The abstract is the summary of three different projects all centered around the generalidea of catalysis which is the general theme of research in the Michaelis laboratory. The firstproject focuses on development of a new heterogeneous catalyst for selective catalysis. In theMichaelis lab, we were interested in the potential of nanoparticle catalysts for regioselectivetransformations. We showed that polymer supported ruthenium nanoparticles performed as areliable catalyst for regioselective reduction of azide to amine. In our study of regioselectivereduction of multiple azide containing substrates, we observed that in presence of ourruthenium nanoparticle catalysts, the least sterically hindered azide group reduced to aminefunctional group. The results were complementary to the conventional methods that employtriphenyl phosphine (Staudinger reaction) as the reductant and target the most electronicallyactive azide group.In the second project, we were looking to develop a new class of hetero-bimetallicNickel-Titanium complexes as an efficient catalyst for organic transformations. We designedand synthesized numerous bidentate ligands including NHC-Phosphine ligand. Our kineticstudies on the Suzuki cross coupling of allylic alcohols and phenyl boronic esters showed thatthe bidentate nature of the ligand was necessary for the success of the catalytic process. Theligand was proved to stabilize the catalyst in the solution by increasing the lifetime of thenickel (0) in the reaction medium. We also discovered a new cooperative titanium-nickelsystem for mild allylic amination of allyl alcohols. The system also represents an idealcatalyst for tandem cyclization amination process.In the Michaelis lab, we were also interested to explore the ability of bimetalliccomplexes in C-H functionalization process. Our efforts in this project led to the discovery ofnew Pallladium dimer complexes with two palladium centers in oxidation state of (I). Thecatalyst showed unique reactivity in C-C bond activation/functionalization. We have alsodiscovered that in presence of catalytic amount of triflic acid and stoichiometric amount ofphenyl boronic acid, cinnamyl alcohol undergoes a boron template dimerization/cyclization.The reaction represents a great synthetic pathway for the synthsis of bis homoallylic alcohols.

Curdlan, a (1,3)-linked linear homopolysaccharide composed of beta-D-glucan, is produced by the bacterium Alcaligenes faecalis var. myxogenes. Several strategies to synthesize chemically modified curdlan derivatives have been reported, but there have been few reports of regioselective functionalization at specific positions of the curdlan backbone, especially of aminated curdlan derivatives which have remarkable potential in biomedical and pharmaceutical applications. We demonstrate herein the design, synthesis and characterization of a family of regioselectively aminated curdlan derivatives including 6-deoxy-6-(bromo/azido/amino/amido/ammonium) curdlans starting from 6-bromo/azido-6-deoxycurdlan. A key reaction that enabled the whole synthesis of new curdlan derivatives at C-6 described in this dissertation was the highly selective bromination of curdlan. The resultant 6-bromo-6-deoxycurdlan, prepared with high regioselectivity, was treated with trialkylamines or heterocyclic amines to produce a range of water-soluble curdlan ammonium salts. The bromide was then nucleophilically displaced by sodium azide to produce the versatile precursor 6-azido-6-deoxycurdlan. Its water solubility was enhanced either by the incorporation of hydrophilic trioxadecanoate esters into O-2/4 positions or by the borohydride reduction to afford 6-amino-6-deoxycurdlan. The iminophosphorane intermediate generated during Staudinger reactions was further investigated for subsequent syntheses: i) 6-amino or 6-amido-6-deoxycurdlan by in situ reaction with water or excess carboxylic anhydride, ii) 6-monoalkylamino curdlan by reductive amination using aldehydes and sodium cyanoborohydride, and iii) 6-dialkylamino-/tri-alkylammoniocurdlans by reacting with methyl iodide. Such derivatives could have properties useful for a range of biomedical applications, including interactions with proteins, encapsulation of drugs, and formulation with genes or other biological compounds. / Ph. D.

