Synthetic efforts towards the stereoselective synthesis of NF00659B1

NF00659B₁ is a novel α-pyrone diterpenoid natural product with potent anti-colon cancer activity. A stereoselective approach to the 2,2-dimethyl oxepanol core of NF00659B₁ is described enlisting a sequence of olefinic ester ring-closing metathesis, epoxidation, and Grignard addition. This strategy paves the way to a total synthesis of NF00659B₁ for further biological studies.     

Conformationally Restricted Dinucleotides: Tandem Ring-Closing Metathesis and Hydrogenation Approach

Abstract

Cyclic dinucleotides with saturated connections between a nucleobase and the phosphate are synthesised using a tandem ring-closing metathesis (RCM) and hydrogenation protocol and found to be significantly stabilised towards ammonia.     

Partial synthesis of ganglioside and lysoganglioside lipoforms as internal standards for MS quantification

Within recent years, ganglioside patterns have been increasingly analyzed by MS. However, internal standards for calibration are only available for gangliosides GM1, GM2, and GM3. For this reason, we prepared homologous internal standards bearing nonnatural fatty acids of the major mammalian brain gangliosides GM1, GD1a, GD1b, GT1b, and GQ1b, and of the tumor-associated gangliosides GM2 and GD2. The fatty acid moieties were incorporated after selective chemical or enzymatic deacylation of bovine brain gangliosides. For modification of the sphingoid bases, we developed a new synthetic method based on olefin cross metathesis. This method was used for the preparation of a lyso-GM1 and a lyso-GM2 standard. The total yield of this method was 8.7% for the synthesis of d17:1-lyso-GM1 from d20:1/18:0-GM1 in four steps. The title compounds are currently used as calibration substances for MS quantification and are also suitable for functional studies.     

Synthesis, characterization and olefin metathesis studies of a family of ruthenium phosphonium alkylidene complexes

The synthesis of four ruthenium phosphonium alkylidene complexes [(H₂IMes)Cl₂RuCH(PCy₃)]⁺[A]⁻ (1, A = B(C₆F₅)₄; 2, A = BF₄; 3, A = OTf; 4, A = BPh₄), differing only in the anion is described. The X-ray structures of 1, 3 and 4 show them to be isostructural in the cation, with no interaction between the Ru centers and the anion. Ring closing metathesis of a substrate to a six-membered methylcyclohexene at 0 °C in CD₂Cl₂ using 1 mol% catalyst, shows that catalysts 1-4 behave very similarly, and exhibit superior activity in comparison to Grubbs second generation and fast-initiating catalysts.     

Chiral pool synthesis of calystegine A3 from 2-deoxyglucose via a Brown allylation

Calystegine A₃ is a naturally occurring nortropane iminosugar of which there previously have been three total syntheses. Inspired by our previous work we here report on a fourth approach using 17 steps from 2-deoxy-d-glucose applying a diastereoselective allylation protocol.     

Design,synthesis, and opioid activity of arodyn analogs cyclized by ring-closing metathesis involving Tyr(allyl)

Kappa (κ) opioid receptor selective antagonists are useful pharmacological tools in studying κ opioid receptors and have potential to be used as therapeutic agents for the treatment of a variety of diseases including mood disorders and drug addiction. Arodyn (Ac[Phe^1–3,Arg⁴,d-Ala⁸]Dyn A-(1–11)NH₂) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al. J Med Chem 2002;45:5617–5619) and prevents stress-induced reinstatement of cocaine-seeking behavior following central administration (Carey et al. Eur J Pharmacol 2007;569:84–89). To restrict its conformational mobility, explore possible bioactive conformations and potentially increase its metabolic stability we synthesized cyclic arodyn analogs on solid phase utilizing a novel ring-closing metathesis (RCM) reaction involving allyl-protected Tyr (Tyr(All)) residues. This approach preserves the aromatic functionality and directly constrains the side chains of one or more of the Phe residues. The novel cyclic arodyn analog 4 cyclized between Tyr(All) residues incorporated in positions 2 and 3 exhibited potent κ opioid receptor antagonism in the [³⁵S]GTPγS assay (K_B?=?3.2?nM) similar to arodyn. Analog 3 cyclized between Tyr(All) residues in positions 1 and 2 also exhibited nanomolar κ opioid receptor antagonist potency (K_B?=?27.5?nM) in this assay. These are the first opioid peptides cyclized via RCM involving aromatic residues, and given their promising pharmacological activity represent novel lead peptides for further exploration.     

Stereoselective total synthesis of a potent natural antifungal compound (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one

A practical stereoselective synthesis of (6S)-5,6,dihydro-6-[(2R)-2-hydroxy-6-phenyl hexyl]-2H-pyran-2-one (1), a potent natural antifungal compound, is described. The sequence involves diastereoselective iodine-induced electrophilic cyclization, epoxide ring opening with a vinyl Grignard reagent and ring closing metathesis (RCM) as the key steps.     

Monitoring ring-closing metathesis: Limitations on the utility of H NMR analysis

The utility and limitations of ¹H NMR methods for monitoring the progress of ring-closing metathesis (RCM) reactions are examined. ¹H NMR analysis of RCM reactions that yield macrocyclic and medium-ring products can be more problematic than is generally recognized. Interpretation is complicated by the formation of oligomers with an NMR signature identical or closely similar to that of the diene precursor, the RCM target, or a composite of the two. DOSY-NMR can aid in resolving ambiguities in signal assignment, but reliable quantitation requires ancillary methods.     

A Concise Synthetic Approach to β,γ-Dehydrocurvularin: Synthesis of (±)-Di-O-Methyl-β,γ-dehydrocurvularin

A concise synthesis of di-O-methyl-β,γ-dehydrocurvularin, the di-O-methylated derivative of the naturally occurring nematicidal macrolide, β,γ-dehydrocurvuralin, was accomplished by starting from a commercially available aromatic carboxylic acid in a three-step sequence consisting of esterification, Friedel-Crafts acylation, and microwave-promoted ring-closing metathesis.     

O-Glycosidation reactions promoted by in situ generated silver N-heterocyclic carbenes in ionic liquids

We herein report O-glycosidation reactions promoted via silver N-heterocyclic carbene complexes formed in situ in ionic liquids. Seven different room temperature ionic liquids were screened for the glycosidation reaction of 4-nitrophenol with tetra-O-acetyl-α-d-galactopyranosyl bromide. Good to excellent yields were obtained using Ag–NHC complexes derived from imidazolium halide salts to promote the glycosidation reaction, whereas yields considered moderate to low were obtained without use of the silver carbene complex. Anion metathesis of the ionic liquids with inexpensive alkylammonium halides also resulted in silver N-heterocyclic carbene formation and subsequent O-glycosidation in the presence of silver carbonate. Effective utility of this methodology has been demonstrated with biologically relevant acceptors (including flavones and steroids) where O-β-glycoside products were obtained selectively in moderate to good yields. We have also demonstrated that the Ag–NHC complex is a superior promoter to traditionally used silver carbonate for the glycosidation of polyphenolic acceptors. The ionic liquids used in the study could be recycled three times without apparent loss in activity.