current challenges in catalysis and synthesis challenges in catalysis and synthesis thursday...

Current Challenges in Catalysis and Synthesis

Thursday December 13, 2012 - Geneva Friday December 14, 2012 - Lausanne

CUSO-Science Days jointly organized by EPF Lausanne and the University of Geneva

Plenary Speakers

Matthew Gaunt University of Cambridge - UK

André Charette

University of Montreal - Canada

CUSO Science Days 2012

Scientific Program

Day 1 December 13, 2012 – University of Geneva –

Auditoire A-100

09:30 – 09:50 Welcome Coffee 09:50 – 10:00 Opening Remarks

PL 1 10:00 – 11:20 Prof. A. B. Charette (University of Montreal) New Methods for Cyclopropane Synthesis – an In-depth Investigation of Catalysts’ Structure

OC 1 11:20 – 11:40 Florian De Nanteuil (EPFL – Waser group) OC 2 11:40 – 12:00 Hailing Li (UniGe – Alexakis group) OC 3 12:00 – 12:20 Duc N. Tran (EPFL – Cramer group)

12:20 – 14:15 Lunch Auditoire 1S059 OC 4 14:15 – 14:35 Cyril Piemontesi (EPFL – Zhu group) OC 5 14:35 – 14:55 Tanguy Saget (EPFL – Cramer group) OC 6 14:55 – 15:15 Pablo Marcelo Perez-Garcia (EPFL – Hu group) Hall Sciences III

15:15 – 16:15 Coffee Break & Poster Session (13 posters) Reto Frei, Jean-Baptiste Gualtierotti, Christian Invernizzi, Toms Kalnins, Yifan Li, Raja Nandhagopal, Yann Odabachian, Van Manh Pham, Bing Sun, Damien Thevenet, Gergely Tolnai, Rémi Vanel, Antoine Wallabregue

Auditoire A-100 PL 2 16:15 – 17:35 Prof. M. J. Gaunt (University of Cambridge)

New Copper-catalysed Reactions

CUSO Science Days 2012

Scientific Program

Day 2 December 14, 2012 – Ecole Polytechnique Fédérale Lausanne –

Room Genopode A

09:30 – 10:00 Welcome Coffee at BCH Cafeteria PL 3 10:00 – 11:20 Prof. A. B. Charette (University of Montreal)

Direct C-H Bond Activation Reactions: from Heterocycles to Cyclopropane Derivatives

OC 7 11:20 – 11:40 Thierry Achard (UniGe – Lacour group) OC 8 11:40 – 12:00 Patrick Burch – (Uni Basel – Gademann group) OC 9 12:00 – 12:20 Jezabel Praz (UniGe – Alexakis group)

12:20 – 14:15 Lunch Room CM 4 OC 10 14:15 – 14:35 Géraldine Labrador (UniGe – Lacour group) OC 11 14:35 – 14:55 Dmitry Katayev – (UniGe – Kündig group) OC 12 14:55 – 15:15 Matthieu Tissot (Unige – Alexakis group)

15:15 – 16:15 Coffee Break & Poster Session (13 posters) Ivan Franzoni, Nicolas Germain, Sylvie Goncalves, Jérôme Gouin, Nicolas Humbert, Evgeny Larionov, Alice Lefranc, Houhua Li, Daniela Masi, Pradeep Nareddy, Sandip Pujari, Cecilia Tortoreto, Mahesh Vishe

PL 4 16:15 – 17:35 Prof. M. J. Gaunt (University of Cambridge)

New Concepts in Palladium Catalyzed C–H Bond Functionalization

17:35 Closing Remarks

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Prof. M. J. Gaunt – University of Cambridge (UK) Matthew Gaunt graduated from the University of Birmingham with 1st Class Honours for Chemistry in 1995. He moved to the University of Cambridge to carry out his graduate studies as a Wellcome Trust Scholar with Dr. Jonathan B. Spencer, finishing in 1999. Following this he was awarded a prestigious GlaxoWellcome Postdoctoral Fellowship that he took to the University of Pennsylvania to work with Professor Amos B. Smith. He returned to the UK in 2001 to work with Professor Steven Ley as a Junior Research Fellow at Magdalene College, and was also awarded a Ramsay Memorial Fellowship. He began his independent research career in October 2003 at the University of Cambridge and was awarded a Royal Society University Research Fellow in October 2004. In October 2006 he was appointed Lecturer in Organic Chemistry, and a Philip & Patricia Brown Next Generation Fellow at the University of Cambridge. In October 2010 he was promoted to Reader in Chemical Synthesis. In October 2012 he was promoted to Professor. The Group's research interests are focused on the invention of catalytic strategies for chemical synthesis and the development of cascade processes for the rapid assembly of natural products. ----------------------------------------------------------------------------------------------------------------------------------

Prof. A. B. Charette – University of Montreal (Canada) André B. Charette was born in 1961 in Montréal, Québec, Canada. Upon completion of his B.Sc. from Université de Montréal in 1983, he pursued his graduate studies at the University of Rochester, earning his M.Sc. (1985) and Ph.D. (1987) with Professor Robert Boeckman, Jr. Following an NSERC postdoctoral fellowship at Harvard University with Professor David A. Evans, he began his academic career at Université Laval in 1989. In 1992, he returned to his alma mater, where he is today full professor and holder of a Canada Research Chair. His research focuses on the development of new methods for the stereoselective synthesis of organic compounds and natural products. Among his recent honors are the R. U. Lemieux (2006) and Alfred Bader (2009) awards (2009) from the Canadian Society for Chemistry, the Urgel Archambault Award (2006), the ACS Cope Scholar Award (2007), and the prestigious Prix Marie-Victorin (2008) from the Government of Québec. The Group’s research interests are in the area of stereoselective synthesis of organic compounds. It includes asymmetric cyclopropanation using chiral auxiliaries and novel reagents and the device of conceptually novel approaches to catalyst and reaction design with important applications in the synthesis of chiral amines and heterocyclic derivatives. ----------------------------------------------------------------------------------------------------------------------------------

Oral Presentations

Catalytic Formal [3+2] Annulations of Aminocyclopropanes for the Enantiospecific Synthesis of Five-Membered Rings.

Florian de Nanteuil, Jérôme Waser

Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne

Switzerland [email protected]

Donor-Acceptor cyclopropanes1 are powerful and versatile building blocks for organic synthesis as they leads to a reactive formal 1,3 dipole intermediates. Consequently, their use as homologous olefin equivalents in diverse annulation processes is now well-established. When considering the importance of nitrogen-containing functional groups in drugs and natural products, it is surprising that donor-acceptor aminocyclopropanes2 were never used in formal cycloaddition reactions. This is probably due to the formidable challenge associated with the synthesis and catalytic activation of these compounds, which have been used only as structural elements so far. Through Lewis-Acid activation, we report herein the first catalytic formal [3+2] annulations of aminocyclopropane with silyl enol ethers3, aldehydes4 and ketones5. Complete control over the diastereoselectivity of the reaction was achieved. The obtained aminocyclopentanes or aminotetrahydrofurans are useful building blocks and further functionalization gives easy access to scaffolds found in various bioactive compounds.

