Chiron Approach Research Articles

Chiron approach toward the synthesis of the fused tricyclic core of epi-parvistemonine A

A stereoselective synthesis of fused tricyclic framework of epi-parvistemonine A from D-glucono-δ-lactone is described. The synthetic strategic is based on the stereoselective construction of the 7-membered cyclic skeleton via a cross-metathesis reaction followed by a Michael type cyclization promoted by Tf2O.

Bioinspired synthesis and biological evaluation of ent-protulactones A and B.

The bioinspired and stereoselective synthesis of the furo[3,2-b] furan lactone (-)-protulactone A and the dioxabicyclo[3.3.1]nonane lactone (+)-protulactone B has been achieved based on the chiron approach. The synthesis features the utilization of a number of one-pot, sequential transformations, including a cascade reaction of reductive elimination and nucleophilic addition in a one-pot process and a one-pot sequence via cross-metathesis/acetonide deprotection/O-Michael addition/lactonization to streamline the synthesis route and avoid the tedious work of product purification. Synthetic protulactones and their analogues were evaluated for their in vitro antiproliferative activity against selected tumor cell lines (MCF-7 and Capan 2) and showed minor cytotoxicity.

Divergent Synthesis and Biological Evaluation of 2,6-Disubstituted Tetrahydropyran-Containing Natural Products: Parvistone E, Goniothalesdiol A, 6-epi-Goniothalesdiol A, and 8-epi-9-Deoxygoniopypyrone

AbstractThe concise and efficient synthesis of (+)-goniothalesdiol A and (–)-parvistone E (leiocarpin A), as well as the first total syntheses of (–)-6-epi-goniothalesdiol A and (–)-8-epi-9-deoxygoniopypyrone acetate, have been achieved in four or five longest linear steps based on the chiron approach. The potential biological activities of four 2,6-disubstituted tetrahydropyran-containing natural products were explored based on a panel of human cancer cell lines, BV-2 microglia and 3T3-L1 preadipocytes. Our results indicate that these four natural products display significant adipogenic activity in 3T3-L1 preadipocytes, but do not have clear effects on cancer cell proliferation or LPS stimulated microglia activation.

Synthesis and potential antidiabetic and lipid-lowering activities of putative asperidine B and its desmethyl analogue

Putative asperidine B is an unnatural 2,6-disubstituted piperidin-3-ol and a structural isomer of (+)-preussin, a well-known pyrrolidin-3-ol alkaloid. This work reports the first enantioselective synthesis of putative asperidine B and its desmethyl analogue via a chiron approach starting from d-isoascorbic acid as well as evaluation of their free-radical scavenging, antidiabetic, and anti-hyperlipidemic activities. Both putative asperidine B and its desmethyl analogue markedly reduced the total reactive oxygen species (ROS) without cytotoxicity in hepatocellular carcinoma (HepG2) cells. The desmethyl analogue was a potent inducer for two antioxidant gene expression, glutathione peroxidase and superoxide dismutase, whereas putative asperidine B only induced superoxide dismutase. In addition, putative asperidine B exerted potent antidiabetic activity via α-glucosidase inhibition (IC50 = 0.143 ± 0.001 mg/mL) comparable to that of acarbose, an antidiabetic drug. Consistent with the parent asperidine B (preussin), both putative asperidine B and its desmethyl analogue inhibited cholesterol absorption in the intestinal Caco-2 cells. These novel and promising antioxidant, antidiabetic, and lipid-lowering effects of piperidin-3-ols could offer a starting point for this class of compounds for obesity and diabetic drug discovery.

Recent advances in the syntheses of guaianolides.

Sesquiterpene lactones, especially guaianolides representing a bigger class of natural products, have served as appealing candidates for total synthesis due to their varied bio- and pharmaceutical activities. This tutorial review delineates the creative efforts of many researchers in the total syntheses of different complex guaianolides recently published in the literature. Many of the syntheses display meticulous interplay between new methods and the ingenuity of strategies achieved through well-planned routes. In some cases, the Chiron approach has come in quite handy, wherein the structural features and stereochemistry of select molecules could map well with naturally available starting materials. A few catalytic methods like diastereoselective aldol reaction, enediyne or dienyne metathesis, or photochemical methods have been efficiently used. This compilation also aims to enhance the diversity space based on these natural products and further interest in the sustainable total synthesis of this class of compounds and related molecules.

