Gold (I) catalyzed intermolecular cycloadditions of allenes

FacultaddeQuímica–DepartamentodeQuímicaOrgánica CentroSingulardeInvestigaciónenQuímicaBiológicayMateriales Moleculares(CIQUS) Gold (I) catalyzed intermolecular cycloadditions of allenes Memoria que, para optar al grado de Doctor en Química por la Universidad de Santiago de Compostela, presenta Hélio Manuel Ferreira Faustino Santiago de Compostela, Mayo 2014 D. JOSÉ LUIS MASCAREÑAS CID, CATEDRÁTICO DEL DEPARTAMENTO DE QUÍMICA ORGÁNICA DE LA UNIVERSIDAD DE SANTIAGO DE COMPOSTELA Y D. FERNANDO JOSÉ LÓPEZ GARCÍA, “CIENTIFICO TITULAR DEL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTÍFICAS, CERTIFICAN: Que la memoria adjunta, titulada “Gold (I) catalyzed intermolecular cycloadditions of allenes”, que para optar al grado de Doctor en Química presenta Don Hélio Manuel Ferreira Faustino, ha sido realizada bajo nuestra dirección, en los laboratorios del departamento de Química Orgánica y del Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS) de la USC. Considerando que constituye trabajo de tesis, autorizamos su presentación en la Universidad de Santiago de Compostela. Y para que así conste, expiden el presente certificado en Santiago de Compostela, a 5 de Mayo de 2014. Fdo.: José Luis Mascareñas Cid Fdo.: Fernando López García ACKNOWLEDGMENTS The work on this thesis was possible, due to the help and support of many people, who in one way or another had a positive contribution. Therefore I would like to express my gratitude to: My advisors José Luis Mascareñas and Fernando Lopez for their support and guidance throughout this thesis. The groups of Agustí Lledós and José M. Lassaletta for the productive collaborations. Professor Nuno Maulide and his entire group for the nice stay at the Max Plank. Professors Paulo Almeida, Maria José Alves, Gil Fortes and Ignácio Lopez for the opportunity to work in their labs, this was crucial to reach the PhD grant. To professors Luis Castedo, Juan Granja, Concepción Bello and their groups for the occasional support in seminars and daily working problems. Ramón and Mentxa for their help with the nuclear magnetic resonance spectroscopy. To my colleagues Andrés, David, Jaime, Javier Francos, Juan Duran, Iván, Lara, Lucia, Marisel, Moises, Noelia Casanova, Noelia Quiñones, Paloma, Ronald and all the Bio lab for the companionship, all the good times we had working and outside the lab. To Sergio Piñeiro for some of the funniest moments and valuable help in the lab. To Isaac Alonso and Nuno Gil, for being incredible lab mates and precious friends. To all my friends and family, for so many reasons that I cannot enumerate them. To Márcia, for being at my side. Finnaly I should acknowledge the Fundação para a Ciência e Tecnologia (Portugal) and POPH/FSE for a PhD grant (SFRH/BD/60214/2009). TABLE OF CONTENTS Presentation ....................................................................................................................... 1 Abbreviations and Acronyms ........................................................................................ 2 Introduction ...................................................................................................................... 3 1. Synthesis and transition metal catalysis .......................................................................... 5 2. Catalysis by gold ................................................................................................................ 10 2.1 – Reactivity of gold complexes ....................................................................................... 10 2.2 - Gold (I) catalyzed cycloadditions ................................................................................ 15 2.2.1 Synthetic relevance of cycloaddition reactions ..................................................................... 15 2.2.2 - Gold (I) catalyzed intramolecular cycloadditions .............................................................. 18 2.2.3 - Gold (I) catalyzed intermolecular cycloadditions .............................................................. 28 2.3 - Enantioselective Gold (I) catalysis .............................................................................. 33 3 – Allenamides ....................................................................................................................... 42 3.1 - Preparation of allenamides ...................................................................................................... 42 3.2 - Cycloadditions of allenamides ................................................................................................ 44 3.3 - Gold catalyzed reactions of Allenamides ............................................................................... 48 General objectives ......................................................................................................... 51 Chapter I – Gold(I)-Catalyzed Intermolecular (4+2)Cycloadditions between Allenamides and Dienes .............................................................................................. 53 1. Objective .............................................................................................................................. 55 2. Precedents in the construction of 6 and 7 membered carbocycles using transition metal catalyzed intermolecular cycloadditions ................................................................ 