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In the presence of amines, the degradation of glutaconaldehyde in acidic medium can be prevented. By exploitation of this behavior, primary amines are transformed into their corresponding pyridinium salts, including those substrates that remain unreactive toward the Zincke salt, which is the reagent typically used to perform this transformation. The use of glutaconaldehyde also allows control of the nature of the counterion of the pyridinium with no need for additional salt metathesis reaction.

A variety of ene-yne cross metathesis reactions were performed using unsaturated phosphonate and phosphate reagents, affording the corresponding phosphorylated 1,3-diene products in good to excellent yields. These difficult ene-yne metatheses employed a Grubbs catalyst bearing a cyclic amino alkyl carbene ligand. A variety of terminal alkynes of varying substitution underwent the reaction, and different phosphorus-containing alkenes were found to give the conjugated diene products in high yields. The resulting dienes were further transformed by Horner-type Wittig reactions and a Diels-Alder cycloaddition.

The first synthesis of the marine benzoxepane hydroquinone cyclosiphonodictyol A and its bis(sulfato) from commercial (+)-sclareolide is reported. The key steps of the synthetic sequence (11 steps, 46% global) are the nucleophilic attack of a hindered tertiary alkoxide, a ring-closing metathesis reaction, and the Diels-Alder cycloaddition of a dienol acetate.

Structurally diverse [5,n] bicyclic systems with cis ring junction stereochemistry were accessed readily through RRM (ring rearrangement metathesis) reaction of properly functionalized [2.2.1]norbornene skeletons. Several bicyclic enones, ketones, alcohols, and ethers acted as the substrates and yielded the respective linearly fused [5,n] bicyclic systems stereoselectively after the RRM reaction. Such [5,5]bicyclic enone scaffolds were then synthetically manipulated to core structural analogue of naturally occurring liner triquinane hirsutene having cis-syn-cis stereochemistry.

7,5-Fused azabicycloalkane scaffolds, carrying a quaternary stereocenter at C3 position of the lactam ring, can act as effective reverse-turn mimics and have proven to be useful intermediates for the preparation of Arg-Gly-Asp (RGD)-based cyclopentapeptides (cRGD) with nanomolar activity as αvβ3/αvβ5 integrin antagonists. Here, we report the synthesis of new azabicycloalkane scaffolds endowed at the C6 position with a para-substituted phenethyl side chain, which could be exploited to obtain cRGD-based bioconjugates that may find promising applications in anticancer therapy. By performing a domino cross enyne metathesis/ring-closing metathesis (CEYM/RCM) in the presence of styrene derivatives, followed by catalytic hydrogenation of the diene system, we easily converted a dipeptide precursor into the desired C6-functionalized azabicycloalkane scaffolds. The presence of a suitably protected p-amino group on the styrene moiety could be exploited, after deprotection, either to directly conjugate a bioactive co...

The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentenones through the efficient [2 + 2 + 1] cycloaddition of dicobalt alkyne complexes with alkenes. While intermolecular and intramolecular variants are widely known, transannular versions of this reaction are unknown and the basis of this study. Macrocyclic enyne and dienyne complexes were readily synthesized by palladium(II)-catalyzed oxidative macrocyclizations of bis(vinyl boronate esters) or ring-closing metathesis reactions followed by complexation with dicobalt octacarbonyl. Several reaction modalities of these macrocyclic complexes were uncovered. In addition to the first successful transannular Pauson-Khand reactions, other intermolecular and transannular cycloaddition reactions included intermolecular Pauson-Khand reactions, transannular [4 + 2] cycloaddition reactions, intermolecular [2 + 2 + 2] cycloaddition reactions, and intermolecular [2 + 2 + 1 + 1] cycloaddition reactions. The structural and reaction requirements for each process are presented.

International audience; The synthesis of the C1–C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted δ-lactone framework.

A zinc-catalyzed intermolecular alkyne-carbonyl metathesis reaction of ynamides with isatins followed by an amide to ester conversion has been developed, which produces the indolone derivatives with a fully substituted alkene species in good to high yields. The salient features of this reaction include the following: mild reaction conditions, an inexpensive zinc catalyst, a broad substrate scope, the excellent regiocontrol and stereoselectivity, and amenable to the gram scale.

