Ring-closing Metathesis Product Research Articles

Application of Ring-Closing Metathesis for the Synthesis of Macrocyclic Peptidomimetics as Inhibitors of HCV NS3 Protease

An efficient synthetic approach for the preparation of macrocyclic peptidomimetics for inhibition of HCV NS3 is presented. The macrocyclic core is built using ring-closing metathesis (RCM) of a tripeptidic diene. The presented approach allows the introduction of heteroatoms in strategic places along the macrocyclic ring. The methyl ester moiety in the RCM products was synthetically manipulated to install a keto-amide moiety via a Passerini reaction.

Facile and E-Selective Intramolecular Ring-Closing Metathesis Reactions in 310-Helical Peptides: A 3D Structural Study

The ring-closing metathesis reaction can be used to cross-link allylated serine residues situated at the i and i + 3 positions in 310-helical peptides containing the helicogenic amino acid, α-aminoisobutyric acid (Aib). An octapeptide with the sequence Boc-Aib-Aib-Aib-Ser(Al)-Aib-Aib-Ser(Al)-Aib-OMe was found to undergo a facile and >20:1 E-selective ring-closing metathesis (RCM) reaction catalyzed by the Grubbs second-generation catalyst to yield an 18-membered macrocycle. The formation of this cross-link does not significantly disturb the peptide's native 310-helicity, as judged by an X-ray diffraction study of the acyclic diene, the E-olefin RCM product, and its hydrogenated derivative. A heptapeptide system with the sequence Boc-Val-Ser(Al)-Leu-Aib-Ser(Al)-Val-Leu-OMe also underwent an efficient RCM reaction, albeit with diminished E-selectivity. It is apparent from these studies that a minimal, RCM-derived, macrocyclic constraint can be readily incorporated into 310-helical peptides.

Olefin Metathesis as an Inorganic Synthetic Tool: Cross and Ring Closing Metathesis Reactions of Diruthenium-Bound ω-Alkene-α-carboxylates

Diruthenium compounds containing one omega-alkene-alpha-carboxylate ligand, Ru2Cl(D(3,5-Cl2Ph)F)3(O2C(CH2)nCH=CH2) (n=1 (1a) and 2 (1b)), were prepared from the reaction between Ru2Cl(D(3,5-Cl2Ph)F)3(O2CCH3) (D(3,5-Cl2Ph)F=N,N'-bis(3,5-dicholorophenyl)formamidinate) and the corresponding omega-alkene-alpha-carboxylic acid. Compounds 1a and 1b both underwent olefin cross metathesis reactions catalyzed by (Cy3P)2Cl2Ru(=CHPh) to afford the dimerized compounds [Ru2Cl(D(3,5-Cl2Ph)F)3]2(mu-O2C(CH2)nCH=CH(CH2)nCO2) (n=1 (2a) and 2 (2b)). Similarly, diruthenium compounds containing two omega-alkene-alpha-carboxylate ligands, cis-Ru2Cl(D(3,5-Cl2Ph)F)2(O2C(CH2)nCH=CH2)2 (n=1 (3a), 2 (3b), and 3 (3c)), were prepared by substituting the acetate ligands in cis-Ru2Cl(D(3,5-Cl2Ph)F)2(O2CCH3)2 with the corresponding omega-alkene-alpha-carboxylate ligands. Compounds 3 exhibited different reactivity under olefin metathesis conditions: both 3b and 3c underwent the intramolecular ring closing reaction quantitatively to afford compounds cis-Ru2(D(3,5-Cl2Ph)F)2(mu-O2C(CH2)nCH=CH2(CH2)nCO2)Cl with n=2 (4b) and 3 (4c), respectively, but 3a displayed no metathesis reactivity. Molecular structures of compounds 1a/1b, 2a/2b, 3a/3b, and 4b were established via X-ray diffraction studies, confirming the formation of cross and ring closing metathesis products. Voltammograms of compounds 2 are nearly identical to those of compounds 1, indicating the absence of electronic interactions mediated by the tether derived from olefin metathesis.

