RESUMEN
The first total synthesis of myxobacteria metabolite icumazole A (1) is reported. Key steps in the route include an organocatalyzed asymmetric self-aldol reaction followed by an acetate aldol reaction to form the stereotriad present in the oxazole moiety, an intramolecular Diels-Alder reaction to form the isochromanone, and an acetylide addition and selective methylation. The final steps involved a high-yielding modified Cadiot-Chodkiewicz coupling and stereoselective reduction to secure the Z,Z-diene and afford 1.
RESUMEN
An approach to more highly oxidized alkyl citrates by direct regio- and stereoselective oxidations is reported. The total synthesis and structural assignment of alkyl citrate L-731-128 are described, and the synthesis of its C4 oxidized congener L-731,127 utilized a regio- and stereoselective enolate oxidation with oxygen gas. A highly stereoselective Rubottom oxidation of a cyclic silylketene acetal then enabled oxidation at C2 to afford the cinatrins C1 and C3.
RESUMEN
An inexpensive Fe(III) SALPN catalyst for MHAT reactions such as reductions of α,ß-unsaturated carbonyl compounds and olefin cross couplings is reported. The majority of these reactions proceeded in good yields and high stereoselectivities with low catalyst loadings at room temperature.
RESUMEN
This review details the biological activity, biosynthesis and synthesis of isochromanone metabolites isolated from myxobacteria. Strategies towards the synthesis of the isochomanone and oxazole fragments of these natural products are highlighted.
Asunto(s)
Productos Biológicos , Myxococcales , Myxococcales/metabolismo , Productos Biológicos/metabolismo , OxazolesRESUMEN
The acyloin natural products are a family of bioactive compounds isolated from fungi and myxobacteria. The total synthesis of 7 members of the acyloin family was achieved via a HWE reaction followed by Mukaiyama-Isayama hydration, using novel Co(II) and Co(III) Schiff base SALPN complexes as catalysts for the key enone hydration step. Furthermore, we have shown that a mild acyloin rearrangement is possible under Mukaiyama hydration conditions, which was crucial in the success of this approach.
Asunto(s)
Productos Biológicos , Catálisis , Alcoholes Grasos , Bases de SchiffRESUMEN
The development of a flow-assisted synthesis of alkyl citrate natural products is described. The flow route harnesses a number of steps including the generation of ketene silyl acetal, a formal [2 + 2] cycloaddition, and a methanolysis cascade to efficiently generate a highly substituted, and stereodefined tetrahydrofuran intermediate. A heterogeneous pseudo-Finkelstein reaction and zinc-mediated elimination furnish a key alkene alkyl citrate fragment in high yield over a multistep sequence that provides direct entry to compounds such as (-)-CJ-13982 (1), (-)-CJ-13,981 (2), L-731,120 (3), and related natural products. The flow methodology developed in this study enables a new machine-assisted approach toward the efficient and scalable synthesis of the alkyl citrate family of natural products.
Asunto(s)
Productos Biológicos , Acetales , Citratos , Ácido Cítrico , Reacción de CicloadiciónRESUMEN
The total synthesis of viridiofungins A (1) and B (2) via ß-lactone 3 in 13 steps is reported. Key steps included an HF-mediated rearrangement of cyclobutene diester 9 to form a bicyclic lactone 6, an olefin cross metathesis between disubstituted alkene 3 and alkene 4 in which isomerization was suppressed, and a novel ß-lactone ring opening to form the amide. Deprotection then gave either viridiofungin A (1) or B (2) in high yield.
RESUMEN
This review details the isolation, biosynthesis, biological activity and synthesis of spiroacetals from the myxobacterium Sorangium cellulosum. The strategies utilised to access the challenging structures and stereochemistry of these natural products are highlighted.