[1] Reissig, H-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151-1196. [2] Reisser, O. Chem. Rev. 2003, 103, 1603-1624. [3] de Nanteuil, F.; Waser J. Angew. Chem. Int. Ed. 2011, 50, 12075. [4] Benfatti F.; de Nanteuil, F.; Waser J. Org. Lett. 2012, 14, 386. [5] Benfatti F.; de Nanteuil, F.; Waser J. Chem. Eur. J., 2012, DOI: 10.1002/chem.201103971

OC 1

Copper-Catalyzed Enantioselective Synthesis

of Axially Chiral Allenes

Hailing Li Department of Organic Chemistry - University of Geneva

Quai Ernest Ansermet, 30; 1211, Geneva 4 Switzerland

[email protected]

Allene compounds have drawn more and more attention as a frequent building block and a versatile intermediate for organic synthesis.[1] Among the existing methodologies for their preparation, the copper-mediated 1,3-substitution of carbon nucleophiles on propargylic electrophiles is one of the most direct and efficient manners. A series of optically active chiral allenes could be obtained through chirality transfer, the main drawback was that these approaches required the stoichiometric amount of enantioenriched starting materials which were specific for each case and sometimes hard to prepare. Herein, we reported a simple copper-catalyzed enantioselective synthesis of axially chiral chloroallenes from prochiral propargylic substrates, employing catalytic amount of easily prepared chiral SimplePhos ligand. Exclusive formation of desired allenes was observed with good enantioselectivities. Further transformations to trisubstituted allenes or terminal alkynes with propargylic quaternary carbon centre keep high level of enantiopurity.[2]

[1] Reviews and highlights on allenes: a) Modern Allene Chemistry (Eds.: N. Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2005; b) A.

Hoffmann-Röder, N. Krause, Angew. Chem. Int. Ed. 2004, 43, 1196-1216; c) S. Ma, Acc. Chem. Res. 2003, 36, 701-712; d) S. Ma, Chem. Rev. 2005, 105, 2829-2871; e) S. Ma, E.-i. Negishi, J. Am. Chem. Soc. 1995, 117, 6345- 6357; f) A. S. K. Hashmi, Angew. Chem. Int. Ed. 2000, 39, 3590- 3593; g) S. Yu, S. Ma, Angew. Chem. Int. Ed. 2012, 51, 3074-3112.

[2] H. Li, D. Müller, L. Guénée, A. Alexakis, manuscript in preparation.

OC 2

Formal [3+2] Cycloaddition Initiated by Rhodium-Catalyzed C‒H Activation

Duc N. Tran, Nicolai Cramer

Laboratory of Asymmetric Catalysis and Synthesis – EPF Lausanne EPFL SB ISIC LCSA BCH 4305, CH-1015 Lausanne


Catalytic functionalization of carbon-hydrogen bond plays a central role in the current chemical development. It has the potential to streamline the synthesis of complexe molecules starting from simple building blocks. Its advantages have been demonstrated throughout several total synthesis.1 However, a broad application is still held back by harsh reaction conditions, high catalyst loading and narrow substrate scopes. In particular, some popular directing groups, such as 2-pyridinyl group, are not practical from a synthetic point of view. In order to address these issues, we focused our research in developing more versatile directing groups which can participate to a cascade transformation.2 Theses processes allow to control at the same time regio-, chemo-, diastereo- as well as enantioselectivity.

[1] Review about C-H activation in total synthesis: L. McMurry, F. O’Hara, M. J. Gaunt Chem. Soc. Rev. 2011, 40, 1885-1898. [2] D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2010, 49, 8181-8184; D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2011, 50, 11098-

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OC4

Chiral Monodentate Phosphines and Carboxylic Acids:

Cooperative Effects in Palladium-Catalyzed Enantioselective

C(sp3)-H Functionalization

Tanguy Saget LCSA – EPF Lausanne

EPFL SB ISIC LCSA / 1015 Lausanne (max. 1 line) Switzerland

[email protected]

The enantioselective functionalization of C(sp3)–H bonds is a challenging task in asymmetric catalysis. Over the last decade, elucidation of the concerted metalation-deprotonation (CMD) mechanism for the palladium-catalyzed C(sp3)–H activation has largely contributed to the progress in this area.[1] However, the harsh reaction conditions required for such transformations and the lack of suitable ligands hampered the development of asymmetric versions. Herein, we report the enantioselective intramolecular arylation of unactivated methyl and methylene C(sp3)–H bonds with excellent selectivities.[2] The key of our strategy is based on the design of new electron-rich monodentate phosphines working in cooperation with a bulky carboxylate which acts as a relay of chirality during the enantiodiscriminating CMD step.

[1] S. Rousseaux, S. I. Gorelsky, B. K. W. Chung, J. Am. Chem. Soc. 2010, 132, 10692 [2] T. Saget, S. J. Lemouzy, N. Cramer, Angew. Chem. Int. Ed. 2012, 51, 2238. [

OC 5

Nickel-Catalyzed Diastereoselective Alkyl-Alkyl Kumada Coupling Reactions

Pablo M. Pérez García

Laboratory of Inorganic Synthesis and Catalysis - EPFL SB-ISI-LSCI, BCH 3214, Lausanne 1015


Current advances in transition metal catalysis have resulted in remarkable advance in enantioselective alkyl-alkyl coupling1, however diastereoselective cross-coupling of this type is largely unexplored. Knochel and co-workers recently developed highly diastereoselective Negishi Pd-catalyzed coupling of 1,3- and 1,4-substituted cyclohexylzinc reagents with aryl, heteroaryl, and alkylnyl halides2. These studies demonstrated high diastereocontrol using the conformational preference of Pd-cyclohexyl intermediates, which were produced by transmetallation with cyclohexyl zinc reagents. Similar analogous nickel cyclohexyl intermediates might be generated through oxidative addition of cyclohexyl halides on a nickel catalyst. Here, we3 show that the well-defined nickel pincer complex 14 catalyses alkyl-alkyl Kumada coupling reactions of 1,3- and 1,4-substituted cyclohexyl halides and tetrahydropyrans with excellent diastereoselectivity. The mechanistic investigation of the coupling reactions provides evidence that the radical activation of alkyl halides is reversible. [1] a) B. Saito, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 6694-6695; b) P. M. Lundin, G. C. Fu, J. Am. Chem. Soc. 2010, 132, 11027-11029;

c) N. A. Owston, G. C. Fu, J. Am. Chem. Soc. 2010, 132, 11908-11909; d) Z. Lu, A. Wilsily, G. C. Fu, J. Am. Chem. Soc. 2011, 133, 8154-8157; e) S. L. Zultansky, G. C. Fu, J. Am. Chem. Soc. 2011, 133, 15362-15364.

[2] a) T. Thaler, B. Haag, A. Gavryushin, K. Schober, E. Hartmann, R. M. Gschwind, H. Zipse, P. Mayer, P. Knochel, Nat. Chem. 2010, 2, 125-130; b) S. Seel, T. Thaler, K. Takatsu, C. Zhang, H. Zipse, B. F. Straub, P. Mayer, P. Knochel, J. Am. Chem. Soc. 2011, 133, 4774-4777; c) T. Thaler, L. N. Guo, P. Mayer, P. Knochel, Angew. Chem. Int. Ed. 2011, 50, 2174-2177.

[3] P. M. Perez Garcia, T. Di Franco, A. Orssino, P. Ren, X. L. Hu, Org. Lett. 2012, 14, 4286-4289. [4] Z. Csok, O. Vechorkin, S. B. Harkins, R. Scopelliti, X. L. Hu, J. Am. Chem. Soc. 2008, 130, 8156-8157.

