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Bentley, Scott Alexander. "Asymmetric conjugate addition reactions." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:9e619a66-6277-48c2-8a2e-24f8206e52b3.
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This thesis is concerned with the asymmetric conjugate addition reactions of a range of chiral nucloeophiles. Chapter 1 introduces the conjugate addition reaction as a valuable carbon-carbon and carbon-heteroatom bond forming reaction in organic chemistry, and explores the asymmet- ric conjugate addition of a range of chiral and achiral carbon and nitrogen nucleophiles to a range of acceptors. Chapter 2 explores the use of the N-benzyl-N-(α-methylbenzyl)amino group as a chi- ral auxiliary, by employing the attempted conjugate additions of both N-benzyl-N-(α- methylbenzyl)hydrazine and N -benzyl-N -(α-methylbenzyl)hydroxylamine as chiral ammo- nia and water equivalents respectively. Chapter 3 describes the asymmetric and stereoselective preparation of a range of 4,4- disubstituted isoxazolidin-5-ones from the conjugate addition of lithium (S)-N-tert-butyl- dimethylsilyloxy-N -(α-methylbenzyl)amide. The isoxazolidin-5-ones are then globally de- protected via hydrogenolysis, giving rise to the corresponding β2,2,3-amino acids. Chapter 4 focuses on the development of a protocol to effect the conjugate addition of a chiral aniline equivalent. The scope of the reaction is delineated by varying both the nu- cleophile and the α,β-unsaturated ester. Finally, cyclisation of the β-N-arylamino esters to the corresponding tetrahydroquinolines is explored, and an application to the synthesis of the natural product (−)-angustureine is presented. Chapter 5 contains full experimental procedures and characterisation data for all com- pounds synthesised in Chapters 2, 3 and 4.
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Convine, Nicola Jane. "Stereoselective conjugate addition of cyanide." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424510.
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Albrow, Victoria Elizabeth. "Ferrocenyl ligands for asymmetric conjugate addition." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436818.
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Fraser, Paul Kenneth. "New methodology for asymmetric conjugate addition." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416268.
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Vries, Andreas Hendrikus Maria de. "Catalytic enantioselective conjugate addition of organometallic reagents." [S.l. : [Groningen] : s.n.] ; [University Library Groningen] [Host], 1996. http://irs.ub.rug.nl/ppn/152408681.
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Sian, Sudipinder K. "Nickel catalysis of asymmetric conjugate addition reactions." Thesis, University of Manchester, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.682190.
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The potential for inducing chirality upon 1,4-conjugate addition to alpha/beta unsaturated carbonyls has captivated the interest of many chemists for over 20 years. Metals such as copper, cobalt and nickel have been used as the catalytically active metal centres in these enantioselective reactions. The work presented in this thesis describes the development of a new nickel catalysed system, the attempts at employing it on a range of substrates and ultimately making the chemistry stereoselective. The Introduction reviews metal-mediated syntheses popularly used in organic reactions. Emphasis is put on the development of the conjugate addition reaction. The use of various organocopper reagents, either in stoichiometric or catalytic amounts, in these reactions is described. The impact of organozinc reagents in this field of chemistry is discussed, and its application in the recent, successful advances in this area. In order to investigate the scope of nickel catalysed reactions, initial studies covered the extent of the applicability of the catalyst on a range of substrates, both from commercial sources and some prepared in-house. The Results and Discussion describes the attempts at inducing enantioselectivity. Due to limitations in the compatibility between the catalyst and the chiral ligands, a new pre-catalyst, nickel tert-butoxide, was prepared. Preliminary results of using this catalyst for the first time in conjugate addition reactions are documented. One example of a reduction of an allylic acetate has also been discovered. Attempts at reduction on other allylic acetates were undertaken. The endeavours at designing a new, chiral catalytic system with this catalyst are discussed, with the emphasis on employing hydroxyphosphine ligands. Difficulties in controlling the oxidation state of phosphine in their syntheses preceded the screening of a number of ligands with the catalyst. Although low enantioselectivities were recorded, in some cases, there was acceleration in rates of reaction and the catalyst was found to tolerate a range of ligands possessing a variety of functionalities. In, summary, a new nickel(II) catalyst has been identified which may be active in carbon-hydrogen and a number of carbon-carbon bond forming reactions. Finally, the Experimental section is a collection of experiments and related data carried out during the project.
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Penrose, Stephen David. "Recent advances in rhodium-catalysed conjugate addition reactions." Thesis, University of Bath, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492243.
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The research presented herein is concerned with the exploration of rhodium-catalysed addition reactions with organoboranes encompassing the 1,4-addition enolate protonation to benzyl acrylate esters, and the synthesis of chiral organoboranes for use in the synthesis of natural products Hermitamides A and B. Chapter 1 introduces the area of rhodium-catalysed conjugate addition as a tool for asymmetric synthesis. An extensive discussion of this methodology is included and recent advances in the area will be highlighted. In addition to this some recently published alternatives to organoboranes are outlined and their use in rhodium-catalysed chemistry documented. Chapter 2 discusses the tandem process of rhodium-catalysed conjugate addition enolate protonation, a recently observed asymmetric development. By using a novel route to benzyl acrylic esters the synthesis of α,α′-dibenzyl esters is achieved in excellent yields and selectivity. This study highlights the fact that when dealing with 1,1-disubstituted activated alkenes it is more difficult to produce enantioselective results as the chirality is determined in the protonation step and not during insertion. Some insights into the mechanism are proposed based on the outcomes observed. Chapter 3 describes the total synthesis of Lyngbic Acid and related structures Hermitamides A and B. Synthesis of these natural products are achieved by synthesis of an enantiopure organoborane species and its subsequent coupling via rhodium catalysis. Some interesting insights into the addition of alkenyl organoborane species to unsubstituted 1,1-activated alkenes are detailed. Chapter 4 describes the synthesis and characterisation for the compounds discussed in the previous chapters.
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Kalogirou, A. "Development of the conjugate addition/nitro-Mannich reaction." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1389217/.
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This thesis describes the development of the conjugate addition/nitro-Mannich reaction and its use in the synthesis of useful molecules like pyrrolidin-2-ones and piperazin-2-ones. The introductory chapter of this thesis outlines the literature related to the nitro-Mannich reaction, describing the different existing methodologies for performing the reaction in diastereo- and enantioselective manner. The synthetic applications of the reaction are also described, especially its uses in the synthesis of biologically active natural products. Moreover, the syntheses and uses of two classes of compounds, pyrrolidin-2-ones and piperazin-2-ones are briefly discussed. The results and discussion chapter starts by presenting the use of a one-pot conjugate addition/nitro-Mannich/lactamisation reaction in the synthesis of densely functionalised pyrrolidin-2-ones. The development of an asymmetric protocol, as well as some functionalisations of the pyrrolidinone core are also described. Our efforts to synthesise human neutrophil elastase inhibitor GW311616A using the developed methodology are then detailed. The next part of the results and discussion chapter portrays the development of a conjugate addition/nitro-Mannich reaction of non-zinc nucleophiles to ethyl 3-nitroacrylate and β-nitrostyrene. The scope and limitations of the reaction were investigated using a variety of different nucleophiles including amines, thiols, phosphines, alcohols, enolates and nitriles. Finally, our work towards synthesising the biologically active piperazin-2-one piperazirum, using the nitro-Mannich methodology is described. The diastereoselective synthesis and characterisation of a densely functionalised piperazin-2-one was accomplished. A detailed description of the experimental details and analytical data for all novel compounds is described in the experimental section. Tables of coupling constants and X-ray crystallographic data are presented in the appendices section, followed by a list of literature references.
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Zarotti, Pablo. "Investigations of ligands for Cu-catalyzed conjugate addition reactions /." Zürich : ETH, 2006. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=16591.
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Baldwin, I. Craig. "New methodology involving allylic substitution and conjugate addition reactions." Thesis, Loughborough University, 1996. https://dspace.lboro.ac.uk/2134/27583.
