Synthesis, resolution and biological applications of water-soluble Cationic [4]helicenes

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Thesis

Reference

Synthesis, resolution and biological applications of water-soluble Cationic [4]helicenes

MEHANNA, Nathalie

Abstract

Ce travail de thèse s'inscrit dans la fonctionnalisation des DMQA, une classe spéciale d'hélicènes cationiques, en modifiant les chaines latérales pour des applications biologiques.

Ces chaines latérales polaires et de différentes longueurs ont influencé énormément leur protocole de dédoublement considéré auparavant infaillible et la séparation des dérivés correspondants a nécessité des conditions optimisées sur colonne semi-préparative de haute performance (HPLC) pour isoler les molécules désirées (rendements de 82 à 95%). Des études photophysiques de ces composés effectuées pour la première fois, ont démontré un mode de liaison stéréoselectif vis-à-vis de l'ADN, surtout pour l'énantiomère d'hélicité M. Une nouvelle famille de DMQA biotinés a également été synthétisée et a fait l'objet d'une autre étude photophysique ciblant la compréhension des mécanismes à la surface et à l'intérieur d'une protéine. D'autres travaux ont été effectués par la suite, notamment une umpolung des dérivés cationiques en dérivés carbanioniques nucléophiles avec d'excellents résultats [...]

MEHANNA, Nathalie. Synthesis, resolution and biological applications of water-soluble Cationic [4]helicenes. Thèse de doctorat : Univ. Genève, 2010, no. Sc. 4253

URN : urn:nbn:ch:unige-145523

DOI : 10.13097/archive-ouverte/unige:14552

Available at:

http://archive-ouverte.unige.ch/unige:14552

Disclaimer: layout of this document may differ from the published version.

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Département de chimie organique Professeur Jérôme Lacour

Synthesis, Resolution and Biological Applications of Water-Soluble Cationic [4]Helicenes

THÈSE

présentée à la Faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention chimie

par

Nathalie MEHANNA

de Akoura (Liban)

Thèse N° 4253

GENÈVE

Atelier d’impression ReproMail-UniMail

2010

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Les résultats rapportés dans ce manuscrit ont été obtenus dans le cadre d’un travail de thèse réalisé au sein du laboratoire du Prof. Jérôme Lacour, dans le département de Chimie Organique de l’Université de Genève, du 01 décembre 2005 au 20 avril 2010.

Je tiens à exprimer ma reconnaissance au Prof. Jérôme Lacour pour m’avoir permis de réaliser ce travail de thèse au sein de son laboratoire, pour la confiance et l’autonomie qu’il m’a accordées.

Je voudrais remercier le Dr. Narcis Avarvari, du Laboratoire Chimie et Ingénierie Moléculaire (Angers, France) et le Dr. Jiri Mareda, de l’Université de Genève, pour avoir eu l’amabilité de bien vouloir juger ce travail de thèse.

J’exprime toute ma gratitude aux personnes du service RMN (André Pinto, Rupali Shivapurkar et le Dr. Damien Jeannerat) pour leur compétence et leur disponibilité, au service de spectrométrie de masse notamment Philippe Perrotet et Eliane Sandmeier, au Dr. Gérald Bernardinelli pour la détermination de structures par diffraction des rayons X.

Toute ma reconnaissance est aussi dédiée au Prof. Zhiming Li de l’Université de Fudan (Chine) et au Dr. Jiri Mareda et Daniel Emery de l’Université de Genève pour les calculs théoriques, ainsi qu’à Alexandre Fürstenberg, Oksana Kel et Dr. Petr Sherin du groupe du Professeur Eric Vauthey pour les études physiques

J’aimerais remercier également Mireille Heimindenger pour son aide administrative, ainsi que les techniciens Maud Marot et Stéphane Grass et l’apprenti Jérémy Dorenbos.

Je voudrais chaleureusement saluer les personnes qui m’ont le plus soutenues durant ces 4 années, mes amis qui ont toujours cru en mes capacités aussi bien humaines que chimiques, notamment Aude, Carlotta, Jihane ainsi que Ludovic, Jezabel et Chrysanthi pour le soutien et les moments rigolos quand je prenais ma pause de rédaction dans leur labo.

Je n’oublie pas que ces quatre années passées m’ont permis de faire des amitiés de toutes les provenances et nationalités.

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Enfin, je tiens à remercier tout particulièrement ma famille pour la confiance et leur soutien tout au long de ces années, surtout aux moments les plus difficiles. Je suis infiniment chanceuse de vous avoir à mes côtés.

Un MERCI du fond du cœur à ma mère, à qui je dédie tout ce travail. Sans toi, je n’aurai jamais pu aller de l’avant, tu as su me souffler ta force et ta volonté, une force inébranlable en toutes circonstances. Je ne saurai jamais te remercier assez. Je t’aime!

" I learned that courage was not the absence of fear, but the triumph over it..."

- N.Mandela

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A mon Père, A ma Mère,

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iv ADOTA: azadioxatriangulenium

br: broad signal

CSP: chiral stationary phase CD: circular dichroism

COSY: ¹H‐¹H correlation spectroscopy CV: crystal violet

d: doublet

CH2Cl2: dichloromethane d.e.: diastereomeric excess d.r.: diastereomeric ratio DAOTA: diazaoxatriangulenium DMAP: 4‐dimethylaminopyridine DMQA: dimethoxyquinacridinium DMSO: dimethylsulfoxide

ECD: electronic circular dichroism EtOH: ethanol

e.e.: enantiomeric excess ent: enantiomer

equiv.: equivalent

ESI: electrospray ionization e.r.: enantiomeric ratio Et2O: diethyl ether

HOMO: higher occupied molecular orbital iPrOH: isopropanol

LUMO: Lower unoccupied molecular orbital MS: Mass spectrometry

NMR: Nuclear magnetic resonance

ppm: part per million q: quartet

rac: racemic

Rf: retardation factor RT: room temperature s: singlet

Boc: tert‐butoxycarbonyl t: triplet

TATA: triazatriangulenium THF: tetrahydrofuran

TLC: thin layer chromatography UV: ultraviolet

Symbols

δ: chemical shift

ΔG≠: free energy of activation ΔH≠: enthalpy of activation ΔS≠: entropy of activation ΔG°: Gibbs free energy ε: extinction coefficient λ: wavelength

c: concentration J: coupling constant a = selectivity factor T: temperature t1/2: half life tR: retention time

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Units

°: degree

°C: degree Celsius cal: calories K: Kelvin μl: microliter

mL: milliliter mol: mole mmol: millimole M: molarity s: second min: minute h: hour Å: angstrom nm: nanometers g: grams

mg: milligrams Hz: Hertz

a = selectivity factor T: temperature t1/2: half life tR: retention time

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vi

Résumé

Les premiers hélicènes ont été décrits au début du 20^ème siècle,¹ mais leurs méthodes de synthèse dépendaient toujours de la molécule en question et nécessitaient des voies relativement difficiles à mettre en œuvre.² La découverte dans les années 1960 d’une voie photochimique simple à mettre en œuvre a ravivé ce domaine rendant accessible une panoplie de dérivés.³ Mais la limitation de cette méthode à quelques groupes fonctionnels a suscité d’autres recherches pour obtenir des méthodes plus universelles. D’un autre côté, le développement de cette famille de composés a suscité un vif intérêt par leurs applications dans divers domaines de la science et de la vie courante ce qui a poussé les chercheurs à obtenir ces composés chiraux sous forme d’énantiomères purs.⁴

