14-membered Ring Research Articles

Stereocontrolled total synthesis and biological evaluation of (−)- and (+)-petrosin and its derivatives

Total synthesis of (−)- and (+)-petrosin was accomplished. Stereocontrolled construction of the quinolizidine ring was achieved through a diastereoselective Mannich reaction and an aza-Michael reaction. Head-to-tail dimerization was performed by assembly of the two monomers using Suzuki–Miyaura cross coupling and subsequent ring-closing metathesis to construct the 16-membered ring. Biological evaluation of synthetic (−)- and (+)-petrosin and its derivatives indicated that the bispiperidine structure was necessary for the inhibition of syncytium formation.

Pseudo-polymorphism of Halogen Substituted Tetraaza[14]annulene Complexes

6,8,15,17-tetramethyldibenzo-5,9,14,18-tetraazacyclotetradecinatonickel (II) (tmtaa) bears strain within its 14-membered ring and is known to adopt saddle-shaped structure. As a consequence, tmtaa has an asymmetric apical coordination sites at both sides of the saddle. Our previous study revealed that the chlorine substituted complex, [Ni(tmtaa-4Cl)] shown in Figure (X = Cl), exhibited pseudo-polymorphism with dichloromethane and chloroform. This behaviour is due to the good affinity between halogen substituents and halomethane solvent. In this study, we grew single crystals of [Ni(tmtaa-4Br)] using various halomethane solvent as crystallization solvents and elucidated the role of the solvents related to the generation of pseudo-polymorprhism. We have succeeded in obtaining two kinds of single crystals 1 and 2 from the same vial container using bromoform. From X-ray structural analysis, 1 and 2 formed twist dimer as with previous report, and are found to include bromoform in their crystal structure. Note that these complexes adopted more distorted saddle-shaped structure than normal tmtaa complexes. The Ni-N4 planes were not planar. The difference of 1 and 2 was the degree of distortion around Ni-N4 plane, and 1 was more distorted than 2. The space group of these complexes were Aba2 and C2/c respectively. The interactions that led to the difference in packing of dimers were CH...π interaction in 1 and π...π interaction in 2.

Catalytic Asymmetric Claisen Rearrangement of Gosteli-Type Allyl Vinyl Ethers: Total Synthesis of (−)-9,10-Dihydroecklonialactone B

The enantioselective synthesis of (-)-9,10-dihydroecklonialactone B is described. The catalytic asymmetric Claisen rearrangement of a Gosteli-type allyl vinyl ether was utilized to afford an acyclic α-keto ester building block endowed with functionality amenable to the preparation of the carbocyclic target molecule by suitable postrearrangement transformations: A highly diastereoselective Corey-Bakshi-Shibata reduction of a β-chiral α-keto ester and a reductive homologation of an α-hydroxy ester. A transprotection tactic by a chemoselective intramolecular 6-exo-trig iodoetherification enabled regioselective ring-closing alkene metatheses to afford the 5- as well as the 14-membered ring, however, with mixed success in terms of E/Z selectivity.

Synthesis of SFH-type aluminosilicate zeolite with 14-membered ring and its applications as solid acidic catalyst

The direct-synthesis method for preparing the SFH-type aluminosilicate zeolites, designated as [Al,B]-SFH-D, was successfully improved by adding the calcined SFH-type borosilicate zeolite as seeds into the mother gel in the presence of N,N,N-trimethyl-phenylcyclohexylmethylammonium hydroxide as organic-structure-directing agent. As a control, by the conventional post-synthesis method, the SFH-type aluminosilicate zeolites, designated as [Al,B]-SFH-P, were prepared. Thus prepared SFH-type aluminosilicate zeolites were characterized in details. The high-resolution 27Al MAS NMR results implied that there are marked differences in the distribution of Al atoms in the framework between the zeolites obtained by the direct- and post-synthesis methods. [Al,B]-SFH-D exhibited a higher catalytic performance in the acylation of 2-methoxynaphthalene with acetic anhydride than [Al,B]-SFH-P.

