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The olefin metathesis reaction is a well established and powerful method for the synthesis of alkenes. This reaction can be further classified into the intermolecular process known as cross-metathesis and the intramolecular process known as ring-closing metathesis. The aim of these studies is the use of the two variants of the metathesis reaction for the development of new methods for the synthesis of heteroaromatic structures, in particular the synthesis of polysubstituted pyridines.

Thesis advisor: Amir H. Hoveyda / We have synthesized Ru-carbene isocyanide complexes that promote both ring-opening metathesis polymerization of norbornene as well as cycloisomerization of diethyl diallylmalonate. We have also synthesized a N-heterocyclic carbene complex bearing a biphenylthiol moiety, and we installed this ligand on a Ru-carbene to produce a racemic chiral bidentate Ru-thiolate complex. Although the Ru-thiolate was found to initiate more slowly than the corresponding biphenoxide catalyst, both perform ring-opening/cross-metathesis (ROCM) with similar efficiency. Several other bidentate Ru-complexes were synthesized where the anionic ligand was varied (tosylate, pivalate, and phenylthiolate), as well as a new Re-alkylidene bis-pyrrolide. We have expanded the scope of Ru-catalyzed enantioselective ROCM of cyclopropenes utilizing a variety of ester, ketone, ether, and aliphatic olefin cross-partners. The utility of this method was demonstrated in the enantioselective total synthesis of the marine natural product (+)-sporochnol, which was synthesized in 8% overall yield across eleven linear steps. Additionally, we have developed an enantio- and Z-selective ROCM of enol ethers and oxabicycles; we propose the origin of Z-selectivity to arise from a lower barrier to ruthancyclobutane cleavage/formation for the cis-substituted ruthenacyclobutane vs the trans-substituted ruthenacyclobutane (which is favored for ROCM of oxabicycles and styrene). We also have found that stereogenic-at-Ru complexes are capable of undergoing non-metathesis isomerization through polytopal rearrangements. This observation may explain why cyclopropene ROCM suffers from low enantioselectivity for many substrates. We have developed a diasteroselective ROCM reaction, which utilizes commercially available ruthenium dichloride catalysts in the presence of chiral allylic alcohols and cyclopropenes. Our investigation revealed that the presence of a hydroxyl group dramatically accelerates the rate of ROCM vs the corresponding methyl ether and delivered products in high yield and diastereoselectivity. Furthermore, we found that the methyl ether delivered the opposite diastereomer vs the allylic alcohol; this led us to propose that intramolecular H-bonding between the hydroxyl proton and a chloride ligand controls the diastereoselectivity and enhances the rate of the ROCM. Protic additives have also been found to promote polytopal rearrangements in stereogenic-at-Ru complexes; H-bonding may facilitate olefin metathesis in a similar fashion to polytopal rearrangement by reducing the trans effect during the transition state to ruthenacyclobutane formation. A number of synthetically useful allylic alcohols and strained olefin substrates efficiently provide products in high diastereoselectivity and with good E:Z selectivity (89:11-97:3 dr, 4:1-11:1 E:Z). We have developed a Mo-catalyzed Z-selective cross-metathesis (CM) reaction. A wide range of olefin cross partners were found to be effective for both enol ether and allylic amide substrates (51-97% yield, 81 to 98% Z). We applied our Z-selective CM method to the synthesis of KRN7000, a potent immunostimulant (the Z-allylic amide was obtained in 85% yield and 96% Z). We also utilized Z-selective CM in the formal synthesis of an enol ether plasmalogen C18 (plasm)-16:0 (PC), a lipid membrane component found in mammalian brain tissue (the enol ether was obtained in >98:2 Z selectivity). Z-selective cross-metathesis is therefore a new tool for synthetic chemists to access important building blocks for the synthesis of biologically active molecules. We have developed a Z-selective cross-metathesis of vinyl and allyl boronates. Reactions of both substrate classes proceed to between 50-95% conv and deliver Z-vinylboronate and Z-crotylboronate products in 85-93% Z selectivity. Allylboronate CM provides Z-crotylboronates which can be used for diastereoselective crotylation. The utility of Z-selective vinylboronate CM was demonstrated in the synthesis of a dienyl boronate (obtained in 83% yield and >98% Z) that will be utilized in the total synthesis of the potent anti-cancer agent disorazole C1. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Marc L. Snapper / A catalyst of notoriety Decomposes with great variety. Transformations after metathesis Facilitate tandem catalysis. This reaction has a proclivity For new regioselectivity With methanolic modification: Tandem enyne hydrovinylation. From a diene protonation event, Unexpected reaction with solvent, During catalyst optimization: One-pot enyne hydroarylation. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Development of Ru-Based Catechothiolate Complexes for Z-selective Ring-Opening/Cross-Metathesis and Cross-Metathesis. We have developed a broadly applicable Ru-catalyzed protocol for Z-selective ring-opening/cross-metathesis (ROCM). Transformations are promoted by 2.0–5.0 mol % of a Ru-based catechothiolate complex, furnishing products in up to 97 % yield and >98:2 Z:E ratio. The Z-selective ROCM processes are found to be compatible with terminal alkenes of different sizes that include the first examples involving heteroaryl olefins, 1,3-dienes, and O- and S-substituted alkenes as well as allylic and homoallylic alcohols. Reactions with an enantioenriched α-substituted allylic alcohol are shown to afford congested Z-olefins with high diastereoselectivity. The insights gained from these investigations provided the impetus to develop electronically modified Ru catechothiolate catalysts that are readily accessible from a commercially available dichloro-Ru carbene and an easily generated air-stable zinc catechothiolate. The new complex is effective in catalyzing Z-selective cross-metathesis (CM) of terminal alkenes and inexpensive Z-2-butene-1,4-diol to directly generate linear Z-allylic alcohols, including those that bear a hindered neighboring substituent or reactive functionalities such as a phenol, an aldehyde or a carboxylic acid. Transformations typically proceed with 5.0 mol % of the catalyst within 4–8 hours under ambient conditions, and products are obtained in up to 80% yield and 98:2 Z:E selectivity. Utility is highlighted through synthesis of a molecular fragment en route to anti-tumor agent neopeltolide and in a single-step stereoselective gram-scale conversion of renewable feedstock to synthetically valuable Z-allylic alcohols. Chapter 2. Kinetically Controlled Z- and E-Selective Cross-Metathesis to Access 1,2- Disubstituted Alkenyl Halides. We have discovered that previously unknown halo-substituted molybdenum alkylidenes are capable of participating in highly efficient olefin metathesis reactions that afford linear 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by 1.0–10.0 mol % of a Mo-based pentafluorophenylimido monoaryloxide pyrrolide (MAP) complex that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, delivering a myriad of alkenyl chlorides, bromides and fluorides in up to 91% yield and >98:2 Z:E ratio. Through mechanism-based modification of the aryloxide ligand, a newly synthesized Mo-based MAP complex was shown to be effective in promoting kinetically controlled E-selective CM to access the corresponding thermodynamically less favored E-isomers of alkenyl chlorides and fluorides. Reactions typically proceed within 4 hours at ambient temperature with 1.0–5.0 mol % of the catalyst, which may be utilized in the form of air- and moisture-stable paraffin pellets. Utility of the aforementioned protocols is demonstrated through preparation of biologically active compounds and related analogues as well as late-stage site- and stereoselective fluorination of complex organic molecules. Chapter 3. Molybdenum-Based Chloride Catalysts for Z-Selective Olefin Metathesis. A new class of Mo-based monoaryloxide chloride (MAC) complexes for Z-selective olefin metathesis has been developed. The MAC catalysts are capable of promoting CM with commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene to furnish the higher-energy Z-isomers of trifluoromethyl-substituted alkenes in up to 95% yield and >98:2 Z:E selectivity. Furthermore, otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloroethene and 1,2-dibromoethene can be accomplished with appreciably improved efficiency and Z-selectivity. The method enables synthesis of biologically active compounds and CF3-analogues of medicinally relevant molecules. Density functional theory (DFT) calculations shed light on the origins of the activity and selectivity levels observed in these transformations. Chapter 4. Stereoselective Synthesis of Z- and E-Trisubstituted Alkenes by Merging Cross-Coupling with Cross-Metathesis. We have discovered that challenging acyclic E- and Z-trisubstituted alkenes, particularly alkenyl chlorides and bromides, can be accessed efficiently and in high stereoisomeric purity (up to >98% E and 95% Z) through a sequence involving catalytic cross-coupling followed by stereoretentive CM promoted by Mo-based catalysts. Initial exploratory studies with 1,1-disubstiuted alkenes revealed crucial mechanistic features of the transformations that led us to utilize readily accessible trisubstituted olefins as substrates, in combination with commercially available 1,2-dihaloethenes as cross-partners for CM. Applications to synthesis of biologically active compounds and synthetic precursors underscore utility. The stereoretentive transformations may be extended to trisubstituted non-halogenated alkenes such as aliphatic olefins. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Exploring Ligand Effects in Ruthenium Dithiolate Carbene Complexes. Ruthenium dithiolate metathesis catalysts discovered in the Hoveyda group have been a valuable addition to the field of olefin metathesis. While the catalyst shows unique selectivity and reactivity, quantifying and mapping key interactions in the catalyst framework to elucidate and explain causes is difficult. We, therefore, decided to use the neutral chelating or monodentate ligand, controlling initiation, as a structural probe. By altering its properties and observing changes in the catalyst, we sought to deepen our understanding of these complexes. We established a trans influence series with over 20 catalysts and correlated the impact on catalyst initiation. Further, we show that in the case of strongly σ-donating and π-accepting ligands such as phosphites and isonitriles, the complex exhibits fluxional behavior. The catalysts ground state is elevated to such a degree that thiolate Ruthenium bonds become labile and rapidly exchange. While Ruthenium dithiolate catalysts were readily applied to metathesis polymerization, their use in the synthesis of small molecules was initially less forthcoming. Specifically, reactions involving terminal olefins lead to rapid catalyst deactivation and only low conversion. We were able to determine that the potential energy stored in the trans-influence between the thiolate ligand and the NHC can be released in a sulfur shift to reactive Ruthenium methylidene species. Since methylidenes are formed by reaction with terminal olefins, use of an excess of internal olefins can prevent their formation. Chapter 2. Harnessing Catalyst Fluxionality in Olefin Metathesis. Depending on its use, material requirements can vary significantly. Materials that can easily be adapted to a given application, for example by varying tensile strength, melting point or solubility, are desirable. Controlling the polymers tacticity (the adjacent stereocenters in a polymer chain) is a straight forward way to achieve just that. Ru dithiolate catalysts should give highly syndiotactic polymers due to their single stereocenter undergoing inversion during every metathesis step. The fluxional nature of the catalyst allows for control of polymer tacticity from 50% (atactic) to ≥95% syndiotacticity by changing monomer concentration. We determined the factors which are responsible for fluxionality and synthesized complexes that give either high or low levels of tacticity over a broader range of monomer concentration. Chapter 3. Harnessing Catalyst Fluxionality in Olefin Metathesis. The importance of fluorine-containing molecules is hard to understate, keeping in mind the surge of new methodologies for their synthesis and the medical breakthroughs they enable. However, efficient and practical syntheses of stereodefined alkenyl fluorides are rare. In this context, we have developed enantioselective boryl allylic substitution of allylic fluorides, which yield enantioenriched γ-alkenyl fluoride substituted allyl boronate esters. The reaction is catalyzed by Cu-based catalysts that are prepared in-situ and delivered as products with high yield and enantioselectivity. Mechanistic inquiry shows the reaction is not a concerted allylic substitution. An intermediate Cu alkyl complex is formed after the Cu boron addition is made to the double bond, which only slowly undergoes β-fluorine elimination in the presence of a Lewis acid. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Thesis (PhD) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

