Synthesis of cyclic dienamide using ruthenium-catalyzed ring-closing metathesis of ene-ynamide

[reaction: see text] Ring-closing metathesis of ene-ynamide using the second-generation Grubbs' catalyst produced nitrogen-containing heterocycles, which have dienamide moieties, in high yields. Diels-Alder reaction of the cyclized product and dienophile proceeded smoothly to afford a bi- or tricyclic compound.     

Using cross-metathesis to couple L-phenylalanine to a macrocyclic lactam

Grubbs' second generation ruthenium catalyst was used to couple the amino acid l-phenylalanine to a 17-membered lactam, using cross-metathesis with an E-alkene favored in the process. The best coupling conditions gave the product in 48% yield. The reversibility of the process was also confirmed. Ring-closing metathesis was a key reaction used to form the macrocyclic lactam.     

Thermodynamically controlled cyclisation reactions with double phenylsulfanyl migration

Enantiomerically enriched C2-symmetric tetrols were synthesised by a route involving a 'self-metathesis' reaction with Grubbs' second-generation ruthenium catalyst; these tetrols produced interesting bicyclic products when rearranged under acidic conditions.     

An olefin cross-metathesis approach to vinylphosphonate-linked nucleic acids

[reaction: see text]. The synthesis of vinylphosphonate-linked nucleotide dimers has been achieved using an olefin cross-metathesis (CM) reaction as a key step. The 1,3-dimesityl-4,5-dihydroimidazol-2-ylidine-containing catalyst 5 (Grubbs' second-generation catalyst) was found to be the superior catalyst for this transformation. Both metathesis partners were readily available using known methodology, and the vinylphosphonate-linked dimer was produced with high levels of (E)-selectivity (>20:1) in 58% yield (70% based on recovered starting material).     

Functionalization of octavinylsilsesquioxane by ruthenium-catalyzed silylative coupling versus cross-metathesis

Functionalization of octavinylsilsesquioxane (Vi(8)T(8), 1) by two reactions catalyzed by ruthenium complexes is reported: a silylative coupling reaction catalyzed by [RuHCl(CO)(PCy(3))(2)] (I) and cross-metathesis catalyzed by first- (II) and second-generation (III) Grubbs' catalysts. The two reactions of 1 with styrene take place highly regio- and stereoselectively (the X-ray structure of the product 2 has also been obtained); the cross-metathesis of 1-hexene and allyltrimethylsilane occurs quite effectively, whereas the silylative coupling with these compounds gives a mixture of isomers. Functionalization of 1 with heteroatom-substituted vinyl derivatives (Si, O, N) by silylative coupling reaction has been found to be highly efficient, but cross-metathesis appears to be the more effective method for the synthesis of S-substituted vinyl-silsesquioxane.     

Total synthesis of the cyclopeptide alkaloid paliurine E. insights into macrocyclization by ene--enamide RCM

The total synthesis of (-)-paliurine E is described in 14 steps and 11% overall yield. The first successful application of ene--enamide ring-closing metathesis for macrocyclization serves as the foundation for this synthesis and allowed for a straightforward installation of the challenging cyclic enamide together with the macrocycle. In the course of these synthetic studies, we also found that very subtle and minor structural modification of the enamide resulted in dramatic and unexpected changes of their reactivity since a primary amide or an aromatic aldehyde can be obtained after reaction with Grubbs' second-generation catalyst. Further insights on the macrocyclization by ene--enamide RCM are also discussed.     

Highly selective synthesis of bicyclic quinolizidine alkaloids and their analogues via double RCM reaction of N-alkynyl-N-(1,omega)-alkadienyl acrylamides

The double ring-closing metathesis reaction of N-alkynyl-N-(1,omega)-alkadienyl acrylamides 1 using first- or second-generation Grubbs' catalyst afforded, in a highly selectively manner, the fused bicyclic quinolizidine alkaloid derivatives and their analogues bearing a 1,3-diene moiety, which may further undergo a Diels-Alder reaction with a dienophile to afford N-containing polycyclic compounds. The excellent selectivity of fused/dumbbell-mode cyclization has been realized by the higher reactivity of the electron-rich C=C bond or carbon-carbon triple bond combined with the lower reactivity of the electron-deficient C=C bond toward metallocarbenes and the thermodynamically more stable nature of fused bicyclic compounds 3 vs dumbbell-type bicyclic compounds 4.     

Enyne cross-metathesis with strained, geminally-substituted alkenes: direct access to highly substituted 1,3-dienes

Angle strain in methylene cyclobutane was used to drive a cross-enyne metathesis with 1-alkynes, giving 1,1,3-trisubstituted 1,3-dienes in good isolated yields. An extensive survey of Grubbs' second-generation catalysts led to an optimized reaction conducted at 0 degrees C.     

