Sequential Ring-closing Metathesis Research Articles

A Bicyclic Analog of the Linear Peptide Arodyn Is a Potent and Selective Kappa Opioid Receptor Antagonist.

Kappa opioid receptor (KOR) antagonists have potential therapeutic applications in the treatment of stress-induced relapse to substance abuse and mood disorders. The dynorphin A analog arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]dynorphin A-(1-11)-NH2) exhibits potent and selective kappa opioid receptor antagonism. Multiple cyclizations in longer peptides, such as dynorphin and its analogs, can extend the conformational constraint to additional regions of the peptide beyond what is typically constrained by a single cyclization. Here, we report the design, synthesis, and pharmacological evaluation of a bicyclic arodyn analog with two constraints in the opioid peptide sequence. The peptide, designed based on structure-activity relationships of monocyclic arodyn analogs, was synthesized by solid-phase peptide synthesis and cyclized by sequential ring-closing metathesis (RCM) in the C- and N-terminal sequences. Molecular modeling studies suggest similar interactions of key aromatic and basic residues in the bicyclic peptide with KOR as found in the cryoEM structure of KOR-bound dynorphin, despite substantial differences in the backbone conformations of the two peptides. The bicyclic peptide's affinities at KOR and mu opioid receptors (MOR) were determined in radioligand binding assays, and its KOR antagonism was determined in the [35S]GTPγS assay in KOR-expressing cells. The bicyclic analog retains KOR affinity and selectivity (Ki = 26 nM, 97-fold selectivity over MOR) similar to arodyn and exhibits potent KOR antagonism in the dynorphin-stimulated [35S]GTPγS assay. This bicyclic peptide represents a promising advance in preparing cyclic opioid peptide ligands and opens avenues for the rational design of additional bicyclic opioid peptide analogs.

Metal‐Free Regioselective 1,6‐Conjugate Addition of Sulfide to para‐Quinone Methides: Simple Access to E‐Selective Thiaoxacyclophanes

AbstractWe realized a simple approach involving the 1,6‐conjugate addition (regioselective thiolation) of para‐quinone methides (p‐QMs) with easily available thio‐based nucleophiles. Through ring‐closing metathesis (RCM), this procedure delivered a variety of para‐ and meta‐thiaoxacyclophanes as E‐isomers in good yields. A simple thiol‐free one‐pot approach is reported for the direct synthesis of sulfides and sulfones under green reaction conditions without the use of any metal catalysts. Low‐cost and easily accessible compounds such as p‐QMs and benzyl bromides are used as starting materials in the presence of potassium thioacetate (PTA) and Oxone®. Novel thiaoxacyclophanes were assembled in three simple steps including conjugate addition of PTA, Grignard addition, and RCM sequence.

Synthesis of sulfonyl benzocyclononadienols

We describe a concise, high-yield method for the synthesis of sulfonyl benzocyclononadienols by a two-step synthetic route, including (i) Grignard 1,2-allylation of sulfonyl chalcones, and (ii) sequential ring-closing metathesis of the resulting dienyl tertiary alcohols with Grubbs second-generation catalyst. This protocol provides a highly effective annulation via one carbon-carbon single bond (C-C) and one carbon-carbon double bond (C=C) formations.

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.

Synthetic prodrug design enables biocatalytic activation in mice to elicit tumor growth suppression

Considering the intrinsic toxicities of transition metals, their incorporation into drug therapies must operate at minimal amounts while ensuring adequate catalytic activity within complex biological systems. As a way to address this issue, this study investigates the design of synthetic prodrugs that are not only tuned to be harmless, but can be robustly transformed in vivo to reach therapeutically relevant levels. To accomplish this, retrosynthetic prodrug design highlights the potential of naphthylcombretastatin-based prodrugs, which form highly active cytostatic agents via sequential ring-closing metathesis and aromatization. Structural adjustments will also be done to improve aspects related to catalytic reactivity, intrinsic bioactivity, and hydrolytic stability. The developed prodrug therapy is found to possess excellent anticancer activities in cell-based assays. Furthermore, in vivo activation by intravenously administered glycosylated artificial metalloenzymes can also induce significant reduction of implanted tumor growth in mice.