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Chapter one reviews routes to the generation of α-aminophosphonates and α-aminophosphonic acids. These biologically important compounds are synthesised in both racemic and enantiomerically enriched forms. The second chapter describes the results of conjugate addition reactions of lower order cuprates to diethylvinylphosphonate followed by an electrophilic quench to give a range of alkylphosphonates. The third and fourth chapters are concerned with the generation of enantiomencally enriched α-aminophosphonates and α-aminoesters via palladium catalysed allylic substitution reactions With allyl acetate the resulting products were isolated with an enantiomeric excess of up to 19%. With 1,3-diphenyl-2-propenyl acetate products with both high diastereomeric and enantiomeric excesses were isolated with the best being 75 % de and 97 % ee.
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Solana, González Jorge. "Copper and iridium conjugate addition : cyclisation processes, domino reactions." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/10471.
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Asymmetric conjugate addition of bis(pinacolato)diboron followed by aldol cyclisation of enone diones under the action of a chiral copper catalyst has been developed. This enantioselective process, using a chiral bisphosphine as ligand, allows the formation of bicyclic alcohols with four contiguous stereocentres in high diastero- and enantioselectivity. This catalytic system has been applied to the parallel kinetic resolution of a racemic β- ketoamide. Further functionalization of the bicyclic alcohols synthesised was also possible. A domino addition of arylboronic acids and cyclisation of alkynones via an undescribed iridium 1-4-migration process has been developed. A range of tricyclic compounds using a variety of arylboronic acids have been synthesised in good yields and high diasteroselectivity. The use of chiral bisphosphine ligand together with an iridium salt allows the formation of enantioenriched compounds in moderate yield.
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Andrews, Philip Ian. "New organometallic strategies for conjugate addition and cross-coupling reactions." Thesis, University of Nottingham, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606337.
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Enamine N-oxides have been reported only a very few times in the literature. Investigation into their reactivity has revealed that treatment with catecholborane can generate amines via an electrophilic iminium species, which provides evidence for a proposed reverse polarity reactivity, with respect to existing l,4-additions to nitro alkenes. Deprotonation at the a-carbon of enamine N-oxide double bonds has also been accomplished by 'BuLi, with deprotonation occurring fully after 5 min. Using methodology developed within the group, a novel enamine N-oxide has been synthesised in good yield, although attempts to form a cyclic enamine N-oxide were unsuccessful. The copper-catalysed asymmetric conjugate addition of trimethylaluminium to nitroalkenes was found to give moderate enantioselectivity (46 % ee) using Cu(OAc)2 and a phosphoramidite ligand in diethyl ether. Conjugate addition of dimethyl(alkynyl)aluminium reagents to cyclic and acyclic enones has been achieved in a racemic sense in good to excellent yields employing MTBE as the solvent with three equivalents of alkynylaluminium, although regioselectivity remains an issue depending on the enone substrate. Cross-coupling of dimethyl(alkynyl)aluminiums with aryl bromides, iodides and triflates catalysed by Pd2(dba)J'CHCh or Pd(dba)2 and DavePhos gave acetylene derivatives in good to excellent yields. These results are comparable with previously reported systems and in some cases gave improvements in yield. Using XPhos as ligand and adding DABCO, chlorobenzene was also coupled in moderate yield. Application to tetracene synthesis was not successful. Development of a novel method of alkyne hydroalumination usmg dichloroalane bis(tetrahydrofuran) adduct and catalytic Ti or Zr metallocene complexes gave high yields of vinyl aluminium reagents. Use of these reagents in Pd-catalysed cross-coupling with aryl halides gave good to excellent yields of (E)-alkenes, and is applicable to both aryl and alkyl terminal acetylenes. 1
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Jarvis, Ashley N. "Preparation and ring-opening reactions of N-diphenylphosphinyl vinylaziridines." Thesis, University of Reading, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301977.
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Wu, Hao. "Catalytic Enantioselective Formations of C–B, C–C and C–Si Bonds by Organic Molecules or Transition-Metal Complexes." Thesis, Boston College, 2015. http://hdl.handle.net/2345/bc-ir:104759.
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Thesis advisor: Amir H. HoveydaCatalytic enantioselective reactions are of great importance in synthetic organic chemistry. Thus, development of efficient, selective and easily accessible catalyst for various bond formations is the main task in our laboratories. First, we have developed the first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls, promoted by a chiral Lewis basic N-heterocyclic carbene. The valuable β-boryl carbonyls were further used in complex molecule syntheses. The mechanism of these C–B bond formations was studied in details. We have also developed a practical method for enantioselective addition of an allene unit to aryl-, heteroaryl- and alkyl-substituted Boc-aldimines. These efficient C–C bond formations, catalyzed by an aminophenol-derived boron-based catalyst, were further utilized in succinct syntheses of anisomycin and epi-cytoxazone. Finally, chiral NHC–Cu complexes were employed for site-, diastereo- and enantioselective silyl conjugate additions to acyclic and cyclic dienones and dienoates. The precious enantiomerically enriched allylsilane obtained can be converted into a ketone-aldol type product, which is difficult to access through alternative methods
Thesis (PhD) — Boston College, 2015
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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Saxena, Aakarsh. "New enantioselective metal-catalysed conjugate addition-initiated reactions of alkenyl(aza)arenes." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/7598.
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I. Enantioselective Rhodium-Catalysed Arylation of Electron-Deficient Alkenylarenes β-substituted alkenyl-para-nitroarenes, an unexplored substrate class for catalytic asymmetric addition reactions, undergo highly enantioselective rhodium-catalysed arylations with arylboronic acids in the presence of a dibenzylamide-containing chiral diene ligand. One example of the asymmetric arylation of an alkenyl-p-cyano-m-( trifluoromethyl)benzene is also reported. The scope of this process is broad with variation in the β-position of the alkene, additional substituents on the electrondeficient arene, and sterically and electronically unique arylboronic acids all tolerated. The synthetic utility of the developed methodology is demonstrated by smoothly converting one arylated product into its corresponding indole via the Bartoli reaction. II. Enantioselective Copper-Catalysed Reductive Coupling of Alkenylazaarenes with Ketones Catalytic enantioselective methods for the preparation of chiral azarene-containing compounds are of high value. By combining the utility of copper hydride catalysis with the ability of C=N-containing azaarenes to activate adjacent alkenes toward nucleophilic additions, the enantioselective reductive coupling of alkenylazaarenes with ketones has been developed. The process is tolerant of a wide variety of azaarenes and ketones, and provides aromatic heterocycles bearing tertiary-alcoholcontaining sidechains with high levels of diastereo- and enantioselection.
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Hari, Taylor P. A. "Efforts Toward an Oxa-conjugate Addition Based Approach to (+)-Neopeltolide Synthesis." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23125.
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(+)-Neopeltolide is a highly potent marine polyketide natural product with activity against multiple cancer cell lines in vitro. The nanomolar range of antifungal and anticancer cytotoxicity in this tetrahydropyran (THP)-containing polyketide, combined with its limited natural supply, has led to several syntheses. In this study, the feasibility of an oxa-Michael conjugate addition route to cis-2,6-THP rings is examined through the efforts toward a total synthesis of the macrocyclic core of (+)-neopeltolide using a highly convergent route. This study is based on the successful preliminary results with a simple 14-member ring model system and the synthesis of the key aldehyde intermediate shown below. The highlighted transformation of this synthesis will be a transannular oxa-conjugate addition to generate the cis-2,6-tetrahydropyran ring system. This route also highlights a highly convergent Wittig coupling to generate the full carbon framework of (+)-neopeltolide. One of the key goals of this project is to compare this synthesis with a chemo-enzymatic total synthesis that relies on chemistry catalyzed by polyketide synthase enzymes in the late stage of the synthesis.
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Bennett, Malcolm William. "Design of new asymmetric copper(I)-catalysts for conjugate addition chemistry." Thesis, University of Hull, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310254.
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Welker, Matthias J. H. "Development and synthetic applications of asymmetric copper-catalysed conjugate addition reactions." Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537676.
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Svedendahl, Maria. "Exploring Conjugate Addition Activity in Pseudozyma antarctica Lipase B." Licentiate thesis, KTH, Skolan för bioteknologi (BIO), 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-11598.
