Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 6 uppsatser.

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

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

La chimie des cinnamates ortho-fonctionnalisés est particulièrement riche et variée, comme en témoigne le nombre important de méthodologies de synthèse reposant sur leur utilisation comme substrats précurseurs d'hétérocycles d'intérêt biologique. En effet, suivant la nature du groupe fonctionnel et les conditions opératoires, des substrats à base cinnamique ont déjà été exploités avec succès pour la construction d'un large panel de squelettes hétérocycliques, allant de systèmes cycliques à cinq chaînons (benzofurane, indole, ...) à des cycles à six chaînons (coumarine, quinolin(on)e, ...). Dans ce contexte, ma thèse avait pour objectif principal d'apporter une contribution à cette chimie propre aux cinnamates ortho-fonctionnalisés. Le premier objectif de mon travail a porté sur le développement de nouvelles méthodes de synthèse hétérocyclique employant des cinnamates ortho-fonctionnalisés comme précurseurs. D'une part, une méthode de synthèse de coumarines et de quinolones 3-trifluorométhylées a été mise au point à partir de d'ortho-hydroxy- et d'ortho-aminocinnamates. Une étude mécanistique a également été conduite et a permis de mettre évidence la nature radicalaire de la réaction de trifluorométhylation concernée. D'autre part, nous avons évalué avec succès le potentiel synthétique d'ortho-azidocinnamates pour la construction photoinduite d'indoles et de quinoléines. Le second objectif de mon travail a concerné la conception, la synthèse et l'évaluation photophysique/photochimique de nouvelles sondes photoactivables luminescentes à base d'ions lanthanides. Dans ce cas, le motif cinnamique a été installé sur un complexe de lanthanide non luminescent afin de jouer le rôle d'antenne photoactivable. Après une première étude ayant permis de prouver le concept, toute une série de composés a été préparée afin d'établir des relations structures-propriétés, relations qui nous ont finalement permis d'optimiser la performance de cette nouvelle classe de sondes luminescentes photoactivables. / The chemistry of ortho-functionalized cinnamates is particularly rich and varied, as evidenced by the large number of methods using them as building blocks for the synthesis of biologically-relevant heterocycles. In fact, depending on the nature of the functional group and the reaction conditions, various cinnamic-based substrates have already been successfully employed for the synthesis of a wide range of heterocyclic skeletons, ranging from five-membered ring systems (benzofuran, indole, ...) to six-membered rings (coumarin, quinolin(on)e, ...). In this context, the main goal of my thesis was to make a significant contribution to the chemistry peculiar to ortho-functionalized cinnamates. The first objective of my work dealt with the development of new methods for heterocyclic synthesis using ortho-functionalized cinnamates as building blocks. On one hand, a method for the regioselective synthesis of 3-trifluoromethylated coumarins and quinolones was elaborated starting from ortho-hydroxy- and ortho-aminocinnamates. The reaction mechanism of this trifluoromethylation reaction was further investigated and was found to involve radical participation. On the other hand, ortho-azidocinnamates proved suitable building blocks to achieve the construction of indoles and quinolines via a solvent-dependent photochemical process. The second objective of my work was devoted to the design, synthesis and photophysical/photochemical evaluation of new photoactivatable luminescent probes based on lanthanide ions. In this case, a non-luminescent lanthanide complex was equipped with a cinnamoyl residue in order to act as a photoactivatable sensitizer. A preliminary study allowed us to validate the concept "OFF/ON", and then a series of probes was prepared in order to establish relevant structure-property relationships, hence enabling the optimization of this novel class of photoactivatable luminescent probes.