Stereoselective Synthesis of the Phorboxazole A Macrolide by Ring-Closing Metathesis

[Structure: see text] Described is a regio- and stereoselective ring-closing metathesis (RCM) to form the C2-C3 alkene of the macrolide-containing domain of phorboxazole A. This work demonstrates a dramatic effect of reaction solvent on RCM product (E/Z)-selectivity. This process offers an alternative assembly of the macrolide-containing domain of phorboxazole A, one of the most potent anticancer agents known.

Metathesis studies to cyclic enol phosphonamidates

The development of cyclic, six membered enol phosphonamidates utilizing the ring-closing metathesis (RCM) reaction is discussed. Phosphonamidic monochloridates are generated and further functionalized to an array of acyclic, enol phosphonamidates. Subsequent metathesis affords both desired RCM product and corresponding cross metathesis (CM) dimer. Efforts to optimize formation of desired RCM product, while minimizing CM products are discussed, with interesting steric and electronic factors governing reactivity patterns. This strategy allows for generation of cyclic enol phosphonamidates, with ultimate application to C(6)-substituted analogs of the anti-cancer agent, cyclophosphamide.

Olefin Metathesis in Room Temperature Ionic Liquids Using Imidazolium‐Tagged Ruthenium Complexes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Divergent reactivity of alk-5-ynylidenecyclopropanes in the presence of the 1st or the 2nd generation Grubbs’ catalysts

Alk-5-ynylidenecyclopropanes, by virtue of being equipped with a strained cyclopropane system, can be divergently elaborated into bicyclo[3.3.0]octenes or exocyclopropylidenecycloalkenes depending on whether they react with the first or the second generation Grubbs’ ruthenium carbenes. While the highly reactive second generation system catalyses the formation of ring-closing metathesis products, the less [metathesis] active first generation carbene promotes an intramolecular [3 + 2] cycloaddition to give the bicarbocyclic skeletons.

Diastereoselective Ring-Closing Metathesis to Build a Quaternary Carbon Center

Diastereoselective ring-closing metathesis (RCM) was used to create a quaternary stereogenic center induced by protected hydroxyl groups. The initial stereogenic center was conveniently installed by Sharpless asymmetric epoxidation. The chiral RCM product cyclohexene was converted into a key chiral precursor used for the total synthesis of indole-containing alkaloid (-)-eburnamonine.

Olefin metathesis in room temperature ionic liquids using imidazolium-tagged ruthenium complexes

New recyclable imidazolium-tagged ruthenium catalysts have been developed to perform olefin metathesis in room temperature ionic liquids (RTILs). High level of recyclability combined with a high reactivity were obtained in the ring-closing metathesis (RCM) of a variety of di- or tri-substituted and/or oxygen-containing dienes. Extremely low residual ruthenium levels were detected in the RCM products (average of 7.3 ppm per run). Several examples of olefin cross-metathesis (CM) have been also studied.

Synthesis of Cyano Cyclic Olefins Through Ring-Closing Metathesis.

For Abstract see ChemInform Abstract in Full Text.

A New Route to Enol Ethers.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Cyano Cyclic Olefins through Ring-Closing Metathesis

Ring-closing metathesis has become a very powerful, versatile, and widely used method for the construction of cyclic ring systems in organic synthesis. The superior reactivity of Grubbs second generation catalyst 1, which has air-stability and thermal stability, is very important for the formation of triand tetra-substituted olefins having electron withdrawing groups. Recently, Weinreb, Salim, and Rutjes reported on the formation of carbocyclic and heterocyclic olefin by ring-closing metathesis of halogen (F, Cl, CF3) substituted olefins. Literature survey reveals that most of bisterminal olefins with electron withdrawing groups such as CO2Et, Br, and CN resulted in little to no yield of the RCM product under the condition of using the Grubbs first generation catalyst, but the microwave irradiation on olefin with carboxymethyl substituent (CO2Me) provided the desired product. As part of synthesis of a drug against Alzheimer disease, we became interested in the introduction of a nitrile group to huperzine B analog system. Monocyclic olefins with cyano group were prepared. Alkylations with 2-(bromoethyl)acrylonitrile were carried out to obtain several allylated substrates 3a-e from the carbon and heteroatom nucleophiles 2a-e in DMF in the presence of NaH as base. The RCM reaction of the bisterminal olefins 3a-e with a cyanide group has been explored for a variety of substrates, and some of the results are shown in Table 1. The substrates 3a-e reacted smoothly and furnished the olefinic cyanides containing six to seven membered cycles in high yields (Entry1-5). With successful outcome for the preparation of monocyclic cyanoolefins, we applied this method to the synthesis of tricyclic system of huperzine B analog (Scheme 3). Subjection of olefinic intermediate 6 to the standard condition (5 mol % catalyst 1 and 3 × 10−3 M substrate in CH2Cl2) provided a poor yield (5%) of cyclized product 6a despite the complete consumption of starting material. Thus, the reaction was performed at elevated temperature of 100 C under microwave irradiation with 5 mol % catalytic amount using the concentration of 0.05 M of the substrate in CH2Cl2. After 4 min of the irradiation, the RCM reaction provided an improved yield of 6a with no sign of other undesired reactions based on the recovered starting material. In conclusion, we have revealed an example of the ringScheme 1. Ring-Closing Metathesis (RCM) Reaction of Cyano Bisolefins.

One‐Pot Ring‐Closing Metathesis‐Alkene Cross Metathesis Reactions of Sulfamide‐Linked Enynes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A New Route to Enol Ethers

Dithioorthoformates having various alkoxy groups were obtained by copper(II) bromide-promoted oxidative coupling of bis(phenylthio)methyltributylstannane with alcohols. The dithioorthoformates thus prepared are useful precursors for alkoxymethylidene complexes of titanium, which transform carbonyl compounds into a variety of enol ethers. Even the alkoxymethylidene complexes having a terminal olefin moiety can be prepared and employed for carbonyl olefination without formation of ring-closing metathesis product.

Monolith‐ and Silica‐Supported Carboxylate‐Based Grubbs–Herrmann‐Type Metathesis Catalysts

AbstractThe synthesis of silica‐ and monolith‐supported Grubbs–Herrmann‐type catalysts is described. Two polymerizable, carboxylate‐containing ligands, exo, exo‐7‐oxanorborn‐2‐ene‐5,6‐dicarboxylic anhydride and 7‐oxanorborn‐2‐ene‐5‐carboxylic acid were surface‐immobilized onto silica‐ and ring‐opening metathesis (ROMP‐) derived monolithic supports using “grafting‐from” techniques. The “1st generation Grubbs catalyst”, RuCl2(CHPh)(PCy3)2, was used for these purposes. In addition, a poly(norborn‐2‐ene‐b‐exo, exo‐norborn‐2‐ene‐5,6‐dicarboxylic anhydride)‐coated silica 60 was prepared. The polymer supported anhydride and carboxylate groups were converted into the corresponding mono‐ and disilver salts, respectively, and reacted with the Grubbs–Herrmann catalyst RuCl2(CHPh)(IMesH2)(PCy3) [IMesH2=1,3‐bis(2,4,6‐trimethylphenyl)‐4,5‐dihydroimidazol‐2‐ylidene]. Heterogenization was accomplished by exchange of one chlorine ligand with the polymeric, immobilized silver carboxylates to yield monolith‐supported catalysts 4, 5, and 6 as well as silica‐supported systems 7, 8 and 9. The actual composition of these heterogenized catalysts was proven by the synthesis of a homogeneous analogue, RuCl[7‐oxanorbornan‐2‐(COOAg)‐3‐COO](CHPh)(IMesH2)(PCy3) (3). All homogeneous and heterogeneous catalysts were used in ring‐closing metathesis (RCM) of diethyl diallylmalonate, 1,7‐octadiene, diallyldiphenylsilane, methyl trans‐3‐pentenoate, diallyl ether, N,N‐diallyltrifluoracetamide and t‐butyl N,N‐diallylcarbamate allowing turnover numbers (TON's) close to 1000. In a flow‐through set‐up, an auxiliary effect of pendant silver carboxylates was observed with catalyst 5, where the silver moiety functions as a (reversible) phosphine scavenger that both accelerates initiation and stabilizes the catalyst by preventing phosphine elution. Detailed catalytic studies were carried out with the monolith‐supported systems 4 and 6 in order to investigate the effects of temperature and chain‐transfer agents (CTA's) such as cis‐1,4‐diacetoxybut‐2‐ene. In all RCM experiments Ru‐leaching was low, resulting in a Ru‐content of the RCM products ≤3.5 μg/g (3.5 ppm).