Total Synthesis of the Z-Isomers of the Proposed and Revised Structures of Aspergillide B via an Iodocyclization and Ring-Closing Metathesis Strategy

The synthesis of Z -isomers of both the proposed and revised structures of aspergillide B is described. A divergent route is employed that involves kinetically controlled ring-closing metathesis for the construction of a 14-membered macrocyclic ring, ester formation under Yamaguchi conditions, a Wacker-type oxidative cyclization for creation of the C4 stereogenic center and a previously reported diastereoselective isomerization–iodocyclization strategy for the construction of the 2,6- trans -disubstituted tetrahydropyran subunit.

New Reactions and Products Resulting from Alternative Interactions between the P450 Enzyme and Redox Partners

Cytochrome P450 enzymes are capable of catalyzing a great variety of synthetically useful reactions such as selective C–H functionalization. Surrogate redox partners are widely used for reconstitution of P450 activity based on the assumption that the choice of these auxiliary proteins or their mode of action does not affect the type and selectivity of reactions catalyzed by P450s. Herein, we present an exceptional example to challenge this postulate. MycG, a multifunctional biosynthetic P450 monooxygenase responsible for hydroxylation and epoxidation of 16-membered ring macrolide mycinamicins, is shown to catalyze the unnatural N-demethylation(s) of a range of mycinamicin substrates when partnered with the free Rhodococcus reductase domain RhFRED or the engineered Rhodococcus-spinach hybrid reductase RhFRED-Fdx. By contrast, MycG fused with the RhFRED or RhFRED-Fdx reductase domain mediates only physiological oxidations. This finding highlights the larger potential role of variant redox partner protein–protein interactions in modulating the catalytic activity of P450 enzymes.

Theoretical and experimental investigation on clarithromycin, erythromycin A and azithromycin and descladinosyl derivatives of clarithromycin and azithromycin with 3-O substitution as anti-bacterial agents

The macrolide antibiotics erythromycin A, clarithromycin and azithromycin are all clinically important.

1,3,2-Dithiaphospholanes with an annelated 1,2-dicarba-closo-dodecaborane(12) unit: formation and reactivity

1,3,2-Dithiaphospholanes were prepared, containing an annelated 1,2-dicarba-closo-dodecaborane(12) unit, bearing halogens (F, Cl, Br, and I), H, NEt2, OEt groups, or organo substituents (R = i-Pr, t-Bu, Cy, 3,5-Me2-C6H3-CH2, Ph) at phosphorus. The t-Bu derivative was structurally characterised as its sulfide. The organo-substituted derivatives escape the ring strain by irreversible (R = t-Bu; X-ray analysis) or reversible dimerisation, by which 10-membered rings are formed. Using 1,1-bis(dichlorophosphino)methane, another dimer containing a 14-membered ring could be isolated and structurally characterised. The preferred conformation of the 1,3,2-dithiaphospholanes depends on the nature of the substituent at phosphorus. For instance, the substituents R = t-Bu, NEt2 prefer the equatorial position, as indicated by diagnostic NMR data, supported by DFT calculations [B3LYP/6-311+G(d,p) level of theory]. The calculations also predict the tendency for dimerisation, and calculated NMR parameters are in good agreement, in most cases, with experimental data.

Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1-P2 ligands.

A series of potent macrocyclic HIV-1 protease inhibitors have been designed and synthesized. The compounds incorporated 16- to 19-membered macrocyclic rings between a nelfinavir-like P2 ligand and a tyrosine side chain containing a hydroxyethylamine sulfonamide isostere. All cyclic inhibitors are more potent than their corresponding acyclic counterparts. Saturated derivatives showed slight reduction of potency compared to the respective unsaturated derivatives. Compound containing a 16-membered ring as the P1-P2 ligand showed the most potent enzyme inhibitory and antiviral activity.

Synthesis of New Examples of Corands with 16-Membered P,N-Containing Core Ring

An effective strategy of the synthesis of P,N-containing corands with 16-membered core ring is described. It is based on covalent self-assembly processes in the course of Mannich-type condensations in three component systems: bis(mesitylphosphino)propane-formaldehyde-primary amines. This approach allowed the authors to obtain a series of novel functionalized 1,9-di(aralkyl)-3,7,11,15-tetramesityl-1,9-diaza-3,7,11,15-tetraphosphacyclohexadecanes in very good yields. The study of structure of the synthesized corands showed that all of them were obtained as pure RSSRstereoisomers with similar conformations in the solid state.

