Fitting the catalysts for effective enantioselective C-X bond forming reactions. Theoretically guided ligand design and mechanistic investigations

La creixent demanda de compostos enantiomèricament purs, ha incrementat l’interès pel desenvolupament de metodologies per l’obtenció d'aquests compostos. Entre elles, la catàlisi asimètrica és la tècnica més emprada. En aquesta metodologia, l'elecció lligand quiral és clau per l'obtenció de elevades activitats i enantioselectivitats. En aquest context, aquesta tesis és centra en la síntesis de diferents famílies de lligands quirals altament modulars a partir de productes de partida d'elevada disponibilitat. Més concretament, s’han sintetitzat diverses famílies de lligands heterodadors P-oxazolina (P= fosfina, fosfinit, fosfit, fosforamidit), P-altres grups N-dadors (P= fosfit, fosforamidit, fosfonit i N= tiazol, sulfoximina, hidrazona, amina, piridina), P-tioèter (P= fosfina, fosfinit, fosfit) i una família de lligands fosfina quiral-fosfit. Aquests lligands s'han aplicat en la reacció d’hidrogenació d’olefines funcionalitzades i mínimament funcionalitzades catalitzada per Rh i Ir, la reacció de substitució al·lílica i la reacció de protonació descarboxilativa d’oxindoles ambdues catalitzades per Pd. A més a més, en alguns casos, s'han dut a terme estudis computacionals en combinació amb assajos experimentals per estudiar l'origen de les enantioselectivitats obtingudes o bé per guiar l'optimització dels lligand.La creciente demanda de compuestos enantioméricamente puros, ha incrementado el interés por el desarrollo de metodologías para la obtención de dichos compuestos. Entre ellas, la catálisis asimétrica es la técnica mas utilizada. En dicha metodología, la elección del ligando quiral es clave para la obtención de elevada actividades i enantioselectividades. En este contexto, esta tesis se centra en la síntesis de diferentes familias de ligandos quirales altamente modulares a partir de productos de partida de elevada disponibilidad. Más concretamente, se ha trabajado en la síntesis de ligandos heterodadores P-oxazoline (P= fosfina, fosfinito, fosfito, fosforamidito), P-otros grupos N-dadores (P= fosfito, fosforamidito, fosfonito y N= tiazol, sulfoximina, hidrazona, amina, piridina), P-tioéter (P= fosfina, fosfinito, fosfito) i una familia de ligandos fosfina quiral-fosfito. Estos ligandos se han aplicado en la reacción de hidrogenación de olefinas funcionalitzadas i mínimamente funcionalitzadas catalizada por Rh i Ir, la reacción de substitución alílica y la reacción de protonación descarboxilativa de oxindolas ambas catalizadas por Pd. Además, en algunos casos, se han realizado cálculos computacionales en combinación con ensayos experimentales para estudiar el origen de las enantioselectividades obtenidas o bien para guiar la optimización de los ligandos.The growing demand on enantiomerically pure compounds has stimulated the interest for the development of methodologies to obtain these compounds. Among them, asymmetric catalysis is one of the most employed tools. In this technic, the choice of the chiral ligand is fundamental to obtain high levels of activity and enantioselectivity. In this context, this thesis is focused on the synthesis of several families of highly modular chiral ligands from readily available starting materials. Particularly, we worked on the synthesis of P-oxazoline (P= phosphine, phosphinite, phosphite, phosphoroamidite), P-other N-donor groups (P= phosphite, phosphoroamidite, phosphonite and N= thiazole, sulfoximine, hydrazone, amine, pyridine), P-thioether (P= phosphine, phosphinite, phosphite) and a family of P*-stereogenic phosphine-phosphite ligands. These ligands have been applied in the Rh- and Ir-catalyzed hydrogenation of functionalized and minimally functionalized olefins, Pd-catalyzed allylic substitution reaction and Pd-catalyzed decarboxylative protonation. Furthermore, in some cases, DFT studies in combination with experimental ones have been performed to better understand the origin of the obtained enantioselectivities or in order to guide the ligand optimization

