Synthesis of spirocyclic thiazolidinediones using ring-closing metathesis and one-pot sequential ring-closing/cross metathesis

A novel synthetic route to spirocyclic thiazolidinediones is reported by utilizing ring-closing metathesis (RCM). A selective cross metathesis (CM) of N-allyl azaspiro derivatives with different olefins has been demonstrated to prepare substituted azaspiro-[4.4]nonenediones. The X-ray crystal structure of a spirocyclic thiazolidinedione dimer is described, which has been prepared in two steps from thiazolidinedione using a one-pot sequential ring-closing and self metathesis. Cross metathesis proceeds smoothly with both electron rich and poor olefins. The symmetrical bis-thiazolidinedione spirocyclic system can be used as CM coupling partner with olefins. One-pot sequential RCM-CM has been developed for the synthesis of substituted spirocyclic compounds. The methodology allows a quick access to thia-azaspiro-[4.4]nonene and -[4.5]decene-dione ring systems from readily available starting materials which are not otherwise accessible.     

Synthesis of 4,4-difluoroglycosides using ring-closing metathesis

4-Deoxy-4,4-difluoro-glycosides have been synthesised for the first time via a direct sequence involving ring-closing metathesis and indium-mediated difluoroallylation with 1-bromo-1,1-difluoropropene in water. Two protecting group strategies were explored, one to allow protection of the primary C-6 hydroxyl group throughout the sequence, while the second was intended to allow deprotection after RCM and before dihydroxylation. The benzyl ether could be used in the first role, and pivaloyl is effective in the second. Dihydroxylations were highly stereoselective and controlled by the orientation of the glycosidic C-O bond.     

Synthesis of styrenes using ruthenium-catalyzed ring-closing enyne metathesis

The synthesis of substituted styrenes was achieved by ring-closing enyne metathesis (RCEM)/elimination of enyne substrates 12. The synthetic approach was also effective for a different type of enyne substrate 14, yielding corresponding styrene 15.     

Synthesis of biaryl compounds using tandem ruthenium-catalyzed ring-closing metathesis

Tandem ring-closing enyne metathesis (RCEM)/ring-closing olefin metathesis (RCM) of tetraenynes with Grubbs second-generation catalyst, followed by elimination, was found to be a new and efficient synthetic approach to biaryl compounds. A preliminary asymmetric version of this approach, which used homochiral Ru-alkylidene catalysts, is also presented.     

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.     

Synthesis of the tetracyclic core of the kempanes by a ring-closing metathesis strategy

[reaction: see text] The synthesis of the tetracyclic ring system of the kempane diterpenes was achieved through the highly regio- and stereoselective Diels-Alder reaction of an isopropenyl-diene with 2,6-dimethyl-p-benzoquinone, addition of an allyl group, and ring-closing metathesis of the isopropenyl and allyl groups.     

Synthesis of cyclitols via ring-closing metathesis

A convenient synthesis of enantiomerically pure and differentially protected l-chiro- and myo-inositols as well as conduritols B and F from 2,3,4-tri-O-benzyl-d-xylopyranose via ring-closing metathesis is reported. The facile synthesis of conduritol B constitutes a short formal synthesis of (−)-cyclophellitol.     

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.     

Synthesis of coumarins by ring-closing metathesis using Grubbs’ catalyst

A novel generally applicable synthesis of coumarins from phenolic substrates utilizing ring-closing metathesis is described. This sequence involves O-allylation of phenols followed by ortho-Claisen rearrangement, subsequent based-induced isomerization affording 2-(1-propenyl)phenols, acylation with acryloyl chloride, and finally ring-closing metathesis (RCM) with Grubbs’ second generation catalyst.     

Synthesis of the floresolide B hydroquinone lactone core using ring-closing metathesis

The hydroquinone lactone core of the floresolides was synthesized through a ring-closing metathesis (RCM) approach. Optimal RCM efficiency was obtained at higher reaction concentration. An unexpected Lewis acid-promoted rearrangement of the hydroquinone and other observations relevant to on-going total synthesis efforts are discussed.     

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

Ring-closing metathesis of ene-ynamide, which has alkene and ynamide moieties in a molecule, using a second-generation ruthenium carbene complex produced nitrogen-containing heterocycles, which have a dienamide moiety, in high yields. Diels-Alder reaction of the cyclized product with dienophile proceeded smoothly to give an indole or quinoline derivative in high yield.     