55 Seven membered rings ...................................................................................................................... 55 Six-membered rings ........................................................................................................................... 57 3. Results and discussion ...................................................................................................... 60 3.1 Preliminary studies ...................................................................................................................... 60 3.2 Published manuscripts ................................................................................................................ 63 Article 1 - Gold(I)-catalyzed intermolecular (4+2) cycloaddition of allenamides and acyclic dienes ........................................................................................................................... 63 Article 2 - Mechanistic intricacies of Gold-catalyzed intermolecular cycloadditions between allenamides and dienes ........................................................................................ 71 3.3 Studies on an enantioselective version of the (4+2) cycloaddition ....................................... 87 4. Subsequent work by other authors ................................................................................. 90 5. Conclusion ........................................................................................................................... 91 Chapter II – Gold(I)-Catalyzed Intermolecular (2+2) Cycloadditions between Allenamides and alkenes ............................................................................................. 93 1. Objective .............................................................................................................................. 95 2. Cyclobutanes: relevance and synthetic accessibility ................................................... 96 3.Article 3 - Gold(I)-Catalyzed Intermolecular (2+2) Cycloadditions between Allenamides and Alkenes .................................................................................................. 101 4. Addendum ......................................................................................................................... 111 5. Simultaneous and subsequent related work by other groups ................................ 112 6. Conclusion ......................................................................................................................... 115 Chapter III – Gold(I)-catalyzed cascade cycloadditions between allenamides and carbonyl-tethered alkenes: an enantioselective approach to oxa-bridged medium-sized carbocycles ......................................................................................... 117 1. Objective ............................................................................................................................ 119 2. Medium sized oxa-bridged carbocycles....................................................................... 119 3. Article 4 - Gold(I)-catalyzed cascade cycloadditions between allenamides and carbonyl-tethered alkenes: an enantioselective approach to oxa-bridged mediumsized carbocycles. ................................................................................................................. 129 4. Related simultaneous work by other authors .......................................................................... 137 5. Addendum: Gold(I)-catalyzed multicomponent cascade cycloaddition between allenamides, alkenes and aldehydes ................................................................................ 139 5.1 Objective ...................................................................................................................................... 139 5.2 relevance of the pyrane skeleton .............................................................................................. 140 5.3 Preliminary screenings .............................................................................................................. 143 5.4 Scope of the reaction .................................................................................................................. 144 5.5. Preliminary Screening of Chiral Gold Catalysts ................................................................... 149 Conclusion ........................................................................................................................................ 152 Overall Discussion ....................................................................................................... 153 Conclusion ..................................................................................................................... 157 Resumen ........................................................................................................................ 159 Supporting material..................................................................................................... 165 Supporting material for chapter 1, article 1..................................................................... 167 Supporting material for chapter 1, article 2..................................................................... 183 Supporting material for chapter 2, article 3..................................................................... 