The thesis entitled “Regioselective Functionalization of Indoles using Directing Group Strategy: An Efficient Transition Metal Catalysis” is divided into two sections. Section A, which is presented in three chapters, describes the regioselective alkenylation of indoles using directing group strategy. Whereas, Section B, which is divided in to two chapters, narrates the synthesis of 4-amino indoles using directing group strategy and site selective addition of maleimide to indole at C2-position. Section A Chapter 1. C2-Alkenylation of indoles The indole ring system is one of the most abundant heterocycles present in nature. The synthesis and functionalization of indoles is one of the major areas of focus for synthetic organic chemists.1 Alkenylation of indole at C2-position is a challenging task due to the electrophilic nature of the reaction. For this reason, the functionalization of indole at C2-position is less addressed. In this chapter, a highly regioselective alkenylation of indole at the C2-position has been described by using the Ru(II) catalyst and employing a directing group (DG) strategy.2 This directing group strategy offers rare selectivity for the alkenylation of N-benzoylindole at the C2-position in the presence of the more reactive C3-position. A variety of N-benzoylindole derivatives are shown to undergo alkenylation at C2-positon. Deprotection of the benzoyl group has also been demonstrated, and the resulting products serve as a useful synthon for synthesizing a variety of natural products. A few representative examples are highlighted in Scheme 1.3 1 (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Karamyan, K. A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. 2 (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788. (c) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. 3 Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818. Scheme 1: C2- Alkenylation of indoles Chapter 2 describes a highly regioselective alkenylation of indoles at the C4-position by employing aldehyde functional group as a directing group, and Ru as a catalyst, under a mild reaction conditions. This approach leads to a short synthetic route for C4-alkenylated indoles, which serve as precursors for ergot alkaloids and related heterocyclic compounds.4 Further The potential of the present strategy has been demonstrated by performing (i) scale up reaction, (ii) selective reduction of olefin double bond and (iii) synthesizing substituted 1,3,4,5-tetrahydrobenzo[cd] in two steps with an overall yield of 68%. 1,3,4,5-Tetrahydrobenzo[cd] is one of the key intermediates for synthesizing ergot alkaloids. A few examples are highlighted in Scheme 2.5 4 (a) Horwell, D. C. Tetrahedron 1980, 36, 3123. (b) Kozikowski, A. P.; Ishida, H. J. Am. Chem. Soc. 1980, 102, 4265. (c) Oppolzer, W.; Grayson, J. I.; Wegmann, H.; Urrea, M. Tetrahedron 1983, 39, 3695. (d) Hatanaka, N.; Ozaki, O.; Matsumoto, M. Tetrahedron Lett. 1986, 27, 3169. (e) Horwell, D. C.; Verge, J. P. Phytochemistry 1979, 18, 519. 5 anke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262. Scheme 2: C4- Alkenylation of indoles Chapter 3 of Section A, presents a novel mode of selective alkenylation of indoles using Ru and Rh catalyst. In these alkenylation reactions, selectivity between C2- and C4-positions of indole framework has been achieved by altering the property of directing group. Methyl ketone, as directing group, furnishes exclusively C2-alkenylated product, whereas trifluoromethyl ketone as a directing group changes the selectivity to C4, indicating that electronic nature of the directing group controls the choice between a 5-membered and 6-membered metallacycle. Developing such divergent and selective C-H functionalizations, between C2- and C4-positions, on the indole framework can lead to easy and short synthetic routes for natural, unnatural and biologically-active compounds.6 Further screening of other carbonyl derived directing groups revealed that strong and weak directing groups exhibit opposite selectivity. Experimental 6 (a) Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832. (b) Nathel, N. F. F.; Shah, T. K.; Bronner, S. M.; Garg, N. K. Chem. Sci., 2014, 5, 2184. (c) A Beilstein/Crossfire search shows that more than 600 C4- substituted indole-containing natural products exist and nearly 10,000 bioactive C4-substituted indoles have been reported. controls, deuteration experiments and preliminary DFT calculations lend support to the proposed mechanism. A few representative examples are highlighted in Scheme 3.7 Scheme 3: C4- vs C2-Alkenylation of ndoles Deuterium Labeling studies were carried out to shed light on the site of metallacycle formation and hence the origin of selectivity. Both COCF3 and COCH3 substrates were independently subjected to both standard conditions A and B, along with either D2O or AcOD as deuterium sources (Scheme 4). 7 Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Manuscript submitted. Scheme 4: Deuterium labeling studies The Section B is divided into 2 chapters. Chapter 1 presents a method for synthesizing of 3-(indol-2-yl) succinimide derivatives by using a directing group strategy. Selective functionalization at C2-position of indole in the presence of highly reactive C3-position has been achieved. A conjugate addition, instead of Heck-type reaction, has been achieved by careful selection of the alkene partner (maleimides and maleate esters). This selectivity has been achieved by avoiding β-hydride elimination. Succinimide derivatives are structural motifs that are found in many natural products and drug molecules. Moreover, succinimides can be easily reduced into 5-membered pyrrolidine rings, γ-lactams and lactims, which are part of structural scaffolds of useful natural products.8 Further the application of the protocol has been showcased by performing reduction to obtain pyrrolidine and 1,4 diols. A few representative examples are highlighted in Scheme5.9 8 (a)Crider, A. M.; Kolczynski, T. M.; Yates, K. M. J. Med. Chem. 1980, 23, 324. (b) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577. (c) Uddin, J.; Ueda, K.; Siwu, E. R. O.; Kita, M.; Uemura, D. Bioorg. Med. Chem. 2006, 14, 6954. (d) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437. (e) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N. Tetrahedron 1978, 34, 179. 9 Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Org. Lett. 2015, 17, 4662. Scheme 5: Addition of Maleimide to Indole at C2-position Chapter 2 describes a highly regioselective amidation of unprotected indoles at the C4-position by employing aldehyde functional group as a directing group. This reaction has been performed using Ir(III) catalyst, under mild reaction conditions. Thus, an efficient, simple, short synthetic route for C4-amido indoles has been achieved. C4-Amido indoles are privileged molecules, which serve as precursors for indolactum V,10 teleocidin and related heterocyclic compounds.11 To the best our knowledge, this is the first report of using aldehyde as a directing group for amidation reactions. The potential of the present strategy has been demonstrated by performing scaling up reaction, and deprotection of tosyl group to obtain corresponding amines. A few representative examples are highlighted in Scheme 6.12 10 Garg, N. K. et al., J. Am. Chem. Soc. 2011, 133, 3832 11 Kehler, J. J. Med. Chem. 2014, 57, 5823 12 Lanke, V.; Prabhu, K. R. (Manuscript submitted). Scheme 6: C4- amidation of indoles 7