Asunto(s)
Acetales/metabolismo , Productos Biológicos/metabolismo , Compuestos de Espiro/metabolismo , Acetales/química , Productos Biológicos/química , Conformación Molecular , Sorangium/química , Sorangium/metabolismo , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
The first total synthesis of the alkyl citrate trachyspic acid 19-n-butyl ester (1) is described. A formal [2 + 2]-cycloaddition of the silylketene acetal derived from lactone 6 with di-n-butylacetylene dicarboxylate 7 provided the cyclobutene diester 5 with a dr >20:1. Acid-mediated rearrangement of 5 followed by lactone ring-opening and ester protecting group manipulation eventually provided orthogonally protected aldehyde 3. A Nozaki-Hiyama-Kishi coupling between 3 and vinyl iodide 4 followed by oxidation of the resultant allylic alcohol gave enone 16, which was converted into the triester 17 (dr 6:1) by a spirocyclization/oxidative cleavage/elimination sequence. Removal of the t-butyl esters then afforded trachyspic acid 19-n-butyl ester (1).
RESUMEN
The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of activity. Most family members were identified almost four decades ago and were placed on the shelf due to the numbers of broad-spectrum compounds available at the time. However, in light of rising rates of antimicrobial resistance, there has been a renewed interest in the use of narrow-spectrum antimicrobials. Here, we review the history of this family of compounds, including synthetic approaches, and highlight the recently uncovered genetic basis for nargenicin production. Given the renewed pharmaceutical interest in these compounds, we also investigate structure-activity relationships among these molecules, with a view to the future development of members of this unusual antibiotic family.
Asunto(s)
Antibacterianos/farmacología , Hidrocarburos Aromáticos con Puentes/farmacología , Lactonas/química , Macrólidos/farmacología , Antibacterianos/química , Hidrocarburos Aromáticos con Puentes/química , Humanos , Macrólidos/química , Naftalenos , Relación Estructura-ActividadRESUMEN
The stereoselective 12-step total synthesis of the reassigned structure for citrafungin A (1a) via cyclobutene diester 10 is described. Key steps involved a formal [2 + 2]-cycloaddition, oxa-Michael/cyclobutanone ring-opening cascade to secure the alkyl citrate core, and asymmetric vinylzinc addition to form the C6 stereocenter. In addition, no oxidative adjustments are required to secure the citrate oxidation level.
Asunto(s)
Alquenos/síntesis química , Lactonas/síntesis química , Alquenos/química , Reacción de Cicloadición , Lactonas/química , Estructura Molecular , EstereoisomerismoRESUMEN
Two cis-ß-MnIIISALPN catalysts were synthesised and tested in the Mukaiyama-Isayama hydration of α,ß-unsaturated esters. The MnIIIEtOSALPN(acac) complex 7 is the most active and catalyses hydration with little or no detectable undesired alkene reduction. This catalyst is superior for alkene hydration compared to the originally reported Mn(dpm)3 catalyst.
RESUMEN
The nargenicin family of antibiotics are macrolides containing a rare ether-bridged cis-decalin motif. Several of these compounds are highly active against multi-drug resistant organisms. Despite the identification of the first members of this family almost 40 years ago, the genetic basis for the production of these molecules and the enzyme responsible for formation of the oxa bridge, remain unknown. Here, the 85 kb nargenicin biosynthetic gene cluster was identified from a human pathogenic Nocardia arthritidis isolate and this locus is solely responsible for nargenicin production. Further investigation of this locus revealed a putative iron-α-ketoglutarate-dependent dioxygenase, which was found to be responsible for the formation of the ether bridge from the newly identified deoxygenated precursor, 8,13-deoxynargenicin. Uncovering the nargenicin biosynthetic locus provides a molecular basis for the rational bioengineering of these interesting antibiotic macrolides.
Asunto(s)
Antibacterianos/biosíntesis , Éteres/química , Macrólidos/metabolismo , Antibacterianos/química , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Dioxigenasas/metabolismo , Escherichia coli/efectos de los fármacos , Lactonas/química , Lactonas/metabolismo , Lactonas/farmacología , Macrólidos/química , Macrólidos/farmacología , Pruebas de Sensibilidad Microbiana , Familia de Multigenes , Nocardia/genética , Staphylococcus aureus/efectos de los fármacosRESUMEN
Intrinsic apoptosis resulting from BAX/BAK-mediated mitochondrial membrane damage is regarded as immunologically silent. We show here that in macrophages, BAX/BAK activation results in inhibitor of apoptosis (IAP) protein degradation to promote caspase-8-mediated activation of IL-1ß. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1ß maturation that requires potassium efflux. Remarkably, following BAX/BAK activation, the apoptotic executioner caspases, caspase-3 and -7, act upstream of both caspase-8 and NLRP3-induced IL-1ß maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1ß release. These findings highlight that innate immune cells undergoing BAX/BAK-mediated apoptosis have the capacity to generate pro-inflammatory signals and provide an explanation as to why IL-1ß activation is often associated with cellular stress, such as during chemotherapy.