OC 6

Enol-Acetal Synthesis Via Carbenoid C-H Insertions Into Tetrahydrofurans Catalyzed By CpRu Complexes

Thierry Achard, Cecilia Tortoreto and Jérôme Lacour

Department of Organic Chemistry, University of Geneva Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland

Email: [email protected], [email protected]

CpRu complexes are known to catalyze together the decomposition of α-diazo derivatives [1]. Recently our group has shown that combinations of [CpRu(CH3CN)3][PF6] and diimine ligands lead to O-H insertion and condensation reactions with nitriles, ketones and aldehydes [2]. In a new development that uses α-diazo-β-ketoesters and THF moieties as substrates, we report the kinetically favored formation of C-O instead of C-C bond adducts [3]. The mild reaction conditions yield novel enol-acetal motifs through unprecedented 1,3-C-H insertion reactions. A Lewis acid catalyzed rearrangement to the classical C-C bound adducts is possible.

[1] a) W. Baratta, A. Del Zotto, Chem. Commun. 1997, 2163-2164; b) W. A. Herrmann, R. M. Kratzer, P. Rigo, Organometallics 2000, 19, 3664,3669.

[2] M. Austeri, D. Rix, W. Zeghida, J. Lacour, Org. Lett. 2011, 13, 1394-1397. [3] Tortoreto, T. Achard, W. Zeghida, M. Austeri, L. Guénée, J. Lacour, Angew. Chem. Int. Ed. 2012,51, 5847-5953.

OC 7

Total Synthesis of Gelsemiol and Studies on its Neuritogenic Activity

Patrick Burcha, Manuel Scherera, Massimo Binaghia, Corinna Wentzelb, Peter Scheiffeleb, Karl Gademanna

aUniversity of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel (Switzerland) bUniversity of Basel, Biozentrum, Klingelbergstrasse 50 / 70, CH-4056 Basel (Switzerland)

[email protected]

In an aging society, certain neurodegenerative diseases such as Alzheimer’s or Parkinson’s become more and more prevalent. Today’s treatments are mainly symptomatic and do not address the regeneration of damaged neuronal networks. Therefore, our research is focused on the stimulation of neurite outgrowth by applying natural products that are capable of mimicking neurotrophic factors.1,2

Gelsemiol (1) is known to induce neutrite outgrowth in the PC-12 cell line.3 The first enantioselective total synthesis of gelsemiol (1) is presented in nine steps (14 % overall yield) including an IEDDA reaction was well as a cascade/skeletal rearrangement.4 Chemical studies towards its congeners and intense biological evaluation in multiple cell models will be discussed.

Synthesis:

Biological Evaluation:

Primary Granule Cells Primary Granule Cells PC-12 Cells __________________________________________________________________________________ [1] S. T. DeKosky, S. W. Scheff, Ann. Neurol. 1990, 27, 457-464. [2] S. R. Jensen, O. Krik, O, R. B. J. Nielsen, R. Norrestam, Phytochem. 1987, 26, 1725-1731. [3] M. Ono, K. Oishi, H. Abe, T. Nohora, Chem. Pharm. Bull. 2006, 54, 1421-1426. [4] I. Marko, S. Warriner, B. Augustyns, Org. Lett. 2000, 2, 3123–3125.

OC 8

Evaluation of the Chiral DIANANE Backbone as Ligand for Organolithium Reagents

Praz Jezabel Organic Chemistry - University of Geneva

30, Quai Ernest-Ansermet, CH-1211 Geneva Switzerland

jezebel.praz @unige.ch

Chiral diamines are compounds of greatest interest in organic synthesis and particularly as chiral ligands for various asymmetric reactions. Previously in our laboratory, we observed for 1,2 chiral tertiary diamines a transfer of sterochemical information to the nitrogen atoms which become stereogenic upon chelation with a metal.

The validity of this concept was then illustrated in various reactions such as asymmetric bromine-lithium exchange, enantioselective additions of aryl and alkyllithium reagents to aromatic imines.

Toward this end, we developed a new type of C2-symmetric tertiary diamines derived from the DIANANE backbone. These new chiral ligands with their rigid backbone and fixed larger distance between the two nitrogen atoms were then applied in diverse asymmetric synthesis using organolithium reagents and compared with the previous 1,2 chiral diamine ligands.

[1] Jezabel Praz, Laure Guénée, Sarwar Aziz, Albrecht Berkessel* and Alexandre Alexakis*, Adv. Synth.

Catal. 2012, 354, 1780-1790.

OC 9

Modular Synthesis, Orthogonal Functionalization and Properties of Novel Cationic [6]Helicenes

Geraldine M. Labrador, Johann Bosson, Franck Torricelli, Jérôme Lacour

Department of Organic Chemistry - University of Geneva 30 quai Ernest Ansermet, CH-1211 Geneva 4


Helicenes are omnipresent in chemistry, biochemistry and physics as a result of their many different properties and applications [1]. These can be modulated by selectively introducing substituents to the periphery of the helical cores or by changing the nature of the atoms within. However, such modifications are not always trivial to perform. To overcome this limitation, we have developed a new class of cationic diaza 2, azaoxo 3 and dioxo 4 [6]helicenes.

These derivatives 2 - 4 were prepared in one step from a common advanced intermediate 1. Straightforward, yet orthogonal, functionalization reactions afforded a series of polysubstituted [6]helicenes [2]. The importance of these transformations is evidenced in the strong modulation of the visible absorption and emission properties of these cationic dyes. [1] Y. Shen, C.-F. Chen, Chem. Rev. 2012, 112, 1463-1535. [2] F. Torricelli, J. Bosson, C. Besnard, J. Lacour, submitted

OC 10

Asymmetric Synthesis of Indolines via Pd(NHC)-Catalyzed C(sp3)-H/C(Ar) Coupling Reactions

Dmitry Katayev

Department of Organic Chemistry, University of Geneva 30 quai Ernest Ansermet, CH-1221 Geneva 4


Metal-catalyzed C-C bond formation via C-H activation has emerged as a powerful method in organic chemistry. [1] In this area, a major challenge remains: the selective reaction of unactivated C(sp3)-H

bonds of alkyl units. Using new in-situ generated chiral N-heterocyclic carbene ligands in combination with a Pd catalyst precursor we have recently been able to show for the first time that a highly asymmetric coupling reaction can be realized to give enantioenriched indolines. [2-5] Structural studies show that conformational locking to avoid allylic strain is the key for understanding the role of the different

elements in the NHC* ligands used. [6] Although high temperatures (140 -160 oC) are required for this reaction, excellent asymmetric recognition of an enantiotopic C-H bond in an unactivated methylene unit is achieved.

The studies have now been extended to racemic substrates and we find that these react via regiodivergent reactions (RRM). In the ideal case a racemic mixture reacts to give two distinctly different products that are both highly enantioenriched. [7]

[1] Reviews: a) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu Chem. Soc. Rev., 2009, 38, 3242-3272. b) R. Jazzar, J. Hitce, A. Renaudat,

J. Sofack-Kreutzer, O. Baudoin Chem. Eur. J., 2010, 16, 2654-2672. c) O. Baudoin Chem. Soc. Rev., 2011, 40, 4902-4911. d) H. Li, B.-J. Li, Z.-J. Shi, Catal. Sci. Technol., 2011, 1, 191-206.

[2] M. Nakanishi, D. Katayev, C. Besnard, E. P. Kündig Angew. Chem. Int. Ed. 2011, 50, 7438-7441. V.I.P. (Highlight by SYNFACTS: 2011, 10, 1063).

