With its unrivaled versatility and atom economy, olefin metathesis is arguably the most powerful catalyst methodology now known for the construction of carbon-carbon bonds. When compared to palladium-catalyzed cross-coupling methodologies, however, catalyst productivity lags far behind, even for the “robust” ruthenium metathesis catalysts. Unexpected limitations to the robustness of these catalysts were first widely publicized by reports describing the implementation of metathesis in pharmaceutical manufacturing. Recurring discussion centered on low catalyst productivity resulting from decomposition of the Ru catalysts by impurities, including ppm-level contaminants in the technical-grade solvent. Over the past 7 years, a series of mechanistic studies from the Fogg group has uncovered the pathways by which common contaminants (or indeed reagents) trigger catalyst decomposition. Two principal pathways were identified: abstraction of the alkylidene or methylidene ligand by nucleophiles, and deprotonation of the metallacyclobutane intermediate by Bronsted base. Emerging applications, however, notably in chemical biology, highlight new challenges to catalyst productivity. The first part of this thesis emphasizes the need for informed mechanistic insight as a guide to catalyst redesign. The widespread observation of a cyclometallated N-heterocyclic carbene (NHC) motif in crystal structures of catalyst decomposition products led to the presumption that activation of a C-H bond in the NHC ligand initiates catalyst decomposition. Reducing NHC bulk has therefore been proposed as critical to catalyst redesign. In experiments designed to probe the viability of this solution, the small NHC ligand IMe4 (tetramethylimidazol-2-ylidene) was added to the resting-state methylidene complexes formed in metathesis by the first- and second-generation Grubbs catalysts (RuCl2(PCy3)2(=CH2) GIm or RuCl2(H2IMes)(PCy3)(=CH2) GIIm, respectively). The intended product, a resting-state methylidene species bearing a truncated NHC, was not formed, owing to immediate loss of the methylidene ligand. Methylidene loss is now shown to result from nucleophilic attack by the NHC – a small, highly potent nucleophile – on the methylidene. Density functional calculations indicate that IMe4 abstracts the methylidene, generating the N-heterocyclic olefin H2C=IMe4. The latter is an even more potent nucleophile, which attacks a second methylidene, resulting in liberation of [EtIMe4]Cl. These findings report indirectly on the original question concerning the impact of ligand truncation. The ease with which a small, potent nucleophile can abstract the key methylidene ligand from GIm and GIIm underscores the importance of increasing steric protection at the [Ru]=CH2 site. This chemistry also suggests intriguing possibilities for efficient, selective, controlled methylidene abstraction to terminate metathesis activity while leaving the “RuCl2(H2IMes)(PCy3)” core intact. This could prove an enabling strategy for tandem catalysis applications in which metathesis is the first step. The second part of this thesis, inspired by the potential of olefin metathesis in chemical biology, focuses on the impact of hydroxide ion and water on the productivity of phosphine-free metathesis catalysts. In reactions with the important second-generation Hoveyda catalyst HII, hydroxide anion is found to engage in salt metathesis with the chloride ligands, rather than nucleophilic attack. The resulting Ru-hydroxide complex is unreactive toward any olefins larger than ethylene, while ethylene itself causes rapid decomposition. Proposed as the decomposition pathway is bimolecular coupling promoted by the strong H-bonding character of the hydroxide ligands. Lastly, the impact of the water on Ru-catalyzed olefin metathesis is examined. In a survey of normally facile metathesis reactions using state-of-the-art catalysts, even trace water (0.1% v/v) is found to be highly detrimental. The impact of water is shown to be greater at room temperature than previously established at 60 °C. Preliminary evidence strongly suggests that the mechanism by which water induces decomposition is temperature-dependent. Thus, at high temperature, decomposition of the metallacyclobutane intermediate appears to dominate, but this pathway is ruled out at ambient temperatures. Instead, water is proposed to promote bimolecular decomposition. Polyphenol resin, which can sequester water by H-bonding, is shown to offer an interim solution to the presence of trace water in organic media. These findings suggest that major avenues of investigation aimed at reducing intrinsic catalyst decomposition may likewise be relevant to the development of water-tolerant catalysts.

No description available.