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Multifunctional enzymes have alternative functions or activities, known as “moonlighting” or “promiscuous”, which are often hidden behind a native enzyme activity and therefore only visible under special environmental conditions. In this thesis, the active-site of Pseudozyma (formerly Candida) antarctica lipase B was explored for a promiscuous conjugate addition activity. Pseudozyma antarctica lipase B is a lipase industrially used for hydrolysis or transacylation reactions. This enzyme contains a catalytic triad, Ser105-His224-Asp187, where a nucleophilic attack from Ser105 on carboxylic acid/ester substrates cause the formation of an acyl enzyme. For conjugate addition activity in Pseudozyma antarctica lipase B, replacement of Ser105 was assumed necessary to prevent competing hemiacetal formation. However, experiments revealed conjugate addition activity in both wild-type enzyme and the Ser105Ala variant. Enzyme-catalyzed conjugate additions were performed by adding sec-amine, thiols or 1,3-dicarbonyl compounds to various α,β-unsaturated carbonyl compounds in both water or organic solvent. The reactions followed Michaelis-Menten kinetics and the native ping pong bi bi reaction mechanism of Pseudozyma antarctica lipase B for hydrolysis/transacylation was rerouted to a novel ordered bi uni reaction mechanism for conjugate addition (Paper I, II, III). The lipase hydrolysis activity was suppressed more than 1000 times by the replacement of the nucleophilic Ser105 to Ala (Paper III).
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Reed, Darrell. "Conjugate addition of lithium reagents to #gamma#-oxygenated #alpha#,#beta#-unsaturated ketoesters." Thesis, University of Salford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261925.
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Ball, Anthony. "Inter and intramolecular N-conjugate addition reactions using cinchona derived primary amines." Thesis, University of Nottingham, 2015. http://eprints.nottingham.ac.uk/30507/.
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This thesis describes the conjugate addition of nitrogen nucelophiles to alpha,beta-unsaturated enones using cinchona derived amines. Two separate projects are outlined within, intermolecular and intramolecular N-conjugate addition reactions. The first project involves the investigation of a range of nitrogen nucleophiles in their intermolecular additions to alpha,beta-unsaturated ketones. The reactions were performed using either 9-deoxy-9-epi-aminoquinine or 9-deoxy-9-epi-aminoquinidine as the catalyst with phenylacetic acid as a co-catalyst. These catalysts were found to promote conjugate addition of a range of nitrogen heterocycles to acyclic alpha,beta-unsaturated ketones. In particular, the addition of pyrazoles was found to proceed in high yield and enantioselectivity. In contrast, addition of these nucleophiles to cyclic ketones gave low enantioselectivity. The second project involves the investigation of intramolecular N-conjugate addition processes. In this case, the reactions were performed using 9-deoxy-9-epi-aminoquinine and trifluoroacetic acid as the catalyst system. Several different groups on nitrogen were investigated and the reaction conditions optimised for each group. The ring size and substitution around the ring system formed were also investigated with high yields and enantioselectivites obtained.
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Capps, Steven G. "A Radical Conjugate Addition Approach to the Total Synthesis of Celogentin C." BYU ScholarsArchive, 2008. https://scholarsarchive.byu.edu/etd/1831.
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The synthesis of five chiral DBFOX (dibenzofuran-oxazoline) ligands with either aryl or benzyl substituents will be presented. The requisite amino alcohols were obtained with high enantioselectivity either commercially (DBFOX/Bn), via Sharpless asymmetric aminohydroxylation (DBFOX/Nap, DBFOX/t-BuPh, DBFOX/Pip), or via phase-transfer catalyzed asymmetric alkylation (DBFOX/MeNap). These ligands, complexed with Mg(NTf2)2, were used as Lewis acid promoters of enantioselective radical conjugate additions to α/β-unsaturated nitro-amides/esters. A summary of these results is presented and discussed. These findings led us to believe that our initial binding model between metal, ligand, and substrate was flawed. Thus, we figured that if we started with a functionality known to bind to both nitro groups and carbonyls, and then introduced a chiral element for control, we may be able to improve the beta-carbon enantioselectivity. We have tried to accomplish this via hydrogen-bonding ligands (ureas and thioureas). Initial studies on achiral versions of this concept are discussed.
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Roth, Philippe. "Phosphoramidite ligand design for the enantioselective conjugate addition of alkylzirconium reagents to enones." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:763eb634-4af8-4f9e-b186-88bdcf56ad8d.
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The development of new methods to make carbon-carbon bonds asymmetrically remains a challenge in organic chemistry. Indeed, the development of highly selective methods often proceeds on a trial and error basis. The way chiral information is transferred to the substrate is unclear in many reactions, limiting further development. We focus here on developing an asymmetric conjugate addition of alkylzirconium nucleophiles to Michael acceptors. The development of new phosphoramidite ligands, supported by a computer based model, allowed further development of the reaction. First, existing methods to introduce enantioselectively chirality are described. Then we discuss ligands, and modern ways to parameterise experimental data using computational methods. In chapter two, after discussing the use of alkenes as reagents, especially processes initiated by hydrometallation, we describe a new conjugate addition reaction using cyclic enones that achieves both high yields and levels of enantioselectivity. In chapter three, various applications of phosphoramidite ligands are discussed and we describe the synthesis of a variety of different phosphoramidites and identification of important structural features of these ligands. New, efficient ligands are obtained and a computer model is developed to account for the selectivity of the reaction discussed in chapter two. Chapter four describes the development of an enantioselective synthesis of quaternary centres with novel ligands used to optimise the new system. Lastly, chapter five describes the extension of the method to some linear enones, using different ligands. Overall, we have developed a variety of ligands which were used to expand the enone scope of a conjugate addition and an understanding of what factors make these ligands effective.
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Grant, Kevan Michael. "Synthesis Of 2-substituted N-heterocycles via asymmetric organocatalysed intramolecular N-conjugate addition." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/41244/.
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This thesis describes the use of cinchona derived squaramide catalyst 27 in the asymmetric intramolecular N-conjugate addition of nitrogen nucleophiles with a,B-unsaturated carbonyls. The first chapter describes investigation of intramolecular N-conjugate addition reactions of sulfonamides with aromatic ketones, esters, thioesters and amides generating chiral 2-substituted piperidines, morpholines and oxazinanes. The squaramide catalyst 27 was found to efficiently catalyse the reaction, good yields of cyclic products were obtained with excellent enantioselectivities. Further modification of these products towards natural and drug targets is outlined. A possible mechanism based on observed stereochemistry and in silico modelling of transition states is proposed. The second chapter describes investigation of altered substrates formed by varying functionality linking the a,B-unsaturated carbonyl to the nitrogen nucleophile. For example, 4-Substitued 3,4-dihydro-2H-benzo[e][1,3]oxazin-2-ones and cyclic sulfamates were synthesised this way, but unfortunately enantioselectivity was poor in this case. Finally the influence of chiral substrates on asymmetric cyclisation was investigated during the synthesis of 2,4-disubstituted pyrrolidines. It was found that the intrinsic diastereoselectivity of the cyclisation is difficult to overcome using asymmetric organocatalysis.
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Schilli, Christine Maria. "Novel precursors for polymer protein conjugate synthesis via reversible addition fragmentation chain transfer polymerization." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968492118.
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Flores, Ferrándiz Jesús. "Chiral Aminocarbamates Derived from trans-Cyclohexane-1,2-Diamines as Organocatalysts in Conjugate Addition Reactions." Doctoral thesis, Universidad de Alicante, 2017. http://hdl.handle.net/10045/73589.