197 Addendum ........................................................................................................................................ 211 Supporting material for chapter 3, article 4..................................................................... 213 Supporting material for chapter 3, Addendum .............................................................. 247 1 P Pr re es se en nt ta at ti io on n This thesis is presented as compendium of scientific articles accepted in international journals with peer review, according to article 41 of the regulations for the PhD studies from the University of Santiago de Compostela (“Reglamento de los Estudios de Doctorado de la Universidad de Santiago de Compostela”). According to this regulation we only include those articles that are published or with final acceptance for publication, performed during the academic supervision of the PhD and not included as a part of others PhD thesis. Note: Throughout this thesis, when referring to cycloadditions we use the Huisgen notation, using parentheses, where the numbers refer to the atoms involved in the forming ring (for instance in (4+3), (4+2), (2+2) cycloadditions) to distinguish from the Woodward−Hoffmann notation, using brackets, where the numbers refer to the electrons involved in bonding changes.1 However due to referee’s requirements in some articles we use the brackets notation that is also acceptable. 1 Limanto, J.; Khuong, K. S.; Houk, K. N.; Snapper, M. L. J. Am. Chem. Soc. 2003, 125, 16310–16321. Introduction 8 Figure 1 - Ruthenium catalysts frequently used in the Metathesis reaction. Alkene metathesis is the metathesis reaction type most commonly used. Within this there are several kinds: ring closing and opening metathesis or alkene cross-metathesis. The first step in the catalytic cycle is a (2+2) cycloaddition reaction between olefin 1 and a transition-metal carbene to give a metallacyclobutane. The latter undergoes subsequent collapse in a productive fashion to afford a new olefin product 3 and a new metal carbene (alkylidene), which reenters the catalytic cycle.13b Scheme 4 - Cross-metathesis of olefins. T. J. Donohoe illustrate the potential of this methodology in the synthesis of a precursor of (+)-cis-Sylvaticin, a potent antitumoral agent with demonstrated efficacy in lung and pancreas.14 Scheme 5 - Application of the cross-metathesis reaction to the synthesis of cis-Sylvaticin. The use of transition metal catalysis was also central for the attribution of the Nobel Prize in 2001 to William S. Knowles and Ryoji Noyori "for their work on chirally catalysed hydrogenation reactions" and to K. Barry Sharpless "for his work on chirally catalysed oxidation reactions".15 14 Donohoe, T. J.; Harris, R. M.; Williams, O.; Hargaden, G. C.; Burrows, J.; Parker, J. J. Am. Chem. Soc. 2009, 131, 12854– 12861. 15 a) http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2001/advanced-chemistryprize2001.pdf. b) Knowles, W. S. Angew. Chemie Int. Ed. 2002, 41, 1999–2007. c) Noyori, R. Angew. Chemie Int. Ed. 2002, 41, 2008–2022. c) Sharpless, K. B. Angew. Chemie Int. Ed. 2002, 41, 2024–2032. Gold (I) catalysis 9 An early example of potential of asymmetric catalysis was reported by W. S. Knowles, at Monsanto, in particular, a highly enantioselective hydrogenation of enamides with a rhodium complex containing a chelating diphosphine with two chiral phosphorus atoms (DiPAMP, Scheme 6). The process was used in the syntheses of L-DOPA from enamide 4, affording the protected amino acid 5 in quantitative yield and 95% ee (Scheme 6).16 Scheme 6 – Synthesis of L-DOPA using Rh catalyzed asymmetric hydrogenation. 16 Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946–5952. b) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106–112. Introduction 10 Regardless the great development of transition metal catalysis over the 20th century, the catalytic properties of gold complexes received only modest attention, probably due to the notion that gold is an inert metal. In 1986 T. Hayashi reported a gold-catalyzed asymmetric aldol condensation.17 A few years later, J. H. Teles reported that a phosphine-based cationic gold(I) was able to activate alkynes promoting the nucleophilic addition of alcohols to these C-C unsaturated species (Scheme 7). The gold complexes, prepared mostly from a combination of LAu(I)Me and methanesulfonic acid or from [LAu(NO3)] and BF3·OEt2 would set the basis for the development of a great number of new gold (I) catalytic systems that were reported afterwards. Significantly a footnote in this paper also reports the pioneer use of a gold-NHC-carbene complex as catalyst.18,19 Scheme 7 – Gold catalyzed addition of alcohols to alkynes. Since this report, a tremendous growth in the field of homogeneous gold catalysis was observed, as researchers realized that the low propensity of carbophilic gold(I) complexes to participate in standard redox catalytic cycles, based on oxidative additions and reductive eliminations, was indeed an advantage to develop orthogonal reaction strategies. Indeed, the unique affinity of gold for -unsaturated systems, such as alkynes, alkenes or allenes, allowed the development of novel modes of reaction that do not involve redox processes. Part of these characteristics are attributed to the so called “relativistic effects”, caused by the electrons in s orbitals moving at speeds approaching that of the speed of light. This leads to a contraction of the s orbital and, therefore, relatively low-lying LUMO, which is responsible for the good -acidity needed for the binding and electrophilic activation of C-C multiple bonds. Accordingly, the electrons occupying the external d and f orbitals are better shielded by those at the contracted s and p orbitals, causing the expansion of orbitals d and f.20 Consequently the high-lying highest occupied molecular orbital (HOMO), limits the participation of gold(I) complexes in oxidative additions and related redox process that are very often observed with transition metals such as Rh, Pd or Ni. 17 Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405–6406. 