Sequential ring-closing enyne metathesis and intramolecular Diels–Alder reaction: an approach to the synthesis of the core structure of galiellalactone

Development of a route for the synthesis of the core structure of galiellalactone is described. The key step involves a ring-closing enyne metathesis of an allyl propargyl ether to produce a dihydro furano diene with a latent dienophile. The dienophile, when generated from this latent functionality, underwent an in situ intramolecular Diels–Alder reaction to produce the tricyclic skeleton present in galiellalactone. An approach to the construction of the tricyclic core structure of the fungal metabolite galiellalactone is described using a sequence of ring-closing enyne metathesis and intramolecular Diels–Alder reaction.

Unified Total Synthesis of (-)-Enigmazole A and (-)-15-O-Methylenigmazole A.

The total synthesis of cytotoxic marine phosphomacrolides, (-)-enigmazole A and (-)-15-O-methylenigmazole A, is described in detail. The 2,6-cis-substituted tetrahydropyran ring was efficiently elaborated by using a tandem olefin cross-metathesis/intramolecular oxa-Michael addition reaction. The 18-membered macrolactone skeleton was forged via a Au-catalyzed propargylic benzoate rearrangement/macrocyclic ring-closing metathesis sequence. Late-stage diversification of a common intermediate enabled unified total synthesis of (-)-enigmazole A and (-)-15-O-methylenigmazole A.

Synthesis and Preliminary Biophysical and Cellular Evaluation of Some Ring-Enlarged Analogues of the Anti-Tumor Plant Alkaloid Acronycine

Three oxepinoacridine analogues of the important anti-cancer pyranoacridine natural product acronycine have been synthesized using a combined Claisen rearrangement ring-closing metathesis sequence as key steps to install the oxacyclic ring. Preliminary biophysical studies of these proposed oxepino analogues revealed that they interact with ct-DNA in a manner similar to the pyranoacridones but not possibly as intercalators. Cellular evaluations of these analogues in two human leukemic cell lines have also been carried out. These studies indicate that the ring-enlarged analogues have somewhat lower activity than the naturally occurring ones in the cell lines studied.

Design and synthesis of C 3-symmetric molecules bearing propellane moieties via cyclotrimerization and a ring-closing metathesis sequence.

We have developed an efficient synthetic strategy to assemble C3-symmetric molecules containing propellane moieties as end groups and a benzene ring as a central core. The synthesis of these C3-symmetric molecules involves simple starting materials. Our approach to C3-symmetric compounds relies on a Diels–Alder reaction, cyclotrimerization and ring-closing metathesis as key steps.

Total Synthesis of Laingolide B Stereoisomers and Assignment of Absolute Configuration.

Total synthesis of (-)-(2 R,9 S)- and (+)-(2 S,9 S)-stereoisomers of laingolide B has been accomplished by using sequential ring-closing metathesis (RCM) and alkene isomerization to construct the macrocyclic trans- N-methyl enamide moiety. The Myers alkylation was used to secure the C2 stereochemistry of the two RCM precursors from a common (9 S)-C3-C9 alkyl iodide. The absolute configuration of laingolide B has been assigned as (2 S,9 R) by comparison of the optical rotation data.

Stereoselective Synthesis of Medium-Sized Cyclic Ethers by Sequential Ring-Closing Metathesis and Tsuji-Trost Allylation.

Fully functionalized medium-sized cyclic ethers, of the type found in fused polyether natural products, have been prepared by sequential ring-closing diene metathesis, conversion of the resulting cyclic enone into an allylic enol carbonate, and Tsuji-Trost allylation using a chiral palladium complex. Very high levels of diastereocontrol, favoring the diastereomer in which there is a cis relationship between the allyl group at C-2 of the medium-ring ether and the substituent at C-7/C-8, are obtained in cases where catalyst control and substrate control are matched.

Approach to the Synthesis of Briarane Diterpenes through a Dianionic Claisen Rearrangement and Ring-Closing Metathesis.

The synthesis of the briarane-brianthein A core has been accomplished utilizing an extension of the dianionic Ireland-Claisen rearrangement to establish the C1 quaternary carbon and the adjacent C10 ring juncture stereocenters. Two sequential ring-closing metathesis reactions were exploited to construct the 6-10 trans fused ring system.

ChemInform Abstract: Target Specific Tactics in Olefin Metathesis: Synthetic Approach to cis‐syn‐cis‐Triquinanes and ‐Propellanes.

A concise and simple synthetic approach to cis-syn-cis-triquinanes and -propellanes has been demonstrated via olefin metathesis starting with exo-nadic anhydride. This approach involves a ring-opening and ring-closing metathesis sequence of norbornene derivatives using Grubb’s catalyst. Early-stage diallylation of norbornene derivatives is demonstrated followed by ring-closing metathesis that delivers propellanes exclusively. Surprisingly, ring-opening metathesis, late-stage diallylation, followed by ring-closing metathesis delivers triquinane as well as propellane derivatives.