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 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 &beta;-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 &beta;,&beta;-disubstituted cyclic ketones containing a synthetically versatile vinylsilane is disclosed. Enantioselective conjugate addition of in situ prepared silyl-substituted vinylaluminum reagents to &beta;,&beta;-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

Computational Investigations of Ruthenium-Catalyzed Olefin Metathesis and Rhodium-Catalyzed Olefin Hydroboration Reactions

Transition metal catalysis has proven to be a powerful strategy for olefin functionalization and polymerization reactions. Ancillary ligands play an important role in controlling the reactivity and selectivity of these catalytic reactions. Mechanistically guided rational design of ancillary ligands to achieve desired reaction outcomes has been a long-standing challenge in transition metal catalyzed olefin hydrofunctionalization and metathesis reactions because multiple properties of the ligand, including electron donating ability, steric hindrance, and ligand flexibility, could contribute simultaneously to affect the reaction mechanism, reactivity, and selectivity. To date, development of new catalytic systems has been largely dependent on trial-and-error, as well as chemical intuition. Computational investigation is emerging as an effective tool to provide molecular level understanding of reaction mechanisms, substrate effects, and ligand effects. These theoretical insights can rationalize experimental observations and facilitate ligand design. In this thesis, I present a series of computational studies to probe ligand effects in transition metal catalyzed olefin metathesis and hydroboration reactions. The specific catalytic systems investigated include effects of phosphine ligands on the initiation rate of 2nd generation Grubbs catalyst, effects of switchable N-heterocyclic carbene (NHC) ligands on reactivity of Ru-catalyzed ring-opening metathesis polymerization reactions, and effects of NHC, phosphine, and asymmetric phosphite ligands on reactivity, regio-, and stereoselectivity of Rh-catalyzed olefin hydroboration reactions

Novel phosphaalkene-based late transition metal complexes$bsynthesis and applications

The content of this thesis is presented into four parts. The first part mainly focuses on describing the electronic structure of phosphaalkenes and their synthesis. Phosphaalkenes prepared as a part of this thesis were synthesized using phospha-Wittig reagents in the reaction with suitable aldehydes. Phospha-Wittig reagents have been discussed in detail in the second chapter. The last two chapters comprises of the selected examples to illustrate the strong π accepting properties of phosphaalkene ligands in coordination chemistry and late transition metal catalysis

SYNTHESIS OF META-TERPHENYL SCAFFOLDED MOLECULES FOR CATALYSIS AND SENSOR APPLICATIONS

The utility of the m-terphenyl has been observed in a wide variety of applications since its first discovery. The tunable conformational flexibility contributes to the unique properties and resulting applications thereof. Chapter 1 goes into detail about the concepts used throughout and defines the tools needed to understand the chemistry in the resulting chapters. The primary use of the m-terphenyl herein is as a canopy that shields a pocket created underneath the central ring. Functionalization within this pocket allows metal binding in defined coordination environments. with the use of donor ligands attached to the flanking rings. The applications of these metal complexes are discussed throughout Chapters 2, 3 and 4. Chapters 5 and 6 describe a different approach wherein the focus was on exploiting the defined pocket shape to enhance sensing mechanisms. A good sensor must be selective for one analyte over others; this is typically achieved through electronic or steric considerations. The m-terphenyl canopy can be used to sterically control what analytes can interact with the molecule. Applications of m-terphenyl dizinc complexes that selectively sense pyrophosphates over other analytes are discussed in Chapter 5. The use of a m-terphenyl scaffold in a poly(p-phenylene ethynylene) derivative discussed in Chapter 6 shows how steric porosity control can enhance the rate of nitroaromatic detection by polymer films

Combinatorial and supramolecular saproaches to monodentate phosphorus-ligands for transition metal catalyzed asymmetric reactions.