[3] M. Nakanishi, D. Katayev, C. Besnard, E. P. Kündig Chimia, 2012, 66, 241-243.[4] E. P. Kündig, Y.-X. Jia, D. Katayev, M. Nakanishi Pure Appl. Chem. 2012, 84, 1741. [5] For a chiral monodentate phosphorous-Pd-catalyzed version see: T. Saget, S. J. Lemouzy, N. Cramer Angew. Chem. Int. Ed., 2012, 51,

2238-2242. [6] Y.-X. Jia, D. Katayev, T. M. Seidel, G. Bernardinelli, E. P. Kündig Chem. Eur. J. 2010, 16, 6300-6309. [7] D. Katayev, M. Nakanishi, T. Bürgi, E. P. Kündig Chem. Sci. 2012, 3, 1422-1425. (Highlighted by SYNFACTS: 2012, 8, 0879).

OC 11

Formation of quaternary stereogenic centers by NHC-Cu catalysed asymmetric conjugate addition reactions with Grignard reagents on

polyconjugated cyclic enones

Matthieu Tissot Université de Genève

30, quai Ernest Ansermet, 1211 Genève Switzerland

[email protected]

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The copper catalyzed conjugate addition of various Grignard reagents to polyconjugated enones (dienones and enynones derivatives) are reported. The catalyst system, composed of copper triflate and the NHC ligand L6, led to the unsual selective formation of the 1,4-addition products. The reaction allows the creation of all-carbon chiral quaternary centers with enantiomeric excess up to 99 % ee. The remaining insaturation on the 1,4-adducts gave an access to valuable synthetic transformations. [1] Henon, H.; Mauduit, M.; Alexakis, A. Angew. Chem., Int. Ed. 2008, 47, 9122. [2] Tissot, M.; Pérez Hernandez, A.; Müller, D.; Mauduit, M.; Alexakis, A. Org. Lett. 2011, 13, 1524. [3] Tissot, M.; Pogialli, D.; Hénon H.; Müller, D.; Guenée, L. Mauduit, M.; Alexakis, Chem. Eur. J. 2012, 18, 8731

OC 12

Poster Presentations

The formal homo-Nazarov cyclization – a powerful tool for the synthesis of alkaloid natural products

Reto Frei, Filippo De Simone and Jérôme Waser

Ecole Polytechnique Fédérale de Lausanne 1015, Lausanne


Heterocyclic scaffolds occupy a privileged position among natural and synthetic drugs. Consequently, the discovery and implementation of cyclization reactions to efficiently access such cyclic structures are highly sought after in organic chemistry. In this context, our laboratory developed the first catalytic formal homo-Nazarov cyclization of vinyligous cyclopropyl ketones for the synthesis of polycyclic hetero and non-hetero cyclohexenone derivatives.[1] Herein we report the application of the developed mild and highly regionselective reaction for the cyclization of acyl indole substituted aminocyclopropanes. The effectiveness of the methodology is demonstrated by the efficient formal total synthesis of aspidospermidine and the total synthesis of goniomitine.[2] The broad applicability of the developed formal homo-Nazarov cyclization is further showcased by employing it as key transformation during the first total synthesis of the highly electron-rich aspidosperma type alkaloid jerantinine E.

[1] a) F. De Simone, J. Andres, R. Torosantucci, J. Waser, Org. Lett. 2009, 11, 1023-1026; b) F. De Simone, T. Saget, F. Benfatti, S. Almeida, J. Waser, Chem. Eur. J. 2011, 17, 14527-14538.

[2] F. De Simone, J. Gertsch, J. Waser, Angew. Chem. Int. Ed. 2010, 49, 5767-5770.

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PO 3

DESIGN OF NOVEL ASYMMETRIC ORGANOCATALYSTS

Toms Kalnins; Kirill Shubin; Edgars Suna

Latvian Institute of Organic Synthesis Aizkraukles str. 21, LV-1006, Riga

Latvia [email protected]

Chiral aminothioureas, possessing ethylenediamine moiety, are excellent organocatalysts in asymmetric Michael reaction. Herein we report synthesis and application of propylenediamine moiety containing aminothioureas. A series of chiral thioureas 2-11 has been synthesized to establish relationship between position of catalyst’s chiral center and level of enantiocontrol.

The synthesized aminothioureas 2-11 were tested in Michael reaction between nitrostyrene and various 1,3-dicarbonyl substrates. The best results were obtained with catalysts 7 (94%, 68% ee) and 8 (99%, 47% ee), using ethyl benzoylacetate as 1,3-dicarbonyl species.

PO 4

Direct alkynylation of furans and benzofurans

Yifan LI, Jonathan Brand, Jérôme Waser Laboratory of Catalysis and Organic Synthesis

Institute of Chemical Sciences and Engineering École polytechnique fédérale de Lausanne

CH-1015 Lausanne Switzerland

[email protected]

Furans (benzofurans) and alkynes are important building blocks in medicinal chemistry and material science.1 Currently, the state-of-the art method to access these products involves the Sonogashira alkynylation of pre-functionalized precursors. The synthesis of the required halogenated heteroarenes by deprotonation and/or iodination (or bromination) is often challenging, due to a poor regioselectivity and has a low tolerance to functional groups. Consequently, a mild method to achieve the regioselective direct alkynylation of furans and benzofurans would be highly desirable.

Based on our previous work on the Au-catalyzed alkynylation of indoles, pyrroles, thiophenes and anilines,2 we report herein two different protocols for the direct alkynylation of furans and benzofurans with gold chloride and TIPS-EBX under mild conditions.3 The alkynylation processes at room temperature or 60 oC with good to excellent yield (17 examples, yield 45%-90%). Moreover, for the alkynylation of benzofurans, a new method to activate the TIPS-EBX reagent using zinc triflate as Lewis acid was discovered. The TIPS-EBX reagent used is commercially available, or can alternatively be easily obtained from 2-iodobenzoic acid on 30 g scale.

Completing our previous research, the directly alkynylation of different electron-rich (hetero)arenes has now been achieved with TIPS-EBX. Future works will focus on the investigation of other types of activation for the alkynylation of C-H bonds using TIPS-EBX.

1 a) J.M. Hopkins, B.A. Keay, P.W. Dibble in Comprehensive Heterocyclic Chemistry II, Chapter 3.08 (eds: A.R. Katritzky, C.W, Rees, E.F, Scriven), Elsevier: Amsterdam 2008; b) F. Diederich, P.J. Stang, R.R. Tykwinski in Acetylene chemistry. Wiley-VCH: Weinheim 2005. 2 a) J.P. Brand, J. Charpentier, J. Waser, Angew. Chem., Int. Ed. 2009, 48, 9346-9349. b) ) J.P. Brand, J. Waser, Angew. Chem., Int. Ed. 2010, 49, 7304-7307. c) J.P. Brand, J. Waser, Org. Lett. 2012, 14, 744-747. 3 Y. LI, J.P. Brand, J. Waser, Manuscript in preparation.

PO 5

Catalytic organic transformation of aldehyde to amide by using

ruthenium complexes

N. Rajaa,b, B. Therrienb, R. Ramesha

aSchool of Chemistry, Bharathidasan University, Tiruchirappalli, India bInstitute of Chemistry, University of Neuchatel, 51 Ave de Bellevaux, 2000 Neuchatel, Switzerland

email: [email protected]

In recent years, ruthenium(II) complexes have been proved to be extremely useful catalysts in

organic synthesis such as hydrogenation, oxidation, isomerisation, polymerization, nucleophilic

addition to multiple bonds and carbon–carbon bond formation etc.1 As a result, a great number of

important catalytic organic transformations have already been studied, the development of atom-

efficient catalytic methods for the conversion of aldehyde to amide is currently an extremely active

area of research.2,3 Here we compared the catalytic activity of aldehyde to amide reaction using

arene ruthenium complexes and ruthenium azo complexes in a one-pot process in the presence of

NH2OHÐHCl / NaHCO3.