Transition metal catalyzed ring opening reactions of 2-phenyl-3-vinyl substituted 2H-azirines

Treatment of 2-phenyl-3-vinyl-substituted 2H-azirines with Grubbs' catalyst induces a clean rearrangement and affords products derived from carbon-nitrogen bond cleavage of the 2H-azirine ring. However, when the reaction was carried out using Wilkinson's catalyst in an alcoholic solvent, the only product obtained in high yield corresponded to an α,β-unsaturated oxime.     

A tandem enyne/ring closing metathesis approach to the synthesis of novel angularly fused dioxa-triquinanes

Triquinanes and their oxygenated congeners, oxa- and dioxa-triquinanes, exhibit versatile biological activities in conjunction with synthetically challenging molecular architecture. Owing to these properties, several new strategies have been developed to accomplish the synthesis of these sesquiterpenes. Among the new strategies, cascade radical cyclization strategy has been broadly explored and well studied. Herein, we report our efforts in detail for the synthesis of dioxa-triquinanes using a domino enyne/RCM strategy as the key step. Carbohydrate based synthesis not only allows the use of inexpensive and optically pure starting materials, but also the furanose derivatives, which already possess one of the requisite dihydro-furan moieties in the desired dioxa-triquinane. The other two five-membered rings were constructed simultaneously by the cascade enyne/RCM reaction using the Grubbs' second-generation catalyst. During the course of our synthesis it was observed that the acetonide protection hinders the RCM reaction, after the initial enyne metathesis reaction. The reaction underwent smoothly under argon atmosphere, whilst use of ethylene atmosphere was found to hinder the formation of the tandem enyne/RCM product. The effect of substitution on the key reaction is described here.     

Application of a metathesis reaction in the synthesis of sterically congested medium-sized rings. A direct ring closing versus a double bond migration-ring closing process

An efficient double bond migration-ring closing metathesis reaction leading to cycloheptene derivatives is observed when specific sterically congested 1,9-dienes are treated with the Grubbs' imidazolidene ruthenium catalyst. The simultaneous use of the Grubbs' catalyst and RuClH(CO)(PPh(3))(3) facilitates the tandem bond migration-metathesis process. RuClH(CO)(PPh(3))(3) alone is capable of triggering an unactivated double bond migration that may have preparative applications.     

Ene-yne metathesis of polyunsaturated norbornene derivatives

Norbornene derivatives bearing endo-substituents in the 5- and 6-positions were studied as substrates for ene-yne metathesis cascades. Substrates which contained an internal alkyne and a terminal alkene or alkyne in each sidechain were found to undergo a metathesis cascade leading to pentacyclic bis-dienes and bis-trienes. Attempts to extend the chemistry further to sidechains containing two internal alkynes or two internal alkynes and a terminal alkene were not successful with the first generation Grubbs' catalyst. However, the substrate containing two internal alkynes did react with the second generation Grubbs' catalyst to give a tetra-diene containing product.     

Enantioselective total synthesis of (-)- and (+)-petrosin

The enantioselective total synthesis of (-)- and (+)-petrosin is described. The union of two key segments was executed by Suzuki-Miyaura coupling. The quinolizidine rings were stereoselectively constructed via a diastereoselective Mannich reaction and an aza-Michael reaction. The 16-membered ring was constructed by ring-closing metathesis with the second-generation Grubbs catalyst.     

A New Approach to Inducing Silicon Tethered Ring-closing Metathesis Reactions

IntroductionGrubbs catalyst bis(tricyclohexylphosphine)benzylidene ruthenium( ) dichloride1 can be usedin a variety of ring- closing metathesis (RCM )reactions,cross metathesis(CM) reactions andring- opening metathesis polymerization(ROMP) [1— 4 ] .It remains metathetically active inthe presence of a variety of functional groups,suchas carbonyls,alcohols,and amides[1] .The use ofcatalyst1 in the synthesis has drawn more andmore attention[5— 13] . However,this catalyst is veryexpensive,an…     

Olefin cross-metathesis as a tool in natural product degradation. The stereochemistry of (+)-falcarindiol

[reaction: see text] There are conflicting reports in the literature concerning the absolute sterochemistry at C-3 of the common plant polyacetylene oxylipin (+)-falcarindiol. We have employed olefin cross-metathesis using Grubbs' second generation catalyst and ethylene gas to degrade falcarindiol to the symmetrical 1,9-decadiene-4,6-diyne-3,8-diol. The reaction is completely selective for net removal of the aliphatic side chain. Degradation of (+)-falcarindiol from Tetraplasandra hawaiiensis yields a meso product as shown by chiral HPLC. Hence, (+)-falcarindiol from this source has a (3R,8S)-configuration.     