In recent years, monodentate phosphorus ligands (e.g. phosphites, phosphonites, phosphoramidites and phosphinamines) have held the stage in asymmetric catalysis.1 In addition to their outstanding activity and selectivity, comparable or even superior to those of bidentate ligands, the convenient, fast and practical preparation from commercially available materials underlines their potential for industrial applications. Furthermore, the modular nature of all these ligands allows the synthesis of a variety of representatives, thereby making a combinatorial approach possible. My PhD research project deals with the synthesis of libraries of new chiral monodentate P-ligands and their screening in asymmetric transition metal-catalyzed reactions through two innovative approaches: \uf05f\uf020combination of binaphthol-derived phosphites and C1-symmetric phosphinamines for the selective generation of heteroleptic catalysts in Rh- and Pd-mediated reactions (Ligand Combination Approach, Research line 1); \uf05f\uf020supramolecular ligand-ligand interactions for highly selective transition metal catalysis (Supramolecular Approach, Research line 2). Research line 1 In 2002-3, the groups of Reetz and Feringa independently used a binary mixture of chiral monodentate Pligands in several asymmetric rhodium-catalyzed reactions. By mixing two different ligands (La and Lb) in the presence of a transition metal [M], three species can be formed: [M]LaLa, [M]LbLb (homocomplexes) and [M]LaLb (heterocomplex). The heterocomplex is often more reactive and more (regio-, diastereo-, enantio-) selective than either of the two homocomplexes. Moreover, under thermodynamic control the heterocomplex : homocomplexes ratios usually exceed the statistical value (2 :1 :1). The ideal case would constitute an equilibrium completely in favor of the heterocomplex [M]LaLb, because a single well-defined catalyst would then exist in the reaction mixture and the undesired competition of the less selective homocomplexes would be avoided. We were intrigued by the remarkable selectivities reported for the mixtures of chiral ligands (binolderived phosphites, phosphonites and phosphoramidites) with achiral phosphines.4 In particular, the 1:1 mixture of a chiral phosphite with an achiral phosphine was reported to induce reversal of the enantioselectivity in the Rh-catalysed hydrogenation of N-acetamido acrylate (compared to the chiral phosphite alone). The only possible explanation for this peculiar behaviour is the selective formation of the phosphite-phosphine Rh-heterocomplex, favoured by electronically matching one \uf073-donor ligand (phosphine) and one \uf070-acceptor ligand (phosphite). As enantiomerically pure chiral phosphines are not easy to synthesize, we were wondering whether the phosphine ligands could be substituted by other \uf073- donor phosphorus ligands still retaining the thermodynamic preference for the formation of the heterocomplex. For this reason, we turned our attention to chiral phosphinamines, which are easy to prepare enantiomerically pure, and have electronic properties similar to those of phosphines.5 DFT calculations showed that the phosphite-phosphinamine rhodium heterocomplex is more stable than the two homocomplexes by 11.29 kcal/mol We synthesized a library of monodentate chiral phosphites 1a-d by reacting enantiopure BINOL-PCl with different chiral and achiral alcohols. Monodentate chiral phosphinamines 2a-e were prepared by reaction of Ph2PCl with a number of C2-symmetric secondary amines and C1-symmetric secondary and primary amines. Complexation studies were performed by means of 31P-NMR, using Rh(acac)(C2H4)2 as the rhodium source. When C1-symmetric phosphinamine ligands were employed, the cis-heterocomplexes were formed with selectivity ranging from moderate (70%) to excellent (_ 99%). The homo- and heterocombinations of phosphites and C1-symmetric phosphinamines were then screened in the rhodium-catalyzed hydrogenation of methyl 2-acetamidoacrylate. Remarkably, the 1:1 combination of a BINOL-derived phosphite and a phosphinamine induced reversal of the enantioselectivity, compared both to the phosphite and the phosphinamine alone. This heterocombination induced a peculiar stereochemical outcome also in the palladium-catalyzed asymmetric allylic substitution of rac-1,3- The heterocomplexes formed in this way are expected to have reduced degrees of freedom7 compared to the complexes of normal monodentate ligands, and thus supramolecular ligands somehow resemble traditional bidentate ligands. According to this analogy, they