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The thesis has been divided in two chapters: Chapter I describes the preparation of primary-amine monocarbamates from enantiopure trans-cyclohexane-1,2-diamines and their use as chiral organocatalysts in the enantioselective Michael addition reaction of aldehydes and ketones to maleimides, to synthesize enantiomerically enriched substituted succinimides. In the conjugate addition reaction of aldehydes to maleimides in conventional volatile organic solvents, it has been found that these organocatalysts are able to generate both enantiomers of the corresponding succinimide using only one enantiomeric form of the catalyst, just by changing the polarity of the solvent. Theoretical calculations justify the mechanism through which this inversion of enantioinduction occurred. In addition, these organocatalysts were used in the enantioselective Michael addition reaction of aldehydes to maleimides, using Deep Eutectic Solvents (DES) as recyclable and environmentally sustainable reaction medium, yielding the corresponding succinimides with excellent yields and high enantioselectivities (up to 94%). The succinimides can be extracted from the DES, which retains the chiral organocatalyst, allowing to reuse both solvent and catalyst. Moreover, the conjugate addition of ketones to maleimides using conventional solvents, allows obtaining the corresponding succinimides with excellent yields but with moderate enantioselectivities (up to 66%). Chapter II shows the results obtained in the enantioselective Michael addition reaction of aldehydes and ketones to nitroalkenes, using the former trans-cyclohexane-1,2-diamine-derived aminocarbamates as chiral organocatalysts, obtaining enantioenriched γ-nitrocarbonyl compounds. In the conjugate addition of isobutyraldehyde to nitroalkenes, the corresponding γ-nitroaldehydes were obtained with enantioselectivities up to 84%. In addition, the enantioselective conjugate addition reaction of ketones to nitroalkenes allowed to obtain interesting γ-nitroketones with high enantioselectivities (up to 96%). Theoretical calculations justify the mechanism involved during this enantioselective process.
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Maruyama, Hiroki. "Development of Catalyst-Controlled Regio- and Stereoselective Conjugate Additions of Aldehydes to Electron-Deficient Olefins." Kyoto University, 2018. http://hdl.handle.net/2433/232282.
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Zhou, Yuebiao. "New Strategies for the Development of Catalytic Regio- and Enantioselective Allylic Substitution and Conjugate Addition Reactions:." Thesis, Boston College, 2020. http://hdl.handle.net/2345/bc-ir:108959.
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Thesis advisor: Amir H. HoveydaChapter 1. Catalytic SN2”-Selective and Enantioselective Substitution Reactions. The first broadly applicable strategy for SN2”-selective and enantioselective catalytic allylic substitution will be presented. It will be shown that transformations can be promoted by 5.0 mol% of a sulfonate-containing NHC–Cu complex (NHC = N-heterocyclic carbene), and may be carried out by the use of a commercially available allenyl–B(pin) (pin = pinacolato) or a readily accessible silyl protected propargyl–B(pin). Products bearing a 1,3 diene, a silyl allenyl or a propargyl moiety were obtained in high efficiency and selectivities. Also provided is insight regarding several of the unique mechanistic attributes of the catalytic process, obtained on the basis of kinetic isotope effect measurements and DFT studies. These investigations indicated that cationic π-allyl–Cu complexes are the likely intermediates, clarifying the role of the s-cis and s-trans conformers of the intermediate organocopper species and their impact on E:Z selectivity and enantioselectivity. It will also be shown we were able to highlight the utility of the approach by chemoselective functionalization of various product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products can be converted catalytically and chemoselectively to several synthetically useful derivatives. Chapter 2. NHC–Copper–Hydride-Catalyzed Enantioselective Processes with Allenyl Boronates and its Application in Natural Product Synthesis. Here, the development of a catalytic process that delivers otherwise difficult-to-access organoboron compound will be detailed. These processes involve the combination of a hydride, an allenyl–B(pin) and an allylic phosphate. As will be discussed, two unique selectivity problems were solved: avoiding rapid Cu–H reduction of an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly observed Cu–B exchange. We were able to underscore the considerable utility of the approach by applications to preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and the first enantioselective synthesis of netamine C (anti-tumor), which also served to confirm its stereochemical identity. Chapter 3. Catalytic Enantioselective Prenyl Conjugate Addition Reactions. In this final section, studies leading to the development of the first class of catalytic enantioselective strategies for prenyl conjugate additions will be detailed. At the core of these investigations was finding ways to overcome two problems. One challenge originated from the fact that highly activated allylmetal species often deliver product with low enantioselectivity. The other was that regioselectivity was difficult to control owing to a strong preference for γ-selective additions. As will be described, we were able to address these difficulties by the use of a hydroxy NHC-copper complex and 3,3-dimethyl allyl–B(pin) as a reagent. In the end, we were able to use acyclic as well as cyclic enoates as substrates. The results of DFT studies that provide insight regarding varying selectivity profiles with different chiral ligands will be discussed as well
Thesis (PhD) — Boston College, 2020
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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Lee, Kang-sang. "New Concepts and Catalysts for Enantioselective Synthesis of C-C, C-Si, and C-B Bonds." Thesis, Boston College, 2010. http://hdl.handle.net/2345/1739.
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Thesis advisor: Amir H. HoveydaChapter 1. The development of chiral monodentate N-heterocyclic carbenes (NHCs) is presented. Structurally varied twenty-eight new chiral imidazolinim salts, NHC precursors, were synthesized and characterized. Chapter 2. The first example of Cu-catalyzed enantioselective conjugate additions of alkyl- and arylzinc reagents to unactivated cyclic enones is presented. Transformations are promoted in the presence of 2.5-15 mol % of a readily available chiral NHC-based Cu complex, affording the desired products bearing all-carbon quaternary stereogenic centers in 67-98% yield and in up to 97% ee. Catalytic enantioselective reactions can be carried out on a benchtop, with undistilled solvent and commercially available (not further purified) Cu salts. Chapter 3. A new class of enantioselective conjugate addition (ECA) reactions that involve aryl- or alkenylsilylfluoride reagents and are catalyzed by chiral non-C2-symmetric Cu-based NHC complexes are presented. Transformations have been designed based on the principle that a catalytically active chiral NHC-Cu-aryl or NHC-Cu-alkenyl complex can be accessed from reaction of a Cu-halide precursor with in situ-generated aryl- or alkenyl-tetrafluorosilicate. Reactions proceed in the presence of 1.5 equivalents of the aryl- or alkenylsilane reagents and 1.5 equivalents of tris(dimethylamino)sulfonium difluorotrimethylsilicate. Desired products are isolated in 63-97% yield and 73.5:26.5-98.5:1.5 enantiomeric ratio (47%-97% ee). Chapter 4. An efficient Cu-catalyzed protocol for enantioselective addition of a dimethylphenylsilanyl group to a wide range of cyclic and acyclic unsaturated ketones, esters, acrylonitriles and dienones is presented. Reactions are performed in the presence of 1-5 mol % of commercially available and inexpensive CuCl, a readily accessible monodentate imidazolinium salt as well as commercially available (dimethylphenylsilyl)pinacolatoboron. Cu-catalyzed 1,4- and 1,6-conjugate additions afford the enantiomerically enriched silanes in 72%-98% yield and 90:10->99:1 enantiomeric ratio (er) with up to >25:1 of Z:E selectivity. Chapter 5. A Cu-catalyzed method for enantioselective boronate conjugate additions to trisubstituted alkenes of acyclic a,b-unsaturated carboxylic esters, ketones, and thioesters is presented. All transformations are promoted by 5 mol % of a chiral monodentate NHC-Cu complex, derived from a readily available C1-symmetric imidazolinium salt, and in the presence of commercially available bis(pinacolato)diboron. Reactions are efficient (typically, 60% to >98% yield after purification) and deliver the desired boryl carbonyls in up to >98:2 enantiomer ratio (er). In addition, metal-free, nucleophilic activation of a B-B bond has been exploited in the development of a highly efficient method for conjugate additions of commercially available bis(pinacolato)diboron to cyclic or acyclic a,b-unsaturated carbonyls. Reactions are readily catalyzed by 2.5-10 mol % of a simple NHC. A variety of cyclic and acyclic unsaturated ketones and esters can serve as substrates. Transformations deliver boryl carbonyls bearing tertiary as well as quaternary B-substituted carbons in up to >98% yield
Thesis (PhD) — Boston College, 2010
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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Nelson, Amanda Kay. "Metal-Catalyzed Formation and Transformations of Carbon-Boron Bonds." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/83400.