Les protéines à domaine PDZ, en très grand nombre dans le génome humain, sont impliquées dans des interactions protéine-protéine. Elles participent ainsi à véhiculer des signaux à l’origine de différentes pathologies (cancer, douleur….). L’interruption de l’interaction entre la protéine à domaine PDZ, PSD-95, et le récepteur de la sérotonine, 5-HT2A, entraîne une réduction de l’hyperalgie chez le rat neuropathique. Le développement de molécules capables d’inhiber cette interaction pourrait donc conduire à une nouvelle classe d’antalgiques.Nous avons réalisé, au cours de ces travaux, la synthèse de trois générations de ligands, comportant un noyau indolique, capables d’interagir avec le site S0, site très conservé des protéines à domaines PDZ. Dans un premier temps, nous avons préparé 15 biligands possédant un noyau indolique polysubstitué lié, via un espaceur de longueur variable (2 à 6 atomes de carbone), à différents acides aminés, dans le but d’interagir avec le site S1, montrant beaucoup de diversité en fonction du domaine. Nous avons ensuite, après une étude de relation structure/activité, développé deux autres générations d’indoles polysubstitués présentant notamment des substituants hydrophobes en position 5.Nous avons montré, par RMN HSQC 1H/15N et chromatographie d’affinité, que deux de ces composés sont des inhibiteurs de l’interaction PSD-95/5-HT2A et présentent de fortes interactions avec le site S0 de PSD-95. Ces molécules présentent également des propriétés antalgiques particulièrement intéressantes in vivo. Nous avons également déterminé, par RMN NOESY, la structure du complexe protéine/ligand pour ces deux composés. L’orientation d’une de ces molécules dans le site de la protéine nous permet d’envisager le développement d’une nouvelle génération d’indoles polysubstitués, pouvant interagir avec le site S1 de la protéine et permettant ainsi d’obtenir des inhibiteurs sélectifs de l’interaction PSD-95/5-HT2A. / Protein-protein interactions play a central role in the regulation of biological processes and represent a promissing class of therapeutic targets. It has been recently reported that disrupting the interaction between the PDZ protein PSD-95 and the serotonin receptor 5-HT2A induced an antihyperalgesic effect in diabetic rats. In this context, the development of original ligands capable to inhibit specifically this interaction could lead to a new class of analgesic compounds.We carried out the synthesis of three generations of ligands possessing an indole moiety in order to interact with the highly conserved carboxylate-binding loop (GLGF loop) of PSD-95. Two generations of compounds were developed to find out the position and the nature of the substituents furnishing the best interactions. One generation consists of a family of 15 biligands possessing a substituted indole moiety, coupled with a linker (having from 2 to 6 carbon atoms) via an amid function, ended with various amino acids to interact with the S1 site of the protein, in order to obtain specific ligands.By various biological evaluations, NMR HSQC 1H/15N, chromatography affinity assays and in vivo experiments, we identified two promising inhibitors of the interaction PSD-95/5-HT2A with strong interactions with S0 site of PSD-95. For these compounds, we determined the structure of the complex protein/ligand by NMR NOESY experiments. The orientation of one of these molecules in the S0 site allows us to envisage a new generation of ligands capable to interact with the S1 site of the protein.

Le noyau benzofuro[2,3-b]indoline est une structure complexe que l’on retrouve dans différentes substances naturelles telles que l’azonazine, la voacalgine A, la bipleiophylline ou encore le diazonamide A. Ces produits naturels possèdent une activité biologique intéressante et plus particulièrement le diazonamide A avec un IC50 inférieur à 15ng/mL sur plusieurs lignées cellulaires cancéreuses. De plus, certaines de ces substances n’ont jamais été synthétisées à ce jour. Lors de la biogénèse de ces composés, il est supposé que le motif benzofuroindoline est créé par un couplage oxydant entre un indole et un phénol. Nous avons ainsi entrepris de développer différentes méthodologies de synthèse biomimétiques du motif benzofuroindoline. Inspiré par les biosynthèses de l’azonazine et du diazonamide A, nous avons développé une arylation diastéréodivergente du tryptophane par la tyrosine. Les diverses méthodologies de synthèse de benzofuroindolines existantes effectuant ce couplage ne permettent pas un contrôle stéréosélectif. Nous avons remédiés à ce problème en réalisant une réaction de Friedel-Crafts entre une tyrosine protégée et des exo- et endo-bromopyrroloindolines issues stéréosélectivement du tryptophane. Cette réaction procède avec rétention de configuration et nous permettent une synthèse diastéréodivergente de précurseurs potentiels du diazonamide et de l’azonazine. Une méthodologie générale de synthèse de benzofuroindolines par un couplage oxydant direct entre des indoles 2,3-disubstitués et des phénols a été développée. Cette réaction implique l’oxydation de l’indole par du N-iodosuccinimide. L’iodoindolénine intermédiaire réagit par action d’un sel d’argent, via une réaction de Friedel-Crafts avec le phénol pour donner la benzofuroindoline en une étape. Une bibliothèque de diverses benzofuroindolines a pu être obtenue par cette stratégie.Cette dernière méthodologie a été appliquée à la synthèse de modèles hexacycliques complexes de la voacalgine A et de la bipleiophylline à partir d’indoles apparentées à la pleiocarpamine que nous avons synthétisés. Une autre stratégie de synthèse du motif benzofuroindoline de la voacalgine A et de la bipleiophylline impliquant l’oxydation d’un catéchol en orthoquinone a également été étudiée. / The benzofuro[2,3-b]indoline core is a complex structure present in several natural products such as azonazine, voacalgine A, bipleiophylline and diazonamide A. These products possess an interesting biological activity and especially diazonamide A with an IC50 below 15ng/mL on different cancer cells lines. Some of these compounds have never been synthesize. It is postulated that the biogenesis of the benzofuroindolines natural products implies an oxidative coupling between indoles and phenols. Therefore, we wished to develop a bioinspired synthesis of benzofuroindoline core.Inspired by the biosynthesis of azonazine and diazonamide A, we developed an diastereodivergent arylation of tryptophan by tyrosine. The existing synthetic methodology of benzofuroindoline involving an oxidative coupling do not allow a stereoselective control. We solved this problem by doing a Friedel-Crafts reaction between a protected tyrosine and the exo-, and endo-bromopyrroloindolines obtained stereoselectively from tryptophan. This reaction witch proceeds with a retention of configuration allowed us to access selectively azonazine and diazonamide A precursors. A general methodology of benzofuroindoline synthesis by an oxidative coupling between 2,3-disubstituted indoles and phenols has then been developed. This reaction proceeds by oxidation of the indole with N-iodosuccinimide. The resulting iodoindoline was then engaged in a Friedel-Crafts reaction with a phenol in presence of a silver salt to form the desired benzofuroindoline in a one-pot operation. Through this method, a library of several benzofuroindolines has been created.This last methodology has been applied to the synthesis of complex hexacyclic voacalgine A and bipleiophylline analogs from pleiocarpamine-like indoles. Another strategy towards the voacalgine A and bipleiophylline benzofuroindoline core has also been studied and involves the oxidation of a catechol into an orthoquinone which can react with an indole.

