The research presented in this thesis is a project funded by the EU-network of the Marie Curie project NANO-HOST in collaboration with partner institutes. The aims of this network are to develop innovative methods for the preparation, recovery and reuse of single-site, nanostructured catalytic materials, and further on apply them in combination with specifically engineered reactors for a sustainable production process for making high value fine chemicals. One part of this project was to prepare chiral diphosphine ligands and their complexes for currently challenging reactions, such as asymmetric carbonylations (homogeneous catalysis). Catalytic studies of these chiral diphosphine ligands were carried out in asymmetric hydroxy-and alkoxy-carbonylations and hydrogenation reactions. The second part of this project was the heterogenisation of these chiral homogeneous complexes through collaborations with the network partners and furthermore their catalytic behavior was studied.

There is an increasing necessity for the pharmaceutical industry to develop enantiomerically pure drugs. Up till now, production of enantiomerically pure molecules has been provided by harvesting them from plants or utilising homogeneous catalysis and biocatalysis. None of these methods are efficient means of production, and attention is now being directed towards heterogeneous enantioselective catalysis as the preferred technique. This is on account of the high product yield and ease of separation of catalyst from the reaction mixture. Over the past few decades, a great deal of research has been conducted into investigating the Ni catalysed hydrogenation of β-ketoesters and Pt catalysed hydrogenation of α-ketoesters. These are the most successful systems for enantioselective heterogeneous catalysis. However, they are unsuitable for industrial purposes due to the low thermal and mechanical stability of the modified surfaces. The main goal throughout this project has been the investigation of surface-confined covalent reactions. The motivation of this research is to develop enantioselective heterogeneous catalysis; covalent networks are believed to infer the necessary thermal and chemical stability required to chirally modify catalytic surfaces for docking interactions with reactant species. Covalent organic frameworks (COFs) on surfaces hold potential for a number of chemical applications, and not just in the field of heterogeneous catalysis; for example in areas such as molecular electronics and templating.

With regard to a fast development in the field of fluoroorganic chemisty, the intention of this diploma thesis is focused to utilize of organocatalysis by secondary amines as catalysts for preparation enantiomerically pure compounds containing fluorine atom in its structure. The preparation of these subsances is realized by way of nucleofilic addition to α,β- unsaturated aldehydes using suitable fluorine containing nuclephilic agent 1-(fluoronitromethylsulphonyl)benzene, to get appropriate 1,4-adduct.

1. Enantioselective Pd(II)-Catalysed Nucleophilic Additions of 2- Alkylazaarenes The first project deals with enantio- and diastereoselective palladium(II)-catalysed nucleophilic additions of 2-alkylazaarenes to N-Boc imines and nitroalkenes. Under the optimised reaction conditions high levels of diastereo- and enantioselection of the addition products were achieved. Introduction of the electron-withdrawing group at the aryl ring of the substrate allows running the reaction under mild, experimentally convenient reaction conditions. The new described method allows the enantioselective synthesis of 2-(β-aminoalkyl)azaarenes, which are substructures found in drug candidates molecules for the treatment of type 2 diabetes and schizophrenia. 2. Synthesis of Spirocyclic Enones via Rh(III)-Catalysed C–H Functionalisation The second project describes the synthesis of spirocyclic enones by rhodium(III)- catalysed dearomatising oxidative annulation of 2-alkenylphenols with alkynes and 1,3-enynes. A good to high yield with great regioselectivity was obtained. The further synthetic utility of the product was also investigated and led to the formation of highly functionalised tetracycles via 1,6 conjugation addition reaction.