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Our research seeks new methods for functionalizing organic small molecules using organoboronic derivatives as a versatile handle for late-stage manipulations. Metal-catalyzed formation of new carbon-boron bonds and their subsequent transformations are highlighted.
Among the myriad of unsaturated substrates for conducting borylation reactions, allenes have received minimal attention. These substrates are uniquely advantageous given that diboration results in the formation of both allylic and vinylic boronates. Orthogonal reactivity of the sp2 and the sp3 C-B bonds can allow for chemoselective transformations. However, oxidation of the carbon-boron bond is one example in which the conditions are unselective. To address this shortcoming, a platinum catalyst was developed for the diboration of 1,1-diaryl allenes with a differentially protected diboron reagent, pinB-Bdan. The reaction proceeds regioselectively in high yields to furnish olefins bearing a vinylic Bpin and an allylic Bdan moiety. The subsequent chemoselective transformation of each boron center was demonstrated.
Methods for preparing 1,8-diaminonaphthalene protected vinylboronates conjugated to carbonyl groups are severely limited. A simple and efficient protocol was developed for carrying out an environmentally friendly copper(II)-catalyzed beta-borylation of alkynoates and alkynamides in water and open-to-air. Following the discriminative activation of the more Lewis acidic pinacol protected boron center in pinB-Bdan, a regio-, stereo- and chemoselective beta-borylation of acetylenic substrates delivers (Z)-beta-boryl enoates and primary, secondary, and tertiary enamides under very mild conditions.
As an inexpensive and earth abundant metal, catalysts based on copper are highly desirable. An international collaborative project to develop a copper-catalyzed cross-coupling reaction of beta-boryl carbonyl compounds was explored. Preliminary results found these substrates to be either unstable towards or unreactive under the reactions conditions screened.Ph. D.
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Guo, Xi. "The development and applications of unsymmetrical diboron compounds." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/71393.
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Organoboron compounds have shown a wide variety of applications in both organic synthesis and the pharmaceutical field in the past decades. Transition metal-catalyzed boration of unsaturated compounds has been studied extensively as an efficient method to install C-B bonds. Most of the previous examples employed symmetrical diboron reagents such as B₂(pin)₂ (pin = pinacolate) and B₂(cat)₂ (cat = catecholate). There are, however, limited examples of boration using unsymmetrical diboron reagents. This dissertation discloses two transition metal-catalyzed borations of unsaturated compounds with unsymmetrical diboron compounds.
A Cu-catalyzed β-boration of electrophilic allenoates with a novel sp²-sp³ hybridized diboron reagent (PDIPA) is described. This unsymmetrical diboron reagent is preactivated and allows the boration to go smoothly under mild reaction conditions. The reaction provides β-borylated β,γ- unsaturated esters with exclusive (Z)-double bond geometry. These borylated products are useful intermediates for subsequent Suzuki-Miyaura cross-coupling reaction.
In order to install two C-B bonds in one reaction, a Pt-catalyzed diboration of allenes with a differentially protected diboron reagent (PDAN) is presented. This unsymmetrical diboron reagent is prepared from the sp²-sp³ hybridized diboron compound, and it reacts with a series of 1,1- disubstituted allenes chemo- and regioselectively. Steric control ensures that both boryl moieties add to the terminal double bond, and the pinacol boronate preferentially attaches to the sp-hybridized carbon. The bis-boronyl products can be further converted to other functional groups as well as cross-coupling reactions.
A collaborative project with Department of Physics and Department of Chemical Engineering is also discussed. In this project, a series of 𝑜-nitrobenzyl ligands containing a disulfide group as the anchor to gold surfaces are synthesized. The 𝑜-nitrobenzyl group uncages an amine upon photoexcitation. Attempts to make a water soluble analog failed, however, the mixture of methanol and water as the solvent was sufficient to attach them on gold surfaces.Ph. D.
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McGrath, Kevin Patrick. "Enantioselective Methods for Allylic Substitution and Conjugate Addition Reactions Catalyzed by N-Heterocyclic Carbene-Copper Complexes." Thesis, Boston College, 2016. http://hdl.handle.net/2345/bc-ir:106792.
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Thesis advisor: Amir H. HoveydaChapter 1 Catalytic Enantioselective Addition of Organoaluminum Reagents Catalytic methods involving the enantioselective addition of both commercially available as well as in situ generated organoaluminum reagents are reviewed. An overview of additions to aldehydes, ketones, and imines is provided as well as the difficulties and limitations of such transformations. Furthermore, additions to unsaturation adjacent to a leaving group to form a new stereogenic center are examined. Finally, conjugate addition reactions wherein an organoaluminum reagent is added to an olefin adjacent to a carbonyl or nitro group are discussed. Chapter 2 Synthesis of Quaternary Carbon Stereogenic Centers through Enantioselective Cu-Catalyzed Allylic Substitution with Alkenylaluminum Reagents A method for the formation of 1,4-diene containing quaternary stereogenic centers through catalytic enantioselective allylic substitution is disclosed. The addition of alkyl- and aryl-substituted alkenylaluminum reagents to trisubstituted allylic phosphates is promoted by 0.5–2.5 mol % of a sulfonate-containing bidentate N-heterocyclic carbene–copper complex. Products containing a quaternary stereogenic center as well as a newly formed terminal olefin are obtained in up to 97% yield and 99:1 er with high site selectivity (>98:2 SN2’:SN2). The requisite nucleophiles are generated in situ through hydroalumination of terminal alkynes. The utility of the method is demonstrated through a concise synthesis of natural product bakuchiol. Chapter 3 A Multicomponent Ni-, Zr-, Cu-Catalyzed Strategy for Enantioselective Synthesis of Alkenyl-Substituted Quaternary Carbons Despite the widespread use of conjugate addition in organic synthesis, few reports pertain to the addition of nucleophiles to acyclic systems and none in which the nucleophile is an alkene. Herein, we report the first examples of enantioselective conjugate addition of alkenylmetal reagents to trisubstituted enones to form all-carbon quaternary stereogenic centers. Alkenylaluminum nucleophiles are prepared through a site-selective Ni-catalyzed hydroalumination of terminal alkynes and the requisite E-trisubsituted enones are the products of a regioselective Zr-catalyzed carboalumination/acylation of a terminal alkyne. Products are obtained in up to 97% yield and 99:1 er. A model for enantioselectivity, supported by DFT calculations, is proposed. Chapter 4 Formation of Tertiary Centers through Catalytic Enantioselective Conjugate Addition of Alkenylaluminum Reagents to Acyclic Enones We have developed an enantioselective NHC–Cu catalyzed synthesis of tertiary centers in acyclic systems using in situ generated alkenylaluminum reagents, as current methods typically rely on Rh-catalysis at high temperatures with alkenyl boronic acids in protic solvents. Moreover, most examples include chalcone-derived substrates, which, while more reactive, often preclude further functionalization. With the current method, we are able to couple a variety of alkenyl nucleophiles with α,β-unsaturated ketones. E- or Z-silylalkenylaluminum reagents, derived from hydroalumination of silyl-protected alkynes, lead to products in good yields and high enantioselectivities. Additionally, both the α- and β-alkenylaluminum reagents participate in the reaction. Chapter 5 Development of N-Heterocyclic Carbene–Cu Catalyzed Allylic Substitution of Diboryl Methane to Morita-Baylis-Hillman Derived Allylic Phosphates We have developed a method for the coupling of a geminyl diboron reagent with Morita-Baylis-Hillman derived trisubstituted ester-containing allylic phosphates. With 10 mol % of an in situ generated NHC–Cu complex and 1.5 equivalents of the boron reagent, we are able to form the desired product in high regio- and enantioselectivity with a 2,5-ditert-butyl containing carbene. Simple aryl substituents as well as those containing a halogen or an electron-withdrawing group furnish the desired products in up to 85% yield and 98:2 er. Alkyl-containing substrates are also competent reaction partners, although longer chain aliphatics results in slightly diminished enantioselectivity. We are pursuing the application of this method to the synthesis of α-methylene lactones which can be further functionalized to natural products like tubulin polymerization inhibitor (–)-steganone and glaucoma medication (+)-pilocarpine
Thesis (PhD) — Boston College, 2016
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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O'Brien, Jeannette M. "New Catalysts and Catalytic Methods for Cycloadditions and Conjugate Additions to Alpha, Beta-Unsaturated Carbonyls." Thesis, Boston College, 2012. http://hdl.handle.net/2345/bc-ir:103617.