Une classe spéciale d’hélicènes cationiques, les diméthoxyquinacridiniums (DMQA 1, Schéma 1) a vu le jour en 2000.⁵ Notre groupe a mesuré la barrière de racémisation de ces composés qui s’est avérée être particulièrement élevée pour un hélicène.⁶ Le groupe Lacour a poursuivi l’étude de ces composés et a développé un processus de dédoublement efficace en trois étapes via (i) l’addition d’un sulfoxyde enantiopur,⁷ (ii) une séparation chromatographique des diastéréoisomères résultants et (iii) une fragmentation de Pummerer, processus possible uniquement grâce à la stabilité exceptionnelle des cations générés.⁸

1 Meisenheimer, J.; Witte, K. Chem. Ber. 1903, 36, 4153.

2 Martin, R. H. Angew. Chem., 1974; Vol. 86, pp 727-738. Meurer, K. P.; Vögtle, F. Top. Curr. Chem. 1985, 127, 1- 76. Laarhoven, W. H.; Prinsen, W. J. C. Top. Curr. Chem. 1984, 125, 63-130. Rowan, A. E.; Nolte, J. M. Angew.

Chem., Int. Ed. 1998, 37, 63−68; Katz, T. J. Angew. Chem., Int. Ed. 2000, 39, 1921−1923. Urbano, A. Angew.

Chem. Int. Ed. 2003, 42, 3986-3989 and references therein.

3 Mallory, F. B.; Wood, C. S.; Gordon, J. T. J. Amer. Chem. Soc. 1964, 86, 3094-3102. Liu, L.; Katz, T. J.

Tetrahedron Lett. 1991, 32, 6831-6834. Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem. 1991, 56, 3769-3775.

4 Weix, D. J.; Dreher, S. D.; Katz, T. J. J. Am. Chem. Soc. 2000, 122, 10027-10032. Phillips, K. E. S.; Katz, T. J.;

Jockusch, S.; Lovinger, A. J.; Turro, N. J. J. Am. Chem. Soc. 2001, 123, 11899-11907. Terfort, A.; Gorls, H.;

Brunner, H. Synthesis 1997, 79-86. Kitahara, Y.; Tanaka, K. Chem. Commun. 2002, 932-933. Xu, Y.; Zhang, Y. X.;

Sugiyama, H.; Umano, T.; Osuga, H.; Tanaka, K. J. Am. Chem. Soc. 2004, 126, 6566-6567. Honzawa, S.; Okubo, H.; Anzai, S.; Yamaguchi, M.; Tsumoto, K.; Kumagai, I. Bioorg. Med. Chem. 2002, 10, 3213-3218. Amemiya, R.;

Yamaguchi, M. Org. Biomolec. Chem. 2008, 6, 26-35.

5 Laursen, B. W.; Krebs, F. C. Angew. Chem. Int. Ed. Engl. 2000, 39, 3432-3434.

6 Herse, C.; Bas, D.; Krebs, F. C.; Bürgi, T.; Weber, J.; Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem.

Int. Ed. 2003, 42, 3162-3166.

7 Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Int.

Ed. Engl. 2005, 44, 1879-1883.

8 Laleu, B.; Machado, M. S.; Lacour, J. Chem. Commun. 2006, 2786-2788.

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Schéma 1. Méthode de dédoublement des derivés racémiques de DMQA 1 via l’addition d’un sulfoxyde énantiopure (+)-(R)-9

Ce travail de thèse s’est inscrit dans la fonctionnalisation de ces dérivés pour introduire des chaines latérales compatibles à des études en milieux biologiques. La présence de chaines latérales polaires et de différentes longueurs a eu une grande influence sur le protocole de dédoublement et la séparation des diastéréoisomères correspondants. Le recours à la séparation sur colonne semi-préparative de haute performance (HPLC) a néanmoins permis l’obtention des molécules désirées (avec des rendements allant de 82% à 95%) qui ont subi la fragmentation de Pummerer, pour redonner les hélicènes cationiques sous forme énantiopure (Chapitre II). Suite à une collaboration avec le groupe du Prof. Eric Vauthey, des études photophysiques de ces composés ont ainsi démontré un mode de liaison stéréoselectif vis-à-vis de l’ADN, surtout pour l’énantiomère d’hélicité M (Chapitre III).

L’utilisation par la suite de la 1,3-cycloaddition des alcynes et des azides catalysée par le cuivre (I), plutôt connue sous le nom de «click chemistry», a permis l’accès à une nouvelle famille de dérivés biotinés qui ont fait l’objet d’une autre étude photophysique ciblant la compréhension des mécanismes à la surface et à l’intérieur d’une protéine (Chapitre IV). Les résultats préliminaires issus de cette collaboration sont rapportés à la fin du chapitre.

Le chapitre V résume d’autres travaux envisageables à l’aide de ces carbocations étonnants. Ces derniers ont débuté au cours de ce doctorat; notamment une umpolung des dérivés cationiques mentionnés précédemment en dérivés carbanioniques nucléophiles. En effet, cette méthodologie qui consiste à réduire le centre electrophile par un hydrure et de le déprotonner par la suite pour qu’il agisse comme nucléophile a été efficace dans la formation de divers produits d’addition neutre avec d’excellents rendements (82-92%).

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viii

Summary

The first helicenes were reported in the early 20^th century.¹ At the time, synthetic access depended highly of the expected target and these compounds were forgotten for a while.² With the discovery of the photochemical method in the 1960s, a renewed interest in this chemistry was seen and a wide variety of helical molecules was reported.³ However, limitations as far as functional group tolerance revived the search for new synthetic ways, as well as the discovery of many applications for such a family of compounds in various fields of science and in everyday life.⁴

A special class of cationic helicenes, known as the dimethoxyquinacridinium salts (DMQA 1, Scheme 1) was reported by Laursen and Krebs in 2000.⁵ In collaboration, our group has measured their barrier of racemisation which was shown to be among the highest reported to date for helicenes.⁶ Subsequently, the Lacour group has kept a keen interest in these derivatives and successfully developed a new efficient route to resolve them via (i) the addition of an enantiopure sulfoxide,⁷ (ii) the chromatographic separation of the resulting diastereoisomers and (iii) the discovery of an unprecedented Pummerer fragmentation pathway invaluable for the regeneration of the cations in enantiopure form.⁸ This last step is due to the extreme stability of the cationic species involved.

1 Meisenheimer, J.; Witte, K. Chem. Ber. 1903, 36, 4153.

Chem. Int. Ed. 2003, 42, 3986-3989 and references therein.

3 Mallory, F. B.; Wood, C. S.; Gordon, J. T. J. Amer. Chem. Soc. 1964, 86, 3094-3102. Liu, L.; Katz, T. J.

Tetrahedron Lett. 1991, 32, 6831-6834. Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem. 1991, 56, 3769-3775.

4 Weix, D. J.; Dreher, S. D.; Katz, T. J. J. Am. Chem. Soc. 2000, 122, 10027-10032. Phillips, K. E. S.; Katz, T. J.;

Jockusch, S.; Lovinger, A. J.; Turro, N. J. J. Am. Chem. Soc. 2001, 123, 11899-11907. Terfort, A.; Gorls, H.;

Brunner, H. Synthesis 1997, 79-86. Kitahara, Y.; Tanaka, K. Chem. Commun. 2002, 932-933. Xu, Y.; Zhang, Y. X.;

Sugiyama, H.; Umano, T.; Osuga, H.; Tanaka, K. J. Am. Chem. Soc. 2004, 126, 6566-6567. Honzawa, S.; Okubo, H.; Anzai, S.; Yamaguchi, M.; Tsumoto, K.; Kumagai, I. Bioorg. Med. Chem. 2002, 10, 3213-3218. Amemiya, R.;

Yamaguchi, M. Org. Biomolec. Chem. 2008, 6, 26-35.