Amphibian alkaloids are attractive targets for synthesis due to their biological activity. An important class of amphibian alkaloids is the 2,5-disubstituted pyrrolidine-based family of compounds. There are many synthetic approaches for the preparation of the trans-2,5- disubstituted pyrrolidines, but methods for the construction of the cis-2,5-pyrrolidines are limited. Therefore, it was desired to develop an enantioselective approach for the preparation of cis-2,5-disubsituted pyrrolidines. (+)-Tropin-2-one derived from cocaine was used as starting material to exploit the inherent stereochemistry for construction of the cis-pyrrolidine ring. This permitted the unequivocal assignment of the absolute configuration of the target pyrrolidine. The structurally simple pyrrolidine alkaloid, 225H, was selected as a target to develop a general synthetic approach. The enantioselective synthesis of 225H was achieved in nine steps and good overall yield. The search for potent cannabinoid receptor partial agonist ligands as potential marijuana addiction therapeutic agents has led to an investigation of the synthesis of diaryl ether hybrid analogues of BAY 59-3074. A series of 2-(3-alkyl-5-hydroxyphenoxy)-6- (trifluoromethyl)benzonitriles, 3-(2-cyano-3-(trifluoromethyl)phenoxy)phenylalkanoates, and (3- (benzyloxy)phenoxy)-6-(trifluoromethyl)benzonitriles were synthesized and evaluated in vitro for CB1 affinity. The olivetol diaryl ether analogue was the most potent ligand of the alkyl series, but the diaryl ester analogues exhibited modest affinity for CB1 receptors. The most potent compound of the series was the 2-(3-(benzyloxy)phenoxy)-6- (trifluoromethyl)benzonitrile.