Synthesis of model BC bicycles of taxol using C10–C11 ring-closing metathesis strategy

Model BC ring-systems of taxol 23b and 28b, which lack an oxygenated substituent at C7, have been efficiently synthesized. The key step is a ring-closing metathesis (RCM) to form the 8-membered B ring between C10 and C11. Comparison of the metathesis reaction in this route with the RCM used in a previous study with similar substrates is highlighted.     

Relay ring-closing metathesis (RRCM): a strategy for directing metal movement throughout olefin metathesis sequences

The title concept involves the use of structurally modified RCM substrates that contain extender arms, terminating in a remote reactive alkene. Initiation of an RCM sequence at that reactive alkene is followed by rapid intramolecular relay of the metal center to an initially less reactive alkene in the parent substrate. This permits one to control the relative timing (or direction) of a metathesis sequence. For example, one can reverse the inherent tendency of an unsymmetrical alpha,omega-diene substrate to close, say, left-to-right, to that of right-to-left. Four distinct types of application of the RRCM concept are demonstrated. Among other things, they show the preparation of tetrasubstituted electron-deficient alkenes using G1 [(Cy3P)2(Cl2)Ru=CHPh], complementary control of directionality (endedness), auxiliary benefits (enzyme specificity) from the incorporation of additional steric bulk, the activation of otherwise ineffective substrates for RCM closure, the use of unorthodox alkenes as initiation sites for ring closure, and control of product olefin geometry.     

Synthesis of cyclic phosphonate analogues of (lyso)phosphatidic acid using a ring-closing metathesis reaction

We describe a versatile and efficient method for the preparation of acyloxy-substituted six-membered cyclic phosphonates using the ring-closing metathesis. After closure, the key cyclic phosphonate intermediate was dihydroxylated and converted to a new class of conformationally constrained PA and LPA analogues. The oleoyloxy-substituted cyclic phosphonate 4 had unique receptor-selective properties as a ligand, showing partial activation of the LPA2 GPCR and weak antagonism of the LPA1 GPCR.     

Synthesis of substituted phenols by using the ring-closing metathesis/isoaromatization approach

Ring-closing olefin metathesis (RCM) of 4-methylene-1,7-octadien-3-ones 2, followed by isomerization of the carbon--carbon double bond of 6-methylene-2-cyclohexenones 3 from exo to endo, produced various phenols 4. As an application of the method, the RCM/Mizoroki-Heck reaction of 2 was proven to be also effective for the synthesis of phenols having an additional substituent at ortho-benzylic position.     

Synthesis of the entire framework of tartrolon B utilizing a silicon-tethered ring-closing metathesis strategy

[Structure: see text] A tandem ring-closing metathesis (RCM) of silaketal-tethered dienynes gives rise to bicyclic siloxanes, which upon removal of the silicon tether afford dienediol skeletons with a stereodefined E,Z-1,3-diene motif. The implementation of this methodology has led to the construction of the entire C1-C21 linear carbon skeleton of tartrolon B.     

Synthesis of diversely functionalized pyrrolizidines and indolizidines using olefin ring-closing metathesis

Various nitrogen-fused tricyclic compounds, having benzoindolizidine and benzopyrrolizidines ring systems were synthesized via ene-ene metathesis using the first and second-generation Grubbs catalyst. The ene-ene metathesis proceeded smoothly in refluxing CH₂Cl₂ with 3.0 mol % of G₁, giving good yields (78-86%) of the benzoindolizidine products 12a,b. The benzopyrrolizidine 6 was prepared after optimization in 64% yield by using 5.0+5.0 mol % of G₂. The resulting olefin moiety of the indolizidine framework is a suitable precursor for polyhydroxy structures via the Sharpless process. The structures of the polyhydroxylated adducts were determined by ¹H NMR spectra and single-crystal X-ray analysis.     

Synthesis of vinyl fluorides by ring-closing metathesis

The first ring-closing olefin metatheses of alkenyl α-fluoroacrylamides or acrylates incorporating a fluorinated double bond are reported. Several N-benzyl-N-alkenyl-α-fluoroacrylamides were cyclized in the presence of 2 mol % of Grubbs II catalyst at room temperature to form an unsaturated γ-lactam, and at 80 °C to form the corresponding δ-lactams bearing a fluoro vinyl moiety. At elevated temperature, cyclization of an N-methallyl 2-fluoroacrylamide to form a fluorinated, tetrasubstituted double bond was achieved. Similarly, 3-fluorocoumarin was prepared from (2-vinylphenyl)-α-fluoroacrylate.     

Synthesis of the mycolactone core by ring-closing metathesis

The undecenolide core of mycolactone was synthesized by ring-closing metathesis and the structure confirmed using single-crystal X-ray diffraction techniques.