Target Specific Tactics in Olefin Metathesis: Synthetic Approach to cis-syn-cis-Triquinanes and -Propellanes.

A concise and simple synthetic approach to cis-syn-cis-triquinanes and -propellanes has been demonstrated via olefin metathesis starting with exo-nadic anhydride. This approach involves a ring-opening and ring-closing metathesis sequence of norbornene derivatives using Grubb's catalyst. Early-stage diallylation of norbornene derivatives is demonstrated followed by ring-closing metathesis that delivers propellanes exclusively. Surprisingly, ring-opening metathesis, late-stage diallylation, followed by ring-closing metathesis delivers triquinane as well as propellane derivatives.

Applications of ring closing metathesis. Total synthesis of (±)-pseudotabersonine

A novel approach to the Aspidosperma family of alkaloids was developed and applied to a concise total synthesis of (±)-pseudotabersonine that was accomplished in 11 steps. Key transformations include a stepwise variant of a Mannich-like multicomponent assembly process, a double ring-closing metathesis sequence, and a one-pot deprotection/cyclization reaction.

Ring-closing metathesis and glycosylation reactions: synthesis and biophysical studies of polyether-linked carbohydrate-based macrocyclic nucleosides.

Bis-, tris-, and tetrakisuracil-substituted 12-, 13-, 17-, and 21-membered macrocyclic nucleoside analogues with polyether linkages, including C2-symmetric molecules, have been synthesized through coupling of two appropriately allylated sugar derivatives, derived from D-glucose, followed by a sequential ring-closing metathesis reaction using Grubbs catalysts, double-bond reduction, and nucleoside base insertion under Vorbrüggen reaction conditions. Spectroscopic studies on the interaction of these nucleoside analogues with small molecules, such as the alkaloids berberine and palmatine and the DNA intercalator ethidium bromide, revealed a change in the absorbance and fluorescence of the small molecules suggesting the potential use of these nucleoside molecules as a carrier of small molecules in biological systems. Circular dichroism studies indicated that the complexes of the nucleosides with small molecules undergo aggregation/self-organization. This has been further evidenced by a SEM experiment showing the binding of berberine with one of the nucleoside derivatives, which confirms the occurrence of secondary structure reorganization.

Asymmetric Synthesis of Synargentolide A and Its 3-Epimer Using the RAMP-Hydrazone Methodology

Synargentolide A was synthesized in 11 steps starting from the commercially available 2,2-dimethyl-1,3-dioxan-5-one, employing the SAMP/RAMP-methodology via an α,α′-bis-alkylation to generate the first two stereogenic centers with virtually complete asymmetric induction (de, ee >99%). After the asymmetric synthesis of the triol fragment of the molecule, the δ-lactone moiety was constructed using an asymmetric allylation, esterification, and ring-closing metathesis sequence.

Total synthesis of 14,21-diepi-squamocin-K

A new method to prepare annonaceous acetogenins is described in the synthesis of the 14,21-diepimer (14) of squamocin-K. The synthesis utilized the controlled sequence of ring-closing metathesis (RCM) and cross metathesis (CM) reactions to incorporate the stereocenters and skeleton from (3R,4R)-1,5-hexadiene-3,4-diol and 10-chloro-1-decene. The lactone moiety was attached through nucleophilic substitution and achieved the desymmetrization. Inhibitory activities of 14 against human hormone-refractory prostate cancer cell line (PC-3) were also evaluated.

Sequential ring-closing metathesis–vinyl halide Heck cyclization reactions: access to the tetracyclic ring system of ervitsine

A chemoselective indole-templated ring-closing metathesis is used to assemble the cyclohepta[b]indole substructure of the indole alkaloid ervitsine. A subsequent intramolecular Heck coupling of the resulting alkene functionality with an amino-tethered vinyl halide accomplishes the closure of the unique 2-azabicyclo[4.3.1]decane framework of the alkaloid with concomitant incorporation of the exocyclic E-ethylidene substituent.

α,β-Unsaturated δ-Valerolactones through RCM-Isomerization Sequence

α,β-Unsaturated δ-lactones are accessible via a sequential ring-closing metathesis (RCM) double-bond migration reaction starting from butenoates of allyl alcohols. This approach proceeds efficiently with lower catalyst loadings and higher initial substrate concentrations compared to the alternative RCM of acrylates derived from homoallylic alcohols.