The development of peptides as catalysts for preparing optically active molecules is an ongoing investigation. Efforts at expanding the use of peptides are explored in two ways: investigating novel reactions in which peptides can act as asymmetric catalysts and through expanding the substrate scope of peptides in performing kinetic resolutions. Attempts at furthering the reaction scope of acylsulfonamide-containing peptides to act as BrØnsted acids through promoting the attack of 7-methyl oct-6-ene-1-tosylaziridine (9) by an internal π-nucleophile are discussed herein. Also reported is the use of pentameric peptides containing a π(-methyl)histidine residue in the kinetic resolution of the primary alcohol 4-hydroxymethyl cyclopent-2-enone (76) and the secondary aliphatic alcohol 2- pentanol. Moderate selectivities were observed in the kinetic resolution of 4-hydroxymethyl cyclopent-2-enone (76) and promising results were obtained in the initial screening of catalysts for the resolution of 2-pentanol. / Thesis (MS) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / General and efficient methods for catalytic enantioselective synthesis of tertiary alcohols prepared by the addition of C-Metal nucleophiles to ketones. / Thesis (MS) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. A Review of Catalytic Enantioselective Allylic Substitution (EAS) with Chiral Sulfonate Containing N-heterocyclic Carbenes (NHC). A comprehensive review of enantioselective allylic substitution reactions, which are promoted by a chiral N-heterocyclic carbene metal complex that features a unique sulfonate motif, is provided in this chapter. Reactions are classified into two categories. One class of transformations is catalyzed by a series of easily modifiable sulfonate bearing NHC-Cu complexes, with which a range of nucleophilic organometallic reagents (i.e., organozinc-, aluminum-, magnesium- and boron-based) that carry different carbon-based units are readily utilized in efficient and highly selective C-C bond forming processes. Another set of reactions exclude the use of a copper salt; catalytic amount of a sulfonate containing imidazolinium salt is capable of promoting additions of alkyl Grignard, zinc and aluminum species to easily available allylic electrophiles in a site- and enantioselective fashion. The mechanistic scenarios of both catalytic systems that account for the observed experimental data are discussed in detail. Chapter 2. Cu-Catalyzed Enantioselective Allylic Substitutions with Aryl- and Heteroarylaluminum Reagents. In this chapter, the first examples of EAS reactions of aryl- and heteroaryl-substituted dialkylaluminum reagents to a wide range of trisubstituted allylic phosphates are demonstrated through a facile and selective catalysis rendered possible by an in situ generated sulfonate containing NHC-Cu complex, delivering enantiomerically enriched olefin products that bear an all carbon quaternary stereogenic center. The requisite organometallic species are easily prepared from either the corresponding aryl- and heteroaryl halides, or through efficient and site selective deprotonation at the C-2 position of furan and thiophene; such aluminum entities are readily used in situ without the requirement of purification. Application to small molecule natural product synthesis is also carried out to illustrate the utility of the present protocol. Chapter 3. Cu-Catalyzed Enantioselective Allylic Substitutions with Alkenylaluminum Reagents. This chapter focuses on our research towards construction of enantioenriched tertiary and quaternary stereogenic centers that are substituted with two further functionalizable alkenes. The first combination of the study involves the addition of stereochemically well-defined trisubstituted alkenylaluminum reagents to disubstituted allylic phosphates; the transformation commences with a silyl-directed stereoselective hydroalumination and finishes with an enantioselective Cu-catalyzed EAS promoted by a sulfonate bearing NHC. Such reactions deliver molecules that feature silicon containing trisubstituted olefin adjacent to the tertiary stereogenic center; subsequent conversion of the versatile silicon group to a proton reveals the first set of examples that incorporate pure Z alkene in Cu-catalyzed EAS. The stereoselective and concise synthesis of naturally occurring small molecule nyasol demonstrates the utility of the above method. On a different front, Ni-catalyzed site-selective hydroalumination of terminal alkynes has opened new possibility of introducing 1,1-disubstituted olefins in Cu-catalyzed EAS in the formation of tertiary stereogenic center containing enantioenriched organic building blocks. Such catalytic hydrometallation procedure also allows efficient access to alkenylaluminums that are derived from the conventionally problematic aromatic alkynes. The importance of efficient and selective synthesis of terminal aryl-substituted alkenylaluminum species is showcased in NHC-Cu-catalyzed EAS reactions that construct all-carbon quaternary stereogenic centers; a three-step convergent synthesis of natural product bakuchiol in enantiomerically enriched form highlights the potential of the current protocol in chemical synthesis. Chapter 4 Cu-Catalyzed Enantioselective Allylic Substitutions with Alkenylboronic Acid Pinacol Ester Reagents and Applications in Natural Product Synthesis. Within this chapter, we disclose the efficient utilization of alkenylboron reagents in Cu-catalyzed EAS reactions, which lead to highly site and enantioselective formations of molecules that contain both tertiary and quaternary carbon stereogenic centers. Unlike their aluminum-based counterparts, the use of boron-based reagents allows effective delivery of sensitive organic function groups, such as a carbonyl, which would be incompatible in the hydrometallation process with dibal-H. Our efforts accumulate to the first report of incorporation of all carbon quaternary centers that are substituted with unsaturated ester and aldehyde units in the EAS products; such a method facilitates the concise diastereo- and enantioselective synthesis of Pummerer's ketone and it's trans isomer. Further development of the above protocol towards the construction of tertiary stereogenic centers requires the design of new chiral sulfonate-containing imidazolinium salts as the ligand precursors and has lead to the employment of a broader range of alkenylboron species, which feature readily functionalizable motifs. Subsequent demonstrations in enantioselective synthesis of a variety of small molecule natural products showcase the utility. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / This dissertation describes the first enantioselective 1,2-diboration of cis-substituted 1,3-dienes. In the presence of a platinum catalyst and TADDOL-derived phosphonite ligands, both 4,4-disubstituted and mono-cis-substituted 1,3-dienes undergo regioselective 1,2-diboration to afford the corresponding 1,2-diols upon oxidation in up to 98:2 er and high yield. By achieving enantioselective 1,2-diboration of 1,3-dienes, a new synthetic route to α-chiral (Z)-allylboronate reagents has been developed. In the presence of an aldehyde, these allyl bis(boronate) esters undergo highly diastereoselective allylboration reaction to afford enantioenriched 1,5-homoallylic alcohols bearing all-carbon quaternary centers or syn-propionate motifs. In the presence of 1,4-dicarbonyl compounds, the (Z)-allylboronates undergo a double allylation reaction to afford cyclohexanols with four contiguous stereocenters in good yield and moderate to excellent diastereoselectivity. The tandem diboration/double allylation has been applied to the total synthesis of pumilaside B aglyon, and the partial synthesis 1β-hydroxy arbusculin A and bromophycolide F. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 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.