are often referred to as supramolecular bidentate ligands or self-assembled ligands, thanks to their ability to spontaneously form bidentate systems in solution. These terms also apply to those supramolecular ligands that are only capable of noncomplementary interactions: indeed these systems are still capable of forming rigid and conformationally restricted complexes, although they cannot selectively form heterocomplexes when used in a mixture, which quite reduces their "combinatorial appeal". Prompted by the studies of Prof. Reek and co-workers on the synthesis of supramolecular bidentate heterocomplexes through complementary interactions (e.g. coordinative bondings)8 and by the efficient resolution strategy of racemic N-benzyl _-amino acids (N-Bn-AA) by liquid-liquid extraction using a chiral salen\u2013cobalt(III) complex as enantioselective receptor, accomplished in our laboratories, we decided to use the salen-cobalt(III)-N-benzyl-L-serine complex as a chiral platform for the preparation of new families of supramolecular mono- and bi-dentate P-ligands (Scheme 4 A and B). The salen-cobalt(III)-N-Bn-AA complexes, in fact, possess a rigid framework with the salen ligand in a cis-_-folded arrangement around the octahedral cobalt ion. The remaining two cis coordination sites are occupied by the N-benzyl _-amino acid, which is thus accommodated in the \u201cbinding pocket\u201d of the chiral cobalt complex. 9b Ligands 3 were synthesized in good yields starting from the symmetrical tetra-t-butyl-salen which was transformed into the corresponding cobalt(III) acetate complex, and the acetate ion was exchanged with Nbenzyl- L-serine. In the case of symmetric salen backbone, the complex was obtained pure in high yield and the phosphite moieties were then introduced by reaction with different diol-derived chlorophosphite. In the case of the supramolecular bidentate ligands 4, the unsymmetrical hydroxymethyl-containing salen afforded the corresponding cobalt(III) acetate complex as a mixture of two inseparable diastereoisomers. Complexation of monodentate ligands 3 to rhodium(I) was studied by 31P-NMR spectroscopy, which showed the formation of the desired Rh-complexes. The reactivity of supramolecular monodentate Pligands was investigated in two Pd-catalyzed-allylic alkylation on (E)-1,3-diphenylallyl acetate and Pdcatalized desymmetrization of meso-cyclopenten-2-ene-1,4-diol biscarbamate. We are now exploring new synthetic pathways to obtain the unsymmetrical (S,S)-salen-ligand and the corresponding unsymmetrical (S,S)-salen-cobalt(III)-N-Bn-L-serine bidentate P-ligand in a pure diastereoisomeric fashion. We have also investigated the design and synthesis of a novel class of chiral monodentate phosphite ligands, named PhthalaPhos, which contain a phthalic acid primary diamide moiety. Such phthalamidic group displays both donor and acceptor hydrogen bonding properties that, in principle, can give rise to supramolecular interactions both between the ligands and with the reaction substrate The pre-catalytic Rh complex of one of these ligands was fully characterized and studied by NMR, IR and mass spectroscopy, which confirmed the presence of hydrogen bonds between the coordinated ligands, and the formation of a supramolecular bidentate ligand. The catalytic properties of these new ligands were assessed in the rhodium-catalyzed hydrogenation of benchmark olefins (e.g. methyl 2-acetoamidoacrylate and N-(1-phenylvinyl)acetamide), taking the known phosphite 9 as a touchstone. Four ligands gave e.e. values higher than 97% with methyl 2-acetoamidoacrylate as substrate, and six reached the same level of performance with N-(1-phenylvinyl)acetamide. Remarkably, the reference ligand 9, featuring the same BINOL phosphite moiety, gave only 84% and 90% e.e. respectively for the same substrates, thus suggesting that the phthalimide residue significantly influences the catalytic properties of these ligands. Evaluation of the catalytic properties of the Phthalaphos ligands were also extended to the Rh-catalyzed hydrogenation of more challenging substrates of potential industrial interest, such as N-(3,4-dihydronaphthalen-1-yl)acetamide and (E)-methyl 2-(acetamidomethyl)-3-phenylacrylate. The results of this screening were quite variegated both in terms of activity and enantioselectivity, but the employment of a Phthalaphos ligand gave the highest e.e. value ever obtained on N-(3,4-dihydronaphthalen-1-yl)acetamide with phosphite ligands and the highest e.e. value ever obtained with (E)-methyl 2-(acetamidomethyl)-3-phenylacrylate