Reversible inhibition/activation of olefin metathesis: a kinetic investigation of ROMP and RCM reactions with Grubbs' catalyst

The metathesis activity of Grubbs' catalyst 1 was investigated in the presence of N-donor ligands (1-methylimidazole [MIM], 4-(N,N-dimethylamino)pyridine [DMAP], pyridine, and 1-octylimidazole [OIM]). Ring opening metathesis polymerization (ROMP) reactions of cyclooctene (COE), bulk-ROMP reactions of COE and norbornadiene (NBD), and ring closing metathesis (RCM) reactions of diethyl diallylmalonate (DEDAM) were conducted containing various equivalents of N-donor with respect to catalyst. ROMP reactions could be stopped using MIM (1-5 equiv) and DMAP (2-5 equiv), and slowed with pyridine (1-5 equiv) by factors >100, in benzene solution for 24 h. The stopped reactions could be initiated with excess phosphoric acid (H3PO4), and the reactions proceeded faster than with uninhibited Grubbs' catalyst in the first 4 min after reactivation. Thereafter, the reaction proceeded at the same rate as the reaction with the uninhibited catalyst. ROMP reactions in neat COE and NBD could be inhibited for 72 h using 2 equiv of MIM, DMAP, or OIM and activated with H3PO4 to give polymer gels within minutes or less. RCM reactions could be completely inhibited with MIM (1-5 equiv), but upon treatment with H3PO4, the reaction would proceed at a fraction of the initial rate accomplished by uninhibited Grubbs' catalyst 1. A structural investigation of the inhibited species showed that MIM and DMAP completely or partially transform catalyst 1 into the hexacoordinate species 5a or 5b producing free PCy3, which additionally acts as an inhibitor for the ROMP reaction. Upon reactivation, the PCy3 is protonated along the N-donor ligand; however, over the period of 5 min, the phosphine has been found to coordinate back to the ruthenium catalyst. Therefore, the reaction slows to the same polymerization rate as the reaction using the uninhibited catalyst at this point. Complexes 5a and 5b were isolated, characterized, and employed in ROMP and RCM experiments where they exhibited very low catalytic activity.     

Allylic alkylation and ring-closing metathesis in sequence: a successful cohabitation of Pd and Ru

An allylic alkylation/ring-closing metathesis domino catalytic process, wherein a palladium and a ruthenium catalyst are concomitantly present in the reaction mixture from the outset of the reaction, is developed. Evidence for Grubbs' catalysts activity in allylic alkylation is also reported.     

Experimental and theoretical study on the olefin metathesis of alkenyl Baylis-Hillman adducts using second-generation Grubbs catalyst

[reaction: see text] We have investigated the olefin metathesis from alkenyl Baylis-Hillman adducts using second-generation Grubbs catalyst. In the experiment, the ring-closing metathesis (RCM) product could not be found, while the cross-metathesis (CM) products were found. The computational studies provided consistent explanations for the experimental result. The most limiting factor for the RCM process using second-generation Grubbs catalyst is caused by the high strain and steric effect in the metallacyclobutane intermediates.     

Mild and room temperature C-C bond forming reactions of nucleoside C-6 arylsulfonates

[reaction: see text] Palladium catalyzed cross coupling of nucleoside arylsulfonates and arylboronic acids has been accomplished under mild conditions and at room temperature. Among three structurally similar ligands that differ in their steric and electronic properties, one yielded an effective catalyst in conjunction with Pd(OAc)2. Of the nucleoside arylsulfonates evaluated, the O6-(2,4,6-trimethylphenyl)sulfonate proved optimal, but other alkyl and alkoxy derivatives were also reasonably reactive. On the other hand, a 2-nitrophenyl and a 2-thienyl derivative were ineffective substrates. PhMe and THP were suitable as solvents, yielding good results in several cases, although reactions of some arylboronic acids were faster in PhMe. In contrast, reactions of arylboronic acids bearing strongly electron-withdrawing groups proceeded more successfully in THP. Interplay between several factors that include substituents on the nucleoside arylsulfonate, ligand substituents, and solvent is responsible for successful cross coupling. Using 31P NMR, an initial investigation has been conducted to study the interaction of Pd(OAc)2 with the ligand. At a 1:1 stoichiometry of ligand and Pd(OAc)2, a predominant species, likely a cyclopalladation product, was obtained. At a 2:1 ratio of ligand and Pd(OAc)2, a different species bearing chemically distinct phosphine ligands was observed. Both complexes display catalytic activity, although the 2:1 species may be superior.