18 Hashmi, A. S. K. Gold Bull. 2004, 37, 51–65. 19 Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chemie Int. Ed. 1998, 37, 1415–1418. 18 Hashmi, A. S. K. Gold Bull. 2004, 37, 51–65. 19 Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chemie Int. Ed. 1998, 37, 1415–1418. 20 a) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403. b) Fürstner, A.; Davies, P. W. Angew. Chemie Int. Ed. 2007, 46, 3410– 3449. 2 2. . C Ca at ta al ly ys si is s b by y g go ol ld d 2 2. .1 1 – – R Re ea ac ct ti iv vi it ty y o of f g go ol ld d c co om mp pl le ex xe es s Gold (I) catalysis 11 Figure 2 - Contraction of the 6s and expansion of 5d orbitals. Au(I) has a pronounced preference to produce two-coordinate linear complexes and to induce reactivity it is necessary to abstract one ligand from neutral gold species of the type L-Au-X, something which is usually achieved using a silver salt. Furthermore, it is inherently difficult to chelate bidentate (phosphane) ligands to a single gold atom. Another important consequence of the linear coordination mode of Au(I) complexes is that only one site is available for coordination, since the other is permanently occupied by a ligand. Therefore Au(I) directly binds and activate a single substrate and disfavors processes like cyclometalations.20 Cl Au PPh3 = 179.6 º rAu-P = 2.235 Å rAu-Cl = 2.279 Å Figure 3 – Schematic and crtistal structure representation of Ph3PAuCl.21 As we have seen above, cationic gold cationic gold complexes can be generated in situ from the methyl(triphenylphosphane)gold(I) activated with a strong acid (Scheme 7). Nowadays the generation of such a cationic complex is more comun using a gold (I) chloride complex of type LAuCl, which is activated by a chloride ‘‘abstractor’’ such as a silver(I) salt to generate the mono-ligated cationic catalyst.22 LAuCl AgX AgCl + [LAu]+XX=TfO -, ClO4-,BF 4-,PF 6-,SbF 6-,NTf 2active species Scheme 8 - General Formation of Active Gold(I) Species. The active cationic complexes can also be prepared from chloride abstraction previous to its use and stored if a weakly coordinating counteranion is used, such as NTf2-,22 or a nitrile stabilizator is present.23 21 Baenziger, N. C.; Bennett, W. E.; Soborofe, D. M. Acta Crystallogr. Sect. B Struct. Crystallogr. Cryst. Chem. 1976, 32, 962– 963. 22 Mézailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133–4136. 23 a) de Frémont, P.; Stevens, E. D.; Fructos, M. R.; Mar Díaz-Requejo, M.; Pérez, P. J.; Nolan, S. P. Chem. Commun. 2006, 2045–2047. b) Amijs, C. H. M.; López-Carrillo, V.; Raducan, M.; Pérez-Galán, P.; Ferrer, C.; Echavarren, A. M. J. Org. Chem. 2008, 73, 7721–7730. Introduction 12 Scheme 9 – Formation of Au(I) nitrile stabilized complexes. The abovementioned relativistic facilitate C-C multiple bonds of alkynes, allenes, or olefins coordinate to gold complexes making possible possible a subsequent attack of a nucleophile.24 This electrophilic activation of alkynes was already demonstrated in 1976, when C. B. Thomas reported the hydration of several alkynes in aqueous methanol in the presence of tetrachloroauric acid (Scheme 10),25 and, moreover it became even more evident with the aforementioned nucleophilic addition of alcohols to alkynes reported by J. H. Teles with cationic gold complexes.19 Scheme 10 – Gold catalyzed hydration of alkynes. A large number of Au-catalyzed reactions of alkynes have since been developed.18,20 Among then, the cycloisomerizations of enynes flourish as one of the most studied reactions. The richness of gold chemistry is well manifested in these reactions in which, depending on the conditions, additives and substituents or ligands at gold, a number of different products can be divergently obtained. The Au(I) complex usually activates the alkyne promoting a nucleophilic addition of the alkene. This addition in general occurs by the endo mode (5-exo-dig, IIa) for terminal alkynes, whereas, enynes incorporating substituted alkynes or heteroatoms at the connecting tether usually undergo a 6-endo-dig, pathway (Ia, Scheme 11). Although this is a general tendency, the real picture is much more complex and in many cases is difficult to predict the outcome of the reactions.26 Scheme 11 – Activation of enynes by a gold catalyst. These initial intermediates can evolve in different ways, and subtle changes, such as the substitution of the connecting tether can be enough to the selective obtaining different products. For instance substrate 6 in the presence of Ph3PAuCl/AgSbF6 rearranges to give the cyclopropyl gold(I) carbene II. If 6 contain NTs as connecting ether, IIb rearranges with ring opening to give cation IV that after metal loss gives 7. Using the same conditions, but with a malonate group at the tether, the cyclopropyl gold(I) 24 Hashmi, a S. K. Chem. Rev. 2007, 107, 3180–3211. 