[Alpha]-Amino ketones can serve as important intermediates for the synthesis of biologically active molecules, and making these precursors in a practical manner has long been a challenge for organic chemists. The oxygen-carbon-carbon-nitrogen (O-C-C-N) sequence is common in natural and synthetic compounds of biological interest, due in part to their relatedness to peptides. Because of the many known carbonyl transformations, [alpha]-amino ketones have the potential to form various amine derivatives. Herein we present our research endeavors which led to several novel methods of forming this type of functionality. These endeavors culminated with the development of a two-step hydrazidation/N-N bond cleavage technique for forming [alpha]-amino ketals--which can be readily hydrolyzed to [alpha]-amino ketones. / text

No description available.

The advent of transition metal catalysis has greatly expanded the scope of viable cycloaddition reactions, allowing for the direct synthesis of highly functionalized and complex biologically active compounds. By manipulating various aspects of catalyst structure, including the supporting ligands and the central metal, the function of a catalyst can be modified. In this context, the catalytic properties of dinuclear complexes have not been greatly explored in cycloaddition reactions. Our research has focused on studying the catalytic properties of dinuclear complexes in cycloaddition reactions. Comparative studies between dinuclear and mononuclear Ni-complexes led us to discover and develop an efficient route to synthesize 1,2,4-trisubstituted benzene derivatives from terminal alkynes. The key organometallic intermediates in this process were isolated, and computational studies were performed to unravel a novel bimetallic mechanism for alkyne cyclotrimerizations. As an extension of this study, we have found that the dinuclear catalyst is capable of catalyzing the methylenecyclopropanation of olefins. The reaction uses 1,1-dichloroalkene as a vinylidene precursor along with Zn as a stoichiometric reductant. A wide range of monosubstituted terminal alkenes and relatively unhindered internal alkenes are viable substrates. Furthermore, to understand the mechanism of vinylidene transfer, various stoichiometric and stereochemical experiments were performed. Furthermore, we discovered that mononuclear and dinuclear Ni-complexes are highly efficient in achieving vinylidene insertions into Si–H bonds to synthesize Si-containing heterocyclic molecules. Ongoing efforts are directed toward optimizing the reaction conditions and elucidating the substrate scope of the reaction.