Open Pentameric Calixarene Nanocage

A novel open helmetlike coordination cage has been synthesized based on Co4-calixarene shuttlecock-like secondary building units and in situ generated phosphate anions, where the opening of the cage comprises a large 16-membered ring. The above unprecedented Co20 nanocage presents the first pentameric calixarene coordination compound. Sorption behavior and magnetic properties are also investigated.

Callyspongiolide, a Cytotoxic Macrolide from the Marine Sponge Callyspongia sp.

A novel macrolide, callyspongiolide, whose structure was determined by comprehensive analysis of the NMR and HRMS spectra, was isolated from the marine sponge Callyspongia sp. collected in Indonesia. The compound features a carbamate-substituted 14-membered macrocyclic lactone ring with a conjugated structurally unprecedented diene-ynic side chain terminating at a brominated benzene ring. Callyspongiolide showed strong cytotoxicity against human Jurkat J16 T and Ramos B lymphocytes.

Synthesis, structure, and photoluminescence of a (4,6)-connected Cu(I)–CN–triazolate framework built with a unique heptanuclear hybrid cluster

A 3-D Cu(I)–CN–triazolate hybrid coordination polymer, {Cu9(NH2-BPT)2(BPT)2(CN)7}n (1) (NH2-BPT = 4-amino-3,5-bis(3-pyridyl)-1,2,4-triazole, BPT = 3,5-bis(3-pyridyl)-1,2,4-triazole), has been synthesized via self-assembly of NH2-BPT, CuCN, and K3Fe(CN)6 under hydrothermal conditions. Single-crystal X-ray diffraction data show that four of the five independent copper centers in 1 have a three-coordinated trigonal coordination geometry, and the remaining copper center has a two-coordinated linear geometry. Three Cu ions are linked by one cisoid-BPT and two CN− to form a 16-membered ring subunit, which is joined by the two-coordinate copper center via the triazole N(4)-position to generate an unprecedented [Cu7(BPT)2(CN)4] hybrid heptanuclear cluster. Each heptanuclear motif is linked to two adjacent [Cu7] clusters through four CN− anions, and further to four [Cu–CN–Cu] binuclear clusters through two transoid-NH2-BPT ligands. Each of these [Cu–CN–Cu] units is linked to four neighboring heptanuclear motifs. The overall geometry is a 3-D (4,6)-connected topological framework with Schläfli symbol of (44 × 62)(44 × 610 × 8). Compound 1 also exhibits high thermal stability and strong green fluorescence emission at 536 nm in the solid state.

Studies directed towards the total synthesis of koshikalide: stereoselective synthesis of the macrocyclic core

The stereoselective synthesis of the macrolactone core of the natural product koshikalide is described. Starting with readily available 1,4-butanediol and malic acid as synthons, our synthetic strategy involved the reiterative application of Gilman’s reaction, Swern oxidation and Sharpless asymmetric epoxidation to establish the required stereocentres. Other key steps in the synthesis include Negishi cross coupling and Horner–Wadsworth–Emmons (HWE) reactions for construction of the main fragments. The 14-membered lactone ring was prepared by a selective Mitsunobu macrolactonization approach.

Biocatalytic Synthesis of Pikromycin, Methymycin, Neomethymycin, Novamethymycin, and Ketomethymycin

A biocatalytic platform that employs the final two monomodular type I polyketide synthases of the pikromycin pathway in vitro followed by direct appendage of D-desosamine and final C-H oxidation(s) in vivo was developed and applied toward the synthesis of a suite of 12- and 14-membered ring macrolide natural products. This methodology delivered both compound classes in 13 steps (longest linear sequence) from commercially available (R)-Roche ester in >10% overall yields.

ChemInform Abstract: First Enantioselective Synthesis of Tetracyclic Intermediates en Route to Madangamine D.

AbstractIntermediate (I*) of Madangamine D is prepared in 13 steps.