Thesis advisor: Amir H. Hoveyda / We have devised a broadly applicable catalytic cross-metathesis method for stereoretentive synthesis of Z- and E-trisubstituted α,β-unsaturated esters. Several new Mo-bisaryloxide complexes were prepared, and they showed superior efficiency in synthesizing the Z-trisubstituted enoates (vs. corresponding mono-aryloxide pyrrolide complexes). Synthetic utility of the method was demonstrated through several concise syntheses of bioactive triterpenoids and value-added derivatives of prenyl-containing compounds such as citronellal, citronellol, and geraniol, all of which are isolated from essential oils. This transformation offers a valuable alternative to carbonyl olefination approaches such as Wittig and Horner-Wadsworth-Emmons reactions. / Thesis (MS) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir Hoveyda / Chapter 1: E- and Z-, Di- and Trisubstituted Alkenyl Nitriles through Catalytic Cross MetathesisWe have described the development of several catalytic cross-metathesis strategies, which can deliver a considerable range of Z- or E-disubstituted alkenyl nitriles and their corresponding trisubstituted variants. Through careful examination of the steric and electronic attributes of the starting materials, a Mo-based monoaryloxide pyrrolide or chloride complex may be the optimal choice depending on the reaction type. In the event, equimolar amounts of the two substrates are necessary to maximize reaction efficiency; a pyridine ligand is more desirable than a phosphine ligand, as a stabilizing ligand for a Mo-based complex, for improving reaction stereoselectivity. We also highlighted the utility of this approach with the synthesis of several biologically active compounds, such as LR5182 (Cocaine abuse treatment), alliarinoside (anti-feedant), perhydrohistrionicotoxin (natural product), CC-5079 (anti-cancer) and indatraline (anti-depressant). Chapter 2: Traceless Protection for More Broadly Applicable Olefin Metathesis We have devised an operationally simple in-situ protection/deprotection strategy that significantly expands the scope of kinetically controlled catalytic olefin metathesis. Pretreatment of an olefin containing a protic group with commercially available HB(pin) or HB(trip)2 is sufficient for generating the desired product efficiently through the catalytic cross-metathesis reaction. A wide range of stereochemically defined Z- and E-alkenyl halides and boronates as well as Z-trifluoromethyl-substituted alkenes with a hydroxy or carboxylic acid group were prepared. We also discovered that a small amount of HB(pin) may be used for the removal of residual water and impurities, significantly enhancing the efficiency of a multigram-scale olefin metathesis transformation. Chapter 3: E- and Z-Macrocyclic Trisubstituted Alkenes for Natural Product Synthesis and Skeletal Editing We have introduced a reliable catalytic strategy for the synthesis of a variety of macrocyclic trisubstituted olefins in either stereoisomeric form. This was achieved by overcoming the unexpected difficulties through careful mechanistic studies, including addressing complications arising from pre-metathesis alkene isomerization. Macrocyclic ring-closing metathesis can be performed with a commercially available Mo-based complex and an easily accessible linear diene precursor. Accordingly, we can synthesize a skeletally diverse array of otherwise difficult-to-access macrocyclic alkenes, a critical set of compounds in drug discovery, in either isomeric form. The utility of the method is highlighted in two instances. The first is the near complete reversal of substrate-controlled selectivity in the generation of the macrolactam intermediate, in the total synthesis of the anti-fungal agent Fluvirucin B1. The second is an exceptionally stereoselective late-stage formation of a 24-membered macrocyclic E-trisubstituted alkene, enabling the completion of the total synthesis of a cytotoxic natural product dolabelide C, which is seven times more efficient than that reported previously. Chapter 4: Stereodefined Alkenes with a Fluoro-Chloro Terminus as a Uniquely Enabling Compound Class We have offered a practical solution for the synthesis of trisubstituted alkenyl fluorides by unveiling a widely applicable strategy for stereodivergent synthesis of olefins bearing a fluoro and chloro terminus. The core transformation is unprecedented: cross-metathesis between two trisubstituted olefins, one of which is a commercially available but scarcely utilized trihalo alkene. Alkenes bearing a fluoro,chloro-terminus are versatile substrates for the generation of otherwise difficult-to-access trisubstituted alkenyl fluorides, through stereospecific catalytic cross-coupling reactions. We also highlighted the utility of the method throguh synthesis of, among others, a fluoro-nematic liquid crystal component, peptide analogs bearing an E- or a Z-amide bond mimic, and all four stereoisomers of difluoro-rumenic ester (anti-cancer). / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Ring-opening metathesis polymerization (ROMP) is a great tool for synthesizing polyolefin materials with different topologies, including hyperbranched polymers—polymers with high degrees of branching and many end groups. However, hyperbranched polymer synthesis via ROMP is challenging due to multifunctional-monomer or multi-polymerization requirements. To simplify the synthesis of hyperbranched ROMP polymers, we developed a new synthetic approach: Self-condensing ROMP. The self-condensing ROMP approach involves a ROMP initiator modification to attach a ROMP-polymerizable group (a ROMP monomer), producing a ROMP "inimer" (initiator + monomer). The ROMP inimer initiates the polymerization and becomes a branching unit in the polymer structure, resulting in single-step hyperbranched polymer synthesis. The key challenge is controlling of this approach the ROMP initiator reactivity to avoid initiating polymerization during the ROMP inimer synthesis. Well-defined ruthenium-based olefin metathesis catalysts are common ROMP initiators due to their high stability, reactivity, and functional group tolerance. Thus, we studied the olefin metathesis catalyst activation temperature to enable ROMP initiator-monomer coupling. Based on the catalyst activity, we designed and synthesized a series of ROMP inimers. Then, we synthesized hyperbranched polymers via self-condensing ROMP. The characterization of hyperbranched polymers indicated the effect of branching density on the physical properties of the polymer. This approach introduced a new class of olefin metathesis complexes, ROMP inimers, containing both the initiator and propagating center. This approach provides a way to synthesize hyperbranched polymers from any known ROMP monomers in a single step. This dissertation also includes the synthesis and characterization of a bimetallic Ru complex that could directly synthesize cyclic polyolefin. We also include the synthesis and characterization of copper-ruthenium bimetallic olefin metathesis catalysts. / Doctor of Philosophy / Hyperbranched polymers are a class of polymers having highly branching structures and functional end-groups, and presenting distinct physical and chemical properties compared with linear polymers. Hyperbranched polymers have been used for many applications including processing additives, cross-linkers, compatibilizers, and catalyst supports. Well-defined ruthenium-based olefin metathesis catalysts enable the synthesis of materials with different topologies, functionalities, and chemical and physical properties via ring-opining metathesis polymerization (ROMP). Ligand modifications on ruthenium catalysts have been applied to improve the catalyst stability and reactivity. However, this dissertation modifies olefin metathesis catalysts to synthesize hyperbranched polymers in a single step. This dissertation illustrates catalyst functionalization with a ROMP monomer moiety to synthesize a ROMP inimer (inimer= initiator + monomer). The ROMP initiator—olefin metathesis catalyst—and ROMP monomer coupling produces an "inimer". The inimer can undergo self-condensing ROMP with a ROMP monomer addition to synthesize hyperbranched polymers. This approach introduced a new class of olefin metathesis complexes containing both the initiator and propagating center. This approach also provides a way to synthesize hyperbranched polymers from any known ROMP monomers in a single step.

Polymer functional groups have critical impacts upon physical, chemical and mechanical properties, and thus affect the specific applications of the polymer. Functionalization of cellulose esters and ethers has been under extensive investigation for applications including drug delivery, cosmetics, food ingredients, and automobile coating. In oral delivery of poorly water-soluble drugs, amorphous solid dispersion (ASD) formulations have been used, prepared by forming miscible blends of polymers and drugs to inhibit crystallization and enhance bioavailability of the drug. The Edgar and Taylor groups have revealed that some cellulose omega-carboxyalkanoates were highly effective as ASD polymers, with the pendant carboxylic acid groups providing both specific polymer-drug interactions and pH-triggered release through swelling of the ionized polymer matrix. While a variety of functional groups such as hydroxyl and amide groups are also of interest, cellulose functionalization has relied heavily on classical methods such as esterification and etherification for appending functional groups. These methods, although they have been very useful, are limited in two respects. First, they typically employ harsh reaction conditions. Secondly, each synthetic pathway is only applicable for one or a narrow group of functionalities due to restrictions imposed by the required reaction conditions. To this end, there is a great impetus to identify novel reactions in cellulose modification that are mild, efficient and ideally modular. In the initial effort to design and synthesize cellulose esters for oral drug delivery, we developed several new methods in cellulose functionalization, which can overcome drawbacks of conventional synthetic pathways, provide novel cellulose derivatives that are otherwise inaccessible, and present a platform for structure-property relationship study. Cellulose omega-hydroxyalkanoates were previously difficult to access as the hydroxyl groups, if not protected, react with carboxylic acid/carbonyl during a typical esterification reaction or ring opening of lactones, producing cellulose-g-polyester and homopolyester. We demonstrated the viability of chemoselective olefin hydroboration-oxidation in the synthesis of cellulose omega]-hydroxyesters in the presence of ester groups. Cellulose esters with terminally olefinic side chains were transformed to the target products by two-step, one-pot hydroboration-oxidation reactions, using 9-borabicyclo[3.3.1]nonane (9-BBN) as hydroboration agent, followed by oxidizing the organoborane intermediate to a primary alcohol using mildly alkaline H2O2. The use of 9-BBN as hydroboration agent and sodium acetate as base catalyst in oxidation successfully avoided cleavage of ester linkages by borane reduction and base catalyzed hydrolysis. With the impetus of modular and efficient synthesis, we introduced olefin cross-metathesis (CM) in polysaccharide functionalization. Using Grubbs type catalyst, cellulose esters with terminally olefinic side chains were reacted with various CM partners including acrylic acid, acrylates and acrylamides to afford families of functionalized cellulose esters. Molar excesses of CM partners were used in order to suppress potential crosslinking caused by self-metathesis between terminally olefinic side chains. Amide CM partners can chelate with the ruthenium catalyst and cause low conversions in conventional solvents such as THF. While the inherent reactivity toward CM and tendency of acrylamides to chelate Ru is influenced by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides. We observed that the CM products are prone to crosslinking during storage, and found that the crosslinking is likely caused by free radical abstraction of gamma-hydrogen of the alpha, beta-unsaturation and subsequent recombination. We further demonstrated successful hydrogenation of these alpha, beta-unsaturated acids, esters, and amides, thereby eliminating the potential for radical-induced crosslinking during storage. The alpha, beta-unsaturation on CM products can cause crosslinking due to gamma-H abstraction and recombination if not reduced immediately after reaction. Instead of eliminating the double bond by hydrogenation, we described a method to make use of these reactive conjugated olefins by post-CM thiol-Michael addition. Under amine catalysis, different CM products and thiols were combined and reacted. Using proper thiols and catalyst, complete conversion can be achieved under mild reaction conditions. The combination of the two modular reactions creates versatile access to multi-functionalized cellulose derivatives. Compared with conventional reactions, these reactions enable click or click-like conjugation of functional groups onto cellulose backbone. The modular profile of the reactions enables clean and informative structure-property relationship studies for ASD. These approaches also provide opportunities for the synthesis of chemically and architecturally diverse cellulosic polymers that are otherwise difficult to access, opening doors for many other applications such as antimicrobial, antifouling, in vivo drug delivery, and bioconjugation. We believe that the cellulose functionalization approaches we pioneered can be expanded to the modification of other polysaccharides and polymers, and that these reactions will become useful tools in the toolbox of polymer/polysaccharide chemists. / Ph. D.

Site-selective protein modification has become an important tool to study protein functions in chemical biology. In the preliminary work, allyl sulfides were found to be reactive substrates in aqueous cross-metathesis (CM) enabling the first examples of protein modification via this approach. In order to access the enhanced CM reactivity of allyl sulfide on proteins, facile chemical methods to install S-allyl cysteine on protein surface were developed. In particular, a cysteine-specific allylating reagent – allyl selenocyanate was used on protein substrate for the first time. The substrate scope of allyl sulfide-tagged proteins and factors that affect the outcome of CM was also investigated. A range of metathesis substrates containing different olefin tether of various lengths were screened; allyl ethers were found to be most suitable as CM partners. By reducing the steric hindrance around the allyl sulfide on protein surface through a chemical spacer, the rate and conversion of metathesis reaction on proteins was greatly enhanced. Moreover, allyl selenides were found to be more reactive than allyl sulfides in CM and enabled reactions with substrates that were previously impossible for the corresponding sulfur-analogue. Through this work, substrate selection guidelines for successful metathesis reaction on proteins were established. Rapid Se-relayed CM was further investigated through biomimetic chemical access to Se-allyl selenocysteine (Seac) via dehydroalanine. On-protein reaction kinetics revealed rate constants of Seac-mediated CM to be comparable or superior to off-protein rates of many current bioconjugations. This CM strategy was applied to histone proteins to install a mimic of acetylated lysine (K9Ac, an epigenetic marker). The resulting synthetic H3 was successfully recognized by antibody that binds natural H3-K9Ac. A Cope-type selenoxide elimination subsequently allowed the removal of such modification to regenerate dehydroalanine. Finally, preliminary research efforts towards metabolic incorporation of allyl sulfide-containing amino acid into proteins, and CM on cell surfaces were discussed.

Cardanols are more and more used in the industry of polymers, resins, coatings, friction materials, etc. At right conditions, these lipid-like chemicals can undergo metathesis reaction. The main aim of the diploma thesis is an analysis of products of cardanol metathesis by HPLC-MS/MS. Standard 3,3'-hexadec-8-en-1,16-diyldiphenol, one of the main products of cardanol metathesis, was prepared for quantitative HPLC analysis. The standard was prepared in two steps. The first step was cardanol ethenolysis to give 3-(non-8-enyl)phenol. The second step was self-metathesis of 3-(non-8- enyl)phenol to give 3,3'-hexadec-8-en-1,16-diyldiphenol. The standard was characterised by HPLC/MS, MS/MS, EI-MS, UV/VIS, IR, Raman a NMR spectroscopy. The second part of the thesis is dedicated to the study of a mechanism of double-bond localization method in long chain hydrocarbons by acetonitrile APCI-MS. The formation of adducts [M + 55]+ , which are the key substances of this method, was studied using simple alkene models by MS and MS/MS. At the end, the structure and the mechanism of the formation of adducts [M + 55]+ were suggested. Key words: Cardanol, olefin metathesis, HPLC-MS, double-bond localization, APCI, acetonitrile

Thesis advisor: Amir H. Hoveyda / Chapter 1. Mechanistic Insights and Factors Influencing Polytopal Rearrangements in Stereogenic-at-Ru Carbenes. Herein, the mechanistic elucidation of the stereochemical inversion in stereogenic-at-Ru carbene complexes through olefin metathesis (OM) and non-olefin metathesis (non-OM) based polytopal rearrangements is provided. Our investigations involve the isolation and characterization of previously hypothesized higher-energy (e.g., endo-anti) and lower-energy (e.g., exo-anti) diastereomers, and their interconversion under thermal and/or acid-catalyzed conditions is demonstrated. Furthermore, our computational efforts highlighting the importance of the anionic ligands, due to their critical role in trans influence, dipolar interactions, and e-e repulsions, in polytopal rearrangements are reported. Finally, the positive influence of H-bonding in OM and non-OM processes is also rationalized. (a) Khan, R. K. M.; Zhugralin, A. R.; Torker, S.; O'Brien, R. V.; Lombardi, P. J. and Hoveyda, A. H. "Synthesis, Isolation, Characterization, and Reactivity of High-Energy Stereogenic-at-Ru Carbenes: Stereochemical Inversion Through Olefin Metathesis and Other Pathways," J. Am. Chem. Soc. 2012, 134, 12438-12441. (b) Torker, S.; Khan, R. K. M. and Hoveyda, A. H. "The Influence of Anionic Ligands on Stereoisomerism of Ru Carbenes and Their Importance to Efficiency and Selectivity of Catalytic Olefin Metathesis Reactions," J. Am. Chem. Soc. 2014, 136, 3439-3455. Chapter 2. Highly Z- and Enantioselective Ring-Opening/Cross-Metathesis of Enol Ethers Through Curtin-Hammett Kinetics. The first instances of Z- and enantioselective Ru-catalyzed olefin metathesis are presented. Ring-opening/cross-metathesis (ROCM) reactions of oxabicyclic alkenes and enol ethers and a phenyl vinyl sulfide are promoted by 0.5-5.0 mol % of enantiomerically pure stereogenic-at-Ru complexes with an aryloxy chelate tethered to the N-heterocyclic carbene. Products are formed efficiently and with exceptional enantioselectivity (up to >98:2 enantiomer ratio). Surprisingly, the enantioselective ROCM reactions proceed with high Z selectivity (up to >98% Z). Moreover, reactions proceed with the opposite sense of enantioselectivity versus aryl olefins, which afford