25 Norman, R. O. C.; Parr, W. J. E.; Thomas, C. B. J. Chem. Soc. Perkin Trans. 1 1976, 1983-1987. 26 a) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Comm. 2007, 333–346. b) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350. Gold (I) catalysis 13 carbene IIc rearranges to V, which then undergoes a metal elimination to give 8 (Scheme 12). 27 Scheme 12 - Gold(I)-catalyzed cyclizations of 1,6-enynes. The variety of products obtained from gold catalyzed enyne cycloisomerizations can be further extended, simply by the addition of a nucleophile, like an alcohol, an amine or even an aromatic compound. This nucleophile can intercept the intermediate IId to give products like 9 or 10 (Scheme 13).26,28,27b,29 Scheme 13 - Alkoxycyclization of enynes with gold catalysis. Echavarren and coworkers also demonstrated that carbene intermediates of type IIe can also be trapped intramolecularly by a ketone or an aldehyde to give intermediates like VI, which undergo a Prins-like terminal cyclization with the vinyl gold to afford oxygenbridge bicyclic systems 11 (Scheme 14).30 27 a) Nieto-Oberhuber, C.; Muñoz, M. P.; Buñuel, E.; Nevado, C.; Cárdenas, D. J.; Echavarren, A. M. Angew. Chemie Int. Ed. 2004, 43, 2402–2406. b) Nieto-Oberhuber, C.; Muñoz, M. P.; López, S.; Jiménez-Núñez, E.; Nevado, C.; Herrero-Gómez, E.; Raducan, M.; Echavarren, A. M. Chem. Eur. J. 2006, 12, 1677–1693. c) Cabello, N.; Jiménez-Núñez, E.; Buñuel, E.; Cárdenas, D. J.; Echavarren, A. M. Eur. J. Org. Chem. 2007, 2007, 4217–4223. 26 a) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Comm. 2007, 333–346. b) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350. 28 Muñoz, M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Organometallics 2005, 24, 1293–1300. 27b Nieto-Oberhuber, C.; Muñoz, M. P.; López, S.; Jiménez-Núñez, E.; Nevado, C.; Herrero-Gómez, E.; Raducan, M.; Echavarren, A. M. Chem. Eur. J. 2006, 12, 1677–1693 29 Toullec, P. Y., Genin, E., Leseurre, L., Genêt, J.-P., and Michelet, V. Angew. Chem., Int. Ed. 2006, 45, 7427-7430. 30 Jiménez-Núñez, E.; Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chemie 2006, 45, 5578–5581. Introduction 14 Scheme 14 - Prins cyclizations in Au-catalyzed reactions of enynes. Gold (I) catalyzed cycloadditions 15 2 2. .2 2. .1 1 S Sy yn nt th he et ti ic c r re el le ev va an nc ce e o of f c cy yc cl lo oa ad dd di it ti io on n r re ea ac ct ti io on ns s Modern synthetic chemistry requires efficiency, versatility, economy and ecology. Therefore there is a great interest on the development of processes that generate molecular and stereochemical complexity, in a selective manner, from easily accessible materials.6 In this context a particularly interesting type of reactions are cycloadditions, as they allow the construction of cycles, usually in selective manner, by the simple addition of two or more acyclic fragments.31 In a simplify way, cycloadditions can be classified as forbidden or allowed by the Woodward-Hoffmann rules,32 or the frontier molecular orbital theory of Fukui.33 Those permitted can a priori occur spontaneously or by heating, while those forbidden need photochemical conditions, radical initiators or other promoting agents. The most important type of cycloaddition is the Diels-Alder reaction, as it provides a direct access to six-membered rings, and has the capacity to generate up to four contiguous stereogenic centers in a single step.34 Scheme 15 – Diels-Alder reaction. There are other types of [4+2] annulations, isoelectronic with the Diels-Alder such as the dipolar (3+2) cycloadditions between 1,3-dipoles and dipolarophiles,35 or the (4+3) cycloaddition between allyl cations and dienes.36 Scheme 16 – Thermally allowed [4+2] cycloadditions. 6 a) Wender, P. a.; Bi, F. C.; Gamber, G. G.; Gosselin, F.; Hubbard, R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.; Zhang, L. Pure Appl. Chem. 2002, 74, 25–31. b) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010–3021. c) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657–4673. 31 Kobayashi, S.; Jørgensen, K. A. Cycloaddition Reactions in Organic Synthesis;Wiley-VCH, 2001. 32 Woodward, R. B.; Hoffmann, R. Angew. Chemie Int. Ed. 1969, 8, 781–853. 33 Inagaki, S.; Fujimoto, H.; Fukui, K. J. Am. Chem. Soc. 1976, 98, 4693–4701. 34 a) Vollhardt, K. P. C.; Schore, N. E. Organic Chemistry; 3rd ed.; W.H.Freeman & Co Ltd, 1998. b) Fringuelli, F.; Taticchi, A. The Diels-Alder Reaction: Selected Practical Methods; Wiley: Chichester, U.K., 2002. c) Miller, J. P. Advances in Chemistry Research. Volume 18 - Recent Advances in Asymmetric Diels-Alder Reactions; Taylor, J. C., Ed.; Nova Science Publishers, Inc., 2013; 18, 179–220. d) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2002, 41, 1668–1698. e) Takao, K.-I.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779–4807. 35 a) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley Interscience, 1984. b) Trost, B. M. Angew. Chemie Int. Ed. 1986, 25, 1–20. c) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–810. 36 a) Harmata, M. Acc. Chem. Res. 2001, 34, 595–605. b) Harmata, M. Chem. Commun. 2010, 46, 8886–8903. 