RESUMEN
A stereoselective total synthesis of natural product aspergillide A is reported. The adopted strategy relies on the direct access to the key tetrahydropyran core through a visible light-mediated photoredox reaction from an allylic alcohol and iodoacetic acid. In a single manipulation, a γ-iodo-δ-valerolactone is obtained through an atom transfer radical addition followed by in situ acid-catalyzed lactonization. The obtained lactone possesses three functionalized sites, which were seized to link the required substituents in the final product and thus completing the total synthesis of aspergillide A.
Asunto(s)
Técnicas de Química Sintética/métodos , Macrólidos/síntesis química , Piranos/química , Ciclización , Luz , Macrólidos/química , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
The first total synthesis of (-)-marinisporolide C is described, which establishes unequivocally the relative and absolute configuration of this oxopolyene macrolide. Key features of this synthesis include a series of highly stereoselective aldol reactions followed by directed reductions to build the polyol domain, a Stille cross-coupling reaction to assemble the polyene, and an intramolecular Horner-Wadsworth-Emmons olefination to forge the macrocyclic ring. Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization reaction that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical assignment.
Asunto(s)
Macrólidos/síntesis química , Macrólidos/química , Estructura Molecular , EstereoisomerismoRESUMEN
The first total synthesis of (-)-marinisporolide C was performed in 25 steps (longest linear sequence) and an overall yield of 1%. Due to the high degree of convergence and robustness, the C9-C35 fragment that corresponds to the polyol portion was obtained in gram quantity. Highlights of this synthesis include five highly stereoselective aldol reactions responsible for the construction of five C-C bonds and six stereogenic centers. Additionally, a very efficient Julia-Kocienski reaction was used to install a C22-C23 double bond, and the macrocyclic ring was closed using an intramolecular Horner-Wadsworth-Emmons olefination.
Asunto(s)
Macrólidos/síntesis química , Actinobacteria/química , Aldehídos/química , Macrólidos/química , Biología Marina , Estructura Molecular , EstereoisomerismoRESUMEN
The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1-C19 and C20-C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19-C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1-C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.
Asunto(s)
Aldehídos/química , Carbono/química , Cetonas/química , Macrólidos/síntesis química , Polímeros/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
Macrolide lactones, the so called cucujolides derived from unsaturated fatty acids, are aggregation pheromones of cucujid grain beetles. Thirty years ago, Oehlschlarger etâ al. showed that (3Z,6Z)-dodeca-3,6-dien-11-olide (4) and the respective 12-olide (7) attract the sawtoothed grain beetle Oryzaephilus surinamensis, whereas (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5) increases the response synergistically. The frass of this beetle is attractive for its parasitoid Cephalonomia tarsalis, which potentially can be used for pest control. A GC/MS analysis of attractive frass showed the presence of 5, together with an unknown isomer. Cucujolideâ V was tentatively identified also in the femoral glands, pheromone-releasing structures, of the Madagascan mantelline frog Spinomantis aglavei. Therefore, a new route to synthesize doubly unsaturated macrolides allowing the flexible attachment of the side chain was developed. A straightforward method to obtain Zâ configured macrolides involves ring-closing alkyne metathesis (RCAM) followed by Lindlar-catalyzed hydrogenation. This methodology was extended to homoconjugated diene macrolides by using RCAM after introduction of one Zâ configured double bond in the precursor by Wittig reaction. A tungsten benzylidyne complex was used as the catalyst in the RCAM reaction, which afforded the products in high yield at room temperature. With the synthetic material at hand, the unknown isomer was identified as the new natural product (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideâ X (8). Furthermore, the route also allowed the synthesis of cucujolideâ V in good yield. The natural products were identified by the synthesis of enantiomerically pure or enriched material and gas chromatography on chiral phases. The new macrolide (R)-8 proved to be biologically active, attracting female O.â surinamensis, but no males. The synthetic material allowed the identification of (R)-5 in both the beetle and the frog.