R H

O

R NH2

ORu complexes / NaHCO3

Solvent / refluxH2ONH2OH.HCl

[1] R. Drozdzak, B. Allaert, N. Ledoux, I. Dragutan, V. Dragutan, F. Verpoort, Coord. Chem. Rev. 2005, 249, 3055 – 3074. [2] D. Gnanamgari, R.H. Crabtree, Organometallics 2009, 28, 922 – 924. [3] N. Raja, M. Ulaganatha Raja, R. Ramesh, Inorg. Chem. Commun. 2012, 19, 51 – 54.

PO 6

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PO 7

A�Rapid�and�Modular�Access�to�Arylsultams�by��Rh(III)$Catalyzed�C$H�Activation��

�Manh�V.�Pham,�Baihua�Ye,�Nicolai�Cramer*�

Laboratory�of�Asymmetric�Catalysis�and�Synthesis,�EPF�Lausanne�EPFL�SB�ISIC�LCSA,�CH«1015�Lausanne�

Switzerland�[email protected]�

��

The� sulfonamide� group� is� a� classical� and� important� pharmacophore� in� medicinal� chemistry.�Arylsultams�represent�as�well�an� important�motif�due�to�their�wide�range�of�biological�activities.[1]�Several� methods� and� strategies� to� synthesize� sultams� have� been� reported.� However,� all� of� them�require�several�steps�from�commercially�available�materials�and/or�functionalized�substrates.[2]��Directed� C«H� bond� activations� have� recently� attracted� significant� attention� because� of� their�efficiency� and� atom� economical� alternative� to� classical� synthesis.[3]� In� this� respect,� several� new�Rh(III)«catalyzed�processes�have�emerged�over�the�past�years.[4]�We�report�our�findings�on�applying�Rh(III)«catalyzed�C«H�activation�of�arylsulfonamide�derivatives�and�their�subsequent�cyclisation�with�internal�alkynes�to�provide�an�efficient�and�highly�yielding�route�to�arylsultams.[5]��

�

��[1]� T.�J.�Carty,�A.�Marfat,�P.�F.�Moore,�F.�C.�Falkner,�T.�M.�Twomey,�Agents�Actions�1993,�39,�157.�[2]� a)�I.�R.�Greig,�M.�J.�Tozer,�P.�T.�Wright,�Org.�Lett.�2001,�3,�369;�b)�M.�Jiménez«Hopkins,�P.�R.�Hanson,�Org.�Lett.�2008,�10,�2223.�[3]� D.�A.�Colby,�R.�G.�Bergman,�J.�A.�Ellman,�Chem.�Rev.�2010,�110,�624.�[4]� G.�Song,�F.�Wang,�X.�Li,�Chem.�Soc.�Rev.�2012,�41,�3651.�[5]� M.�V.�Pham,�B.�Ye,�N.�Cramer,�Angew.�Chem.�Int.�Ed.�2012,�51�(DOI:�10.1002/anie.201206191)��

PO 8

Hydrogenation of Quinoline by Hectorite-Supported

Ruthenium Nanoparticles

Bing Sun, Farooq-Ahmad Khan, Georg Süss-Fink* Institut de Chimie, Université de Neuchâtel

CH-2000 Neuchâtel Switzerland

[email protected]

Reduction of N-heteroaromatic compounds such as quinoline is of great importance, since valuable intermediates thus obtained are widely used as building blocks for specialty fine chemicals [1] and for petrochemicals [2]. Under mild conditions, a sufficient catalyst, which can selectively hydrogenate pyridine ring and be robust to keep from deactivation by the N-containing compound, is still in search. Hectorite is, just as montmorillonite, a naturally occurring clay, which can be defined as layers of negatively charged two dimensional silicate sheets held together by cationic species in the interlaminar space, which are susceptible to ion exchange [3-5]. Ruthenium-supported hectorite obtained by ion-exchange with [(C6H6)Ru(H2O)3]2+ cations [6,7] offered us a fundamental material to expand our study on its catalytic properties.

Ruthenium nanoparticles intercalated in hectorite are found to efficiently catalyze the hydrogenation of quinoline under mild conditions. The selectivity (>99%) could be switched by the choice of the reaction medium to give either 1,2,3,4-tetrahydroquinoline (solvent H2O) or decahydroquinoline (solvent cyclohexane), respectively. [1] A. R. Kartritzky, S. Rachwal, B. Rachwal, Tetrahedron 1996, 52, 15031-15070.[2] G. Perot, Catalysis Today 1991, 10, 447-472. [3] T. J. Pinnavaia, Science 1983, 220, 365-371.[4] J. L. Valverde, A. de Lucas, P. Sànchez, F. Dorado, A. Romero, Appl. Catal. B 2003, 43, 43-56.[5] B. M. Choudary, M. L. Kantam, K. V. S. Ranganath, K. K. Rao, Angew. Chem. Int. Ed. 2005, 44, 322-325.[6] Georg Süss-Fink, Farooq-Ahmad Khan, Julien Boudon, Vladislav Spassov, Journal of Cluster Science, 2009, 20, 341-353.[7] Farooq-Ahmad Khan, Armelle Vallat, Georg Süss-Fink, Catalysis Communications, 2011, 12, 1428-1431.

conversion 99.6%, selectivity 99.3%, TOF 219 h-1

conversion > 99.9%, selectivity > 99 %, TOF 75 h-1

PO 9

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PO 10

C2 Selective Direct Alkynylation of Indoles

Gergely L. Tolnai Institute of Chemical Sciences and Engineering - Ecole Polytechnique Fédérale de Lausanne,

EPFL SB ISIC LCSO, BCH 4306 (Bât. BCH), CH-1015 Lausanne Switzerland

[email protected]

Heterocycles are omnipresent in organic and medicinal chemistry. In the context of sustainable chemistry, it is essential to develop direct C-H functionalization methods to generate new heterocyclic structures.[1] Whereas arylation and vinylation methods are already well developed, alkynylation has been much less investigated, despite the fact that acetylenes are one of the most useful building blocks in organic chemistry.

In our laboratory, we have introduced ethynyl benziodoxolone (EBX) reagents as electrophilic alkynylation reagents and used them in the gold-catalyzed functionalization of biologically important indole and pyrrole heterocycles.[2] In particular, the use of TIPS-EBX (1) gave excellent selectivity for the 3-alkynylation of indoles.

In this work, we report the use of Pd catalysis for an unprecedented C2-selective alkynylation[3], a process that has been realized only for 3-substituted indoles in the past.[4]

Our convenient, robust method gives a single-step access to variously substituted alkynyl indoles with very high C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions and the obtained silylated alkynes are easily deprotected to give terminal acetylenes. In conclusion, the new Pd-catalyzed method gave a complementary selectivity when compared with Au catalysis, and demonstrated for the first time that the Pd-catalyzed C-H alkynylation of (hetero)arenes is possible using hypervalent iodine reagents. Future work will focus on the alkynylation of other types of C-H bonds based on the synergism between hypervalent iodine chemistry and palladium catalysis.

[1] Godula, K.; Sames, D. Science 2006, 312, 67. [2] Brand, J. P.; Charpentier J.; Waser, J. Angew. Chem., Int. Ed. 2009, 48, 9346. [3] Gergely L. Tolnai, Stephanie Ganss, Jonathan Brand and Jérôme Waser, manuscript in preparation [4] Yang, L.; Zhao, L. A.; Li, C. J. Chem. Commun. 2010, 46, 4184.

PO 11

Modular synthesis of carbenium ions as fluorescent dyes

Jérôme Gouin , Antoine Wallabregue, Rémi Vanel and Jérôme Lacour*

a Department of Organic Chemistry - University of Geneva Quai E. Ansermet 30, CH-1211 Geneva.