Ring-Closing Metathesis of Enynes Tethered by an N-O Bond: Synthesis of 1,2-Oxaza Polycycles by Diels-Alder Reaction of the Ring-Closing Metathesis Products

Ring-closing metathesis (RCM) reaction of enynes tethered by an N-O bond produced 6- to 8-membered 1,2-oxaza heterocyclic compounds in high yields. Diels-Alder reaction of the cyclic 1,3-dienes with various dienophiles afforded bi- or tri-cyclic compounds efficiently.

The Photophysics of 6-(1-Pyrenyl)hexyl-11(1-pyrenyl)undecanoate Dissolved in Organic Liquids and Supercritical Carbon Dioxide: Impact on Olefin Metathesis

The Leitner and Fürstner groups reported (Fürstner, A.; Koch, D.; Langemann, K.; Leitner, W.; Six, C. Angew Chem., Int. Ed. Engl. 1997, 36, 2466) on the ring closing metathesis (RCM) of a 16-membered diene dissolved in supercritical CO2 (scCO2). The authors found that the cyclic product, indicative of an intramolecular RCM event, was formed in excellent yield when the CO2 density was high, but oligomers were formed by an acyclic diene metathesis (ADMET) pathway at lower CO2 densities. These results suggest that changes in the CO2 density lead to changes in the intra- vs intermolecular interactions between the 16-membered diene dissolved in scCO2. To assess this issue in more detail, we have prepared 6-(1-pyrenyl)hexyl-11-(1-pyrenyl)undecanoate [1-Py(CH2)10COO(CH2)61-Py] in which we replaced the terminal alkenes of Letiner and Fürstner's original diene with the fluorophore pyrene. We have studied the pyrene excimer formation of 1-Py(CH2)10COO(CH2)61-Py when it is dissolved in five organic solvents (cyclohexane, dichloromethane, ethanol, acetonitrile, and dimethyl sulfoxide) and supercritical carbon dioxide (scCO2) to determine how the tail segments interact with each other. The result show that the excimer formation mechanism is completely different when 1-Py(CH2)10COO(CH2)61-Py is dissolved in scCO2 or organic liquids. In liquids, excimer formation is purely dynamic in nature, there are two formation pathways to the excimer, and all the rates can be understood with the help of Kamlet−Taft linear solvent energy relationships. In scCO2, we found that the 1-Py(CH2)10COO(CH2)61-Py excimer-to-monomer intensity ratio (E/M) correlates directly with (1) the observed RCM yield for Leitner and Fürstner's original 16-membered diene and (2) the solvent refractive index function. The steady-state and time-resolved fluorescence of 1-Py(CH2)10COO(CH2)61-Py dissolved in scCO2 show that there are two excimers that form in scCO2 and their relative contributions change in a systematic way with changes in the CO2 pressure/density. Interestingly, the typical dynamically formed excimer species that emits at 470−480 nm (E1) forms within 2 ns of optical excitation; however, it is not the dominant species at low CO2 densities. E1 is equivalent to the species that goes on to form the RCM product in Leitner and Fürstner's original reaction. The second excimer (E2) emits in the 410−440 nm region. E2 is associated with intermolecular preassociated forms of the pyrene residues within a collection of 1-Py(CH2)10COO(CH2)61-Py molecules, and this species dominates at low CO2 densities. E2 is equivalent to the species that goes on to form the oligomeric product in the original Leitner and Fürstner reaction. As the CO2 density increases, the E1 excimer contribution increases relative to the E2 excimer contribution. The combination of the fluorescence and reaction outcome results are used to explain Leitner and Fürstner's previous density-dependent RCM yields.