Asunto(s)
Productos Biológicos/síntesis química , Macrólidos/síntesis química , Feromonas/química , Animales , Productos Biológicos/química , Catálisis , Escarabajos , Femenino , Macrólidos/química , Masculino , EstereoisomerismoRESUMEN
We have synthesized new derivatives of the macrolide antibiotics erythromycin and azithromycin. Novel deoxysugar moieties were attached to these standard antibiotics by biotransformation using a heterologous host. The resulting compounds were tested against several standard laboratory and clinically isolated bacterial strains. In addition, they were also tested in vitro against standard and drug-resistant strains of human malaria parasites (Plasmodium falciparum) and the liver stages of the rodent malaria parasite (Plasmodium berghei). Antibacterial activity of modified erythromycin and azithromycin showed no improvement over the unmodified macrolides, but the modified compounds showed a 10-fold increase in effectiveness after a short-term exposure against blood stages of malaria. The new compounds also remained active against azithromycin-resistant strains of P. falciparum and inhibited growth of liver-stage parasites at concentrations similar to those used for primaquine. Our findings show that malaria parasites have two distinct responses to macrolide antibiotics, one reflecting the prokaryotic origin of the apicoplast and a second, as-yet uncharacterized response that we attribute to the eukaryotic nature of the parasite. This is the first report for macrolides that target two different functions in the Plasmodium parasites.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Azitromicina/análogos & derivados , Azitromicina/farmacología , Cloroquina/farmacología , Resistencia a Medicamentos , Eritromicina/análogos & derivados , Eritromicina/farmacología , Macrólidos/síntesis química , Macrólidos/farmacología , Malaria/tratamiento farmacológico , Malaria/parasitología , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei/crecimiento & desarrollo , Plasmodium falciparum/crecimiento & desarrolloRESUMEN
Migrastatin, a macrolide natural product, and its structurally related analogs are potent inhibitors of cancer cell metastasis, invasion and migration. In the present work, a specialized fragment-based method was employed to develop QSAR models for a series of migrastatin and isomigrastatin analogs. Significant correlation coefficients were obtained (best model, q2 = 0.76 and r2 = 0.91) indicating that the QSAR models possess high internal consistency. The best model was then used to predict the potency of an external test set, and the predicted values were in good agreement with the experimental results (R2 pred = 0.85). The final model and the corresponding contribution maps, combined with molecular modeling studies, provided important insights into the key structural features for the anticancer activity of this family of synthetic compounds based on natural products.
Asunto(s)
Macrólidos/química , Macrólidos/farmacología , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Piperidonas/química , Piperidonas/farmacología , Relación Estructura-Actividad Cuantitativa , Movimiento Celular/efectos de los fármacos , Bases de Datos Factuales , Macrólidos/síntesis química , Modelos Moleculares , Conformación Molecular , Invasividad Neoplásica , Piperidonas/síntesis química , EstereoisomerismoRESUMEN
A concise nonaldol approach for the stereoselective construction of all-anti polypropionate fragments was developed. The iterative epoxide-based methodology consists of the syn-selective epoxidation of cis homoallylic alcohols with use of the VO(acac)(2)-catalyzed conditions followed by epoxide cleavage with a propynyl aluminum reagent as key steps. The methodology was applied to the synthesis of the all-anti C6-C10 fragment of streptovaricin U.
Asunto(s)
Macrólidos/síntesis química , Propionatos/química , Propionatos/síntesis química , Catálisis , Compuestos Epoxi/química , EstereoisomerismoRESUMEN
An efficient, convergent synthesis of a differentially protected C20-C38 segment of the brasilinolides is described. Iterative 1,4-syn aldol additions and ketone reductions were employed to construct the two related stereotetrads, while a sequence of Horner-Wadsworth-Emmons (HWE) coupling, CBS reduction, and Sharpless AE installed the epoxy alcohol functionality.
Asunto(s)
Macrólidos/síntesis química , Catálisis , Cetonas/química , Macrólidos/química , Estructura Molecular , Piranos , EstereoisomerismoRESUMEN
Two highly convergent syntheses of a fully protected C1-C19 polyol subunit of the brasilinolide family of immunosuppressive macrolides are described, exploiting boron-mediated 1,5-anti aldol couplings to form the C8-C9 and C13-C14 bonds.
Asunto(s)
Carbono/química , Macrólidos/síntesis química , Polímeros/química , Aldehídos/química , Macrólidos/química , EstereoisomerismoRESUMEN
A highly convergent and efficient total synthesis of the potent antitumor polyketide (-)-callystatin A is described. The synthesis required 19 steps from N-propionyl oxazolidinone 23 and produced the desired product in 3.5% overall yield.