Parmi les analogues de sucres, les iminosucres constituent la classe la plus prometteuse au niveau biologique. En effet, leur structure, dans laquelle l'atome d'oxygène intracyclique est remplacé par un atome d'azote, leur confère des propriétés uniques d'inhibition de glycosidases et/ou glycosyltransférases, et en fait donc de très bons candidats thérapeutiques. L'introduction d'un substituant pseudo-anomérique carboné permet de mimer la partie aglycone du substrat de l'enzyme et d'accéder aux iminosucres C-glycosides, des composés chimiquement stables qui sont des inhibiteurs sélectifs et puissants des glycosidases.Afin d'accélérer la découverte de molécules d'intérêt thérapeutique, il est nécessaire de trouver des voies de synthèses conduisant à une plus grande diversité structurale. La méthodologie que nous avons mise au point est basée sur la débenzylation régiosélective de la position 2 de C-allyl glycosides exploitant une iodocyclisation. Cette dernière a été appliquée avec succès à la C-allyl-1-déoxynojirimycine puis étendue à plusieurs iminosucres de configurations variées en séries pipéridine et pyrrolidine.L'introduction de diversité moléculaire a été réalisée à partir de la C-allyl-1-déoxynojirimycine O-débenzylée régiosélectivement en position 2. Nous avons ainsi obtenu plusieurs iminosucres de configurations D-gluco- et D-manno- portant différentes fonctionnalités en position 2. La mise au point de cette synthèse a donc permis d'accéder à une grande variété de C-allyl iminosucres à partir d'un synthon unique. L'accès à des iminosucres bicycliques de structures inédites a également été possible en exploitant un C-allyl 2-céto iminosucre obtenu par notre méthodologie de débenzylation régiosélective. / Iminosugars constitute undoubtedly the most promising class of sugar analogues, their unique glycosidase and/or glycosyltransferase inhibition profile making them promising therapeutics. To generate more potent and selective inhibitors called C-glycoside iminosugars, introduction of a stable pseudoanomeric substituent is usually performed, the improved efficacy being attributed in part to the information brought by the aglycon moiety.The main challenge associated with this class of iminosugars C-glycosides is currently the design of efficient and general routes enabling introduction of structural diversity at a late stage from advanced synthons to accelerate the discovery of biologically relevant molecules. In this context, we have explored a strategy based on a regioselective debenzylation at C-2 and a stereocontrolled nucleophilic substitution assisted by the N-benzyl group. We have successfully applied this methodology on the C-allyl-1-deoxynojirimycin and extended it to several iminosugars in the piperidine and pyrrolidine series.The introduction of molecular diversity was performed from the C-allyl-1-deoxynojirimycin selectively O-debenzylated at position 2. We obtained several iminosugars in the D-gluco- and D-manno- series bearing various functionalities at position 2. This strategy allowed us to access a wide range of C-allyl iminosugars from one single synthon. We have also described the access to unknown bicyclic iminosugars starting from a C-allyl 2-keto iminosugar obtained by our regioselective debenzylative methodology.

The synthetic progress towards yaku'amide A is described. The study leads to development of new synthetic methodologies. Base-free regioselective aminohydroxylation is convenient to deliver β-tert-hydroxyamino acids. A sequence consisting of alkylative esterification, Martin sulfurane mediated anti dehydration, a tandem azide reduction-O→N acyl transfer allows the rapid access of E- and Z-dehydroisoleucine-containing peptides from β-tert-hydroxyisoleucine derivatives. Those methods are effective in constructing complicated peptides and advanced subunits of yaku'amide A.

In this thesis, carbohydrate mimicry is investigated through the syntheses of carbohydrate analogues and evaluation of their inhibitory effects on carbohydrate-processing enzymes. Galactofuranosides are interesting structures because they are common motifs in pathogenic microorganisms but not found in mammals. M.tuberculosis, responsible for the disease tuberculosis, has a cell wall containing a repeating unit of alternating (1→5)- and (1→6)-linked β-D-galactofuranosyl residues. Synthetic inhibitors of the enzymes involved in the biosynthesis of the cell wall could find great therapeutic use. The first part of this thesis describes the first synthesis of the hydrolytically stable carbasugar analogue of galactofuranose, 4a-carba-β-D-Galf, and the synthetic work of synthesising β-linked pseudodisaccharides containing carba-Galf, which were tested for glycosyltransferease inhibitory activity. The pseudodisaccharide carba-Galf-(β1→5)-carba-Galf was found to be a moderate inhibitor of the glycosyltransferase GlfT2 of M.tuberculosis. The thesis also describes how a general method towards biologically relevant α-linked carba-Galf ethers was developed. The final part of this thesis is focussed on the formation of nitrogen-linked monosaccharides without the participation of the anomeric centre. Such a mode of coupling is called tail-to-tail neodisaccharide formation. The couplings of carbohydrate derivatives via the Mitsunobu reaction are successfully reported herein. The method describes the key introduction of an allylic alcohol in the electrophile and the subsequent functionalisation of the alkene to obtain the neodisaccharide. Two synthesised neodisaccharides presented in this thesis have been sent to be tested for glycosidase inhibitory activity. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.

In the context of ongoing efforts toward C-aryl glycoside synthesis, a recently developed approach to form C-aryl glycals from 2-deoxysugar lactones was expanded to form novel substrates. This approach has been applied to the synthesis of various furyl glycals, allowing access to C-aryl glycals via a benzyne furan (4+2) cycloaddition methodology. The hydroboration-oxidation of said C-aryl glycals has allowed access to C(2)-oxygenated C-aryl glycosides via the benzyne cycloaddition approach. An approach to the total synthesis of 5-hydoxyaloin A is detailed, in which regioselective benzyne furan (4+2) cycloadditions were achieved via the use of a silicon tether. Two approaches to the anthrone core have been applied; one in which an unsymmetrically-substituted aryl ring is first constructed by means of a silicon tether, and one in which the unsymmetrically-substituted ring is formed last, also utilizing a silicon tether. The latter approach has allowed access to the anthrone core of 5-hydroxyaloin A, and only a final desulfurization remains in order to access the natural product. / text