5 Laursen, B. W.; Krebs, F. C. Angew. Chem. Int. Ed. Engl. 2000, 39, 3432-3434.

Int. Ed. 2003, 42, 3162-3166.

7 Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Int.

Ed. Engl. 2005, 44, 1879-1883.

8 Laleu, B.; Machado, M. S.; Lacour, J. Chem. Commun. 2006, 2786-2788.

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Scheme 1. Resolution of racemic-DMQA 1 salts via the addition of enantiopure sulfoxide (+)-(R)-9

The object of this thesis was to functionalize these structures with different side-chains (R = Me,

nPr, (CH2)2OH…) of different lengths and polarity in order to induce possible biological properties. To our surprise, the nature of these substituents highly affected the resolution protocol and the ease of separation of the resulting diastereoisomers 10. Fortunately, the recourse to semi-preparative HPLC successfully permitted the isolation of the desired molecules (82-95%

yields) which then were subjected to the Pummerer fragmentation to regenerate the DMQA in enantiopure form (Chapter II). In collaboration with the group of Prof. Eric Vauthey, photophysical studies of these derivatives showed a stereoselective binding towards DNA, especially with the M enantiomer. Those results will be reported in Chapter III.

Another derivatization of the side chains with azide functional groups was considered and permitted the use of «click chemistry» or the copper-(I)-catalyzed alkyne azide Huisgen 1,3- cycloaddition for the synthesis of a new family of biotinylated derivatives. This required to develop several strategies and to isolate compounds of often very high polarity in racemic and both enantiomeric forms. The photophysical study was carried out aiming this time at understanding the mechanisms at the surface and in the binding pocket of a protein, namely avidin/streptavidin (Chapitre IV). Preliminary results on the biological assay will be reported at the end of the chapter.

Chapter V summarizes some of the projects that have been started but not completely finished;

especially the umpolung of DMQA derivatives from carbocations to carbanions. This methodology consisted of first reducing the cation to obtain a neutral species that can later be deprotonated to afford a nucleophile. The new nucleophile can now attack a number of electrophiles to form novel neutral adducts in excellent yields (82-92%).

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x

Chapter I: General Introduction

I-1.Preamble

This manuscript will deal with positively charged helical scaffolds, and as such, this chapter will involve a brief description of helicenes, their aza analogues, to finally lead to a special class of cationic [4]helicenes known as the quinacridinium salts. All the molecules in this chapter shall be indicated to with a designating number preceded by a letter B to indicate that they belong to this bibliographic chapter.

Helicenes are a specific class of helical molecules comprised of ortho-condensed aromatic rings that form unique twisted nonplanar π-electron systems.¹ The combination of translation and rotation movements in such molecules gives the helical shape. Helix formation minimizes steric strain; as a consequence, helices are usually formed as a way of the molecule to relieve itself of the steric hindrance.

Figure I-1 Representation of a helice and its inherent chirality compared to human hands (Left) and of the double-strand helical shape of DNA (Right)

Chem. Int. Ed. 2003, 42, 3986-3989.

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2 | P a g e I-2.Concept of helical chirality

As can be seen from figures I-1 and I-2, helicity is an important type of chirality. Due to their nonplanar structure, helicenes are inherently chiral, even in the absence of any stereogenic center.¹ They exist in two possible enantiomeric forms and are generally compared to a screw and its rotating motion around an imaginary central axis. They are defined as having a right- handed or P-configuration (for Plus (+)/Δ) if clockwise oriented, or having a left-handed or M- configuration (for Minus (−)/Λ) if counterclockwise oriented.^2,3 (Figure I-2).

Figure I-2: Example of a helical molecule, the [6]helicene B1 in both of its enantiomeric forms

I-3.Nomenclature of helicenes:

It was Newman,⁴ who introduced the name “helicenes” to refer to ortho-condensed aromatic hydrocarbons in which all benzene rings are angularly annelated, such as to give helically shaped molecules.⁵ Wynberg later brought up the term heterohelicenes⁵ to differentiate fully carbonated helicenes from the ones containing heteroatoms such as nitrogen, oxygen, sulfur, etc.

Helicenes are generally considered as structural analogues of phenanthrene B2, from the smallest described 1,10-phenanthroline-N,N’-dioxide B3,⁶ to the higher analogs (Figure I-3).

In the following chapters of this manuscript, the molecules we shall deal with belong to this subclass of helicenes, the heterohelicenes. Aza and thiaheterohelicenes are among the most described in the literature since the thorough interest given to them by Wynberg.⁷

2 For a description of M and P nomenclature and how it is used to describe the stereochemistry of helicenes, see:

Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994; Chapter 14, pp 1121, 1163-1166.

3 R. S. Cahn; C. K. Ingold; V. Prelog Angew. Chem., Int. Ed. Eng. 1966, 5, 385.

4 Newman, M.S. and D. Lednicer J. Am. Chem. Soc. 1956, 78(18), 4765-4770.

5 Wynberg, H., M.B. Groen, and H. Schadenberg, J. Org. Chem. 1971, 36(19), 2797-2809.

6 Rozen, S. and Dayan, S Angew. Chem. Int. Ed. 1999, 38, 3471-3473.

7 Wynberg, H.; Groen, M. B.; Schadenberg, H. J. Org. Chem. 1971, 36, 2797-2809. Tribout, J.; Martin, R. H.;

Doyle, M.; Wynberg, H. Tetrahedron Lett. 1972, 13, 2839-2842.

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Figure I-3: Structural analogues of phenanthrene B2: 1,10-phenanthroline N,N’ dioxide B3 and [6]helicene B1

Usually, the number of ortho-fused rings involved in the overall helicity is indicated between brackets before the designating term “helicene”. As such, penta, hexa and heptahelicenes are simply: [5], [6] and [7]helicene respectively.

I-4.Synthesis and properties of carbohelicenes

Although known at the beginning of the 20^th century, these structures remained scarcely described in the early stages, since their syntheses were highly dependent on the designated targets and necessitated very diverse methods.⁸

[5] helicene B4 was the first “true”⁹ helicene to be described in 1918 by Weitzenböck but its isolation was not achieved until 1933 by Pschorr cyclization.¹⁰ However, the first report of such a screw-like molecule goes back to 1903, when Meisenheimer and Witte introduced the diaza[5]helicene B5, obtained via reductive cyclization of 2-nitronaphthalene.¹¹ In 1927, the [6]pyrrolohelicene B6 was synthesized by Niszel and Fuchs via a double Bucherer reaction.¹²

8 Laarhoven, W. H.; Cuppen, Th. H. J. M.; ibid, 1973, 92, 553. Laarhoven, W. H.; Veldhuis, R. G. M. Tetrahedron Lett., 1972, 28, 1823. Katz, T. J.; Pesti, J. J. Amer. Chem. Soc. 1982, 104, 346-347. Schreiner, P. R.; Fokin, A. A.;

Reisenauer, H. P.; Tkachenko, B. A.; Vass, E.; Olmstead, M. M.; Blaser, D.; Boese, R.; Dahl, J. E. P.; Carlson, R.