Characterization of the components of meleumycin by liquid chromatography with photo-diode array detection and electrospray ionization tandem mass spectrometry

Reversed-phase liquid chromatography coupled with photo-diode array (PDA) detection and electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to characterize the components of meleumycin, a 16-membered macrolide antibiotic produced by fermentation. In total 31 components were characterized in commercial samples, including 12 impurities that had never been reported before and 12 others that were partially characterized. The structures of these unknown compounds were deduced by comparison of their fragmentation patterns with those of known components. Their ultraviolet spectra and chromatographic behavior were used to confirm the proposed structures: e.g. λmax shift from 232nm to 282nm would indicate the presence of an α-, β-, γ-, δ-unsaturated ketone instead of a normal α-, β-, γ-, δ-unsaturated alcohol in the 16-membered ring of the examined components. Compared to other methods, this LC/MSn method is particularly advantageous to characterize minor components at trace levels in multi-components antibiotics, in terms of sensitivity and efficiency.

Antimicrobial activities of clarithromycin against recent obtained clinical isolates

In order to evaluate antimicrobial activities of clarithromycin (CAM), minimum inhibitory concentrations (MICs) of CAM and control drugs were determined against clinical isolates that were obtained from outpatients in 1994 and 1996. The results are summarized as follows; 1. It was not showed that CAM-resistant strains were increasing among Staphylococcus spp., beta-streptococci, Moraxella subgenus Branhamella catarrhalis, Haemophilus influenzae, Bordetella pertussis, Campylobacter jejuni subsp. jejuni, Chlamydia trachomatis and Mycoplasma pneumoniae. It appeared that resistances to CAM and macrolides (MLs) were increasing among Streptococcus pneumoniae and Peptostreptococcus spp. 2. The drug susceptibility patterns to MLs were similar and detection frequencies of induced resistant strains that were resistant to only 14-membered ring MLs including CAM and constitutive resistant strains that were resistant to 14 and 16-membered ring MLs were high among Streptococcus pneumoniae and Peptostreptococcus spp. It appears that MLs-resistance systems are linked to each other, and that this was a cause of increasing MLs-resistance among these bacterial species. 3. Notwithstanding of antibiotic resistance problems, CAM is still useful since it maintains strong antimicrobial activities against M. (B.) catarrhalis, B. pertussis, C. jejuni subsp. jejuni, C. trachomatis and M. pneumoniae, and it controls arginate producing abilities of mucoide strains of Pseudomonas aeruginosa.

Development of Related HCV Protease Inhibitors: Macrocyclization of Two Highly Functionalized Dienyl-ureas via Ring-Closing Metathesis

A novel assembly of two structurally related 14-membered ring macrocyclic hepatitis C virus protease inhibitors is presented. Key to their successful construction was an ultimate ring-closing metathesis step on the respective highly functionalized dienyl-ureas. In the case of IDX316, this procedure significantly outperformed the original macrocyclizations in terms of reaction conditions, impurity profile, product isolation, and basic efficiency metrics. Simple nonchromatographic purification methods achieved sub-10-ppm ruthenium content in the isolated product. Overall yields to IDX316 from all five starting materials ranged from 11 to 40%, and the estimated process mass intensity was improved by a factor of 50 relative to the original unscalable discovery-based routes. Application of similar methodology in the case of IDX320 and first scale-up to half-kilogram batch sizes was demonstrated.

Total Synthesis of Amphidinolide F

A concise total synthesis of the cytotoxic marine natural product amphidinolide X (1) is described. A key step of the highly convergent route to this structurally rather unusual macrodiolide derivative consists of a newly developed, highly syn selective formation of allenol 6 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 5 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 6 was then cyclized with the aid of Ag(I) to give dihydrofuran 7 containing the (R)-configured quarternary sp3 chiral center at C19 of the target. The anti-configured chiral centers at C10 and C11 were formed by the palladium-catalyzed, Et2Zn-promoted addition of propargyl mesylate 12 to the functionalized aldehyde 11. The key fragment coupling at the C13−C14 bond was achieved by the “9-MeO-9-BBN” variant of the alkyl-Suzuki reaction. Finally, the 16-membered macrodiolide ring was formed by a Yamaguchi esterification/lactonization strategy.