Asunto(s)
Apoptosis , Caspasas/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Mitocondrias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Animales , Caspasa 3/metabolismo , Caspasa 7 , Caspasa 8/metabolismo , Activación Enzimática , Macrófagos/metabolismo , Ratones , Agregado de Proteínas , Proteolisis , Transducción de SeñalRESUMEN
An efficient and step-economic new approach to alkyl citrate natural products from a cyclobutene diester is presented. The key sequence involves a formal [2 + 2]-cycloaddition of a silylketene acetal with dimethylacetylene dicarboxylate to provide the cyclobutene diester 14 with 4.5:1 stereoselectivity. Exposure of diester 14 in acidic methanol effected a hydrolysis, intramolecular oxy-Michael reaction, and cyclobutanone methanolysis cascade to give the triester 15. Iodination and elimination then afforded a key alkyl citrate alkene intermediate, which was converted into the natural products (-)-CJ-13,982 (1), (-)-CJ-13,981 (2), and (-)-L-731,120 (3) via a cross-metathesis and subsequent reduction.
RESUMEN
The total syntheses of both the natural and unnatural enantiomers of the alkyl citrate natural product CJ-13,982 (1) from the common d-ribose-derived acid 6 are described.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Ácidos Palmíticos/síntesis química , Productos Biológicos , Citratos/química , Indicadores y Reactivos , Conformación Molecular , EstereoisomerismoRESUMEN
A unprecedented base-induced trimerization of bromovinylsulfone 1 afforded the cyclohexene 6 as a single diastereoisomer. Optimization of this reaction gave the adduct 6 in 49% yield. A mechanistic rationale for the trimerization involving consecutive SN2' additions and [3,3]-rearrangements and a final stereoselective intramolecular conjugate addition is proposed and supported by M06-2X density functional theory calculations.
RESUMEN
The chemical modification of macrolide natural products into aza- or lactam analogues is a strategy employed to improve their metabolic stability and biological activity. The methods for the synthesis of several lactam analogues of macrolide natural products are highlighted and aspects of their biological properties presented.
Asunto(s)
Antibacterianos/química , Productos Biológicos/química , Lactamas Macrocíclicas/química , Macrólidos/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Productos Biológicos/farmacología , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/farmacología , Macrólidos/farmacología , Modelos Moleculares , Conformación MolecularRESUMEN
The total synthesis of a biotinylated derivative of methyl rocaglate is described. This compound was accessed from synthetic methyl rocaglate (2) via formation of the propargyl amide and subsequent click reaction with a biotin azide. Affinity purification revealed that biotinylated rocaglate (8) and methyl rocaglate (2) bind with high specificity to translation factors eIF4AI/II. This remarkable selectivity is in line with that found for the more complex rocaglate silvestrol (3).
Asunto(s)
Benzofuranos/química , Biotina/química , Factor 4A Eucariótico de Iniciación/química , Animales , Benzofuranos/síntesis química , Benzofuranos/farmacología , Biotina/síntesis química , Biotina/farmacología , Factor 4A Eucariótico de Iniciación/metabolismo , Ratones , Conejos , Triterpenos/químicaRESUMEN
An approach to the dihydrooxepino[4,3-b]pyrrole core of diketopiperazine natural products which utilizes a vinyl pyrrole epoxide Cope rearrangement was investigated. It was found that an ester substituent on the epoxide was essential for the [3,3]-rearrangement to occur. Density functional calculations with M06-2X provided explanations for the effects of the pyrrole and ester groups on these rearrangements.