M. K. J.Amer. Chem. Soc. 2009, 131, 11292-11293.

9 By true, we mean carbohelicene.

10Cook, J. W. J. Chem. Soc. 1933, 1592.

Pschorr Reaction allows the preparation of biaryl tricyclics by intramolecular substitution of one arene by an aryl radical. This radical is generated in situ from an aryl diazonium salt by copper catalysis. Alternative one-electron donors that are more soluble have recently been discovered. F. W. Wassmundt, W. F. Kiesman, J. Org. Chem., 1995, 60, 196-201

11Meisenheimer, J.; Witte, K. Chem. Ber. 1903, 36, 4153.

12Fuchs, W.; Niszel, J. Ber. Dtsch. Ges. 1927, 60, 209; Carbazol synthesis from Naphthalene or Naphthylamine and Phenylhydrazin by means of Hydrogenosulfite.

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4 | P a g e Figure I-4: [5]helicene B4, diaza[5]helicene B5, diaza[6]helicene B6 and 1,12-dimethyl-[4]helicene B7.

These very diverse methods have acted as a major drawback towards this chemistry and it was with the pioneering work of Newman¹³ regarding the synthesis of [6]helicene B1 that the interest in these structures reemerged. Another breakthrough was achieved with Mallory’s report on phenanthrenes in 1964¹⁴ and following that, Martin’s claim that all that was required was to expose diarylthylenes of type B8 to light and oxidant to form these attractive scaffolds in fair to excellent yields. This oxidative photochemical conversion of trans-stilbene motifs, being the oldest and most widely used methodology allowed access to various derivatives of this class of compounds, fully carbonated and with heteroatoms of different lengths from [6] to [14] ortho- fused rings.

SchemeI-1: Photodehydrocyclization of trans-stilbene B7 into phenantrene B2.

The photocyclisation is a disrotatory allowed process (4n+2 electrons involved) and is interesting because of its extreme simplicity. The required building blocks, 1,2-diarylethylenes or bis(arylvinyl)arenes, are usually easy to make in excellent yields, either by Wittig reaction or similarly simple methods. The stereochemistry of the starting alkene is unimportant, due to the well known cis-/trans photoequilibrium. Also, substituted helicenes can be prepared provided that the substituent is already present in the building motifs prior to cyclisation. Nevertheless,

13 Newman, M. S.; Lutz, W. B.; Lednicer, D. J. Amer. Chem. Soc. 1955, 77, 3420-3421. Newman, M. S.; Lednicer, D. J. Am. Chem. Soc. 1956, 78, 4765-4770.

14 Mallory, F. B.; Wood, C. S.; Gordon, J. T. J. Amer. Chem. Soc. 1964, 86, 3094-3102.

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some functional groups are not tolerated (such as acetyl, dimethylamino and nitro groups).

Although in principle, the photocyclisation process can give rise to many isomers, it is rarely the case and usually the only cyclised product observed is the helicene. But in the cases of exception, the formation of undesired compounds, such as perylene derivatives, can be prevented using the improved method of Katz, by the introduction of bromine auxiliaries which protect their own and ortho positions from substitution, affording the control of the regioselectivity.¹⁵

Katz also reported that an excess of iodine instead of the catalytic amount suggested previously, with propylene oxide as a scavenger for the in situ generated HI could give access to higher yields and purities of the products.¹⁶ This procedure allowed the formation of the parent [5]helicene B4 in 83% overall yield from stilbene precursors.

Nevertheless, the non-applicability of this methodology to every possible compound, the low amounts of materials obtained as well as its low tolerance for functional groups, have directed increasing efforts at finding other alternatives.

A number of recent efforts have been directed at finding new non-photochemical routes for helicene synthesis.¹⁷ Among them Friedel-Crafts acylation,¹⁸ intramolecular oxidative cyclization,¹⁹ Diels-Alder reactions of benzoquinones by Katz, cyclisation of ammonium or

15Liu, L.; Katz, T. J. Tetrahedron Lett. 1991, 32, 6831-6834.

16Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem. 1991, 56, 3769-3775.

17 For recent nonphotochemical syntheses, see: Carreno, M. C.; Garcia-Cerrada, S.; Urbano, A. J. Am. Chem. Soc.

2001, 123, 7929. Carreno, M. C.; Garcia-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A. Chem. Commun. 2001, 1452.

Okubo, H.; Nakano, D.; Anzai, S.; Yamaguchi, M. J. Org. Chem. 2001, 66, 557. Eskildsen, J.; Krebs, F. C.; Faldt, A.; Sommer-Larsen, P.; Bechgaard, K. J. Org. Chem. 2001, 66, 200. Murguly, E.; McDonald, R.; Branda, N. R.

Org. Lett. 2000, 2, 3169. Okubo, H.; Nakano, D.; Yamaguchi, M.; Kabuto, C. Chem. Lett. 2000, 1316.

Modlerspreitzer, A.; Fritsch, R.; Mannschreck, A. Collect. Czech Chem. Commun. 2000, 65, 555. Minuti, L.;

Taticchi, A.; Marrocchi, A.; Gacs-Baitz, E.; Galeazzi, R. Eur. J. Org. Chem. 1999, 3155. Carreno, M. C.;

Hernandez-Sa´nchez, R.; Mahugo, J.; Urbano, A. J. Org. Chem. 1999, 64, 1387. Stara´, I. G.; Stary´, I.;

Kolla´rovicˇ, A.; Teply´, F.; Vyskocˇil, Sÿ.; Saman, D. Tetrahedron Lett. 1999, 40, 1993. Gingras, M.; Dubois, F.

Tetrahedron Lett. 1999, 40, 1309. Dubois, F.; Gingras, M. Tetrahedron Lett. 1998, 39, 5039. Okubo, H.;

Yamaguchi, M.; Kabuto, C. J. Org. Chem. 1998, 63, 9500. Minuti, L.; Taticchi, A.; Marrocchi, A. Synth. Commun.

1998, 28, 2181. Tanaka, K.; Suzuki, H.; Osuga, H. J. Org. Chem. 1997, 62, 4465. Tanaka, K.; Suzuki, H.; Osuga, H.

Tetrahedron Lett. 1997, 38, 457. Minuti, L.; Taticchi, A.; Marrocchi, A.; Gacs-Baitz, E. Tetrahedron 1997, 53, 6873. Cossu, S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith, A. J. Tetrahedron 1997, 53, 6073.

Pischel, I.; Grimme, S.; Kotila, S.; Nieger, M.; Vo¨gtle, F. Tetrahedron: Asymmetry 1996, 7, 109. Larsen, J.;

Bechgaard, K. J. Org. Chem. 1996, 61, 1151. Yamaguchi, M.; Okubo, H.; Hirama, M. Chem. Commun. 1996, 1771.

Dore, A.; Fabbri, D.; Gladiali, S.; Valle, G. Tetrahedron: Asymmetry 1995, 6, 779. Stara´, I. G.; Stary´, I.; Tichy´, M.; Za´vada, J.; Hanusˇ, V. J. Am. Chem. Soc. 1994, 116, 5084.

18Newman, M. S.; Lednicer, D. J. Am. Chem. Soc. 1956, 78, 4765-4770.

19Rau, H.; Schuster, O. Angew. Chem., Int. Ed. Engl. 1976, 15, 114. Pereira, D. E.; Neelima; Leonard, N. J.