Les travaux de recherche présentés dans cet ouvrage ont été effectués dans le but de développer des catalyseurs pour la réaction d'halolactonisation énantiosélective. Deux approches différentes ont été réalisées. Dans l'introduction, il sera mention des précédents de la littérature sur la réaction d'halolactonisation énantiosélective. Aussi, une contrainte traitant d'une réaction en compétition lors de la réaction d'halolactonisation énantiosélective sera expliquée. Cette particularité devra être contournée lors du développement d'une nouvelle méthodologie asymétrique. Au premier chapitre, la première approche pour effectuer la réaction de façon énantiosélective sera abordée. Un cycle catalytique où il y aura oxydation d'un composé chiral d'iode (I) en iode (III) sera proposé. Au second chapitre, une autre méthodologie sera développée pour l'halolactonisation énantiosélective. Dans ce chapitre, les composés haloiodanes seront étudiés plus en profondeur. Leurs synthèses et leurs réactivités seront étudiées afin de mieux comprendre ces composés. Par la suite, un cycle catalytique impliquant un acide de Bronsted chiral sera développé. Au troisième chapitre, un sujet complètement différent sera traité, celui de la chimie des diazirines. Actuellement, les diazirines sont utilisées principalement comme source de carbènes, mais dans cet ouvrage il sera démontré que les diazirines peuvent agir comme source d'azote électrophile. Cette propriété est très intéressante et sera exploitée pour effectuer la synthèse d'indoles de façon expéditive et divergente.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Substituted heterocycles are common building-blocks for biologically relevant molecules and represent challenging synthetic targets. Due to limited methods available for their preparation and derivatization, direct C-H functionalization protocols offer considerable advantages. Radical chemistry has shown great potential in this regard; however traditional approaches are unattractive due to poor selectivity and harsh reaction conditions. Visible light photoredox catalysis, on the other hand, is a mild alternative for alkyl radical generation and has proven its utility in organic synthesis. The work encompassed in this thesis details the efforts towards the development of practical photoredox-based functionalizations of heterocycles. Specific focus is placed upon overcoming obstacles pertaining to H-atom abstraction, back electron transfer, and redox strength of photocatalysts to achieve efficient C-Br bond reductions, amine oxidations, and C-C bond formations. In pursuit of these objectives, a C2-selective malonation of indoles and other electron-rich heteroarenes was accomplished in high yields using photocatalyst Ru(bpy)3Cl2, p-CH3OC6H4NPh, and blue LEDs as the light source. Use of a triarylamine over a trialkylamine suppressed H-atom abstraction and promoted C-C bond formation. Subsequent exploitation of the reductive quenching cycle of Ru(bpy)3Cl2 and use of Cl3CBr as an alternative oxidant led to an oxidative nucleophilic trapping of tetrahydroisoquinolines to provide a diverse set of analogues. Finally, photoredox catalysis was utilized for the creation of C-C bonds in the context of complex molecule synthesis. A variety of bromopyrroloindolines and indoles were coupled to furnish C3-C3' and C3-C2' bisindole alkaloids, which was successfully applied to the total synthesis of gliocladin C and related analogues. Moreover, fine-tuning of the redox cycle with photocatalyst Ir(ppy)2(dtbbpy)PF6 and LiB(cat)2 as the reductive quencher enabled the coupling less-reactive substrates and suppression of back electron transfer.

No / When subjected to positive ion electrospray ionisation (ESI+) mass spectrometry (MS), indoles with a 3-alkyl substituent show a propensity to form novel [2M-H](+) 'covalently bound dimers'. This process, which appears to be initiated in the nebuliser of the instrument, is mechanistically interesting, analytically useful and potentially significant in organic synthesis. A selection of 2- and 3-substituted indoles have been synthesised and analysed by ESI-MS. The formation of the 'homo' and 'hetero' dimers of these compounds has been investigated using ESI+ mode. The mechanism of formation of the observed 'dimeric' species has been probed by synthesising authentic samples of the dimeric compounds. 'Dimeric' species corresponding to [2M-H](+) have been observed for all 3-substituted indoles studied, but not for indoles substituted in just the 2-position. By infusing equimolar mixtures of labelled and unlabelled indoles through the instrument, the expected approximately statistical mixture of homo- and heterodimeric species has been observed. Further experiments have established that this novel dimerisation occurs in the droplets formed in the nebuliser of the instrument. It has been shown that 3-substituted indoles form [2M-H](+) dimers in high abundance in the spray obtained from the nebiliser of an ESI+ instrument. The mechanism for the dimerisation does not involve the known 2M dimeric species that is readily formed in the solution-phase chemistry of indoles.