Catalytic Organosilane Activation with Copper Complexes

The development of reactive organometallics has become a vital part synthetic chemistry. Organosilanes potentially represent a cheap, robust, and environmentally benign precursor to reactive organometallics, but the nature of the very stable C−Si bond has generally prevented their use as precursors to more reactive organometallics. We present investigations into copper fluoride complexes which activate organosilanes in anhydrous media under mild conditions, effecting transmetalation to produce stable and in some cases isolable organocopper species containing sensitive functional groups including carbonyl groups, aryl bromides, benzylic chlorides, and alkyl ketones. This discovery allows us to better understand the fundamental reactivity of presumed intermediates in copper-catalyzed reactions and to develop new catalytic bond-forming processes including allylations of aldehydes, 1,4-addition of vinyl epoxides, and intramolecular ring closures

Stereodivergent Catalysis

This review covers diastereo- and enantiodivergent catalyzed reactions in acyclic and cyclic systems using metal complexes or organocatalysts. Among them, nucleophilic addition to carbon–carbon and carbon–nitrogen double bonds, α-functionalization of carbonyl compounds, allylic substitutions, and ring opening of oxiranes and aziridines are considered. The diastereodivergent synthesis of alkenes from alkynes is also included. Finally, stereodivergent intramolecular and intermolecular cycloadditions and other cyclizations are also reported.We thank the Spanish Ministerio de Economia y Competitividad (MINECO) (projects CTQ2013-43446-P, CTQ2014-53695P, and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI), and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat Valenciana (PROMETEO2009/039 and PROMETEOII/2014/017), and the University of Alicante for financial support

Transition-metal-catalyzed functionalization of alkynes with organoboron reagents: new trends, nechanistic insights, and applications

Catalytic functionalization of alkynes with organoboron reagents provides a straightforward access to stereochemically defined multisubstituted alkenes, which are structural motifs commonly found in bioactive compounds and organic materials. Recent progress has substantially broadened the scope of this field on several fronts. Strategies for regioselectivity control in the 1,2-migratory insertion across unsymmetrical internal alkynes, as well as for the direct access to products with anti-insertion stereochemistry, have been devised. The alkenyl-to-aryl 1,4-metal migration upon metal insertion has been recently exploited in powerful cascade sequences leading to complex polycyclic scaffolds, including the development of enantioselective processes. Elegant enantiospecific and dynamic kinetic resolution methods have been developed for accessing chiral allenes from propargylic alcohol derivatives. Mechanistic manifolds have emerged based on single-electron transfer (SET) that have provided a fresh impetus for alkyne 1,2-difunctionalization with complementary stereoselectivity to processes relying on 1,2-insertion of R-M species. Herein, we discuss the most recent advances in transition-metal-catalyzed functionalization of alkynes using organoboron reagents, categorized according to the type of mechanistic outcome. Emphasis is placed on mechanistic aspects, synthetic utility, limitations, and challenges for future researchWe thank the Ministerio de Ciencia e Innovación (MICINN) and Fondo Europeo de Desarrollo Regional (FEDER, UE) for financial support (Agencia Estatal de Investigación/Project PGC2018-098660-B-I00). J.C. thanks the Ministerio de Educación, Cultura y Deporte (MECD), for an FPU fellowship. Inés Manjón is gratefully acknowledged for her assistance with the final edition of the manuscrip

Catalyzed Mizoroki–Heck Reaction or C–H activation

In the last few decades, research on the elaboration by palladium-catalytic processes of C-C bonds or the activation of C–H bonds has increased considerably. Yet there is still room for much improvement in terms of selectivity, or enantioselectivity, via the development of new ligands or the study of the catalytic effect of other metals to carry out the same chemical transformations. In addition, the attention paid to environmentally friendly methods in terms of the quantities of catalysts, ligands, and solvents is currently indispensable. The Mizoroki-Heck reaction is one of these important catalytic methods which generates C-C bonds in organic synthesis and is also possible by C-H activation. This book, titled “Catalyzed Mizoroki-Heck Reaction or C-H activation” focuses on new advances in the formation of C-C bonds or new C-H activation methods. It contains original research papers and short reviews on the synthesis of biologically active compounds using these catalytic processes, the identification of new catalysts, of new conditions allowing selectivity or enantioselectivity, the activity and stability of catalyst under turnover conditions, and all improvements in catalytic processes