hydrolysis proceeds at a rate faster than racemisation of the alpha-chiral centre. Non-hydrolysable, non-racemic analogues (small molecule probes) were designed and synthesised, replacing the lactone with a ketone. OdDHL analogues were found to be relatively unstable to decomposition unless they were difluorinated between the beta-keto amide. Stability studies on a non-hydrolysable, cyclohexanone analogue indicated that racemisation of the alpha-chiral centre was relatively slow. This analogue was assayed to show that the L-isomer is likely to be responsible for the QS autoinducing activity in P. aeruginosa and Serratia strain ATCC39006.

Butalactin (1a) and lactone II (2a) have been synthesized starting from (S)-malic acid and sorbic acid by a straightforward route. The absolute stereochemistry of 1a and 2a was unambiguously established by this synthesis., (Copyright 2004 The Royal Society of Chemistry)

The potential of a solid-phase asymmetric resin-capture-release strategy for high-throughput synthesis has been evaluated. Fukuzawa's Sm(ii)-mediated, asymmetric approach to gamma-butyrolactones was selected to illustrate the feasibility of such a process. Alpha,beta-unsaturated esters immobilised on an ephedrine chiral resin have been applied in an asymmetric approach to gamma-butyrolactones. Lactone products are obtained in moderate isolated yields with selectivities up to 96% ee. In addition, we have shown that the ephedrine resin can be conveniently recovered and recycled although in some cases lower yields were obtained on reuse of the chiral resin. A short synthesis of a moderate DNA-binding microbial metabolite using asymmetric resin-capture-release is also described., (Copyright 2004 The Royal Society of Chemistry)

A series of analogues of butyrolactone I, a natural product isolated from Aspergillus terreus that selectively inhibits the CDK2 and CDK1 kinases and that has been found to exhibit an interesting antiproliferative activity, have been synthesized. Its antitumor activity has been tested. Molecular models of the complex between butyrolactone I and the CDK2 active site have been built using a combination of conformational search and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues are rationalized based on the molecular models.