Switzerland [email protected], [email protected], [email protected]

Our group is interested in the development of stable carbenium ions[1] (helicenes and triangeleniums), these polyaromatic compounds exhibit good fluorescent properties which can be tune with the heteroatoms within the scaffold. We have previously reported the use of TriAzaTrianguleniums (so called TATA) as Phase Transfer Catalyst (PTC)[2] and we are now currently investigating the applications of other trianguleniums, the AzaDiOxaTriangulenium and DiOxaAzaTriangulenium (respectively ADOTA and DAOTA) as fluorescent probes for cell membrane imaging, solvatochromism dyes[3] and multipodal platforms.

Herein we also report the chemical (pH-sensitive, pKa 8.95) and physical properties of novel quinacridine-based [4]helicenes 2 and the applications of such derivatives in synthetic chemistry.

[1] Laursen, B. W.; Krebs, F. C. Angew. Chem. Int. Ed. Engl. 2000, 39, 3432. Herse, C.; Bas, D.; Krebs, F. C.; Bürgi, T.; Weber, J.;

Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem. Int. Ed. Engl. 2003, 42, 3162. Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.;

Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem. Int. Ed. Engl. 2005, 44, 1879. Mobian, P.; Nicolas, C.; Francotte, E.; Bürgi, T.; Lacour, J. J. Am. Chem. Soc. 2008, 130, 6507. Baisch, B.; Raffa, D.; Jung, U.; Magnussen, O.; Nicolas, C.; Lacour, J.; Kubitschke, J.; Herges, R. J. Am. Chem. Soc. 2009, 131, 442. Guin, J.; Besnard, C.; Lacour, J. Org. Lett. 2010, 12, 1748. Hamacek, F.; Besnard, C.;

Mehanna, N.; Lacour, J. Dalton Trans. 2012, 41, 6777. [2] Nicolas, C.; Lacour, J. Org. Lett. 2006, 8, 4343 [3] Reichardt, C.Chem. Rev. 1994, 94, 2319-2358

PO

mailto:[email protected]



Jérôme Waser

Text Box

12

Palladium Catalyzed γ-arylation of α,β-unsaturated Aldehydes

Ivan Franzoni, Clément Mazet* Department of Organic Chemistry - University of Geneva

Quai Ernest Ansermet 30, 1211 Geneva 4 Switzerland

[email protected]

In the last two decades, the α-arylation of enolizable carbonyl compounds has advanced with significant strides.[1] In this contest, aldehydes have revealed particularly challenging substrates.[2] Our group has recently reported an enantioselective intramolecular α-arylation of α-branched aldehydes using novel (P,N) ligands.[3]

In a direct continuation of this work, and based on the vinylogous analogy,[4] we set out to develop a related γ-arylation of α,β-unsaturated aldehydes. We present herein our preliminary results in this direction.

[1] a) C. Johansson, T. Colacot Angew. Chem. Int. Ed. 2010, 49, 676; b) F. Bellina, R. Rossi Chem. Rev. 2010, 110, 1082; c) C. Mazet Synlett. 2012, 23, 1999.

[2] a) Y. Terao, Y. Fukuoka, T. Satoh, M. Miura, M. Nomura Tetrahedron Lett. 2002, 43, 101; b) G. D. Vo, J. F. Hartwig Angew. Chem. Int. Ed. 2008, 47, 2127; c) J. García-Fortanet, S. L. Buchwald Angew. Chem. Int. Ed. 2008, 47, 8108.

[3] P. Nareddy, L. Mantilli, L. Guénée, C. Mazet Angew. Chem. Int. Ed. 2012, 51, 3826. [4] a) R. C. Fuson Chem. Rev. 1935, 16, 1; b) Y. Terao, T. Satoh, M. Nomura, M. Miura Tetrahedron Lett. 1998, 39, 6203.

PO 13

New Chiral NHC Ligands for the Copper-Catalyzed Asymmetric Conjugate Addition of Grignard Reagents

Nicolas Germain

Department of Organic Chemistry – University of Geneva Quai Ernest Ansermet, 30. CH-1211 GENEVA 4


Since asymmetric conjugate additions (A.C.A.) represent a powerful methodology allowing direct access to enantioenriched ketones, we kept our attention on some specific remaining challenges.[1] At this time, only few copper-catalysed nucleophiles were able to be introduced selectively on trisubstitued enones, promoted by various types of NHC’s chiral ligands.[2] This work discloses recent advances in the A.C.A. of the highly desirable Grignard reagents to �-substituted cyclic enones.[3]

Several ligands have been synthetized in high yields and involved in catalysis for the addition of

ethylmagnesium bromide leading to chiral 3,3-cyclohexanone (up to 93% ee). The best ligand was then engaged in optimized conjugate additions of various Grignard reagents allowing for the formation of quaternary centers with high level of regio- and enantioselectivity with only 0.75mol % of catalyst loading. Noteworthy is the addition of alkylmagnesium bromide for the construction of 3,3-cyclopentanone (up to 86% ee), highlighted by useful chiral synthon synthesis. Such level of selectivity for A.C.A. of alkylmagnesium bromide to 5-membered rings is unprecedented.

[1] A. Alexakis, J.E. Bäckvall, N. Krause, O. Pamies, M. Dieguez, Chem. Rev. 2008, 108, 2796-2823. [2] a) D. Martin, S. Kehrli, A. Alexakis J. Am. Chem. Soc. 2006, 128, 8416-8417; b) S. Kehrli, D. Martin, D. Rix, M. Mauduit, A. Alexakis,

Chem. Eur. J. 2010, 16, 9890-9904. [3] N. Germain, M. Magrez, S. Kehrli, M. Mauduit, A. Alexakis, Eur. J. Org. Chem. 2012, 5301-5306.

PO 14

Enantioselective Copper Catalyzed 1,4-addition to challenging 1,2-Dicarbonyl like Michael acceptors

Sylvie Goncalves, Ludovic Gremaud, Alexandre Alexakis* Department of Organic Chemistry - University of Geneva

Quai Ernest-Ansermet 30, CH-1211 Geneva 4 Switzerland

[email protected]

The copper-catalyzed asymmetric conjugate addition (ACA) of organometallic reagents to Michael acceptors is among the most important methodologies to form a C-C bond in an enantioselective manner. In this field, a variety of α,β-unsaturated compounds have been successfully used.�1� However, α,β-unsaturated aldehydes are more challenging substrates because of their high reactivity toward the undesired 1,2-addition and aldol by-products.�2� More recently, α,β-unsaturated 1,2-dicarbonyl compounds emerged to be a new class of challenging Michael acceptors for this key transformation.�3� Scope and limitations of the ACA to such substrates will be presented as well as their potential synthetic applications.

O

Z

R

Z = H, EWG

2 eq. R'3Al5 mol% CuTC5 mol% (R)-BINAP

THF / -78°CO

Z

R

R'*

1,4/1,2 up to 100/0ee's up to 99%R' = alkyl

R'MgBr or R'2Zn5 mol% CuTC

5.25 mol% chiral ligand

Et2O / -78, -20 or 0°CO

H

R

R'*

1,4/1,2 up to 100/0ee's up to 92%R' = alkyl, aryl

this work : Z = EWGprevious work : Z = H

R = alkyl, aryl

[1] a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221; (b) Alexakis, A.; Backväll, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796; (c) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824.

[2] Palais, L.; Babel, L.; Quintard, A.; Belot, S.; Alexakis, A. Org. Lett. 2010, 12, 1988. [3] Gremaud, L.; Alexakis, A. Angew. Chem. Int. Ed. 2012, 51, 794.