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Thesis advisor: Marc L. SnapperChapter 1. A Practical Synthesis of 3-Acyl Cyclobutanones by [2 + 2] Annulation. Mechanism and Utility of the Zn(II)-Catalyzed Condensation of alpha-Chloroenamines with Electron-Deficient Alkenes. We have developed a catalytic method for the synthesis of highly functionalized 3-acyl cyclobutanones which are useful building blocks for a variety of natural products. Methods for cyclobutanone synthesis have traditionally been limited to Lewis-acid promoted rearrangement of oxaspiropentanes or cyclizations of ketene and syntheses involving keteneiminium salts have required stoichiometric quantities of a Lewis acid. Furthermore, the mechanism for these types of cyclizations remains unknown. This portion of my research focused on an efficient, catalytic method for the synthesis of 3- acyl cyclobutanones and providing insight into the mechanism for cycloaddition. Chapter 2. Enantioselective Synthesis of Boron-Substituted Quaternary Carbons by NHC-Cu-Catalyzed Boronate Conjugate Additions to Unsaturated Carboxylic Esters, Ketones, or Thioesters. We have developed an enantioselective NHC-Cu-catalyzed conjugate addition of boronate esters to acyclic, trisubstituted alpha, beta-unsaturated carbonyl compounds. Enantioselective conjugate addition of a boronic acid pinacol ester through the use of bis(pinacolato)diboron [B2(pin)2,] to alpha, beta-unsaturated aliphatic and aryl esters promoted by 5 mol % of an NHC-Cu catalyst afforded tertiary beta-boryl carbonyls in high efficiency and enantioselectivity. Trisubstituted alpha, beta-unsaturated esters and thioesters were found to be reactive substrates in the presence of a stoichiometric quantity of methanol. Chapter 3. Metal-Free Catalytic C-Si Bond Formation in an Aqueous Medium and C-B Bond Formation in a Protic Medium. Enantioselective NHC-Catalyzed Silyl and Boryl Conjugate Additions to Cyclic and Acyclic alpha, beta-Unsaturated carbonyls. We have developed a method for enantioselective metal-free silyl conjugate additions through the use of dimethylphenylsilyl) boronic acid pinacol ester [PhMe2SiB(pin)] catalyzed by chiral N-heterocyclic carbenes (NHCs) in basic aqueous thf. Optimization of metal-free conditions demonstrated that the presence of water was required for high efficiency. alpha, beta-Unsaturated cyclic ketones and lactones were examined as substrates, and acyclic ketones, esters and aldehydes were also competent substrates for silyl conjugate addition. beta-Silyl carbonyls were isolated in up to >98% yield and >98:2 er. Chapter 4. Elucidation of Mechanism for Enantioselective NHC-Catalyzed Silyl Conjugate Addition. We propose a catalytic cycle for NHC-catalyzed enantioselective silyl conjugate addition. Mechanistic studies of NHC-catalyzed enantioselective silyl conjugate additions are presented. Optimization of conditions for an inefficient alpha, beta-unsaturated electron-deficient ketone provided insight into the roles for dbu and water. Kinetic data indicate that conjugate addition is first order in PhMe2SiB(pin) and carbene, and DFT calculations support the formation of an NHC-silyl anion as a reactive intermediate in the catalytic cycle
Thesis (PhD) — Boston College, 2012
Discipline: Chemistry
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Shen, Lixin. "Design and synthesis of 3,3'-disubstituted-binaphthyl alkynyl boron reagents for asymmetric conjugate addition of alkynyl groups to enones and 1,2-addition to aldehydes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0006/NQ44782.pdf.
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Buttard, Floris. "3-Vinyl-1,2,4-triazines comme plateformes bifonctionnelles pour la synthèse de nouvelles structures tétrahydro-[1,6]-naphthyridines." Thesis, Orléans, 2018. http://www.theses.fr/2018ORLE2032.
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Le développement de nouvelles méthodes de synthèse de molécules hétérocycliques originales représente un enjeu actuel majeur en chimie organique. L’objectif est de fournir de nouveaux outils chimiques pour le développement de molécules actives en chimie médicinale et/ou pour l’étude de la biologie chimique, tout en contribuant à l’exploration de l’espace chimique.Dans ce contexte, le travail effectué au cours de cette thèse de doctorat a visé à élaborer de nouvelles voies de synthèse de motifs tétrahydro-[1,6]-naphtyridines. La pierre angulaire des méthodologies développées réside dans l’utilisation des 3-vinyl-1,2,4-triazines comme des plateformes synthétiques bifonctionnelles. Ces composés ont été développés pour réagir à la fois comme accepteurs de Michael et comme aza-diènes dansdes cycloadditions de Diels-Alder à demande électronique inverse. Un intérêt tout particulier a été porté à lamise au point de stratégies synthétiques innovantes, par des réactions en cascade permettant une synthèse rapide et efficace des molécules cibles, et des approches de catalyse organique visant des transformations énantiosélectives.La synthèse de nouvelles 3-vinyl-1,2,4-triazines et le développement de stratégies de réactions d’addition conjuguée/cycloadditions en cascade et de synthèses monotopes organocatalysées ont fournis l’accès à une vaste gamme de nouvelles tétrahydro-[1,6]-naphthyridines diversement substituéesThe development of new methods for the synthesis of original heterocyclic molecules represents a current concern in organic chemistry, aiming to furnish medicinal chemistry and chemical biology with new chemical tools and contribute to the exploration of chemical space.In this context, the work which was carried out during this PhD thesis focused on the elaboration of new approaches for the synthesis of tetrahydro-[1,6]-naphthyridine scaffolds. The original use of 3-vinyl-1,2,4-triazines as bifunctional synthetic platforms, able to react both as Michael acceptor and as aza-diene in inverse-electron-demand Diels-Alder cycloadditions, is the keystone our methodology is based upon. The development of domino reactions – allowing quick and efficient synthesis of targeted compounds – remaineda perpetual concern evolving along side our preoccupation to access enantioselective transformations relying on organocatalysis.The synthesis of new 3-vinyl-1,2,4-triazines platforms and the elaboration of domino conjugate addition/cycloadditions and orgonocatalyzed one-pot synthesis strategies enabled to synthetize a wide panelof new diversly substituted tetrahydro-[1,6]-naphthyridines compounds
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Selim, Khalid Bashir Shaaban. "Development of chiral ligand-copper(1)-catalyzed asymmetric conjugate addition and allylic substitution with organometallic reagents." 京都大学 (Kyoto University), 2009. http://hdl.handle.net/2433/126604.
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Christou, Stephania. "Application of transition metal-mediated conjugate addition reactions to the synthesis of novel anti-tumour agents." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/application-of-transition-metalmediated-conjugate-addition-reactions-to-the-synthesis-of-novel-antitumour-agents(43488de6-e8f9-4d3a-8d66-5ccb17350e90).html.
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The Streptomyces metabolite 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC), the antheminones and the carvotacetone derivatives are all bioactive natural products, whose structure is based on the α oxymethyl-a,β-cyclohexenone moiety. Both COTC and antheminone A have been shown to exhibit cytotoxic and cancerostatic activity with low toxicity. The potent biological activity of these natural products has instigated numerous investigations into the synthesis of novel analogues in an attempt to determine the key structural features necessary for optimum bioactivity. The synthesis of a small library of novel anti-tumour agents which are structurally related to the natural products COTC and antheminone A is described, using the chiral pool material (-)-quinic acid as a starting material. At the outset, the aim of this project was to develop and optimise copper-mediated conjugate addition reactions and rhodium catalysed conjugate addition reactions of organoboron reagents to functionalised cyclic enones and subsequently, to apply the methodologies to the synthesis of the novel analogues. A range of novel mono-hydroxylated analogues bearing aryl side chains were prepared and their antiproliferative activity was assessed towards the A549 non-small cell cancer cell line. The biological assays revealed important structure-activity relationships and the most bioactive compound of this series had an IC50 value of 1.2 µM. In addition, the design and synthesis of a new class of GSH-activated prodrugs is described. These novel compounds are activated by GSH leading to intracellular release of an NQO1 inhibitor. The most potent compound of this new class of compounds had an IC50 value of 710 nm.