Tetrahedron 1990, 46, 5895. Larsen J.; Bechgaard, K. J. Org. Chem. 1996, 61, 1151.

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6 | P a g e phosphonium salts,²⁰ metal-catalysed [2+2+2] cycloisomerisation,²¹ olefin metathesis,²² carbenoid couplings,²³ and tandem radical cyclisation. Two elegant strategies are depicted below.

A tin-mediated, non-reducing tandem radical cyclisation developed by Harrowven in 2002, gave a new short and effective route to the parent [5]helicene and some of its derivatives in modest to good yields (35-49%, 58% for [5]helicene) (Scheme I-2).²⁴

Scheme I-2: Tandem radical cyclization process developed by Harrowven, affording [5]helicene B4.

Another approach to a carbohelicene was reported in 1998, by Gingras and Dubois, using a McMurry coupling of a dialdehyde (as shown by Tanaka on heterohelicenes²⁵) or carbenoid-type coupling of bis(bromomethyl) moieties as the key step.²⁶ The method was useful for the formation of [5] and [7]carbohelicene B4 and B14 derivatives. (Scheme I-3).

20Bestman, H. J.; Both, W. Angew. Chem. 1972, 84, 293. Stara´, I. G.; Stary, I.; Tichy, M.; Za´vada, J.; Hanus, V. J.

Am. Chem. Soc. 1994, 116, 5084.

21 Teply, F.; Stara, I. G.; Stary, I.; Kollarovic, A.; Saman, D.; Rulisek, L.; Fiedler, P. J. Am. Chem. Soc. 2002, 124, 9175-9180. Stara, I. G.; Stary, I.; Kollarovic, A.; Teply, F.; Saman, D.; Fiedler, P. Collect. Czech. Chem. Commun.

2003, 68, 917-930. Teply, F.; Stara, I. G.; Stary, I.; Kollarovic, A.; Saman, D.; Vyskocil, S.; Fiedler, P. J. Org.

Chem. 2003, 68, 5193-5197. Alexandrova, Z.; Stara, I. G.; Sehnal, P.; Teply, F.; Stary, I.; Saman, D.; Fiedler, P.

Collect. Czech. Chem. Commun. 2004, 69, 2193-2211. Stara, I. G.; Alexandrova, Z.; Teply, F.; Sehnal, P.; Stary, I.;

Saman, D.; Budesinsky, M.; Cvacka, J. Org. Lett. 2005, 7, 2547-2550.

22 Collins, S. K.; Grandbois, A.; Vachon, M. P.; Côté, J. Angew. Chem. Inter. Ed. 2006, 45, 2923-2926.

23 Dubois, F.; Gingras, M. Tetrahedron Lett. 1998, 39, 5039-5040. Gingras, M.; Dubois, F. Tetrahedron Lett. 1999, 40, 1309-1312.

24 Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R. Tetrahedron Lett. 2002; 43, 7345-7347.

25 Tanaka, K.; Suzuki, H.; Osuga, H. Tetrahedron Lett. 1997, 38, 457-460.

26Dubois, F.; Gingras, M. Tetrahedron Lett. 1998, 39, 5039-5040. Gingras, M.; Dubois, F. Tetrahedron Letters 1999, 40, 1309-1312.

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Scheme I-3: Carbenoid and McMurry couplings as a new way to access carbohelicenes.

I-5. Configurational stability, thermal racemization and racemization barrier:

The first few helicenes reported were not very stable at 25 °C and they always racemized even at very low temperatures such as -20 °C.¹

Configurational stability can be increased with the number of ortho-fused rings as shown between [5] and [6]helicene. It is also possible to achieve an increase of steric hindrance by substitution of the carbohelicenes at terminal positions. The “relatively” low potential barriers for these racemizations can be best justified by the fact that all the molecular deformations regarding bond torsions and necessary bending, are spread over a large part of the bonds in the molecule. The helicenes are thus shown to be more flexible than originally thought. Thus, they racemize thermally but in this sense, are rather stable photochemically. The [5]helicene displays a half-life of racemisation t1/2 of 62 min at 57 °C, whereas [6]helicene is known to be much more stable (ΔG^≠= 154.3 kJ/mol; t1/2 = 13.4 min at 196 °C).⁴

Several studies have been undertaken to understand the reaction pathways for thermal racemization of helicenes. In 1974, it was shown by Martin et al. that a conformational pathway

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8 | P a g e is in fact best adapted to explain the process.²⁷ Lindner calculated the energy differences between the ground state and some assumed transition states for a [6]carbohelicene and argued that the most plausible geometry for a transition state is one in which a slippage is involved which allows the racemisation of the compound.²⁸ (Scheme I-4)

Scheme I-4: Racemization mechanism of the 1-methyl[6]helicene B15.

I-6. Resolution methods:

There are a number of methods available for the isolation of enantiopure helicenes, although not equivalently effective.²⁹ For instance, the high improvement of HPLC techniques has been a life- saver in many cases where the separation of racemic mixtures was most strenuous.

Crystallization has also been thoroughly utilized especially in the early days when “hand- picking” crystals was a good way to optically pure material or for the isolation of charge-transfer complexes.

Other ways have included derivatisation of the racemic mixture of enantiomers to obtain chromatographically separable diastereoisomers through addition of chiral auxiliaries. These approaches will only be detailed on two historical and important classes of carbohelicenes.

27 Martin, R. H.; Marchant, M. J. Tetrahedron 1974, 30, 347-349.

28 Lindner, H. J. Tetrahedron 1975, 31, 281-284; Janke, R. H.; Haufe, G.; Würthwein, E.-U.; Borkent, J. H. J. Amer.

Chem. Soc. 1996, 118, 6031-6035; Johansson, M.; Patzschke, M. In; WILEY-VCH Verlag, 2009, 15, 13210-13218.

29 Newman, M. S.; Chen, C. H. J. Org. Chem. 1972, 37, 1312-1314. Newman, M. S.; Wise, R. M. J. Am. Chem. Soc.

1956, 78, 450-454.

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The first resolution³⁰ of a purely aromatic hydrocarbon whose asymmetry comes from its intramolecular overcrowding, was reported for the [6]helicene B1 in 1956 by Newman and Lednicer. In the absence of a peripheral functional group in [6]helicene B1, this was achieved using the α-(2,4,5,7-Tetranitro-9-fluorenylideneaminoöxy)-propionic Acid, or TAPA B16, a new reagent for resolution by charge transfer complex formation, nowadays known as Newman’s reagent. The non-active racemic helicene was dissolved in a benzene solution with TAPA. The subsequent addition of ethanol to the benzene mixture afforded crystallization of the active helicene with the same sign of optical rotation as the TAPA³¹ derivative. It was therefore shown that TAPA can form complexes of different stability with each enantiomer of [6]helicene. This resolving agent is easily obtained by reacting (±)- α-(isopropylideneaminooxy)-propionic acid (B18) with 2,4,5,7-tetranitro-9-fluorenone (B17). The optically active TAPA is afforded by interchange of the active starting material (propionic acid) after its resolution with (−)-ephedrine.