PO 15

Modular synthesis of carbenium ions as fluorescent dyes

Jérôme Gouin , Antoine Wallabregue, Rémi Vanel and Jérôme Lacour* a Department of Organic Chemistry - University of Geneva

Quai E. Ansermet 30, CH-1211 Geneva. Switzerland

[email protected], [email protected], [email protected]

Our group is interested in the development of stable carbenium ions[1] (helicenes and triangeleniums), these polyaromatic compounds exhibit good fluorescent properties which can be tune with the heteroatoms within the scaffold. We have previously reported the use of TriAzaTrianguleniums (so called TATA) as Phase Transfer Catalyst (PTC)[2] and we are now currently investigating the applications of other trianguleniums, the AzaDiOxaTriangulenium and DiOxaAzaTriangulenium (respectively ADOTA and DAOTA) as fluorescent probes for cell membrane imaging, solvatochromism dyes[3] and multipodal platforms.

Herein we also report the chemical (pH-sensitive, pKa 8.95) and physical properties of novel quinacridine-based [4]helicenes 2 and the applications of such derivatives in synthetic chemistry.

[1] Laursen, B. W.; Krebs, F. C. Angew. Chem. Int. Ed. Engl. 2000, 39, 3432. Herse, C.; Bas, D.; Krebs, F. C.; Bürgi, T.; Weber, J.;

Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem. Int. Ed. Engl. 2003, 42, 3162. Laleu, B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernardinelli, G.; Lacour, J. Angew. Chem. Int. Ed. Engl. 2005, 44, 1879. Mobian, P.; Nicolas, C.; Francotte, E.; Bürgi, T.; Lacour, J. J. Am. Chem. Soc. 2008, 130, 6507. Baisch, B.; Raffa, D.; Jung, U.; Magnussen, O.; Nicolas, C.; Lacour, J.; Kubitschke, J.; Herges, R. J. Am. Chem. Soc. 2009, 131, 442. Guin, J.; Besnard, C.; Lacour, J. Org. Lett. 2010, 12, 1748. Hamacek, F.; Besnard, C.; Mehanna, N.; Lacour, J. Dalton Trans. 2012, 41, 6777.

[2] Nicolas, C.; Lacour, J. Org. Lett. 2006, 8, 4343 [3] Reichardt, C.Chem. Rev. 1994, 94, 2319-2358

PO 16

Phosphorus Interconversion of P-stereogenic C1-symmetric Ligands Leave one blank line Calibri 10 – centered - here

Nicolas HUMBERT, Clément MAZET* Department of Organic Chemistry - University of Geneva

Quai Ernest Ansermet 30 CH-1211 Geneva 4 Switzerland

[email protected] Leave two blank lines Calibri 10 – centered – below your address

Our group has recently designed a novel class of C1-symmetric chiral (P,N) ligands 1a-k that were found to provide high yield and enantiomeric excess in the challenging intramolecular �-arylation of �-branched aldehydes.[1,2]

These ligands feature three dinstinct elements of chirality: (1) the axial chirality of the binaphtyl backbone; (2) the central chirality at the benzylic position; (3) a stereogenic phosphorus center. Ligands with a large R1 substituent are usualy prepared as single diastereoisomers (1a-g). For ligands 1h-k having a smaller P-substituent, 2 isomers were obtained in a typical 1.4:1.0 ratio. In the case of 1j, the 2 isomers 1j-(Rax,R,SP) and 1j-(Rax,R,RP) were chromatographically separated and characterized by X-ray analyses. Upon heating the minor isomer 1j-(Rax,R,SP) quantitatively delivered 1j-(Rax,R,RP), thus indicating a formal P-interconversion is taking place. The thermodynamic and kinetic parameters associated with this phenomenon have been obtained. Complexation studies of both diastereomeric ligands to palladium will also be disclosed. [1] C. Mazet, Synlett 2012, 23, 1999-2004. [2] P. Nareddy, L. Mantilli, L. Guénée, C. Mazet, Angew. Chem. Int. Ed. 2012, 51, 3826-3831.

PO 17

A [Pd]‒H-Catalyzed Isomerization of Terminal Epoxides: Scope, Reaction Mechanism, and Potential in Asymmetric Catalysis

Devendra J. Vyas, Evgeny Larionov, Céline Besnard, Laure Guénée and Clément Mazet*

Department of Organic Chemistry - University of Geneva 30, Quai Ernest Ansermet, 1211 Geneva 4


α-Chiral aldehydes are important building blocks in synthetic chemistry. Transition metal-catalyzed enantioselective cross-coupling reactions between carbonyl precursors and aryl surrogates is an elegant approach to access this versatile class of compounds.[1] However, post-reaction epimerization under basic conditions precludes the enantioselective formation of α-chiral aldehydes with a tertiary stereocentre. Subsequently, this synthetic strategy was successfully practised only for the asymmetric intramolecular α-arylation of α-branched aldehydes which generates quaternary stereocentres.[2] Therefore, an atom-economical protocol which would enable access to α-chiral aldehydes with tertiary stereocentres and that would avoid post-reaction epimerization is highly desired. Hereby we report a base-free Pd(II)-catalyzed protocol for the isomerization of 2,2-disubstituted epoxides to obtain α-chiral aldehydes with a tertiary stereocenter (Scheme 1). Catalyst design, synthesis and characterization by X-ray analysis of a novel dinuclear [Pd]‒H complex are presented. The scope of the reaction (20 examples, Scheme 1) and detailed mechanistic studies using the well-defined precatalyst are the key features of this work. A prospective enantioselective protocol which further supports our mechanistic findings is also described.

Scheme 1: Pd(II)-catalyzed isomerization of 2,2-disubstituted epoxides [1] For recent review, see: C. Mazet, Synlett 2012, 23, 1999‒2004. [2] a) J. G-Fortanet, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 8108‒8111; b) P. Nareddy, L. Mantilli, L. Guénée, C. Mazet, Angew.

Chem. Int. Ed. 2012, 51, 3826‒3831.

PO18

Highly Enantioselective Direct Vinylogous Michael Addition of

γ-Butenolide to Enals

Alice Lefranc, Adrien Quintard, Alexandre Alexakis Department of organic Chemistry – University of Geneva


[email protected] In recent years, aminocatalysis and particularly iminium catalysis has become an essential activation mode for the asymmetric β-functionalization of conjugated carbonyl compounds. Our group recently developed Aminal-PYrrolidine (APY) catalysts as powerful tools for aminocatalyzed reactions.[1] In this context, we disclosed the development of an unprecedented and simple direct vinylogous addition of deconjugated butenolide to enals in excellent stereoselectivities (>95% ee).[2] This methodology allows for the efficient preparation of complex γ-butenolide from Angelica lactone derivatives, directly obtained from readily available renewable resources. Furthermore, preliminary mechanistic investigations allowed for a better understanding of the process.

[1] a) A. Quintard, C. Bournaud, A. Alexakis, Chem. Eur. J., 2008, 14, 7504-7507 ; b) A. Quintard, S. Belot, E. Marchal A. Alexakis, Eur. J.

Org. Chem., 2010, 927-936. [2] A. Quintard, A. Lefranc, A. Alexakis, Org. Lett., 2011, 13, 1540-1543.