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Fujioka, Shingo. "Development of phase-transfer-catalyzed asymmetric conjugate addition of nitroalkanes to α,β-unsaturated carbonyl compounds." 京都大学 (Kyoto University), 2006. http://hdl.handle.net/2433/144218.
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Sugimoto, Hisashi. "Studies on Control of Stereo- and Regioselectivity in Conjugate Additions of Aldehydes Catalyzed by Axially Chiral Biaryl-Based Amines." 京都大学 (Kyoto University), 2015. http://hdl.handle.net/2433/199123.
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Thorpe, Steven Brandon. "Activation of diboron reagents: The development of mild conditions for the synthesis of unique organoboron compounds." Diss., Virginia Tech, 2012. http://hdl.handle.net/10919/26669.
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The first successful synthesis and isolation of a boronic acid was reported in 1860 by Frankland in the pursuit of novel organometallic compounds. For more than a century, further studies of boronic acids were sparsely published. Suzuki and Miyaura jumpstarted the field in 1979 with an innovative carbon-carbon bond forming reaction employing an organoboronic acid and a carbon halide under palladium catalysis. Indeed, the Nobel Prize in Chemistry was awarded to Professor Akira Suzuki, along with Professors Richard Heck and Ei-ichi Negishi, in 2010 for their important contributions in palladium-catalyzed cross-coupling chemistry. Over the last 30 years, reports on organoboron compounds have increased exponentially. This dissertation describes the authorâ s contributions to the development of preparative methods for organoboronic acid derivatives using transition metal-catalyzed reactions of diboron reagents.
A unique â mixedâ diboron reagent was developed (PDIPA diboron) that contains sp2- and sp3-hybridized boron atoms, unambiguously confirmed by X-ray crystallography. PDIPA diboron is sufficiently activated internally through a dative-bonding amine to selectively transfer the sp2-hybridized boron regioselectively, in the presence of copper, to electron deficient alkenes including α,β-unsaturated ketones, esters, amides, aldehydes, and nitriles to provide the corresponding boratohomoenolates. A unique β,β-diboration of an α,β-acetylenic ketone was also discovered.
The scope of PDIPA diboron reactions was then expanded to a set of substrates with a more complex structural backbone. Allenoates are α,β,γ-unsaturated esters with orthogonal pi systems, which pose several possible difficulties with the regioselectivity of addition, not to mention known isomerizations catalyzed by copper. However, we successfully installed the boron moiety regioselectively on the β-carbon of a variety of allenoates, providing a vinyl boronic ester, and also observed exclusive formation of the (Z)-isomer from racemic starting materials. The resulting vinyl boronic ester was then shown to be an excellent Suzuki-Miyaura cross-coupling partner, affording a diastereopure, trisubstituted alkene in quantitative yield.
Commercially available bis(pinacolato)diboron has shown remarkable stability towards hydrolysis and autoxidation. Using this reagent, we developed a copper- and amine-catalyzed boration protocol performed entirely in water and open to air. Using only 1 mol% copper, extraordinary activity was observed. UV-Vis, 11B NMR, and solvent kinetic isotope experiments were employed to gain insight into the mechanism, which showed the possibility of autocatalysis. Attempts to control stereoselectivity were not successful, although these results were rationalized by a dynamic catalyst structure.Ph. D.
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Peck, Cheryl Lynne. "Development of Transition Metal-Catalyzed Borylation Protocols using Symmetrical and Unsymmetrical Diboron Reagents." Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/80343.
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The versatility of organoboron compounds has been demonstrated by their use as synthetic intermediates and more recently in therapeutic applications since the FDA approval of Velcade©. As a result, transition metal-catalyzed protocols to incorporate boron reagents into unsaturated compounds have been extensively researched. While an abundance of literature protocols have been reported, the majority utilize harsh reaction conditions in combination with expensive reagents. This dissertation discloses the author’s contributions to the development of efficient, cost-effective, and operationally simple transition metal-catalyzed borylation protocols with alkynes and diboron reagents.
An open-to-air copper(II)-catalyzed aqueous borylation protocol of alkynoates and a symmetrical diboron reagent is reported. Conjugate addition of the boryl-copper species to the electrophilic β-carbon provided β-boryl-α,β-unsaturated esters in moderate to excellent yields. Exclusive (Z)-stereochemistry was confirmed by nOe experiments. The resulting vinyl boronate esters are useful cross-coupling partners.
The scope of the aqueous β-borylation protocol was extended to the unsymmetrical diboron reagent, pinB-Bdan. This alternative protecting group has emerged as an orthogonal protecting group and alters the reactivity of the boron moiety. Activation of the pinacol moiety to form the Lewis acid-base adduct allowed for the chemoselective transfer of the 1,8- diaminonapthalene moiety to the β-carbon.
An alternative novel synthesis of vinyl, allyl diboronate esters from propargylic alcohols has also been described. Formation of a leaving group in-situ with a palladium- and coppercatalyzed protocol can lead to several competing reaction pathways and the formation of multiple products. Fortunately, the resulting vinyl, allyl diboronate esters were stereoselectively synthesized in moderate GC yields despite significate decomposition during purification, as confirmed by stability studies. The terminal diboration of allenes was previously the only reported method for the synthesis of vinyl, allyl diboronate esters.Ph. D.
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Young, Douglas M. "Explorations of Cascading Michael Additions." Thesis, University of Oregon, 2011. http://hdl.handle.net/1794/12069.
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xx, 214 p. : ill. (some col.)Intramolecular cascading Michael additions have the ability to transform simple, symmetric substrates into densely functionalized compounds containing new ring structures and chiral centers. The Rauhut-Currier (RC) reaction, also known as the vinylogous Morita-Baylis-Hillman reaction, utilizes this type of reactivity by cyclizing tethered, activated alkenes using phosphine or thiolate catalysis. This dissertation describes the expansion of the scope of the RC reaction, the introduction and importance of co-catalysts to cascading Michael additions, the development of the first amine-catalyzed RC reaction, and the transformation of cyclization products into fused, polycyclic aromatic compounds. Chapter I reviews the development and applications of the Rauhut-Currier reaction. Chapter II describes the regioselective synthesis of di-substituted indenes and introduces phenol as a rate- and selectivity-enhancing co-catalyst. Although tertiary amine nucleophiles were found to be inferior to phosphines as cyclization catalysts, chapter III discusses the ability of unhindered primary and secondary amines to undergo a diastereoselective, cascading aza-Michael-Michael addition to yield a wide variety of amino-indanes in the presence of an acid catalyst. Recognizing the importance of protic environments and small nucleophiles, the development of the first amine-catalyzed intramolecular RC is introduced in chapter IV. Chapter V describes the conversion of methyl ketone-substituted indenes to fluorene derivatives via an intramolecular aldol reaction. Chapter VI describes the serendipitous discovery and synthesis of indenopyrylium salts. Chapter VII details the novel production of indenopyridines from di-substituted indenes. Lastly, chapter VIII provides a summary and suggests future directions for this research. This dissertation includes previously published and unpublished co-authored material.
Committee in charge: Shih-Yuan Liu, Chairperson; Kenneth Doxsee, Advisor; David Tyler, Member; Michael Haley, Member; A. Dana Johnston, Outside Member
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Krismanich, Anthony. "Studies Related to Tandem Reactivity of 1-Carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene." Thesis, University of Waterloo, 2006. http://hdl.handle.net/10012/2954.