Stereoselective synthesis and anticancer profile of C-alkyl pyrrolidine-diols with a sphingoid base-like backbone

The chiron approach to pyrrolidine-containing isophytosphingosine base-like compounds 21.HCl-23.HCl was developed from the known d-glucofuranose template. The key step of the synthesis was a highly diastereoselective aza-Claisen rearrangement, which created the cornerstone of the target molecules carrying three consecutive stereocentres. Subsequent cross metathesis reaction allowed the installation of a long-chain unit. The five-membered ring formation was accomplished via an intramolecular SN2 process. A single crystal X-ray analysis of the key intermediates confirmed the (2R,3R,4R)- and (2S,3R,4R)-configuration seen in the final derivatives. A comparison of the cytotoxic activity of the novel sphingomimetics (21.HCl-23.HCl) with recently described analogues (compounds 61, 62 and their antipodes) revealed that their antiproliferative profile strongly depends on the stereochemistry of the pyrrolidine substituents as well as the length of the side chain unit. Moreover, with regard to their structure and recent literature findings, compound 22.HCl may possess β-GCase inhibitory activity.

Chiron Approach for the Total Synthesis of Brevipolide M

AbstractAn efficient stereoselective synthesis of brevipolide M was established in 13 linear steps and 17.8% overall yields based on chiron approach. The key steps of our synthesis involved tandem Wittig olefination–tetrahydrofuran cyclization and sequential ring-closing metathesis (RCM)–double-bond migration in one-pot processes.

Stereoselective Total Synthesis of (+)-Brevipolide H from d-Galactal

AbstractAn efficient and concise synthesis of cytotoxic 5,6-dihydro-α-pyrone (+)-brevipolide H has been accomplished in 12 long linear steps in 8.65% overall yield from readily available chiral synthons, d-galactal and ethyl l-lactate. The features of this synthesis are highly diastereoselective Simmons–Smith cyclopropanation and carbohydrate-based chiron approach to rapid access to key 5,6-dihydro-α-pyrone skeleton.

Ag(I)/PPh3-catalyzed diastereoselective syntheses of spiro[indole-3,4'-piperidine] derivatives via cycloisomerizations of tryptamine-ynamides.

A Ag(I)/PPh3-catalyzed chelation-controlled cycloisomerization of tryptamine-ynamide was developed to access the spiro[indole-3,4'-piperidine] scaffold in a racemic and diastereoselective manner. The diastereoselective products were achieved by a chiron approach. Density functional theory (DFT) calculations indicated that strong non-covalent effects between the substrate and catalyst/ligand complex stabilized the spiroindoleninium intermediate via cation-π-π interactions.

A general and concise stereodivergent chiral pool approach toward trans-(4S,5R)- and cis-(4R,5R)-5-alkyl-4-methyl-γ-butyrolactones: Syntheses of (+)-trans- and (+)-cis-whisky and cognac lactones from d-(+)-mannitol

A straightforward synthesis of (+)-trans-(4S,5R)- and (+)-cis-(4R,5R)-whisky lactones starting from d-(+)-mannitol has been reported here in fewer number of efficient steps compared to existing literature processes involving d-mannitol as the chiral pool starting material. Chiron approach directly translated chirality of d-mannitol to one of the two chiral centers in these target molecules. Toward this end, stereoisomerically pure trans- and cis-iodomethyl-γ-lactones were formed in the penultimate step. These two acted as versatile advanced common intermediates as they were also converted to the (+)-trans-(4S,5R)- and (+)-cis-(4R,5R)-cognac lactones, respectively. To the best of our knowledge, till date no synthesis of cognac lactones starting from d-mannitol has been reported. All these lactones are identified as the key aroma components of aged alcoholic beverages.

Phosphinic Acid/NaI Mediated Reductive Cyclization Approach for Accessing the L‐1‐Deoxynojirimycin Using a Two‐Component Three‐Centered (2C3C) Ugi Type Reaction

Main observation and conclusionA catalytic two‐component three‐centered (2C3C) Ugi‐type reaction was developed for the synthesis of L‐1‐deoxynojirimycin (DNJ) isomers using a chiron approach. This new and quite mild catalytic system, comprised of phenylphosphinic acid/NaI, was used to synthesize both the L‐allo‐DNJ and L‐altro‐DNJ in high yield.

A divergent chiron approach for the first total synthesis of (+)-pseudonocardide A, (+)-pseudonocardide C and an epimer of ent-pseudonocardide D.

A concise and divergent chiron approach for the first total synthesis of (+)-pseudonocardide A, (+)-pseudonocardide C and an epimer of ent-pseudonocardide D is reported starting from d-ribose. The salient features of this synthesis are a highly Z-selective Wittig olefination, one-pot formation of γ-butyrolactone and γ-butenolide through [1,4] O-to-O silyl migration followed by lactonization and an intramolecular oxa-Michael reaction.

Advances in Total Synthesis of Some 2,3,5-Trisubstituted Tetrahydrofuran Natural Products.

2,3,5-Trisubstituted tetrahydrofuran moiety is ubiquitous in natural products. These have served as appealing candidates for total synthesis due to their varied bio- and pharmaceutical activities. This tutorial review delineates the ingenious efforts by many researchers in the total synthesis of selected natural products based on a common 2,3,5-trisubstituted tetrahydrofuran core structure. Many of the syntheses display nuanced interplay between new methods and the ingenuity of planned strategies achieved through catalysis or cascade chemistry. In some cases, the chiron approach has come quite handy, wherein the structural features and the stereochemistry in select molecules could map well with naturally available starting materials. This compilation also aims to enhance the diversity space based on these natural products and further interest in sustainable total synthesis.