2 2. .2 2 - - G Go ol ld d ( (I I) ) c ca at ta al ly yz ze ed d c cy yc cl lo oa ad dd di it ti io on n s s Introduction 16 Despite the versatility of these types of cycloaddition is important to note that in most cases the presence of functional groups that activate the components are required. Additionally, and depending on the case, the cycloaddition process may be induced by activating one or more components by a Lewis acid catalyst.37 More recently, organocatalysis,38,39,40 and, in particular, transition metal catalysis, have been shown as highly valuable for the development of new cycloaddition reactions. The coordination of transition metals, even to poorly activated substrates, like olefins, dienes, or alkynes, significantly modifies their reactivity. Thus, this metal activation allows, for instance, to perform room temperature cycloadditions of non-activated substrates, processes that otherwise would require extreme temperatures. In addition, transition metal complexes have also brought new opportunities for the discovery of new catalytic cycloadditions,41 even in enantioselective manner, by using chiral metal complexes. Most of the transition metal-catalyzed cycloadditions involved the use of rhodium, ruthenium, cobalt, nickel or palladium catalysts. These metals are prone to experience redox process, often involving the metallacyclic intermediates and provide the final adduct by reductive elimination. For instance, in the following scheme is shown one of the first examples of a transition metal catalyzed cycloaddition, namely an intramolecular (4+2) cycloaddition reported by P. Wender. Although these reactions between non-activated alkynes and dienes may occur at 150 ° C without the catalyst, the nickel complex allowed the reaction to be performed at room temperature with excellent yields and stereoselectivities. The authors proposed a metalacyclic species like VII as the key intermediate (Scheme 17).42 Scheme 17 – Ni catalyzed (4+2) Cycloaddition. The potential of transition metal catalysis was further illustrated by P. Wender in a remarkable (4+2+2) intermolecular cycloaddition of three different components (norbornene, 2,3-dimethyl-1,3-butadiene, and methyl propargyl ether) (Scheme 18).43 37 a) Yates, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436–4437. For reviews on Lewis Acid Catalyzed Diels Alder reactions see: b) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007–1019. c) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH Verlag GmbH: Weinheim, Germany, 2000. 38 a) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79–87. b) MacMillan, D. W. C. Nature 2008, 455, 304–308. c) Pellissier, H. Tetrahedron 2012, 68, 2197–2232. d) Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703–832. 39 Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243–4244. 40 a) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874–9875. b) Chow, S. S.; Nevalainen, M.; Evans, C. a.; Johannes, C. W. Tetrahedron Lett. 2007, 48, 277–280. 41 Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49–92. 42 Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432–6434. 43 Wender, P. A.; Christy, J. P. J. Am. Chem. Soc. 2006, 128, 5354–5355. Gold (I) catalyzed cycloadditions 17 Scheme 18 - Rhodium(I)-Catalyzed (4+2+2) cycloaddition. The tremendous growth in gold catalysis has also brought opportunities for the development of novel types of cycloaddition reactions, usually involving non-activated unsaturated systems like alkynes, allenes, alkenes or 1,3dienes.44 Contrary to those more classical transition metal cycloadditions promoted by Rh , Ru or Ni, Au catalyzed processes do not involve changes in the oxidation level of the metal, as we will see in the following sections. 44 López, F.; Mascareñas, J. L. Beilstein J. Org. Chem. 2011, 7, 1075–1094. Introduction 24 for the selective activation of allenes in the presence of other reactive functionalities.60 Different structures have been proposed to represent these gold-activated allene complexes, including 2-complexes (A, B and C), planar -allylic cations (D), zwitterionic carbenes (E) or 1bent allenes (F) (Scheme 30).61 In some particular cases, experimental and theoretical evidences support the participation of one of those structures but, in many other cases, the precise nature of these species remains unknown.62 Scheme 30 - Various types of gold-activated allene complexes. In 2007, L. Zhang and co-workers reported a formal intramolecular (3+2) cycloaddition between allenyl MOM ethers and alkenes, reaction in which the allenes behaves as a three carbon partner. The proposed mechanism involves the selective gold activation of the allenyl ether to yield an oxocarbenium. An intramolecular (3+2) cycloaddition with the internal olefin delivered the bicyclo[3.1.0]hexane gold carbene. Fragmentation of the cyclopropane ring with the help of the OH group and protodeauration forms the product 46 in good yield and excellent diastereoselectivities. Scheme 31 - Formal (3+2) cycloaddition of allenyl MOM ethers and alkenes. F. D. Toste developed an interesting gold(I)-catalyzed (2+2) cycloaddition of 1,6allenenes, to afford alkylidene cyclobutane products of type 34.63 The proposed mechanism is based on the generation of a gold(I)-linked allyl cation, which undergoes a 60 Krause, N. In Innovative Catalysis in Organic Synthesis; Andersson, P. G., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2012; pp. 195–209. 