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A set of studies centered around the reactions of the active methine compound 1-carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene (the "ring-opened adduct"), obtained by base-induced ring-opening of the Diels-Alder adduct of 5,5-dicyanocyclopentadiene and methyl acrylate, has been carried out. A plan was devised for the anionic (at the dicyanomethyl carbon) ring-opened adduct whereby its reaction with electrophiles, for example Michael reactions with double-bond acceptors, would generate reactive intermediates that would undergo cyclization by tandem conjugate addition to the a,ß,?,d-unsaturated ring p-system to generate bicyclic compounds. In practice, reaction with di-tert-butyl methylidenemalonate, methyl vinyl ketone, and cyclopentenone generated intermediates that exhibited greater tandem reactivity than was anticipated: the bicyclic enolates were found to cyclize further by Thorpe-Ziegler-like reaction with the proximal nitrile to generate, after facile acid hydrolysis, substituted known tricyclic skeleta termed homobrendanes, specifically, tricyclo[5. 2. 1. 04,8]decenes. An attempt was made to generalize the reaction to other substrates, among them singly-activated Michael acceptors and 1,2-heteroatom electrophiles, but the generalization of the homobrendane forming reaction did not meet with success. Attempted functional group manipulations to probe the conversion of the homobrendane derived from di-tert-butyl methylidenemalonate to the homobrendane natural product 2-isocyanoallopupukeanane revealed the unreactivity of the skeletal double-bond toward electrophiles and the high reactivity of the ring ketone toward nucleophiles, among them mCPBA which brought about Baeyer-Villiger reaction, and chloride and hydroxide, which brought about addition/elimination reactions to cleave the last-formed homobrendane ring. The ring-opened adduct was also envisaged as a potential substrate in intramolecular Heck reactions. To this end, Heck substrates were generated from the ring-opened adduct anion and iodo- and bromo-benzyl halides. A key observation at this stage pertained to the unexpected acidity of the ring-opened adduct C5 proton, which could be deprotonated by DBU to bring about allylic isomerization, a finding that would provide a key insight to the pattern of reactivity later evidenced with alkyl propiolates. Optimization of the Heck substrate-generating reaction was followed by Heck reactions under Jeffery's conditions, which generated angular tricycles as intended, accompanied by aromatic compounds generated by base-induced HCN elimination/rearrangement and dehydrogenation. The Jeffery's conditions were optimized to limit the production of aromatics.
The possibility of ring-opened adduct-derived vinyl silane intermediates undergoing cationic cyclizations led to a minor study based upon the bromination of allylsilanes and the elimination of TMSBr from 1,2-dibromo-3-trimethylsilyl compounds, accessible compounds unaccounted for in the review literature. It was determined that the combination of HBr and Br2 (perhaps as HBr3) was required to eliminate TMSBr, in contravention of the textbook account of electrophilic substitutions being the inherent reactions of allylsilanes and Br2.
Unexpected tandem reactivity was observed in the reactions of the anionic ring-opened adduct and alkyl propiolates under catalytic DBU conditions. Rather than tandem cyclization or simple adduct formation, the allenolate intermediates were determined to undergo extremely facile formal allenolate Cope rearrangements involving the ?,d-double-bond of the parent ring. Excess base intercepted the allenolate by deprotonating ring C5 and effecting 1,2-vinyl transfer by 3-exo-trig addition-elimination. The chemistry of the highly delocalized side-chain carbanion in the Cope product was studied in detail.
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Elhussein, Magdi Awadalla Mohamed. "Synthetic Studies towards (+)-Pancratistatin Using an Asymmetric Conjugate addition and Oxidation of Amine to Amide as Key steps." 京都大学 (Kyoto University), 2009. http://hdl.handle.net/2433/124043.
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Kinahan, Taryn Catherine. "Synthesis of novel sufoximidoyl ligands for use in enantioselective 1,4-conjugate addition reactions of diethyl zinc to enones." Thesis, Aston University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401016.
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Robinson, Richard I. "New methods for the synthesis of cyclic sulfates and the application of novel sulfonyl ligands in conjugate addition." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404783.
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Brown, Michael Kevin. "CU-catalyzed enantioselective conjugate addition of organometal reagents to unsaturated carbonyls : an enantioselective total synthesis of clavirolide C." Thesis, Boston College, 2008. http://hdl.handle.net/2345/964.
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Sandoval, Sergio. "Tandem conjugate addition - cyclization reactors of L-methyl prolinate with [alpha,beta]-unsaturated ketones catalyzed by L-proline /." View online ; access limited to URI, 2008. http://0-digitalcommons.uri.edu.helin.uri.edu/dissertations/AAI3314459.
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Tokunaga, Norihito. "Generation of enantiomerically enriched metal enolates via rhodium-catalyzed asymmetric conjugate addition of arylmetal reagents to electron deficient olefins." 京都大学 (Kyoto University), 2007. http://hdl.handle.net/2433/136790.
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May, Tricia Lee. "Copper-Based N-Heterocyclic Carbene Complexes for Catalytic Enantioselective Conjugate Additions of Alkyl-, Aryl- and Vinyl-Based Nucleophiles to Form All-Carbon Quaternary Stereogenic Centers." Thesis, Boston College, 2011. http://hdl.handle.net/2345/2650.
Full textAbstract:
Thesis advisor: Amir H. HoveydaChapter 1 Enantioselective Conjugate Additions of Carbon Nucleophiles to Activated Olefins: Preparation of Enantioenriched Compounds Containing All-Carbon Quaternary Stereogenic Centers. Methods for enantioselective conjugate addition of nucleophiles to activated olefins generating products containing all-carbon quaternary stereogenic centers are critically reviewed. Enantioselective conjugate addition has been shown to be a powerful and concise approach to construct carbon-carbon bonds to prepare compounds containing sterically hindered stereogenic centers and has seen great advances in the past several years. Owing to the difficult nature of additions to relatively unreactive conjugate acceptors, compared to additions generating tertiary stereogenic centers, and construction of a sterically-hindered bond, in many cases, new and active catalysts had to be developed. The review discusses the areas where significant advances have been made as well as current limitations and future outlook. Chapter 2 Development of New and Active Catalysts for Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylzinc Reagent. Through development of new chiral catalysts, we have found an active and enantiodiscriminating bidentate, sulfonate-containing NHC-Cu catalyst that effects enantioselective conjugate addition of alkyl- and arylzinc reagents on notoriously difficult trisubstituted cyclic enones. Products are prepared with high levels of selectivity and participate in a variety of further functionalizations. The enantioselective additions are efficient and practical, not requiring rigorously anhydrous or oxygen-free conditions. Chapter 3 Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylaluminum Reagents to Trisubstituted Enones. Outlined in this chapter is the first effective solution for Cu-catalyzed enantioselective addition of alkyl and aryl nucleophiles to trisubstituted cyclopentenones generating products bearing a β-all-carbon quaternary stereogenic center. Products are obtained in up to 97% yield and 99:1 er, only requiring 5 mol % of an in situ generated Cu-NHC catalyst. The methodology was highlighted as one of the key steps in the total synthesis of clavirolide C. Not only five-membered rings, but six- and seven-membered rings serve as proficient partners in the enantioselective process. Moreover, in cases for the enantioselective aryl addition, in situ prepared Me2AlAr can be used without purification, filtration, or isolation, only requiring the corresponding aryl halides. The additions have also been extended to trisubstituted unsaturated lactones and chromones. Chapter 4 Cu-Catalyzed Enantioselective Conjugate Addition of Vinylaluminum Reagents to Cyclic Trisubstituted Enones. An enantioselective protocol for the formation of β,β-disubstituted cyclic ketones containing a synthetically versatile vinylsilane is disclosed. Enantioselective conjugate addition of in situ prepared silyl-substituted vinylaluminum reagents to β,β-unsaturated ketones promoted by 5 mol % of chiral Cu-NHC complexes delivers desired products with high efficiency (up to 95% yield after purification) and enantioselectivities (up to >98:<2 er). Several functionalizations utilizing the vinylsilanes, vicinal to an all-carbon quaternary stereogenic center, are shown, including an oxidative rearrangement, vinyl iodide formation and protodesilylation, accessing products not previously attainable. Furthermore, the enantioselective protocol is demonstrated as the key transformation in the total synthesis of riccardiphenol B
Thesis (PhD) — Boston College, 2011
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry