Mountain Scholar :: Browsing by Author "Rovis, Tomislav, advisor"

Browsing by Author "Rovis, Tomislav, advisor"

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Open Access
[1,3]-oxygen to carbon rearrangement for the construction of carbon-carbon bonds between adjacent rings and 1,3-dioxepines in synthesis
(Colorado State University. Libraries, 2007) Frein, Jeffrey Daniel, author; Rovis, Tomislav, advisor
Several methods for the stereoselective formation of carbon-carbon bonds between contiguous rings where a stereogenic center is already present have been examined. The approaches investigated were: a [1,3]-oxygen to carbon rearrangement of cyclic vinyl acetals; an intermolecular enolsilane addition into an in situ generated oxocarbenium ion; an intramolecular conjugate addition of tethered alkoxy enones; and epimerization of several Î±-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have enabled formation of both the traps: anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. The C2-C2' relative stereochemistry of the carbon-carbon bond between the adjacent rings was proven via a chemical correlation. The versatility of 1,3-dioxepines as precursors to the formation of 1,4-diols and 1,2,4-triols has been examined. The rapid synthesis of unsymmetrical 1,3-dioxepines and the installation of a 4-acetoxy substituent as a synthetic handle for further functionalization has been realized. The Lewis acid mediated addition into in situ generated oxocarbenium ions has been developed for variety of different nucleophiles. Furthermore, a highly trans -diastereoselective Heck reaction has been performed on unsymmetrical 1,3-dioxepines and their synthetic utility as precursors to the formation of 2,3,4-alkyl substituted tetrahydrofurans and 2-methoxy-4,5-alkyl substituted tetrahydrofurans have been exploited.
Open Access
Application of metallacycles for the synthesis of small molecules
(Colorado State University. Libraries, 2011) Williams, Catherine Marie, author; Rovis, Tomislav, advisor; Wood, John L., committee member; Finke, Richard G., committee member; Shores, Matthew P., committee member; McNeil, Michael R., committee member
A method for the nickel-catalyzed hydrocarboxylation of styrene derivatives has been developed that affords exclusively the branched carboxylic acids in moderate to excellent yields. The reaction scope is tolerant of a variety of electron-deficient ortho-, meta-, and para-styrene analogues containing ester, ketone, nitrile, and halide functionalities. The reaction is remarkably efficient, proceeding well with as little as 1 mol% Ni(acac)2 and 2 mol% Cs2CO3. A system for carbon dioxide sequestration and release in organic polymers has been investigated. Although evidence supporting successful carbon dioxide fixation has been found, the envisioned system is not a practical means of sequestration and release. A rapid approach for the synthesis of Abyssomicin C has been developed utilizing the desymmetrization of meso-dimethylglutaric anhydride. Closely modeled after Sorensen's synthesis, our route bypasses the more inefficient beginning steps to intercept the completed synthesis at the Diels-Alder precursor.
Open Access
Catalytic asymmetric Stetter reaction: intramolecular desymmetrization of cyclohexadienone and intermolecular reaction of glyoxamide
(Colorado State University. Libraries, 2009) Liu, Qin, author; Rovis, Tomislav, advisor
A series of cyclohexadienones were synthesized through dearomatization of phenols. The asymmetric intramolecular desymmetrizations of these substrates via Stetter reactions afford hydrobenzofuranones in good yields and excellent selectivities. Up to three contiguous stereocenters, as well as quaternary stereocenter, have been generated. An asymmetric intermolecular Stetter reaction of glyoxamides with alkylidenemalonates has been successfully developed. These reactions are catalyzed by a pyrrolidinone-derived carbene catalyst, and proceed in good yields with high asymmetric induction. When alkylidene ketoamides are employed, the reactions afford desired β-ketoamides in good yields, excellent enantioselectivities, and good diastereoselectivities. A carbene-catalyzed asymmetric redox reaction of ynal has been investigated. Cyclohexadienone-tethered ynal and alkylidenemalonate-tethered ynal were demonstrated as suitable substrates for the redox reaction. The desired products were obtained with moderate yields and modest selectivities.
Open Access
Catalytically generated acyl triazoliums as versatile acylating reagents and progress toward the total synthesis of okilactomycin
(Colorado State University. Libraries, 2013) Wheeler, Philip Andrew Merris, author; Rovis, Tomislav, advisor; Shi, Yian, committee member; Ferreira, Eric, committee member; Shores, Matthew, committee member; Fisk, John D., committee member
The first chapter of this dissertation describes the development of reactions involving the NHC-catalyzed acylation of carbon and nitrogen nucleophiles. The overall goal of this work was to expand the scope of the NHC-redox reaction manifold and improve its applicability to the synthesis of products that would be useful to the organic chemistry community. An efficient and simple procedure for the preparation of amides from amine hydrochloride salts and α,β-unsaturated aldehydes was developed. This procedure was then applied to the asymmetric synthesis of α-fluoroamides which are valuable building blocks for the preparation of fluorinated compounds that are highly sought after in pharmaceutical, material, and agrichemical applications. The second chapter describes efforts toward the total synthesis of the complex polyketide natural product okilactomycin, enabled by the rhodium-catalyzed desymmetrization of 3,5-dimethylglutaric anhydride developed previously by our group. Progress includes construction of the entire carbon skeleton in two fragments, poised to be unified and elaborated to the natural product by closely precedented steps. This progress demonstrates the potential of the catalytic, enantioselective desymmetrization of anhydrides to build complexity in rapid fashion.
Open Access
Development of an asymmetric intermolecular stetter reaction and organocatalyst design
(Colorado State University. Libraries, 2012) Glover, Garrett S., author; Rovis, Tomislav, advisor; Wood, John L., committee member; Kanatous, Shane, committee member
The intermolecular Stetter represents a powerful carbon-carbon bond forming reaction that involves addition of an acyl anion equivalent to an untethered Michael acceptor. Despite the appeal of rendering the intermolecular reaction asymmetric, this area remains particularly underdeveloped. We describe a catalytic asymmetric intermolecular Stetter reaction for the coupling of 2-pyridinecarboxaldehydes and β-substituted vinyl triflones. In pursuit of increasing the efficiency of this reaction, we developed a series of base-activated NHC pre-catalysts that are capable of catalyzing the intramolecular Stetter reaction without an external base. As an indirect result of our attempts to form activated pre-catalysts, we discovered a catalyst hydration product, that itself generates free-carbene in solution. Additionally, we gathered conclusive evidence for a previously unknown SNAR type decomposition pathway of an electron deficient triazolinylidene catalyst.
Open Access
Development of an asymmetric NHC-catalyzed cascade reaction and studies towards the asymmetric aminomethylation of enals
(Colorado State University. Libraries, 2015) Ozboya, Kerem, author; Rovis, Tomislav, advisor; Henry, Charles, committee member; McNally, Andrew, committee member; Kennan, Alan, committee member; Inamine, Julia, committee member
A cascade reaction is developed to form complex cyclopentanones using an asymmetric Michael/Benzoin sequence. This reaction employs simple aliphatic aldehydes and ketoesters in conjunction with a chiral amine catalyst and a chiral NHC catalyst. Further investigation reveals a surprising interplay between these two catalysts. This relationship is manifested in a pseudo-dynamic kinetic resolution, which is responsible for the high diastereoselectivity observed. Subsequent work details the discovery of the aminomethylation of enals using NHC catalysis. This reaction utilizes an iminium source as well as cinnamaldehyde derivatives to form gamma-amino butyrate derivatives. Rendering this reaction asymmetric has proven a challenge, despite extensive effort to resolve these issues. In the course of these studies, an unexpected NHC-catalyzed Morita-Baylis-Hillman reaction was observed. Optimal conditions for this reaction were established, proving access to useful amino-enals. In an effort to design suitable catalysts for the asymmetric aminomethylation reaction, a strategy for the late-stage manipulation of NHC catalysts was developed. Key to this strategy is the `protection' of the triazolium salt by reduction to the triazoline. An aryl C-Br bond is then exploited for cross-coupling reactions, building a small library of new catalysts. The triazolium salt is then recovered by oxidation with a trityl salt.
Open Access
Development of asymmetric N-heterocyclic carbene-catalyzed reactions
(Colorado State University. Libraries, 2017) Flanigan, Darrin Miles, author; Rovis, Tomislav, advisor; Chen, Eugene, committee member; Shi, Yian, committee member; Chatterjee, Delphi, committee member
N-Heterocyclic carbenes (NHCs) are ubiquitous organocatalysts in a variety of asymmetric transformations. The benzoin and Stetter reactions, which couple aldehydes to other aldehydes or Michael acceptors, respectively are the most commonly reported reactivity manifold employing NHC catalysts. However, other umpolung reactivity pathways exist, for example, when α,β-unsaturated aldehydes are reacted with NHCs, the Breslow intermediate can react through the double bond of the aldehyde to functionalize at the beta position of the carbonyl. A process that has come to be known has homoenolate reactivity. A range of reactivity manifolds were investigated, including the asymmetric intermolecular Stetter reaction and an enantioselective NHC-catalyzed nucleophilic dearomatization of pyridiniums. In the dearomatization chemistry, a homoenolate equivalent is first generated from an enal and an NHC, which then adds to the pyridinium to generate 1,4-dihydropyridines with high enantioselectivity. This is a rare example of catalytic, asymmetric addition of a nucleophile to the activated pyridinium that prefers C-4 functionalization leading to the 1,4-dihydropyridine product. The asymmetric intermolecular Stetter reaction was also investigated in an attempt to broaden the scope of the reaction to include less activated Michael acceptors, specifically, α,β-unsaturated ketones. The coupling of heteroaryl aldehydes to enones could be achieved with appreciable levels of enantioselectivity (up to 80% ee), but reactivity remains a major challenge with this methodology.
Open Access
Dual nickel- and photoredox-catalyzed enantioselective desymmetrization of meso anhydrides and C-O bond activation via phosphines and photoredox catalysis
(Colorado State University. Libraries, 2018) Stache, Erin Elizabeth, author; Rovis, Tomislav, advisor; Doyle, Abigail G., advisor; Chen, Eugene, committee member; McNally, Andy, committee member; Reynolds, Melissa, committee member; Kipper, Matt, committee member
Described herein is the application of photoredox catalysis in the development of new synthetic methods. A dual nickel- and photoredox catalyzed desymmetrization of meso succinic anhydrides was developed to generate stereodefined cis keto-acids in high enantioselectivity and diastereoselectivity. The approach employed benzylic radicals as a coupling partner, generated from a photoredox catalyzed single-electron oxidation of benzylic trifluoroborates using an inexpensive organic dye. A unique epimerization event was discovered and the degree of epimerization was rendered tunable by changing catalyst loadings to ultimately form the trans diastereomer preferentially in high enantioeselectivity. A method for the C–O bond activation of aliphatic alcohols and carboxylic acids was developed using phosphines and photoredox catalysis. This novel reaction platform was used to generate aliphatic or acyl radicals directly from benzylic alcohols and aliphatic and aromatic acids, and with terminal hydrogen atom transfer, afforded the desired deoxygenated alkanes and aldehydes. Additionally, the intermediate acyl radicals could be intercepted in an intramolecular cyclization reaction to generate new lactones, amides and ketones.
Open Access
Enantioselective rhodium-catalyzed [2+2+2] and [4+2+2] cycloaddition reactions of alkenyl heterocumulenes: applications to alkaloid synthesis
(Colorado State University. Libraries, 2009) Yu, Robert Tzu Hsiang, author; Rovis, Tomislav, advisor
An intermolecular rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and internal alkynes has been developed. In the presence of a catalytic amount of [Rh(C2H4)2Cl]2 and P(4-MeO-C6H4)3, the cycloaddition produces substituted indolizinones and quinolizinones with newly formed sp 3-stereocenters. Depending on the alkynyl partners, a CO migration process can be involved during the cycloaddition to furnish cycloadducts possessing vinylogous amide functionality. The use of TADDOL-based phosphoramidite ligands on rhodium allows for the incorporation of terminal alkynes in a highly enantioselective [2+2+2] cycloaddition with alkenyl isocyanates. Terminal alkyl alkynes provide bicyclic lactams, while the use of aryl alkynes provides complementary access to vinylogous amides through a CO migration process. Product selectivity seems to be governed by a combination of electronic and steric factors, with smaller and/or more electron-deficient substituents favoring lactam formation. The synthetic utility is demonstrated in an expedient asymmetric total synthesis of the alkaloid (+)-lasubine II. A highly enantioselective rhodium-catalyzed [2+2+2] cycloaddition of terminal alkynes and alkenyl carbodiimides has been realized. The cycloaddition with aryl alkynes provides complementary selectivity to the reaction previously described using isocyanates. In addition, this reaction demonstrates the feasibility of olefin insertion into carbodiimide-derived metalacycles, and provides a new class of chiral bicyclic amidines as the major products. A new catalyst system has been realized. The use of chiral biphenyl-based phosphoramidite ligands on rhodium provides an efficient cycloaddition between terminal alkyl alkynes and alkenyl isocyanates. The cycloaddition proceeds through a CO migration pathway, and generates various 5-alkyl indolizinone products with high enantiomeric excess. A four-step asymmetric synthesis of indolizidine (-)-209D has been achieved. A highly enantioselective rhodium-catalyzed [4+2+2] cycloaddition of terminal alkynes and dienyl isocyanates has been developed. The cycloaddition provides a rapid entry to highly functionalized and enantioenriched bicyclic azocines. This reaction represents the first [4+2+2] cycloaddition strategy to construct nitrogen-containing eight-membered rings.
Open Access
Enantioselective β-functionalization of enals via N-heterocyclic carbene catalysis
(Colorado State University. Libraries, 2015) White, Nicholas Andrew, author; Rovis, Tomislav, advisor; Kennan, Alan J., committee member; Chen, Eugene Y.-X., committee member; Williams, Robert M., committee member; Kipper, Matt J., committee member
A series of δ-nitroesters were synthesized through the N-heterocyclic carbene catalyzed coupling of enals and nitroalkenes. The asymmetric coupling of these substrates via the homoenolate pathway afford δ-nitroesters in good yield, diastereoselectivity, and enantioselectivity. This methodology allows for the rapid synthesis of δ-lactams. Using this approach, we synthesized the pharmaceutically relevant piperidines paroxetine and femoxetine. A novel single-electron oxidation pathway for the N-heterocyclic carbene generated Breslow intermediate has been developed. Nitroarenes have been shown to transfer an oxygen from the nitro group to the β-position of an enal in an asymmetric fashion to generate β-hydroxy esters. This reaction affords desired β-hydroxy ester products in good yield and enantioselectivity and tolerates a wide range of enal substrates. A dimerization of aromatic enals to form 3,4-disubstituted cyclopentanones has been investigated. Using a single-electron oxidant, aromatic enals couple to form cyclopenanone products in good yield, good enantioselectivity, and excellent diastereoselectivity. A cross coupling has also been developed to afford non-symmetrical cyclopentanone products.
Open Access
Ligand and reaction development in the Rhodium(III)-catalyzed C-H activation-mediated synthesis of n-heterocycles
(Colorado State University. Libraries, 2013) Hyster, Todd K., author; Rovis, Tomislav, advisor; Finke, Richard G., committee member; Chen, Eugene Y.-X., committee member; Bailey, Travis S., committee member; Kanatous, Shane B., committee member
Described herein are the development of new directing groups and new ligands for Rh(III)- catalyzed, multi-component synthesis of nitrogen containing heterocycles. The amide directing group was found to be an effective coupling partner for the synthesis of isoquinolones. Mechanistic experiments suggested the possibility to activated alkenyl C-H bonds for the synthesis of pyridones. During these studies, development of a new cyclopentadienyl ligand (Cpt) for C-H activation allowed for enhanced regioselectivity in the alkyne insertion event. Oxime directing groups were found to provide pyridines when coupled with alkynes. Again the Cpt ligand impacted the alkyne migratory insertion event. This ligand is also effective in controlling the migratory insertion of alkenes in the synthesis of dihydroisoquinolones. An enantioselective synthesis of dihydroisoquinolones was discovered using a strept(avidin)-based artificial metalloenzyme providing enhanced reactivity, regioselectivity, and enantioselectivity. This artificial metalloenzyme is also effective for controlling the enantioselective synthesis of γ-lactams from diazo compounds and benzamides.
Open Access
Mechanistic investigations and ligand development for rhodium catalyzed [2+2+2] and zinc catalyzed [4+2] cycloadditions
(Colorado State University. Libraries, 2013) Dalton, Derek M., author; Rovis, Tomislav, advisor; Wood, John L., committee member; Kennan, Alan J., committee member; Rappé, Anthony K., committee member; Snow, Christopher D., committee member
Described herein are mechanistic studies and ligand development for Rh(I) catalyzed [2+2+2] cycloaddition reactions of alkene tethered isocyanates and exogenous alkynes. A mechanistic hypothesis has been proposed and supported through experiment. Novel perfluoroaryl Taddol phosphoramidite ligands were developed based on the mechanistic hypothesis. Improvements in product and enantioselectivity were found using the perfluoroaryl Taddol phosphoramidite ligand, CKphos. This catalyst system was studied by NMR, X-ray and DFT calculations. Rh(I)-C6F5 and Co(-1)-C6F5 interactions were found in the course of studying the CKphos catalysts. The Rh-CKphos catalyst system was used in the synthesis of the tricyclic core structure of the cylindricine and lepadiformine alkaloids. Finally a Zn(II)-catalyzed [4+2] cycloaddition of 1- azabutadienes and nitro olefins was discovered and developed as an efficient and selective means to synthesize tetrahydropyridines.
Open Access
N-Heterocyclic carbene catalysis: application to the total synthesis of cephalimysin A, and development of multicatalytic cascade reactions
(Colorado State University. Libraries, 2011) Lathrop, Stephen Paul, author; Rovis, Tomislav, advisor; Wood, John L., committee member; Crans, Debbie Catharina, committee member; Shores, Matthew P., committee member; Kanatous, Shane B., 1968-, committee member
Application of the N-Heterocyclic carbene catalyzed Stetter reaction to the total synthesis of 9-epi-cephalimysin A has been realized. The approach centers on the use of an asymmetric catalytic Stetter reaction to access the spirocyclic core of cephalimysin A. Specifically it was found that a photoisomerization/Stetter protocol allows rapid access to an intermediate readily amenable for further functionalization. This intermediate was further elaborated to three stereoisomers of the naturally occurring cephalimysin A. During the investigation of cephalimysin A an interesting side product was observed that led to the development of several multicatalytic cascade reactions utilizing N-heterocyclic carbenes. Specifically the pairing of secondary-amine catalysts with N-heterocyclic carbenes allowed for the synthesis of densely functionalized cyclopentanones in a single step. Moreover, a synergistic relationship was observed between the two catalysts. This partnership allowed for the products to be achieved in higher selectivity than would have been possible if conducting the reactions in a stepwise fashion.
Open Access
N-heterocyclic carbene catalyzed α-redox reaction: catalytic synthesis of amides and carboxylic acids
(Colorado State University. Libraries, 2011) Vora, Harit, author; Rovis, Tomislav, advisor; Williams, Robert, committee member; Wood, John, committee member; Chen, Eugene, committee member; McNeil, Michael, committee member
N-heterocyclic carbene catalyzed α-redox reaction has been utilized towards the catalytic synthesis of amides utilizing amines and substoichiometric quantities of an acyl transfer reagent in a waste reduced acylation process. The reaction is amenable to a plethora of amines and amine hydrochloride salts as nucleophiles. The reaction is applicable towards a variety α-reducible aldehydes as α,α-dichloro aldehydes, enals, epoxy and aziridnyl aldehydes all provide the respective amides in moderate to excellent yields with the latter in high diastereoselectivity. The asymmetric amidation reaction provides chiral amides in moderate enantioselectivity. Additionally, the N-heterocyclic carbene catalyzed α-redox reaction was also utilized for the synthesis of enantioenriched α-chloro and α-fluoro carboxylic acids. The reaction also provide for a mild installation of a deuterium from D2O furnishing enantioenriched isotopically labeled compounds. Investigations in to the mechanism have revealed that the carbene displays behavior of a phase transfer reagent by shuttling hydroxide from the aqueous phase to the organic phase. Additionally, it has been found that the turnover limiting step in this acylation process in the hydrolysis of the acyl azolium.
Open Access
Organocatalytic, Michael-Stetter reaction and rhodium(I)-catalyzed hydroheteroarylation of acrylates with benzoxazoles: reaction development and investigations into origins of enantioselectivity
(Colorado State University. Libraries, 2015) Filloux, Claire M., author; Rovis, Tomislav, advisor; McNaughton, Brian R., committee member; Prieto, Amy L., committee member; Crans, Debbie C., committee member; Hentges, Shane T., committee member
The chapters that follow describe two independent investigations. Both relay the development of experimental methods for the catalytic, asymmetric addition of carbon-hydrogen bonds to alkenes. In the first chapter, nucleophilic amine and N-heterocyclic carbene cocatalysts cooperate in the organocatalytic, cascade synthesis of benzofuranone products in good yields and high enantioselectivities. Importantly, the cascade protocol is found to outperform a two-pot procedure in which reaction intermediates are isolated and purified before the second step. Mechanistic studies reveal that additives and geometry of an olefin intermediate crucially influence reaction enantioselectivity. In the second method, a bulky Rh(I)-bisphosphine complex catalyzes the asymmetric, intermolecular addition of benzoxazoles to methacrylate derivatives in fair to excellent yields and good to excellent enantioselectivities. Detailed deuterium labeling and epimerization studies provide considerable insight into the reaction mechanism: C-H activation is reversible; migratory insertion is likely enantiodetermining; and the bulky- bisphosphine ligand likely boosts reactivity and selectivity by discouraging deleterious ligation of benzoxazole starting materials to on- or off-cycle rhodium complexes and by impeding coordination-induced product epimerization.
Open Access
Progress toward the total synthesis of stemocurtisine and asymmetric synthesis of endoperoxide anticancer agents via Brønsted acid cascade catalysis
(Colorado State University. Libraries, 2012) Rubush, David Michael, author; Rovis, Tomislav, advisor; Kennan, Alan, committee member; Crans, Debbie, committee member; Chen, Eugene, committee member; Kanatous, Shane, committee member
A viable route toward the pyrido-azepine core of stemocurtisine involving an N-heterocyclic carbene catalyzed Stetter reaction has been realized. The key steps involve a formal [3+2] cycloaddition of enones with isocyanoacetates and a catalytic asymmetric intramolecular Stetter reaction. Additionally, a diastereoselective intramolecular Stetter reaction was achieved to access highly substituted pyrrolidines. Asymmetric Brønsted acid catalyzed cascade reactions were also investigated. A diastereoselective acetalization/oxa-Micahel cascade has been developed to provide dioxolanes and oxazolidines using diphenylphosphinic acid as a catalyst. The enantioselective variant of this reaction was explored with minor success. The desymmetrization of p-peroxyquinols using a Brønsted acid catalyzed acetalization/oxa-Michael cascade was achieved in high yields and selectivities for a variety of aliphatic and aryl aldehydes. Mechanistic studies suggest that the reaction proceeds through a dynamic kinetic resolution of the peroxy-hemiacetal intermediate. The resulting 1,2,4-trioxane products were derivatized and show potent cytotoxicity toward specific cancer cells.
Open Access
Reaction development and mechanistic investigation of rhodium-catalyzed pyridine synthesis via C-H activation
(Colorado State University. Libraries, 2014) Neely, Jamie M., author; Rovis, Tomislav, advisor; McNally, Andrew, committee member; Fisk, John D., committee member; Neilson, James R., committee member; Inamine, Julia M., committee member
Described herein are two complementary rhodium-catalyzed methods for the synthesis of substituted pyridines from unsaturated oxime derivatives and alkenes. In the first, formal [4+2] cycloaddition of O-pivaloyl α, β-unsaturated oxime esters and activated terminal alkenes was discovered to proceed in high yields and with excellent selectivity for 6-substituted pyridine products. Mechanistic experiments were found to be consistent with a reversible C-H activation step and a C-N bond forming, N-O bond cleaving process en route to pyridine formation. Rhodium-catalyzed coupling using unactivated alkene substrates was shown to present important information regarding the influence of the alkene component on product distribution. In a second method, access to 5-substituted pyridine derivatives was achieved by decarboxylative annulation of α, β-unsaturated oxime esters and β-substituted acrylic acid derivatives. In this case, carboxylic acids were found to serve as traceless activating groups for selective alkene incorporation. A wealth of mechanistic insight was gained by identification of and decomposition studies regarding catalytically relevant rhodium complexes.
Open Access
Rhodium(III)-catalyzed amide-directed C-H activation and [4+2] cycloaddition for modular assembly of nitrogen heterocycles
(Colorado State University. Libraries, 2017) Semakul, Natthawat, author; Rovis, Tomislav, advisor; Kennan, Alan, committee member; Shi, Yian, committee member; McCullagh, Martin, committee member; Kipper, Matt, committee member
This dissertation describes the ligand and reaction developments by amide-directed rhodium(III)-catalyzed C(sp2)-H bond activation followed by amidoannulation with alkenes to form nitrogen-containing heterocycles. Chapter 1 details the ligand development for stereoselective synthesis of [4.1.0] dihydroisoquinolones through benzamidation of cyclopropenes mediated by Rh(III) catalysis. Quantum chemical calculations revealed the important role of heptamethylindenyl (Ind*) ligand and O-substituted ester of benzhydroxamate for achieving high diastereoselectivity in cyclopropene insertion. Efforts toward stereoselective synthesis of [4.1.0] dihydroisoquinolones have been also studied by streptavidin-based artificial metalloenzyme. Chapter 2 presents the stereoselective synthesis of [4.2.0] dihydroisoquinolones via the benzamidation of cyclobutenes. The transformation proved to have a broad substrate scope and functional group tolerance that generates the cyclobutane-fused azacycles with excellent diastereoselectivity. The artificial metalloenzymes can render this reaction asymmetric furnishing the dihydroisoquinolone products in moderate enantioselectivity. Chapter 3 communicates Rh(III)-catalyzed C-H activation and [4+2] annulation reaction of N-pivaloyloxy acrylamides with alkenes for an efficient synthesis of α,β-unsaturated-δ-lactams. This process offers a platform for the rapid assembly of a diverse set of delta-lactams from simple and abundant precursors. These lactams could serve as useful building blocks to access substituted piperidines.
Open Access
Rhodium-catalyzed cycloadditions to construct nitrogen heterocycles and progress towards the synthesis of ionomycin
(Colorado State University. Libraries, 2014) Oberg, Kevin Martin, author; Rovis, Tomislav, advisor; Kennan, Alan J., committee member; Ferreira, Eric M., committee member; Neilson, James R., committee member; Kanatous, Shane B., committee member
The ability to construct molecules in a rapid, atom-economical fashion is a major goal of organic chemistry. This work describes four topics; pyridone synthesis, mechanistic understanding in [2+2+2] cycloadditions, pyrimidinone synthesis, and progress towards ionomycin. The first chapter describes the synthesis of 4,6-substituted 2-pyridones and 3,5-substituted 4-pyridones from the rhodium-catalyzed [2+2+2] cycloaddition of two alkynes and an isocyanate. Our group demonstrated that an enantioselective rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and alkynes generates indolizidinone and quinolizidinone products. Although trends for product and regioselectivity were established, the underlying mechanism was unclear. The second chapter describes X-ray analysis of rhodium·phosphoramidite complexes in conjunction with other mechanistic work to elucidate a theory that explains product and regioselectivity in this reaction. This system is amazing in that it illuminates the factors contributing to oxidative cycloadditions in a spectacular fashion by delivering two different products. The third chapter describes the enantioselective synthesis of pyrimidinones from a rhodium-catalyzed [4+2] cycloaddition of α, β-unsaturated imines and isocyanates. The final chapter describes our group's progress toward the synthesis of ionomycin using rhodium-catalyzed desymmetrization of anhydrides with zinc nucleophiles.
Open Access
Synthesis of nitrogen-containing molecules by zinc-catalyzed [4+2] cycloaddition and photoredox-catalyzed C-H functionalization
(Colorado State University. Libraries, 2017) Chu, John Chun Kit, author; Rovis, Tomislav, advisor; Kennan, Alan, committee member; Prieto, Amy, committee member; Kanatous, Shane, committee member
This work first describes an enantioselective Zn-catalyzed [4+2] cycloaddition of 1-azadienes and nitro-alkenes for the synthesis of medicinally valuable piperidines. The detrimental coordination of 1-azadienes to the Zn catalysts undermines the stereochemical control of the reaction. Fortunately, a novel bisoxazoline ligand limits this undesired coordination and delivers high stereoselectivity. Mechanistic studies suggest the reaction proceeds via a stepwise mechanism in which aza-Michael addition is followed by cyclization. This proposed mechanism also explains the successful cycloaddition between two electron-deficient reaction partners. Secondly, amide-directed carbon-carbon bond formation at unactivated sp3 C-H bonds has been achieved using photoredox catalysis. The reaction features a hydrogen atom abstraction from the C-H bond to a nitrogen radical generated from the amidyl N-H bond, leading to formation of a carbon-centered radical. Trapping of the resulting alkyl radical with an electrophilic alkene gives the desired C-C bond formation. Experimental evidence supports the generation of the nitrogen radical through a stepwise deprotonation/oxidation event in a closed catalytic cycle. The potential to incorporate other functionalities in the C-H bonds, as well as g functionalization of carbonyl compounds, is disclosed.