Azabicyclo[4.3.0]- and [5.3.0]alkanone amino acid derivatives were easily prepared by submitting the same starting dipeptide to a direct ring-closing enyne metathesis or an ethylene-mediated cross-enyne metathesis/ring-closing metathesis, respectively. The reactivity of the newly synthesized 6,5- and 7,5-fused bicyclic scaffolds was then investigated to obtain variously functionalized derivatives with potential applications in the field of peptides/peptidomimetics.

Cyclohexyl-l-callipeltose, an aminodeoxysugar subunit of Callipeltoside A, was synthesized in six steps and 40% overall yield from readily available (S)-4-methylpent-4-en-2-ol and cyclohexyloxyallene. The signature step is represented by Pd-catalyzed asymmetric intermolecular hydroalkoxylation that generates the key dihydropyran intermediate upon combination with the ring-closing metathesis reaction. Notably, an unnatural diastereomer of the target compound could also be obtained with comparable efficiency simply by using the enantiomeric ligand.

Azonia aromatic heterocycles are an important subclass of aza-heterocyles as they are the structural motif of relevant cationic alkaloids, and they have a wide range of potential applications such as bioactive compounds and organic materials. In this Synopsis, recent and novel approaches to their synthesis are surveyed, with particular emphasis on ring-closing metathesis reactions and annulation reactions based on C-H activation.

The asymmetric total synthesis of lancifodilactone G acetate was accomplished in 28 steps. The key steps in this synthesis include (i) an asymmetric Diels–Alder reaction for formation of the scaffold of the BC ring; (ii) an intramolecular ring-closing metathesis reaction for the formation of the trisubstituted cyclooctene using a Hoveyda–Grubbs II catalyst; (iii) an intramolecular Pauson–Khand reaction for construction of the sterically congested F ring; (iv) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment of lancifodilactone G; and (v) a Dieckmann-type condensation reaction for installation of the A ring. The strategy and chemistry developed for the total synthesis will be useful in the synthesis of other natural products and complex molecules.

A short and convergent stereoselective total synthesis of biologically potent cytospolide P has been accomplished from acrolein. The salient features of our synthetic strategy include modified Crimmins aldols, Yamaguchi esterification, and Grubbs ring-closing metathesis reaction.

A highly efficient one-pot multistep process involving an asymmetric Pd(II)-catalyzed Overman rearrangement and a Ru(II)-catalyzed ring-closing metathesis reaction has been developed for the preparation of (R)- or (S)-aminocyclopenta-2-enes. The rapid strategy employed and the relatively mild conditions of the one-pot process allowed the multigram synthesis of the carbocycles in high enantiomeric excess (92% ee). The synthetic utility of these compounds was demonstrated by the stereoselective incorporation of hydroxyl groups, generating cis-4- and cis-5-aminocyclopenta-2-en-1-ols, important building blocks for medicinal chemistry.

The synthesis of 2,3-disubstituted pyrroles via TMSOTf-assisted cyclization reaction of 3,5,5-trimethyl-2,3-epoxycyclohexan-1-ones incorporating a (3-arylpropargyltosylamino)methyl tether at the C-2 position is described. The reaction starts with an acid-promoted semipinacol rearrangement to give a ring contraction cyclopentanone moiety bearing an arylpropargylaminoacetyl side chain. A subsequent alkyne-ketone metathesis affords the pyrrole derivatives in good yields. The 3,4-disubstituted furan analogues can also be available from 3,5,5-trimethyl-2,3-epoxycyclohexan-1-ones with a tethered arylpropargyl methyl ether at the C-2 position and BF3·OEt2 under an atmosphere of oxygen.

We report the enantioselective total synthesis of (+)-lysergic acid using two different strategies, which featured three metal-catalyzed reactions for the construction of the BCD three rings, involving Pd-catalyzed indole synthesis for the construction of the B ring, a ring-closing metathesis reaction for the formation of the D ring, and an intramolecular Heck reaction to forge the C ring. In synthetic strategy I, the synthesis was achieved in 20 steps following the ring construction sequence of BDC. In synthetic strategy II, the synthetic route was shortened to only 12 steps by following the ring construction sequence of DBC and using a 4-chlorotryptophan derivative for the intramolecular Heck reaction. Moreover, we also discussed an unsuccessful synthetic strategy.

Functionality preferences of metathesis Ru carbenes to various alkenes and alkynes with electronic and steric diversity were determined by using time-dependent fluorescence quenching. The functionality preferences depend not only on the properties of multiple bonds but also on the ligands on Ru. There was a good correlation between functionality preference and the metathesis reaction outcome. The correlation between functionality preference and exo/endo product ratio offers a solution to resolve the mechanistic issue related with alkene- vs alkyne-initiated pathway in ring-closing enyne metathesis. The correlation indicates the preference is likely to dictate the reaction pathway and eventually the outcome of the reaction. The Ru catalyst favoring alkyne over alkene provides more endo product, indicating that the reaction mainly initiates at the alkyne. By changing the substitution pattern, the preference can be reversed to give an exclusive exo product.

The marine natural product haliclamide has been synthesized based on macrocyclization by ring-closing olefin metathesis. Using either enantiomer of two of the four building blocks that were employed to assemble the diene precursor for the metathesis reaction, three non-natural isomers of haliclamide were also prepared. On the basis of the comparison of the (1)H and (13)C NMR spectra of the individual stereoisomers with literature data for the natural product, the configuration of the previously unassigned stereocenters at C9 and C20 of haliclamide could be determined to be S for both carbons. The absolute configuration of haliclamide thus is 2S, 9S, 14R, 20S. The antiproliferative activity of synthetic haliclamide against several human cancer cell lines was found to be in the high μM range. The compound showed no antifungal or antibiotic activity.

The combination of Ichikawa’s rearrangement and a ring-closing metathesis reaction of allyl carbamates is presented as a method for the preparation of 5-amino-substituted 2,5-dihydro-benzo[b]oxepines, 2,5-dihydro-benzo[b]azepines, and 2,5-dihydro-benzo[b]thiepins. It was demonstrated that the use of nonracemic allyl carbamates enables the synthesis of enantioenriched benzo-fused seven-membered heterocycles. Finally, it was shown that further functionalization of the obtained structures allows access to pharmacologically active 5-amino-substituted 2,3,4,5-tetrahydro-1-benzo[b]oxepine scaffolds.

As a guide for selective reactions toward either Z- or E-alkene in a metathesis reaction, the relative preference of metathesis Ru catalysts for each stereoisomer was determined by a method using time-dependent fluorescence quenching. We found that Ru-1 prefers the Z-isomer over the E-isomer, whereas Ru-2 prefers the E-isomer over the Z-isomer. The Z/E-alkene preference of the catalysts precisely predicted the Z/E isomeric selectivity in the metathesis reactions of diene substrates possessing combinations of Z/E-alkenes. For the diene substrates, the rate order of the reactions using Ru-1 was Z,Z-1,6-diene > Z,E-1,6-diene > E,E-1,6-diene, while the completely opposite order of E,E-1,6-diene > Z,E-1,6-diene > Z,Z-1,6-diene was exhibited in the case of Ru-2.

This work describes a synthetic approach to the carbocyclic skeleton of isospongian diterpenes that uses the commercially available monoterpene (S)-carvone as a C-ring synthon, which is incorporated into the tetracyclic isospongian framework via a C -> ABC -> ABCD ring annulation strategy using intramolecular Diels-Alder and ring-closing metathesis reactions. This approach has been successfully used to prepare both the title natural isospongians and several nonnatural oxygenated analogues. A preliminary evaluation of the inhibitory activity of the small collection of synthesized isospongians on the mammalian mitochondrial respiratory chain revealed that most were able to inhibit the integrated electron transfer chain (NADH oxidase activity) in the micromolar range., We thank the Spanish Ministerio de Ciencia e Innovacion (MICINN) and the company EPA S.L. (Cadet, Spain) for their continuous support of our work (Projects BQU2002-00272 and AGL2009-12940-C02-02). We also thank the S.C.S.I.E. of the University of Valencia for providing access to their NMR facilities and E. Estornell and V. Romero for biological assay support.

The synthesis of (E)-3'-phosphonoalkenyl and 3'-phosphonoalkyl modified nucleoside analogues with a β-D-erythrofuranose moiety is reported. The highly stereoselective olefin cross-metathesis reaction was applied to introduce the phosphonoalkenyl group at the 3'-position of the sugar moiety with absolute (E)-selectivity. The 3',6'-cyclomonophosphonic acids of 3'-phosphonoethyl-β-D-erythrofuranosyl nucleosides were synthesized via a dehydrative intramolecular cyclization reaction. None of the synthesized compounds shows significant in vitro activity against HIV, HCV, and RSV.

An efficient and operationally simple synthesis of the neodolestane diterpenoids (±)-heptemerone G and (±)-guanacastepene A is reported. The common tricyclic scaffold (±)-4 was prepared from 2-methylcyclopent-2-en-1-one via 23 isolated intermediates in 5.1% yield. The key features include a novel annulation sequence combining tandem conjugate addition, methylenation, and metathesis reaction and completely diastereoselective transformation of the azulene derivative 23 into rings AB building block 32. Stereochemistry of alkylation of both saturated trans-azulene enolate 38 and its α,β-unsaturated counterpart 48 was examined. Rather surprisingly, a different facial selectivity was recorded. Several synthetic methods were modified or developed, including an alternative methodology for the Wharton-type rearrangement, ketalization of epimerizable ketone under mild conditions, and efficient alkylation of a ketone via its kinetic enolate.

1-Allyl(propargyl)-6-allyl(propargyl)oxy-1,4,5,6-tetrahydropyridines, obtained through a CAN-catalyzed four-component reaction, were transformed into highly functionalized pyrido[2,1-b][1,3]oxazepines by ring-closing metathesis (RCM) and ring-closing enyne metathesis (RCEYM) processes, which constitute the first examples of the preparation of 1,3-oxazepine systems using metathesis reactions.

The ring-closing metathesis reaction of 1-butenyl-2-vinylpyridinium salts and 2-butenyl-1-vinylpyridinium salts using Grubbs second generation and Hoveyda-Grubbs catalysts proved to be an efficient approach to 3,4-dihydro- and 1,2-dihydroquinolizinium salts and the corresponding quinolizinium derivatives by an improved thermal oxidation in the presence of Pd/C without solvent. A comparative study showed that the quinolizinium system was obtained in better yields through the 3,4-dihydroquinolizinium route, thus allowing the synthesis of quinolizinium derivatives or improvements in the yields of some examples reported previously.

We report an approach that allows the efficient synthesis of the designed sphingoid base analogues in which the conformational restriction is introduced by incorporation of a cyclic moiety between the 2-amino group and the C-4 carbon atom of the sphingoid base. Our synthesis features a tandem enyne/diene-ene metathesis reaction that provides access to the designed framework. The diene moiety of the metathesis product is stereoselectively elaborated for the synthesis of the designed analogues. The preliminary biological evaluation indicates that the designed constrained analogues are much more effective than prototype natural sphingoid bases at inhibiting cancer cell growth.

The synthesis of enantiomerically pure, cyclic, gamma,gamma-difluorinated beta-amino acids with various ring sizes has been carried out with a cross-metathesis (CM) reaction being one of the key steps, followed by a Dieckmann-type condensation to bring about the cyclization. Subsequent catalytic hydrogenation under microwave irradiation with (-)-8-phenylmenthol as a chiral auxiliary led to the successful chemo- and diastereoselective chemical reduction of the resulting cyclic beta-enamino esters. The efficiency and scope of the CM reaction with different types of fluorinated imidoyl chlorides and unsaturated esters has also been studied in order to determine the optimal reaction conditions with regard to selectivity and reactivity.

New scaffolds for the stereoselective synthesis of diversely functionalized chiral enantiopure indolizidines and pyrrolizidines were synthesized from the cross and ring-closing metathesis reactions of appropriate intermediates, readily available from L-pyroglutamic acid. The versatility of this strategy was demonstrated by the synthesis of an indolizidine-based azasugar analogue and of the natural alkaloid (+)-monomorine.

The first total synthesis of 15(R)-Me-PGD2 3 is reported. The synthesis is based on the enantioselective and stereospecific syntheses of synthon 17 and its attachment to the five-membered ring by a olefin cross metathesis reaction. This approach permits the introduction of a side chain with a predetermined stereogenic center into the prostanoid ring, resulting in the synthesis of 15R-methyl prostaglandin D2 and allows rapid access to other prostanoids.

Sequential catalysis has evolved as a powerful concept within the past years and allows the more efficient use of catalytically active expensive transition metals in organic synthesis. In this paper we present the stereoselective cross-metathesis-dihydroxylation of various olefins with chiral auxiliary substituted acrylamides. The chiral information (i.e., the auxiliary) introduced in the metathesis reactions allows for a stereoselective subsequent RuO4-catalyzed dihydroxylation. The sequence is concluded by an unusual kinetic resolution of the diastereomeric diols obtained in the oxidation reaction. As a consequence a variety of structurally diverse enantiomerically enriched diols are obtained. To the best of our knowledge the results summarized in this paper represent the first highly efficient diastereoselective RuO4-catalyzed oxidation.

Efficient synthetic routes to construct multisubstituted benzo[1,2-b:5,4-b']difurans and benzo[1,2-b:4,5-b']difurans from bis(allyloxy)bis(alkynyl)benzenes or bis(alkynyl)dihydroxybenzenes and allylic halides utilizing palladium-catalyzed double annulations is reported. By further applying a double ring-closing metathesis reaction, pentacyclic compounds were also prepared.

The dimethyltitanocene methylenation of N-acylamides derived from ortho-vinylanilines, ortho-allylaniline, and ortho-vinylbenzylamine provides the corresponding enamides, which upon exposure to the second generation Grubbs ruthenium catalyst give access to indoles, 1,4-dihydroquinolines, and 1,2-dihydroisoquinolines, respectively. This sequential protocol also allows the synthesis of dihydrobenzoazepines, although the ring-closing metathesis (RCM) step is complicated by the alkene isomerization processes. From certain substrates, the direct annulation is observed in the titanium-mediated step, which is likely to occur through an olefin metathesis−intramolecular olefination sequence.

N,N-Bis(3-butenyl)amines can be prepared by the double allylation of either (2-azaallyl)stannanes or (2-azaallyl)nitriles, both of which thereby act as synthetic equivalents to amine alpha,alpha'-dications (2-azaallyl dications). Allylmagnesium bromide is the reagent of choice for the double allylation of both substrates, although allyllithium also effects the double allylation of (2-azaallyl)nitriles. Ring-closing metathesis can be performed on the N-protected amines, or with in situ protonation, on the free amines to provide 2,3,6,7-tetrahydroazepines. (2-Azaallyl)nitriles can also be monoallylated to provide N-(3-butenyl)aminonitriles, whereas the double allylation of (2-azaallyl)stannanes cannot be stopped at monoallylation. (2-Azaallyl)silanes undergo monoallylation to give N-(3-butenyl)aminosilanes but do not undergo double allylation.

The asymmetric synthesis of polyfunctionalized piperidine- and pyrrolidine-based scaffolds, specifically designed for the preparation of cyclic, conformationally constrained beta-amino acids, is realized combining a biocatalytic access to a versatile chiral building block with a wide range of transformations based on olefin metathesis.

The first efficient asymmetric synthesis of obolactone 1 has been accomplished in 11 steps and with a 15% overall yield in which Brown's enantioselective allylation reactions and ring-closing metathesis reaction are key steps.

Careful selection of the metathesis catalyst, solvent, and reaction conditions allows for the efficient and regioselective synthesis of isomeric fluorinated and nonfluorinated lactam derivatives II and III from precursor amides I through a ring-closing metathesis (RCM) reaction or a tandem RCM-isomerization protocol, respectively. The presence of the gem-difluoro moiety in the starting materials exerts a pivotal effect by directing the isomerization step, making the overall tandem transformation a regioselective process. The scope, limitations, and synthetic usefulness of this protocol are also discussed.

[reactions: see text] The metathesis reaction is used as a key step for the synthesis of the indolo[2,3-a]carbazole core of rebeccamycin 13 and the sulfur analog of furostifoline 21. Using the same methodology for the attempted synthesis of furostifoline, we unexpectedly formed tert-butyl-2a-methyl-1,2,2a,10c-tetrahydro-6H-cyclobuta[c]furo[3,2-a]carbazole-6-carboxylate 26 from the unstable diene, tert-butyl 2-(2-isopropenyl-3-furyl)-3-vinyl-1H-indole-1-carboxylate 25, presumably via a spontaneous pi8 electrocyclization reaction.

[reaction: see text] An efficient convergent approach has been developed for the construction of novel, non-natural, carbohydrate-based macrolides. The key step in the synthesis is the formation of the macrocyclic ring via a ring-closing metathesis reaction. The obtained macrolide analogues have been screened for biological activity against gram-positive and gram-negative bacteria, including resistant strains, yeasts, and molds.

An efficient and concise total synthesis of (+)-lentiginosine (1) starting from an L-tartaric acid-derived nitrone using organometallic addition, indium-catalyzed reduction, and ring-closing metathesis reaction as the key steps is reported. Structural analogues of (+)-1 have been also synthesized, and their inhibitory activity toward 22 commercially available glycosidases has been evaluated.

Although salen and its analogues are versatile chelate ligands in inorganic and organometallic chemistry, synthesis of unsymmetrical salen derivatives consisting of two different salicylideneimine moieties is difficult because of the C=N bond recombination. To develop stable analogues of salen-type ligands, we synthesized a series of new ligands salamo (=1,2-bis(salicylideneaminooxy)ethane) on the basis of O-alkyl oxime instead of the imine moiety. Eight salamo ligands 1a-h were prepared in 64-88% yields as colorless crystals from the corresponding salicylaldehydes 2a-h. The crystal structure of 1a-c suggests that the oxime-OH form is more predominant than the keto-NH form. The reaction of 2a-e with excess 1,2-bis(aminooxy)ethane gave monooximes 3a-e in 59-86%, which further reacted with a different salicylaldehyde to afford unsymmetrical salamo ligands 4-8 as stable crystals in 51-70%. No reaction took place when a mixture of salamo derivatives 1a and 1b was treated at 40 degrees C in H2O/MeCN (5:95). However, the metathesis reaction of salen derivatives 9a and 9b completed in 2 h to give a statistical mixture. Monooxime 3b was much more stable than monoimine 11 which is difficult to be isolated. These results indicate the extremely high stability of the salamo derivatives 1 and precursors 3.

Isoquinoline derivatives were synthesized from cyclobutenylmethylamine derivatives having an alkyne moiety in a tether using a second-generation ruthenium carbene complex under ethylene gas in good yields.

Allylic hydroxy phosphonates and their derivatives can be interconverted by using cross metathesis with second generation Grubbs catalyst. The absolute stereochemistry of the starting phosphonate is conserved in the product. Cross metathesis reaction of the acrolein-derived phosphonate 2a yields a series of functionalized allylic hydroxy phosphonates. However, the cross metathesis reaction is often accompanied by competing dimerization and alkene migration reactions leading to a reduction in yield. The cinnamaldehyde- and crotonaldehyde-derived phosphonates 2b and 2c were also examined. In general, the metathesis reactions of phosphonates 2b and 2c are considerably slower than those for phosphonate 2a leading to mixtures. Several hydroxyl-protected derivatives of the phosphonate 2a (methyl carbonate 3a, acetate 4a, N-tosyl carbamate 5a, TBDMS 6a, and acetoacetate 7a) undergo metathesis without competing side reactions to give substituted allylic phosphonates in good to excellent yield.

A concise approach to (-)-phaseolinic acid starting from commercially available (S)-oct-1-yn-3-ol is disclosed. The key steps are a ring-closing metathesis reaction to prepare a C(2)-symmetrical allylic diol and its desymmetrization to a gamma-butyrolactone by using an Ireland-Claisen rearrangement. The 2S,3S,4S configuration of the levogyre natural product has been confirmed.

A novel ruthenium-catalyzed tandem ring-closing metathesis (RCM) double-bond isomerization reaction is described in this paper. The utility of this method for the efficient syntheses of five-, six-, and seven-membered cyclic enol ethers is demonstrated. It relies on the conversion of a metathesis-active ruthenium carbene species to an isomerization-active ruthenium-hydride species in situ. This conversion is achieved by using various additives. Scope and limitations of the different protocols are discussed, and some mechanistic considerations based on (31)P and (1)H NMR spectroscopic studies are presented.

Cross-metathesis of a range of conjugated enynes with alkenes turns out to proceed with preferential formation of Z-isomers over E-isomers up to >25:1. Careful studies including substrate modification and control experiments revealed that the reaction proceeds under kinetic rather than thermodynamic control. Driving forces for this substrate-dependent Z-selectivity are attributed to the steric hindrance between substituents on the reacting enynes and NHC ligand of the ruthenium catalyst in the putative metallacyclobutane, as well as chelation effects of suitably positioned functional groups to Ru, which is strongly supported by ab initio calculations.

N-Protected beta-aminoethanesulfonyl chlorides (2a-e) were used in the preparation of sulfonamides 4, 8, 11a-c, and 15. Ring-closing metathesis of sulfonamides 4 and 8 did not lead to the expected nine-membered cyclic peptidosulfonamides. In contrast, the allylated peptidosulfonamides 11a-c and 15 turned out to be suitable precursor systems for ring-closing metathesis using second-generation Grubbs catalyst and nine-membered cyclic peptidosulfonamides were obtained in 47-60% yields. The possibility for incorporation of these cyclic peptidosulfonamides into a peptide sequence was illustrated by the incorporation of an amino acid on the "S"- or "N"-terminus leading to 16 and 18-20, respectively. A model of cyclic peptidosulfonamide 16 hints at an extended-like structure.

A new protocol for synthesis of 2-heterocylylacetic acid derivatives involving conjugate addition of allyl mercaptan to an acrylate containing a tethered olefinic site followed by RCM (ring-closing metathesis) is described. In this series, sulfanyl derivatives were unreactive, while sulfoxide and sulfone analogues provided the corresponding thiazocines in fair to excellent yields. Use of the sulfoxide oxidation state as a protecting group for sulfides inert to RCM is demonstrated also. Thus, oxidation of sulfide 9 [N-allyl-N-[2-(allylthio)-4-(1H-indol-1-yl)-4-oxobutyl]-4-methylbenzenesulfonamide] followed by cyclization yielded the corresponding thiazocine sulfoxide 12. Deprotection (deoxygenation) of 12 was accomplished using Lawesson's reagent, producing 1-[[4-[4-(methylphenyl)sulfonyl]-3,4,5,8-tetrahydro-2H-1,4-thiazocin-2-yl]acetyl]-1H-indole (21) in 67% unoptimized yield.

Enynes connected through aromatic rings are used as substrates for metathesis reactions. The reactivity of three ruthenium carbene complexes is compared. The resulting 1,3-dienes are suitable precursors of polycyclic structures via a Diels-Alder process. Some domino RCM-Diels-Alder reactions are performed, suggesting a possible beneficial effect of the ruthenium catalyst in the cycloaddition process. Other examples require Lewis acid cocatalyst. When applied to aromatic ynamines or enamines, a new synthesis of vinylindoles is achieved. Monitorization of several metathesis reactions with NMR shows the different behavior for ruthenium catalysts. New carbenic species are detected in some reactions with an important dependence on the solvent used.

The synthesis of a range of highly functionalized peptidomimetic macrocycles has been accomplished using ring-closing metathesis and enyne tandem cross-metathesis-ring-closing metathesis reactions. This approach gives access to rigidified macrocycles modeled on the structures of cyclic peptides and designed to be biologically stable. The potential for peripheral functionalization of these templates has been demonstrated using Diels-Alder reactions, palladium(0) coupling reactions, and amide formation both in the solution phase and using polymer-supported syntheses.

A new strategy for the facile synthesis of azabicyclo[m.n.1]alkenes (m = 3-5; n = 3, 2) has been developed that involves the ring-closing metathesis (RCM) reaction of cis-2,6-dialkenyl-N-acyl piperidine derivatives. The requisite 2,6-dialkenylpiperidines may be readily prepared in six steps starting from glutarimide (11) or three steps from 4-methoxypyridine (25). In one example that establishes the practical utility of the procedure, the functionalized 8-azabicyclo[3.2.1]octane 32, which is a potential intermediate for the syntheses of various tropane alkaloids, was prepared. Additionally, a new route for the construction of the bridged tetrahydro-beta-carboline ring system 5 has been developed that features the ring-closing metathesis of the enyne 45 to construct the bridging ring in 46. This concise route to 46 also features a potentially general and useful procedure for the one-step preparation of a terminal alkyne from an ester function. Selective oxidation of the vinyl group in 46 afforded the unsaturated aldehyde 47, which may serve as a useful intermediate in syntheses of several Sarpagine alkaloids.