A Chiron Approach to the Stereoselective Total Synthesis of Phomonol and Phytotoxic Nonenolides

A common strategy from d‐glucono‐δ‐lactone to the pyran natural product phomonol and the phytotoxic nonenolides has been developed. The key steps include a one‐pot conversion of d‐glucono‐δ‐lactone to β‐hydroxy‐γ‐vinyl‐γ‐lactone and diastereoselective Grignard reaction. The synthesis of phomonol also involved cross‐metathesis and intramolecular oxa‐Micheal addition, while that of nonenolides was based on Yamaguchi esterification and intramolecular ring‐closing metathesis (RCM).

Enantiodivergent syntheses of (+)- and (−)-1-(2,6-dimethylphenoxy)propan-2-ol: A way to access (+)- and (−)-mexiletine from D-(+)-mannitol

Chiron approach was used to acquire optically pure (R)- and (S)-1-(2,6-dimethylphenoxy)propan-2-ol, immediate precursors of (S)- and (R)-mexiletines, respectively. Two different routes were followed from a D-mannitol-derived optically pure common precursor to get the enantiomeric alcohols separately. Comparison of their specific rotation values with the corresponding literature values as well as exact mirror-image relationship between their CD curves proved their high enantiopurity. These alcohols were then transformed to the corresponding amine-drugs in an efficient one-step process instead of two steps described in the literature.

Chiron approach to fully functionalized cyclohexane frame of (+)-Resiniferatoxin

The commercially available (−)-Shikimic acid is used to construct the fully functionalised cyclohexane frame (C-ring) of (+)-Resiniferatoxin. The key reactions involve stereo-selective epoxide opening with trimethylaluminium and vinyl Grignard reaction.

Synthesis and Lipophilicity of Trifluorinated Analogues of Glucose.

In this work, we have developed synthetic routes for novel trifluorinated glucopyranose analogues using a Chiron approach. This strategy used inexpensive levoglucosan as a starting material, and we achieved a microwave glycosylation method as a key step. All analogues adopted standard 4 C1 glucopyranose conformations, and a gauche-gauche conformation for the fluoromethyl group (C5-C6 linkage) was ascertained for congeners with a fluorine atom at C-6. Finally, the lipophilicity of trifluorinated glucose analogues was assessed with a log P determination method based on 19F NMR spectroscopy.

Stereoselective Synthesis of Molecular Square and Granny Knots.

We report on the stereoselective synthesis of both molecular granny and square knots through the use of lanthanide-complexed overhand knots of specific handedness as three-crossing “entanglement synthons”. The composite knots are assembled by combining two entanglement synthons (of the same chirality for a granny knot; of opposite handedness for a square knot) in three synthetic steps: first, a CuAAC reaction joins together one end of each overhand knot. Ring-closing olefin metathesis (RCM) then affords the closed-loop knot, locking the topology. This allows the lanthanide ions necessary for stabilizing the entangled conformation of the synthons to subsequently be removed. The composite knots were characterized by 1H and 13C NMR spectroscopy and mass spectrometry and the chirality of the knot stereoisomers compared by circular dichroism. The synthetic strategy of combining building blocks of defined stereochemistry (here overhand knots of Λ- or Δ-handed entanglement) is reminiscent of the chiron approach of using minimalist chiral synthons in the stereoselective synthesis of molecules with multiple asymmetric centers.

Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside-LecA Interactions.

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono- and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation-optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19 F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C-3 and C-4 showed weaker affinities with LecA as compared to those with the fluorine atom at C-2 or C-6. This research has focused on the chemical synthesis of "drug-like" low-molecular-weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.

Chiron approach from D-mannitol to access a diastereomer of the reported structure of an acetogenin, an amide alkaloid and a sex pheromone

A short, simple and convenient chiron approach to (3R,4S,5R)-(−)-3,5-dihydroxy-4-decanolide, a hitherto unknown diastereomer of the reported structure of a naturally occurring acetogenin, (+)-polyporolide has been accomplished starting from a commercially available, inexpensive chiral pool molecule D-(+)-mannitol in nine efficient steps. An advanced intermediate synthesized from D-(+)-mannitol in six steps toward this end was further employed successfully to access two different natural products bearing two contiguous stereogenic centers. As a result, first chiron approach to formal total synthesis of an amide alkaloid, (4R,5R,2E)-4,5-dihydroxy-1-(piperidin-1-yl)dec-2-en-1-one and total synthesis of a male sex pheromone in parasitic Hymenoptera, (4R,5R)-(−)-5-hydroxy-4-decanolide have also been achieved.