E- isomers exclusively. DFT calculations and deuterium-scrambling experiments, indicating fast interconversion between endo- and exo-Fischer carbene diastereomers, support a Curtin-Hammett situation. On this basis, models accounting for the stereoselectivity levels and trends are provided. Furthermore, the correlation of Fischer carbene character to the observed chemoselectivity in ROCM with enol ethers is also disclosed. Finally, a general proposal for the substrate-controlled Z selectivity in OM is also discussed. (a) Khan, R. K. M.; O'Brien, R. V.; Torker, S.; Li, B. and Hoveyda, A. H. "Z- and Enantioselective Ring-Opening Cross-Metathesis with Enol Ethers Catalyzed by Stereogenic-at-Ru Carbenes: Reactivity, Selectivity, and Curtin-Hammett Kinetics," J. Am. Chem. Soc. 2012, 134, 12774-12779. (b) Torker, S.; Koh, M. J.; Khan, R. K. M. and Hoveyda, A. H. "Origin of Z selectivity in Olefin Metathesis Reactions of Certain Terminal Alkenes Catalyzed by Typically E-Selective Ru Carbenes," manuscript submitted. Chapter 3. A New Class of Highly Efficient Ru Catalysts for Z-Selective Olefin Metathesis. Herein, we outline a general design for Z-selective OM, which led to the development of a new class of stereogenic-at-Ru carbene complexes (Ru4-9). Furthermore, we demonstrate that the newly developed dithiolate complexes Ru4b and Ru5 efficiently promote high activity and selectivity in ROMP reactions of norbornene and cyclooctene. Notably, the catechothiolate Ru4b catalyzes Z-selective ROCM with a broad scope of alkenes involving various functional groups (e.g., alcohols, enol ethers, vinyl sulfides, amides, heterocycles, and conjugated 1,3-dienes). More importantly, we disclose that the catecholate complex Ru4a is kinetically non-selective in OM and readily decomposes in the presence of mildly acidic moieties (e.g., alcohols and CDCl3). Subsequently, Ru9 is developed to efficiently promote highly Z-selective CM of a diol cross-partner with a wide range of alkene substrates. Most remarkably, the aforementioned protocol is employed in two natural product syntheses and the OM-based Z-selective cracking of oleic acid, which is unprecedented with existing Ru-carbenes and Mo/W-alkylidenes. (a) Khan, R. K. M.; Torker, S. and Hoveyda, A. H. "Readily Accessible and Easily Modifiable Ru-Based Catalysts for Efficient and Z-Selective Ring-Opening Metathesis Polymerization and Ring-Opening Cross-Metathesis," J. Am. Chem. Soc. 2013, 135, 10258-10261. (b) Koh, M. J.; Khan, R. K. M.; Torker, S. and Hoveyda, A. H. "Broadly Applicable Z- and Diastereoselective Ring-Opening/Cross-Metathesis Catalyzed By a Dithiolate Ru Complex," Angew. Chem., Int. Ed. 2014, 53, 1968-1972. (c) Khan, R. K. M. ; Torker, S. and Hoveyda, A. H. "Reactivity and Selectivity Differences Between Catecholate and Catechothiolate Ru Complexes. Implications Regarding Design of Stereoselective Olefin Metathesis Catalysts," J. Am. Chem. Soc. 2014, 136, 14337-14340. (d) Koh, M. J.; Khan, R. K. M.; Torker, S.; Yu, M.; Mikus, M. S. and Hoveyda, A. H. "Synthesis of High-Value Alcohols, Aldehydes and Acids by Catalytic Z-Selective Cross-Metathesis" manuscript submitted. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Different catalytic approaches have been applied to new -lactams preparations. olefin metathesis has been successfully performed with 3--methylidene--lactams. It was verified that 3--methylidene--lactams olefin metathesis is applicable to preparation of biologically active -lactam of Ezetimibe-type.