Figure I-5: Synthesis of TAPA, Newman’s reagent

Another example by Katz et al.,³² utilized (1S)-camphanates as chiral resolving agent to afford optically pure helicene-quinone derivatives, after removal of the auxiliary.³³ Its presence was also useful in determining the absolute configuration of the isolated non-racemic helicenes. As a general rule, the M helicene attached to the (1S)-camphanates eluted faster than the one bearing the P helicity. Such a trend was also reported by Venkatamaran³⁴ and Dötz.³⁵ This elution order

30 Newman, M. S.; Lednicer, D. J. Am. Chem. Soc. 1956, 78, 4765-4770.

31 Newman, M. S.; Lutz, W. B.; Lednicer, D. J. Amer. Chem. Soc. 1955, 77, 3420-3421.

32 Newman, M. S.; Chen, C. H. J. Org. Chem. 1972, 37, 1312-1314.

33 Thongpanchang, T.; Paruch, K.; Katz, T. J.; Rheingold, A. L.; Lam, K.-C.; Liable-Sands, L. J. Org. Chem. 2000, 65, 1850-1856.

34 Field, J. E.; Muller, G.; Riehl, J. P.; Venkataraman, D. J. Am. Chem. Soc. 2003, 125, 11808-11809.

35 Schneider, J. F.; Nieger, M.; Naettinen, K.; Lewall, B.; Niecke, E.; Dötz, K. H. Eur. J. Org. Chem. 2005, 1541- 1560.

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10 | P a g e was rationalized as due to a preferred antiperiplanar conformation in the case of the M derivative vs a synperiplanar conformation for its antipode.³⁶

B22 B21

N

O O

tBu

OR*

O

O Ph

Ph

Et Et

OR*

BrOR*

S

OR*

R*O

B20

OR OR OR

OR

B19 OR*

OR*

OMe OR*

R*O

OMe

B23 O

R* = camphanate =

O O

(S) 1

Figure I-6: Selected examples of helicene-like compounds resolved by introducing (1S)-camphanate moiety as chiral auxiliary.

I-7. Properties of helicenes:

Martin wrote at the end of his review in 1974:³⁷ “it is our intimate conviction that further work on these unique molecules... should be highly rewarding in many fields of chemistry.”

Indeed, because of their non-planar dissymmetric backbone, helicenes present an intriguing variety of properties and applications from areas of chiroptical³⁸ and photochromic materials.³⁹ excellent self-assembly,⁴⁰ in domains such as asymmetric catalysis,⁴¹ supramolecular chemistry⁴²

36 Thongpanchang, T.; Paruch, K.; Katz, T. J.; Rheingold, A. L.; Lam, K.-C.; Liable-Sands, L. J. Org. Chem. 2000, 65, 1850-1856.

37 Martin, R.H., The helicenes, in Angew. Chem. 1974. p. 727-38.

38 Graule, S.; Rudolph, M.; Vanthuyne, N.; Autschbach, J.; Roussel, C.; Crassous, J.; Réau, R. J. Amer. Chem. Soc.

2009, 131, 3183-3185.

39 Furche, F.; Ahlrichs, R.; Wachsmann, C.; Weber, E.; Sobanski, A.; Vögtle, F.; Grimme, S. J. Am. Chem. Soc.

2000, 122, 1717-1724; Norsten, T. B.; Peters, A.; McDonald, R.; Wang, M. T.; Branda, N. R. J. Am. Chem. Soc.

2001, 123, 7447-7448; Verbiest, T.; Sioncke, S.; Persoons, A.; Vyklicky, L.; Katz, T. J. Angew. Chem. Int. Ed.

2002, 41, 3882-3884; Field, J. E.; Muller, G.; Riehl, J. P.; Venkataraman, D. J. Am. Chem. Soc. 2003, 125, 11808- 11809; Wachsmann, C.; Weber, E.; Czugler, M.; Seichter, W. Eur. J. Org. Chem. 2003, 2863-2876; Champagne, B.;

Andre, J.-M.; Botek, E.; Licandro, E.; Maiorana, S.; Bossi, A.; Clays, K.; Persoons, A. ChemPhysChem. 2004, 5, 1438-1442; Lebon, F.; Longhi, G.; Gangemi, F.; Abbate, S.; Priess, J.; Juza, M.; Bazzini, C.; Caronna, T.; Mele, A.

J. Phys. Chem. A 2004, 108, 11752-11761.

40 Nuckolls, C.; Katz, T. J.; Castellanos, L. J. Amer. Chem. Soc. 1996, 118, 3767-3768. Dai, Y.; Katz, T. J. J. Org.

Chem. 1997, 62, 1274-1285. Nuckolls, C.; Katz, T. J. J. Amer. Chem. Soc. 1998, 120, 9541-9544.

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molecular machines⁴³ and material sciences⁴⁴ have been reported and thoroughly studied by Katz and coworkers.⁴⁵

Introduction of peripheral functional groups onto helicene skeletons have also been the focus of many other research groups⁴⁶ since the functionalisation could account for many changes in their properties. The introduction of polar hydroxy groups and amines, carboxylates or diphosphines have given access to applications in catalysis,⁴¹ molecular recognition⁴⁷ and DNA interaction.⁴⁸ This last property will be detailed in chapter III. Katz and coworkers have mostly developed helicenebisquinones and these moieties have shown fascinating self-assembling properties. As a matter of fact, all these mentioned derivatives are neutral.

Nevertheless, most carbohelicenes have properties rather far from the compounds of study (vide infra, chapters II-V) and as such, details will not be further given. Emphasis will, on the other hand, be made on azahelicenes and quinacridinium derivatives in particular.

41 Reetz, M. T.; Beuttenmuller, E. W.; Goddard, R. Tetrahedron Lett. 1997, 38, 3211-3214. Terfort, A.; Gorls, H.;

Brunner, H. Synthesis 1997, 79-86. Reetz, M. T.; Sostmann, S. J. Organomet. Chem. 2000, 603, 105-109. Reetz, M.

T.; Sostmann, S. Tetrahedron 2001, 57, 2515-2520.

42 Murguly, E., R. McDonald, and N.R. Branda, Org. Lett. 2000, 2, 3169-3172; Kitahara, Y. and K. Tanaka, Chem.

Commun 2002, 932-933; Tanaka, K., H. Osuga, and Y. Kitahara, J. Org. Chem. 2002, 67, 1795-1801.

43 Kelly, T. R.; Cai, X.; Damkaci, F.; Panicker, S. B.; Tu, B.; Bushell, S. M.; Cornella, I.; Piggott, M. J.; Salives, R.;

Cavero, M.; Zhao, Y.; Jasmin, S. J. Amer. Chem. Soc. 2006, 129, 376-386.

44 Dai, Y. J.; Katz, T. J. J. Org. Chem. 1997, 62, 1274-1285; Fox, J. M.; Lin, D.; Itakagi, Y.; Fujita, T. J. Org. Chem.

1998, 63, 2031-2038; Stone, M. T.; Fox, J. M.; Moore, J. S. In Org. Lett., 2004; Vol. 6, pp 3317-3320; Miyasaka, M.; Rajca, A.; Pink, M.; Rajca, S. Chem. Eur. J. 2004, 10, 6531-6539; Miyasaka, M.; Rajca, A.; Pink, M.; Rajca, S.

J. Am. Chem. Soc. 2005, 127, 13806-13807.

45 Katz, T.J. Angew. Chem. Int. Ed. 2000, 39, 1921-1923.

46 Dreher, S. D.; Paruch, K.; Katz, T. J. J. Org. Chem. 2000, 65, 806-814. Paruch, K.; Vyklicky, L.; Wang, D. Z.;

Katz, T. J.; Incarvito, C.; Zakharov, L.; Rheingold, A. L. J. Org. Chem. 2003, 68, 8539-8544. Fox, J. M.; Goldberg, N. R.; Katz, T. J. J. Org. Chem. 1998, 63, 7456-7462.