61 Gandon, V.; Lemière, G.; Hours, A.; Fensterbank, L.; Malacria, M. Angew. Chemie Int. Ed. 2008, 47, 7534–7538. 62 López, F.; Mascareñas, J. L. Beilstein J. Org. Chem. 2013, 9, 2250–2264. 63 Luzung, M. R.; Mauleón, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402–12403. Gold (I) catalyzed intramolecular cycloadditions 25 cyclization to give a new carbocationic species of type XX, in which the gold center establishes a stabilizing electrostatic interaction with the benzylic carbocation (Scheme 7).64 A subsequent ring closure provides the observed bicyclo[3.2.0]heptanes 34 featuring a four membered carbocycle (Scheme 32). Scheme 32 - Gold(I)-Catalyzed (2+2)-Cycloaddition of Allenenes. On the other hand, our group demonstrated the possibility of using allenes as treecarbon components in (4+3) intramolecular cycloadditions with dienes (35) promoted by Pt or Au catalysts. The (4+3) process can be achieved with PtCl2,65 or with cationic Au(I) catalysts containing a σ-donating N-heterocyclic carbene ligand (Au4) which allows these reactions to proceed in milder conditions (Scheme 33).66 Later, F. D. Toste reported similar results with the related substrates, using a highly donating biaryl di-tertbutylphosphine ligand (Au5).67 Scheme 33 – Pt and Au(I) catalyzed (4+3) Cycloadditions of allenedienes. Remarkably, when allenes are dialkylated at the distal position, a judicious choice of the ligand (in case of gold salts) allows to obtain either the (4+3) or a formal (4+2) cycloadduct. Thus when these substrates are treated with a gold(I) catalyst bearing a π64 González, A. Z.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 5500–5507. 65 Trillo, B.; López, F.; Gulías, M.; Castedo, L.; Mascareñas, J. L. Angew. Chemie Int. Ed. 2008, 47, 951–954. 66 Trillo, B.; López, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledós, A.; Mascareñas, J. L. Chem. Eur. J. 2009, 15, 3336–3339. 67 Mauleón, P.; Zeldin, R. M.; González, A. Z.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 6348–6349. Introduction 26 acceptor ligand, such as a triarylphosphite (Au6), (4+2) products like 37 are obtained (Scheme 34).68,67 Scheme 34 - Gold(I)-catalyzed (4+2) cycloadditions of allenedienes. Combined experimental and theoretical data suggests that both process share the initial formation of a metal allyl cation XXI which undergoes a concerted [4C(4) + 3C(2)] cycloaddition with the diene moiety, giving a cycloheptanic carbene intermediate XXIIa. It’s now when the process becomes divergent: while σ-donor ligands at the gold promote a 1,2-hydrogen shift, and therefore lead to a seven-membered carbocycle (36), a gold(I) catalyst bearing a -acceptor ligand promote a ring contraction process (1,2-alkyl shift) that affords cyclohexene containing bicycles (37, Scheme 35).66,68 Scheme 35 – Divergent mechanism for the (4+3) and (4+2) gold catalyzed cycloadditions of allenedienes. Latter, a related (4+3) cycloaddition was also developed by B. W. Gung, namely, an interesting transannular cycloaddition of substrate 38 equipped with a furan (4C) and a propargyl acetate, which formally acts as an allene surrogate (Scheme 36).69 68 Alonso, I.; Trillo, B.; López, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledós, A.; Mascareñas, J. L. J. Am. Chem. Soc. 2009, 131, 13020–13030. 69 a) Gung, B. W.; Craft, D. T. Tetrahedron Lett. 2009, 50, 2685–2687. b) Gung, B. W.; Craft, D. T.; Bailey, L. N.; Kirschbaum, K. Chem. Eur. J. 2010, 16, 639–644. Gold (I) catalyzed intramolecular cycloadditions 27 Scheme 36 - Gold-catalyzed transannular (4+3) cycloaddition reactions. Based on the mechanistic hypothesis for the (4+3) and (4+2) cycloadditions of allenedienes, F. D. Toste revisited the gold(I)-catalyzed reaction of allenenes to determine whether the ligand could also determine the result of the cycloaddition (See Scheme 32, page 25).63,64 Indeed, when a gold catalyst such as Au5/AgSbF6, a (3+2) cycloaddition leading to bicyclo[4.3.0]nonanes 39 was observed (Scheme 37).67 AgSbF6(5%) CH2Cl2,rt PAuCl tBu tBu Au5 TsN Ph TsN [Au] H Ph TsN HPh [Au] TsN HPh 39, 94% [Au] -[Au] • Scheme 37 - Gold(I)-Catalyzed (3+2)-Cycloaddition of Allenenes. 63 Luzung, M. R.; Mauleón, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402–12403. 64 González, A. Z.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 5500–5507. Introduction 28 2 2. .2 2. .3 3 - - G Go ol ld d ( (I I) ) c ca at ta al ly yz ze ed d i in nt te er rm mo ol le ec cu ul la ar r c cy yc cl lo oa ad dd di it ti io on ns s In 2009, a few months before my incorporation to the group, Fürstner published a review emphasizing the need of developing gold-catalyzed intermolecular transformations. He stated that “a priori, there is no need to tie the two reaction partners together, thus making intermolecular transformations feasible, even though the number of successful cases still remains somewhat limited”.70 These limitations concerning gold catalyzed intermolecular transformations were even more dramatic for the specific case of intermolecular cycloadditions, as only a small number of cases had been reported. One of them consisted of a gold-catalyzed intermolecular hetero-dehydro-Diels-Alder cycloaddition between dienynes and non-activated nitriles, reported by J. Barluenga in 2008. Treatment of dienynes 40 with various aliphatic or aromatic nitriles, in the presence of catalytic amounts of a