Phenylboronic acid mediated triple condensation reactions of phloroglucinol and unsaturated carbonyl compounds

[reaction: see text] A remarkable phenylboronic acid mediated triple condensation reaction of phloroglucinol (1,3,5-trihydroxybenzene) with a series of alpha,beta-unsaturated carbonyl compounds is reported. This experimentally simple reaction afforded novel C3-symmetric 2H-chromene derivatives. These derivatives represent structural analogues of the natural product xyloketal A, which has been reported to be a potent inhibitor of acetylcholine esterase.     

Biomimetic type approach to the tricyclic core of xyloketals. Application to a short, stereocontrolled synthesis of alboatrin and first synthesis of xyloketal G

A convenient approach to the linear tetrahydrofurano benzopyran ring system of xyloketals is described. An orthoester Claisen rearrangement of a chromenol and an intra-molecular cationic cyclization are the key steps in the synthesis. A short, stereocontrolled and high yield synthesis of the phytotoxic metabolite alboatrin was achieved employing this strategy. A unique case of Lewis acid catalyzed isomerization of epi-alboatrin to alboatrin was observed. Subsequently this methodology was extended for the first total synthesis of xyloketal G, where a one pot reaction of three steps viz., acetylation, isomerization and demethylation occurred during acetylation of a mixture of nor-o-methyl xyloketal G and nor-o-methyl epi xyloketal G in presence of AlCl₃ to furnish xyloketal G in very good overall yield.     

Selective Mono‐allylation of 1,3‐Diketones and Their Use in the Synthesis of 3‐Allyl Chromones and Benzannulated 6,5‐Bicyclic Ketals

The selective mono‐allylation of 1,3‐diketone containing compounds is described. The reaction proceeds under mild reaction conditions and in moderate to high yield (66–99 %). Using this procedure to access the key mono‐allylated intermediate, the hitherto difficult to access 3‐allyl chromones were synthesized in excellent yield (87–98 %). Finally, the utility of this newly developed procedure was showcased through the rapid synthesis of the scaffold of the xyloketal family of natural products.     

A Rapid Synthesis of 4‐Oxazolidinones: Total Synthesis of Synoxazolidinones A and B

A five‐step total synthesis of the marine natural product synoxazolidinone A was achieved through a diastereoselective imine acylation/cyclization cascade. Synoxazolidinone B and a series of analogues were also prepared to explore the potential of these 4‐oxazolidinone natural products as antimicrobial agents. These studies confirmed the importance of the chlorine substituent for antimicrobial activity and revealed simplified dichloro derivatives that are equally potent against several bacterial strains.     

Synthesis and spectroscopic characterisation of a combinatorial library based on the fungal natural product 3-chloro-4-hydroxyphenylacetamide

Parallel solution-phase chemistry has yielded a series of secondary amide analogues of the fungal natural product 3-chloro-4-hydroxyphenylacetamide. 3-Chloro-4-hydroxyphenylacetic acid was coupled to a variety of primary amines using 1-ethyl-3-(3'-dimethylamino- propyl)-carbodiimide hydrochloride. The desired products were obtained in good yield and high purity following rapid silica purification. All analogues were spectroscopically characterised using NMR, UV, IR and MS data. One compound displayed moderate cytotoxicity against the human melanoma and prostate cell lines, MM96L and DU145.     

Optimization of antibacterial cyclic decapeptides

A previously developed method for cyclic peptide synthesis was demonstrated to be able to provide convenient access to large combinatorial libraries of analogues, and this methodology was applied to the optimization of natural product cyclic decapeptides. Using this method, a 192-member library was designed and successfully constructed on the basis of the natural products tyrocidines, streptocidins, and loloatins to increase the therapeutic indices of these antibiotics. Library screening identified nine analogues whose therapeutic indices were increased by up to 90-fold in comparison to the natural products. Three of these analogues showed significant increase in antibacterial potency and concurrent drastic decrease in hemolytic activity. Since the natural products target the bacterial cell wall, the newly discovered analogues are promising leads for drug development against drug-resistant bacteria.     

Synthesis of gramicidin S and its analogues via an on-resin macrolactamization assisted by a predisposed conformation of the linear precursors

A simple and efficient preparation of gramicidin S and its analogues is described. It involves solid-phase peptide synthesis and on-resin macrolactamization without side chain protection, affording cyclic products in high yield and high purity. The high specificity of the cyclization reaction was shown to originate in the formation of a pre-organized conformation of the linear biosynthetic precursor of gramicidin S. This facile method will provide convenient access to the analogues of the natural product for functional optimization to counter microbial resistance.     

A practical synthesis of (all-Z)-eicosa-3,6,9,12-tetraene, a pheromone component isolated from emerald moths

A short and practical synthesis of (all-Z)-eicosa-3,6,9,12-tetraene, a component of the emerald moth pheromone is reported. Two different methodologies are used both starting with the natural polyunsaturated fatty acid (all-Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA). The methodology can be used for the syntheses of a homologous series of analogues of the pheromone that may be practical for analytical purposes of similar natural products.     

The generation of "unnatural" products: synthetic biology meets synthetic chemistry

Natural product analogue generation is important, providing tools for chemical biology, enabling structure activity relationship determination and insight into the way in which natural products interact with their target biomolecules. The generation of analogues is also often necessary in order to improve bioavailability and to fine tune compounds' activity. This review provides an overview of the catalogue of approaches available for accessing series of analogues. Over the last few years there have been major advances in genome sequencing and the development of tools for biosynthetic pathway engineering; it is therefore becoming increasingly easy to combine molecular biology and synthetic organic chemistry in order to enable expeditious access to series of natural products. This review outlines the various ways of combining biology and chemistry that have been applied to analogue generation, drawing upon a series of examples to illustrate each approach.     

Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp3)−H Activation Strategy

This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (−)-epicoccin G and (−)-rostratin A using a double C(sp³)−H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8’ alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis-triflate substrate. This bis-triflate served as the functional handles for the key transformation of the synthesis: a double C(sp³)−H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (−)-epicoccin G and to the more challenging (−)-rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (−)-epicoccin G and (−)-rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue.     

A brief synthesis of (-)-englerin A

Englerins A and B are guaiane sesquiterpenes that were isolated from the bark of Phyllanthus engleri, a plant indigenous to east Africa. The englerins consist of a 5-6-5 fused tricyclic structure with an ether bridge and two ester-bearing stereogenic centers, including a highly unusual glycolate residue. Englerin A is a potent and selective inhibitor of the growth of six human renal cancer cell lines. We report herein an efficient, eight-step synthesis of englerin A that leverages simple carbonyl-enabled carbon-carbon bond formations. Our route is amenable to the production of a diverse series of analogues for structure-function studies and determination of the mode of action of these natural products.     

Synthesis and structural anomaly of xyloketals-unique benzoxacycles: A review

Xyloketals, unique bioactive compounds, isolated from mangrove fungus Xylaria sp. (no. 2508), having multiple pharmacological, therapeutic properties, have prompted enormous research on their stereochemistry, bioactivity and synthetic attempts made toward this novel family. This review brings forward a systematic and comprehensive survey of the method of both racemic and enantioselective synthesis, reactivity, and biological properties associated with the xyloketal derivatives and their analogues.     

Synthesis and biological evaluation of aromatic analogues of conduritol F, L-chiro-inositol, and dihydroconduritol F structurally related to the amaryllidaceae anticancer constituents

Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, l-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.     

Synthesis and stability of a homologous series of triynol natural products and their analogues

A series of polyyne natural products 1, 13, and 31 and analogues 14, 21, and 22 are synthesized in six steps. The key step is a Fritsch-Buttenberg-Wiechell rearrangement in which a triyne framework is formed from the appropriate dibromoolefin precursor. Terminal conjugated triynes 13 and 14 are obtained as highly unstable products that rapidly decompose under ambient conditions. The stability of triynols increases via either the addition of methylene units (i.e., 6 --> 31 --> 1) or addition of terminal substituents (i.e., 13 --> 21 or 31).     

Iso-migrastatin congeners from Streptomyces platensis and generation of a glutarimide polyketide library featuring the dorrigocin, lactimidomycin, migrastatin, and NK30424 scaffolds

Iso-Migrastatin (10) has been shown to be the main natural product of Streptomyces platensis, which undergoes a facile, H2O-mediated rearrangement into dorrigocin A (2), 13-epi-dorrigocin A (11), dorrigocin B (3), and migrastatin (1). Eight new congeners (12-19) of 10 were characterized. They can undergo the same H2O-mediated rearrangement into the corresponding 1, 2, 3, and 11 analogues (20-43) or 1,4-Michael addition with cysteine to afford the corresponding analogues (44-51) of NK30424 A and B (5, 6). This study generated a 47-member library of glutarimide polyketides, setting the stage to investigate the SAR for this family of natural products. These results also established the absolute stereochemistry of 5 and 6 and shed new light into the post-polyketide synthase steps for 10 biosynthesis.     

Total synthesis and molecular target of largazole, a histone deacetylase inhibitor

Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the preparation of a series of key analogues, and the molecular target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biological evaluation of largazole and its key analogues, including an acetyl analogue, a thiol analogue, and a hydroxyl analogue, suggested that histone deacetylases (HDACs) are molecular targets of largazole and largazole is a class I HDAC inhibitor. In addition, structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.     

C6-C8 bridged epothilones: consequences of installing a conformational lock at the edge of the macrocycle

A series of conformationally restrained epothilone analogues with a short bridge between the methyl groups at C6 and C8 was designed to mimic the binding pose assigned to our recently reported EpoA-microtubule binding model. A versatile synthetic route to these bridged epothilone analogues has been successfully devised and implemented. Biological evaluation of the compounds against A2780 human ovarian cancer and PC3 prostate cancer cell lines suggested that the introduction of a bridge between C6-C8 reduced potency by 25-1000 fold in comparison with natural epothilone D. Tubulin assembly measurements indicate these bridged epothilone analogues to be mildly active, but without significant microtubule stabilization capacity. Molecular mechanics and DFT energy evaluations suggest the mild activity of the bridged epo-analogues may be due to internal conformational strain.     

Total synthesis of aldehyde-containing Garcinia natural products isomorellin and gaudichaudione A

The natural products, isomorellin and gaudichaudione A, with a 4-oxa-tricyclo[4.3.1.0^3,7] dec-8-en-2-one scaffold were synthesized for the first time using an efficient method. The key improvement of this method was the simultaneous bisalkylation of 5,6-dihydroxyxanthone with the bulky 2-methylbutyne group. This method obviously shortened the synthetic route and enhanced the total yield. Four analogues named forbesione, desoxymorellin, desoxygaudichaudione A, and gambogin containing the same caged structure were prepared using this method.     

Mitsunobu coupling of nucleobases and alcohols: an efficient, practical synthesis for novel nonsugar carbon nucleosides

A simple facile synthesis of substituted purine derivatives has been developed by using Mitsunobu conditions for an alcohol and a respective nucleobase. A wide range of alcohols produces good to excellent yield (>90%). The resulting purine analogues show good regioselectivity with N-9 substitution as the dominant products in most of the cases. Application of diastereospecific alcohols reveals a complete inversion of the carbon stereogenic center giving a single diastereomer. More than two dozen novel nucleobase derivatives have been prepared in high yield.