47 Owens, L.; Thilgen, C.; Diederich, F.; Knobler, C. B. Helv. Chim. Acta 1993, 76, 2757-2774. Wang, D. Z.; Katz, T. J. J. Org. Chem. 2005, 70, 8497-8502. Murguly, E.; McDonald, R.; Branda, N. R. Org. Lett. 2000, 2, 3169-3172.

Reetz, M. T.; Sostmann, S. Tetrahedron 2001, 57, 2515-2520.

48 Xu, Y.; Zhang, Y. X.; Sugiyama, H.; Umano, T.; Osuga, H.; Tanaka, K. J. Am. Chem. Soc. 2004, 126, 6566-6567.

Honzawa, S.; Okubo, H.; Anzai, S.; Yamaguchi, M.; Tsumoto, K.; Kumagai, I. Bioorg. Med. Chem. 2002, 10, 3213- 3218.

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12 | P a g e I-8. Synthesis and properties of azahelicenes

Azahelicenes,⁴⁹ a subgroup of helicenes containing at least one sp²-hybridized nitrogen atom within the helicene framework, have more recently caught the attention of the scientific community.⁵⁰ Their use in asymmetric catalysis,⁵¹ in metal complexation (for instance with Ag+)⁵⁵, proton affinities, self-assembly is extremely interesting.

They have been mainly synthesized by the photochemical route⁵² as shown by Caronna⁵³ who managed to obtain through this route very diverse monoaza and diaza helicenes B26 (Scheme I- 5). The position of the nitrogen was varied in the end target by modifying the precursors.

Relatively few other routes have been used for this class of molecules.⁵⁴

Scheme I-5: Photochemical approach to diverse mono and diaza derivatives B26

The interesting approach pioneered by Starý, Stará et al. to afford helicenes via metal catalyzed [2+2+2] cycloisomerisation reactions was successfully employed in the formation of 1,14- diaza[5]helicene B28 and 1- and 2-aza[6]helicene B29 from triyne key precursors B27 (Scheme

49 Recent review: Dumitrascu, F.;Dumitrescu, D. G.; Aron I. ARKIVOC 2010, 1-32.

50 Sato, K.; Arai, S. Heterohelicenes Containing Nitrogen Aromatics: Azahelicenes and Azoniahelicenes In Cyclophane Chemistry for the 21st Century Takemura, H., Ed., Research Signpost: Kerena, India, 2002, 173 – 197.

51 Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, A. J. Amer. Chem. Soc. 2010, 132, 4536- 4537. Samal, M.; Mísek, J.; Stará, I. G.; Starý, I. Collect. Czech. Chem. Commun. 2009, 74, 1151.

52 Sato, K.; Okazaki, S.; Yamagishi, T.; Arai, S. J. Heterocyclic Chem 2004; 41, 443-447. Bazzini, C.; Brovelli, S.;

Caronna, T.; Gambarotti, C.; Giannone, M.; Macchi, P.; Meinardi, F.; Mele, A.; Panzeri, W.; Recupero, F.; Sironi, A.; Tubino, R. Eur. J. Org. Chem. 2005, 2005, 1247-1257.

53 Bazzini, C.; Brovelli, S; Caronna, T.; Gambarotti, C.; Giannone, M.; Macchi, P.; Meinardi, F.; Mele, A.; Panzeri, W.; Recupero, F.; Sironi, A.; Tubino, R. Eur. J. Org. Chem. 2005, 1247-1257. Caronna, T.; Fontana, F.; Longhi, G.;

Mele, A.; Sora, I. N.; Panzeri, W.; Viganò, L. Arkivoc, 2009, 145. Abbate, S.; Bazzini, C.; Caronna, T.; Fontana, F.;

Gambarotii, C.; Gangemi, F.; Longhi, G.; Mele, A.; Sora, I. N.; Panzeri, W. Tetrahedron 2006, 62, 139.

54 El Abed, R.; Ben Hassine, B.; Genet, J.-P.; Gorsane, M.; Marinetti, A. Eur. J. Org. Chem., 2004; 1517-1522.

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I-6).⁵⁵ The resolution of the monoaza derivatives was successful using chiral HPLC and their absolute configuration determined by comparing the CD spectra with the one known of hexahelicene.⁵⁵ These compounds were shown to be useful for metal complexation.⁵⁵

Scheme I-6: [2+2+2] cycloisomerisation to form 1- and 2-aza[6]helicene B29

Takenaka reported very recently the use of a Stille-Kelly reaction of dihalogenated cis-stilbene- type precursors to form azahelicene derivatives that were active as hydrogen bond donor catalysts (Scheme I-7).⁵⁶ Another method was also recently published using a mixed catalyst of PtCl4 and InCl3 and a double C-H activation process which gave the desired molecule in 80 % yield (Equation I-1).⁵⁷

55 Mísek, J.; Teplý, F.; Stará, I. G.; Tichý, M.; Saman, D.; Císarová, I.; Vojtísek, P.; Starý, I. Angew. Chem. Inter.

Ed. 2008, 47, 3188-3191.

56 Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, J. Amer. Chem. Soc. 2010, 132, 4536- 4537.

57 Storch, J.; Cermák, J.; Karban, J.; Císarová, I.; Sýkora, J. J. Org. Chem. 2010, 75, 3137-3140.

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14 | P a g e Scheme I-7: Radical-mediated cyclisation to afford azahelicene B31.

Equation I-1: Metal-catalyzed process for the synthesis of 2-aza[6]helicene B33.

A completely different type of azahelicene was recently reported by the group of Venkatamaran.

These derivatives of triphenylamine were constructed in the aim of developing well-ordered compounds for further use in material sciences,⁵⁸ using a strategy initially demonstrated by Hellwinkel.⁵⁹ The synthesis was modified and better yields were obtained.⁷³

58 Field, J.E., T.J. Hill, and D. Venkataraman, Bridged triarylamines: A new class of heterohelicene. Abstracts of Papers, 224th ACS National Meeting, Boston, MA, United States, August 18-22, 2002, 2002: p. ORGN-483; Field, J.E. and D. Venkataraman, HeterotriangulenesStructure and Properties. Chemistry of Materials, 2002. 14(3): p.

962-964.

59 Hellwinkel, D. and G. Aulmich, Modified tetrahelicene systems. II. 9,13b-Dihydro-5,5,9,9-tetramethyl-5H- naphth[3,2,1-de]anthracen-13b-ylium and -13b-ide salts. Chem. Ber., 1979. 112(7): p. 2602-8; Hellwinkel, D., G.

Aulmich, and W. Warth, Rearrangement reactions in intramolecular electrophilic cyclizations in the triphenylmethane series. Chem. Ber., 1980. 113(10): p. 3275-93; Hellwinkel, D., G. Aulmich, and M. Melan,

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Ullmann coupling, followed by transformation of the ester functions into the acid chlorides which can undergo an in situ cyclization with SnCl4 afforded the azahelicenes B37. The conditions were carefully chosen to avoid chlorination of the helicene core. Interestingly, the nitrogen atom can be oxidized to a radical cation, a property that can be used for the study of charge transport and conductance in helicenes. The substituent at the top of the helicene is there to stabilize the radical cation formed. Such a theory was confirmed by cyclic voltammetry studies which showed a quasi reversible one-electron oxidation at the oxidation potentials of the heterohelicenes and no evidence of dimerisation which happens when the radical form is not stable enough in solution to exist as such.