PO 19

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PO 20

Investigation of DOS Library Compounds for the Treatment of Malaria

Daniela Masi, Jennifer Beaudoin, Eamon Comer, Justin Dick, Jeremy Duvall, Mark Fitzgerald, Richard

Heidebrecht, Amanda Lukens, Lisa Marcaurelle, Carol Mulrooney, Benito Munoz, Roger Wiegand, Dyann Wirth, and Michael Foley

Chemical Biology Platform - The Broad Institute of Harvard and MIT 7 Cambridge Center, Cambridge, MA, 02142

USA [email protected]

A whole-organism P. falciparum high throughput assay was performed on a set of 8000 diverse compounds in the Broad Diversity Oriented Synthesis library collection. At a dose of 5 mM, 560 hits inhibited the growth of P. falciparum >90%. Representative compounds from this set were independently resynthesized and their activities verified, and a lead with an EC50 of 120 nM against chloroquine resistant P. falciparum (Dd2) was chosen for further investigation. Multiple analogs have been prepared optimizing for potency and solubility with EC50s as low as 180 pM and water solubilities up to 500 mM.

PO 21

Palladium-Catalyzed Asymmetric α-Arylation of Aldehydes

Pradeep Nareddy, Clément Mazet* Department of Organic Chemistry - University of Geneva


[email protected] Our group has an interest in developing catalytic methods to access chiral aldehydes in view of further use in synthesis. In this context, we have recently developed an asymmetric isomerization of primary allylic alcohols [1] and an asymmetric hydroboration of terminal alkenes [2]. Although, high levels of enantioselectivity were obtained for both reactions, none of these methods provides to access �-chiral aldehydes with a quaternary stereocenters. The underdeveloped Pd-catalyzed α- arylation of aldehydes pioneered by Miura [3] is an attractive strategy to access such motifs [4].

Herein, we will present the synthesis of a novel class of chiral (P,N) ligands which, display unprecedented selectivity levels for the Pd-catalyzed intra-molecular �-arylation of �-branched aldehydes [5]. [1] a) L. Mantilli, D. Gérard, S. Torche, C. Besnard, C. Mazet. Angew. Chem. Int. Ed. 2009, 48, 5413; b) L. Mantilli, C. Mazet. Chem.

Commun, 2010, 46, 445; c) L. Mantilli, D. Gérard, S. Torche, C. Besnard, C. Mazet. Chem. Eur. J. 2010, 16, 12736. [2] C. Mazet, D. Gérard. Chem. Commun. 2011, 47, 298. [3] Y. Terao, Y. Fukuoka, T. Saoth, M. Miura, M. Nomura. Tetrahedron Lett. 2002, 43, 101. [4] J. García-Fortanet, S. L. Buchwald. Angew. Chem. Int. Ed. 2008, 47, 8108. [5] P. Nareddy, L. Mantilli, L. Guénée, C. Mazet. Angew. Chem. Int. Ed. 2012, 51, 3826.

PO 22

Novel [1,2]-Stevens Rearrangement of Tröger Base Derived N+-N− Ylides

Sandip A. Pujari, Laure Guénée and Jérôme Lacour* Department of Organic Chemistry - University of Geneva

30, quai Ernest Ansermet, Geneva 4 (max. 1 line) Switzerland

[email protected]

With the intrinsic goal of investigating the stereoselective [1,2]-Stevens rearrangement of chiral tertiary amines, in particular with Tröger bases, initially our group has reported the sequential two step protocol involving quaternary ammonium salt formation.1 Subsequently, a one-pot transition metal mediated diazo decomposition protocol was developed for the direct ylide formation, which allowed the enantiospecific synthesis of configurationally stable ethano-Tröger derivatives with high enantiomeric purity (ee up to 99%) and diastereocontrol (dr up to 49:1, at quaternary stereocenter).2

Herein, we describe an efficient [1,2]-Stevens rearrangement of N+-N- ylides generated by treatment of methano-Tröger bases 1 with nitrene intermediates to afford the novel hydrazino-derivatives 2. Further, extension of this reaction to ethano-Tröger bases 3 leads to a completely new type of rearrangement affording unusual 13,13´-disubstituted methano-tröger 4 in a single step. The preliminary results of this novel transformation using chiral ethano-Tröger bases and the details of reaction mechanism will also be presented.

[1] C. Michon, A. Sharma, G. Bernardinelli, E. Francotte, J. Lacour, Chem. Commun., 2010, 46, 2206-2208. [2] a) A. Sharma, L. Guénée, J. V. Naubron, J. Lacour, Angew. Chem.,Int. Ed., 2011, 50, 3677-3680; b) A. Sharma, C. Besnard, L. Guénée,

J. Lacour, Org. Bimol. Chem. 2012, 10, 966-969.

PO 23

Enol-Acetal Synthesis Via Carbenoid C-H Insertions Into Tetrahydrofurans Catalyzed By CpRu Complexes

Cecilia Tortoreto, Thierry Achard and Jérôme Lacour

Department of Organic Chemistry, University of Geneva Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland

Email: [email protected], [email protected]

CpRu complexes are known to catalyze together the decomposition of α-diazo derivatives [1]. Recently our group has shown that combinations of [CpRu(CH3CN)3][PF6] and diimine ligands lead to O-H insertion and condensation reactions with nitriles, ketones and aldehydes [2]. In a new development that uses α-diazo-β-ketoesters and THF moieties as substrates, we report the kinetically favored formation of C-O instead of C-C bond adducts [3]. The mild reaction conditions yield novel enol-acetal motifs through unprecedented 1,3-C-H insertion reactions. A Lewis acid catalyzed rearrangement to the classical C-C bound adducts is possible.

[1] a) W. Baratta, A. Del Zotto, Chem. Commun. 1997, 2163-2164; b) W. A. Herrmann, R. M. Kratzer, P. Rigo, Organometallics 2000, 19, 3664,3669.

[2] M. Austeri, D. Rix, W. Zeghida, J. Lacour, Org. Lett. 2011, 13, 1394-1397. [3] Tortoreto, T. Achard, W. Zeghida, M. Austeri, L. Guénée, J. Lacour, Angew. Chem. Int. Ed. 2012,51, 5847-5953.

PO 24

One-Step Synthesis of Functionalized Polyether Macrocycles Leave one blank line Calibri 10 – centered - here

Mahesh Vishe,[a] Radim Hrdina,[a] Daniele Poggiali,[a] Céline Besnard,[b] Laure Guénée [b] Jérôme Lacour *[a]

Department of Organic Chemistry - University of Geneva,

Quai Ernest Ansermet 30, CH-1211 Geneva Switzerland

[email protected]

Macrocycles are generally synthesized from linear molecules using intramolecular reactions.[1] Recently our group has developed several one-step syntheses of medium sized rings[2] and polyether macrocycles by multi-condensation reactions of simple (naked) ether and diazo reactants under high concentration and non-templated conditions. [3]

Here in an extension of this research we present a series of Rh(II)-catalyzed[4] reactions of diazocarbonyls and substituted tetrahydrofuranes and tetrahydropyranes that afford 16- to 18-membered macrocycles in a single step and yields up to 84 %. A rather high functional group tolerance is exhibited. Mechanistic rationals for these macrocyclisation reactions will also be presented.

[1] H. An, J. S. Bradshaw, R. M. Izatt, Chem. Rev. 1992, 92, 543. [2] R. Ballesteros-Garrido, D. Rix, C. Besnard, J. Lacour, Chem. Eur. J. 2012, 18, 6626. [3] W. Zeghida, C. Besnard, J. Lacour, Angew. Chem. Int. Ed. 2010, 49, 7253.; D. Rix, R. Ballesteros Garrido, W. Zeghida, C. Besnard, J.

Lacour, Angew. Chem. Int. Ed. 2011 , 50, 7308. [4] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to

Ylides; Wiley: New York, 1998.

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