A molécula de 3-metilpiperidina (3-Mepip) foi investigada como ligante ancilar em um novo complexo do tipo [RuCl2(PPh3)2(amina)] em polimerização via metátese de olefinas ciclicas por abertura de anel (ROMP) de norborneno (NBE) e norbornadieno (NBD). A síntese do novo complexo foi realizada partindo-se do complexo precursor [RuCl2(PPh3)3], e foi caracterizado por: EPR, análise elementar de CHN, infravermelho (FTIR) e RMN de 31P. Com base nos resultados obtidos é possível propor um complexo pentacoordenado com geometria pirâmide de base quadrada (PBQ), estando os íons cloretos trans-posionados no plano equatorial da esfera de coordenação do metal, com a amina ocupando a posição apical da pirâmide devido ao seu forte caráter doador σ. As reações de ROMP dos monômeros NBE e NBD utilizando o novo complexo foram realizadas em atmosfera de argônio em função da razão molar de molar [monômero]/[Ru] (1000, 3000, 5000, 7000 e 10000), tempo (5, 30 e 60 min) e temperatura (25 e 50 °C). Com um volume de 5 µ de etildiazoacetato (EDA), 25 °C e uma razão molar de 5000 de monômero a 5 min, obteve-se 65 % de poliNBE com Mn = 0,8 x 105 e IPD igual a 1,9. Os polímeros obtidos com NBD apresentaram um rendimento em torno de 20% a 25 °C por 5 min. Reações de polimerização em atmosfera aberta resultaram em valores de rendimento próximos dos observados em atmosfera de argônio, sugerindo dessa forma que o novo complexo é resistente a processos oxidativos provocados pelo O2 da atmosfera ambiente. As reações de polimerização foram realizadas na presença de outros diazocompostos benzildiazoacetato (BDA) e tertbutildiazoacetato (TBDA) como fontes de carbenos, afim de avaliar a influência eletrônica e estérica provocada pelos diferentes grupo R desses diazocompostos. Foi observado que o etildiazoacetato (EDA) apresentou os melhores valores de rendimento dos polímeros isolados, provavelmente devido ao balanço nas características estéricas e eletrônicas desse diazo frente ao centro de Ru(II). / The 3-methylpiperidine (3-Mepip) molecule was investigated as ancillary ligand in a novel [RuCl2(PPh3)2(amine)] type complex for ring-opening metathesis polymerization (ROMP) of norbornene (NBE) and norbornadiene (NBD). The synthesis of the new complex was performed from the precursor complex [RuCl2(PPh3)3], and it was characterized by: EPR, CHN elemental analysis, infrared (FTIR) and 31P NMR (1H). From the obtained results it was possible to propose a pentacoordenado complex with square-shaped pyramid geometry (PBQ), with chloride ions trans-positioned in the equatorial plane of the coordinating metal sphere, with the amine occupying the apical position of the pyramid due to its strong σ-donor character. The ROMP reactions of NBE and NBD monomers using the new complex were performed under argon atmosphere as a function of the [monomer]/[Ru] molar ratio (1000, 3000, 5000, 7000 and 10000), reaction time (5, 30 and 60 min) and temperature (25 and 50 ° C). With a volume of 5 µL of ethyldiazoacetate (EDA), at 25 °C and a 5000 molar ratio of monomer for 5 min, 65% polyNBE was obtained with Mn = 0.8 x 105 and IPD equal to 1.9. The polymers obtained with NBD showed 20% yield at 25 °C for 5 min. The polymers obtained with norbornadiene showed a yield of about 20% at 25 °C for 5 min. Polymerization reactions in air atmosphere resulted in values close to those observed in argon atmosphere, suggesting that the complex presents resistance to oxidative processes caused by O2 from the ambient atmosphere. The polymerization reactions were performed in the presence of other diazocompounds benzyldiazoacetate (BDA) and tert-butyldiazolacetate (TBDA) as sources of carbenes. In order to evaluate the electronic and steric influence caused by the different R groups of these diazocompounds, it was observed that ethyldiazoacetate EDA) presented the best yield values of the isolated polymers, probably due to the balance in the steric and electronic characteristics of this diazo in front of the Ru(II) center.

This thesis details progress towards the development of an organocatalytic carbonyl-olefin metathesis of norbornene. This transformation has not previously been done catalytically and has not been done in practical manner with stepwise or stoichiometric processes. Building on the previous work of the Lambert lab on the metathesis of cyclopropene and an aldehyde using a hydrazine catalyst, this work discusses efforts to expand to the less stained norbornene. Computational and experimental studies on the catalytic cycle are discussed, including detailed experimental work on how various factors affect the difficult cycloreversion step. The second portion of this thesis details the use of chiral cyclopropenimine bases as catalysts for asymmetric Michael reactions. The Lambert lab has previously developed chiral cyclopropenimine bases for glycine imine nucleophiles. The scope of these catalysts was expanded to include glycine imine derivatives in which the nitrogen atom was replaced with a carbon atom, and to include imines derived from other amino acids.