The solid-state study showed the helical twist of these derivatives as well as the increasing overlap of the terminal rings when going from one compound to the higher analogue. Also, a zig- zag π-stacking is depicted, when they are in a racemic mixture. The interplanar angles between the terminal rings increase from 43.4 to 58.8⁶⁰ to 60.1 for the dinaphthyl one. One phenol derivative was resolved using the (1S)-camphanates derivatization methodology of Katz et al, as mentioned before.⁶¹

Scheme I-8: Synthesis of helicene-like molecules B37 by the method of Venkatamaran

Polycyclic compounds of the triangulene type. II. Threefold ortho-bridged triphenylmethane derivatives. Chem.

Ber., 1981. 114(1): p. 86-108.

60 A value very close to the one of hexahelicene, 58.5°.

61 Field, J.E., et al., Circularly Polarized Luminescence from Bridged Triarylamine Helicenes. J. Am. Chem. Soc., 2003. 125(39): p. 11808-11809.

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16 | P a g e Cationic helicene-like molecules can form supramolecular interactions between each other and even with their corresponding counterion.⁶² Apart from these classes of derivatives where the nitrogen is in the center or inside the helicity, there are other compounds where the nitrogen atom is at the periphery of the twisted scaffold.

I-9. Highly Stable Azahelicenes: DMQA

Recently, thanks to the leading work of Laursen and Krebs, a variety of highly stable aza- bridged heterocyclic carbenium ions (B38 to B41) have been reported.^63,64 These polycyclic moieties, shown in Figure I-7, display many interesting chemical and physical properties.⁶³ These compounds have been considered as attractive synthetic targets for the development of novel and original synthetic,⁶⁵ asymmetric,⁶⁶ photochemical and topological applications.⁶⁷

Conveniently, all these derivatives (B38 to B41) are easily prepared from a single chemical precursor that is the tris(2,6-dimethoxybenzene) methylium ion B42 (vide infra, Scheme I-9).

Consecutive nucleophilic aromatic substitution (SNAr) of the methoxy groups of B42 by primary amines affords efficiently and successively B39, B40 and B41. In fact, each introduction of a nitrogen bridge is more difficult than the previous one. It is thus possible to obtain separately the different products in which two, four, or six of the ortho-methoxy groups of 11 are substituted by a nitrogen atom and this can be controlled by the experimental conditions.⁶³

62 Senechal-David, K.; Toupet, L.; Maury, O.; Le Bozec, H. Crystal Growth & Design 2006, 6, 1493-1496.

63 Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem., Int. Ed. Engl. 2005, 44, 1879-1883. Herse, C.; Bas, D.; Krebs, F. C.; Buergi, T.; Weber, J.; Wesolowski, T.;

Laursen, B. W.; Lacour, J. Angew. Chem., Int. Ed. Engl. 2003, 42, 3162-3166. Laursen, B. W. Ph. D. Thesis, Univ.

Copenhagen 2001, RisØ-R-1275 (EN). Laursen, B. W. Triangulenium salts. Risoe Natl. Lab., Roskilde, Den., 2001.

Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. Engl. 2000, 39, 3432-3434. Laursen, B. W.; Krebs, F. C.;

Nielsen, M. F.; Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am. Chem. Soc. 1999, 121, 4728. Laursen, B. W.;

Krebs, F. C.; Nielsen, M. F.; Bechgaard, K.; Christensen, J. B.; Harrit, N. J. Am. Chem. Soc. 1998, 120, 12255- 12263.

64 Interestingly B39, B40 and B41 are among the most stable carbocations of the literature (pKR+ of 19.4 for B39 and 24.3 for B40).

65 Nicolas, C.; Lacour, J. Org. Lett. 2006, 8, 4343-4346.

66 Villani, C.; Laleu, B.; Mobian, P.; Lacour, J. Chirality 2007, 19, 601-606.

Int. Ed. 2003, 42, 3162-3166. Laleu, B.; Herse, C.; Laursen, B. W.; Bernardinelli, G.; Lacour, J. J. Org. Chem. 2003, 68, 6304-6308. Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J.

Angew. Chem. Int. Ed. 2005, 44, 1879-1883. Nicolas, C.; Herse, C.; Lacour, J. Tetrahedron Lett. 2005, 46, 4605- 4608. Laleu, B.; Machado, M. S.; Lacour, J. Chem. Commun. 2006, 2786-2788. Mobian, P.; Banerji, N.;

Bernardinelli, G.; Lacour, J. Org. Biomol. Chem. 2006, 4, 224-231. Baisch, B.; Raffa, D.; Jung, U.; Magnussen, O.

M.; Nicolas, C.; Lacour, J.; Kubitschke, J.; Herges, R. J. Am. Chem. Soc. 2009, 131, 442-443. Mobian, P.; Nicolas, C.; Francotte, E.; Bürgi, T.; Lacour, J. J. Am. Chem. Soc. 2008, 130, 6507-6514.

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Figure I-7. Highly stable heterocyclic carbenium ions B38 to B41 (R = n-alkyl).

More specifically, in term of synthesis, the reaction at room temperature (20 °C) of the readily available B42 with alkylamines in slight excess (2.5 equiv.) and NMP as polar solvent gives tetramethoxyphenylacridinium salts B38 (TMPA⁺) in excellent yields after 20 hours (70- 90%). For the formation of the double nitrogen bridged dimethoxyquinacridinium (DMQA⁺) salts B39 the reactions proceeds also in NMP, but much faster (~ 1 hour) with more elevated temperatures (80 - 110 °C) and a large excess of amines (25 equiv.). The DMQA⁺ cations B39 are usually obtained in moderate to good yields (50 to 80%). The triply nitrogen-bridged triazatriangulenium (TATA⁺) salts B40 require even higher temperatures and longer reaction times and are formed after heating to 130-190 °C. In this case, reactions cannot be achieved with low boiling point amines except with the addition of benzoic acid to the reaction mixture allowing the reflux temperature to be raised. Finally, partially bridged B39 can be converted into another fully ring-closed derivative, this time with an oxygen bridge instead of a nitrogen. The diazaoxa-triangulenium salts (DAOTA⁺, B41) are obtained by intramolecular ring closure upon heating with molten PyrH⁺Cl^- (~ 200 °C) as solvent or LiI as reagent.

Each step introducing a new nitrogen atom continually decreases the reactivity of the resulting products; this is mainly due on one hand, to the increased planarity of these structures that facilitates electron resonance delocalization of the central charge and also because nitrogen atoms are much better electron-donating groups than oxygen atoms thus stabilizing more and more the central electron poor carbon. The structural modifications due to the introduction of the aza-bridges induce a lowering of the gap between filled and empty molecular orbitals of the molecules (in other words between the HOMO and LUMO) which is also the reason behind their bright and beautiful colors. Indeed, these molecules (B38 to B41) are dyes, ranging from red orange (B38), green (B39) to pink (B40-41) and B39-41 are highly fluorescent when submitted

Synthesis, resolution and biological applications of water-soluble Cationic [4]helicenes

Thesis

Reference

Synthesis, resolution and biological applications of water-soluble Cationic [4]helicenes

Synthesis, Resolution and Biological Applications of Water-Soluble Cationic [4]Helicenes

Résumé

Summary

Table of contents

Chapter I: General Introduction