gold(I) complex, efficiently afforded the pyridines 41 with satisfactory yields (Scheme 38). The initial coordination of the alkyne to the gold catalyst provides the intermediate XXIII. The regioselective nucleophilic attack of the nitrile, followed by a cyclization and aromatization yields the reaction products 41.71 Scheme 38 - Gold-catalyzed intermolecular cycloaddition of dienynes with nitriles. Y. Yamamoto reported an earlier example of a intermolecular gold catalyzed cycloaddition, although it is not fully intermolecular. In particular these authors reported the gold (III) catalyzed (4+2) benzannulation between orthoalkynylbenzaldehydes 42 and external alkynes, a process that yields substituted naphthalenes 43 and related polyaromatics with good regioselectivity.72 Later, B. F. Straub reported a DFT study on these cycloadditions. According to the theoretical data, an initial 5-endo nucleophilic attack of the carbonyl moiety on the metal–alkyne complex generates a carbonyl ylide intermediate, which undergoes a dipolar (3+2) cycloaddition with the alkyne to afford an oxabridged carbene species. A subsequent 1,2-alkyl 70 Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208–3221. 71 Barluenga, J.; Fernandez-Rodríguez, M. A.; García-García, P.; Aguilar, E. J. Am. Chem. Soc. 2008, 130, 2764–2765. 72 Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650–12651. Gold (I) catalyzed intermolecular cycloadditions 29 migration yields XXIV and a final elimination finally affords the naphthyl ketones 43 (Scheme 39). 73 Scheme 39 - AuCl3-Catalyzed Benzannulation. In 2009, J. Zhang reported a gold(I)-catalyzed tandem cyclization/(3+3) cycloaddition of 2-(1-alkynyl)-2-alken-1-ones 44 with nitrones. This reaction proceeds with high levels of regiospecificity and diastereoselectivity to produce highly substituted furo[3,4d][1,2]oxazines 45. A plausible mechanism includes the formation of the furyl-Au 1,3dipole intermediate XXV followed by a (3+3) cycloaddition reaction with the nitrone to afford the oxazine derivative 45.74 Scheme 40 - Gold-catalyzed 1,3-dipolar cycloaddition of 2-(1-alkynyl)-2-alken-1-ones with nitrones The same group also reported (4+3) cycloadditions of 2-(1-alkynyl)-2-alken-1-ones with  ,  -unsaturated imines,75 and 1,3-diphenylisobenzofurans,76 (Scheme 41). In both cases the formation of a furyl-Au 1,3-dipole intermediate XXV, previously proposed for the 73 Straub, B. F. Chem. Commun. 2004, 1726–1728. 74 Liu, F.; Yu, Y.; Zhang, J. Angew. Chemie Int. Ed. 2009, 48, 5505–5508. 75 Gao, H.; Zhao, X.; Yu, Y.; Zhang, J. Chem. Eur. J. 2010, 16, 456–459. 76 Gao, H.; Wu, X.; Zhang, J. Chem. Commun. 2010, 46, 8764–8766. Introduction 30 1,3-dipolar cycloaddition with nitrones (Scheme 40), is considered key for the cycloadditions. Scheme 41 - Au-catalyzed (4+3) cycloaddition of 2-(1-alkynyl)-2-alken-1-ones. Recently, the group of R.-S. Liu developed an interesting intermolecular gold-catalyzed (2+2+3) cycloaddition of 1,6-enynes 46 with nitrones.77 The authors propose a mechanism consisting of a concerted cycloaddition between the nitrone and a cyclopropylgold carbenoid with a strong alkenylgold carbocation character. The resulting cycloadducts are obtained in good or excellent yields. Scheme 42 - Intermolecular gold-catalyzed (2+2+3) cycloadditions of 1,6-enynes with nitrones. In all of the abovementioned intermolecular cycloadditions of alkynes, the gold activated alkyne was intramolecularly intercepted by an internal nucleophile, and the resulting intermediate reacted with an external component. In 2010 A. M. Echavarren reported a fully intermolecular (2+2) cycloaddition between aromatic alkynes and -disubstituted alkenes to give cyclobutenes 47 regioselectively (Scheme 43). 78 77 Gawade, S. A.; Bhunia, S.; Liu, R. Angew. Chemie Int. Ed. 2012, 51, 7835–7838. 78 López-Carrillo, V.; Echavarren, A. M. J. Am. Chem. Soc. 2010, 132, 9292–9294. Gold (I) catalyzed intermolecular cycloadditions 31 Scheme 43 - Gold(I)-catalyzed intermolecular (2+2) cycloaddition of alkynes with alkenes. F. D. Toste took advantage of the possibility of generating gold carbenes from propargyl esters to develop an intermolecular cyclopropanation of olefins (Scheme 44).79 Scheme 44 - Gold(I)-catalyzed olefin cyclopropanation with propargyl esters. The same authors demonstrated that these carbenes can also be used as a 3C component in an interesting cycloaddition reaction with  ,  -unsaturated imines that affords azepine derivatives.80 The mechanistic proposal involves the intermolecular addition of the imine to the gold carbene XXVI, delivering the allyl gold intermediate XXVII. A final cyclization provides the seven-membered heterocyclic products 48 in moderate to good yields. Scheme 45 - Synthesis of azepines by a gold-catalyzed intermolecular (4+3) cycloaddition. Azomethine imines 49 can also be used as intermolecular 3C cycloaddition components (Scheme 46).81 These (3+3) annulations take place through a stepwise mechanism related to that previously shown (Scheme 45) for the formation of azepines. 79 Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002–18003. 80 Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 9244–9245. 81 Shapiro, N. D.; Shi, Y.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 11654–11655. Introduction 32 Scheme 46 - Gold-catalyzed (3+3)-annulation of azomethine imines with propargyl esters. When I started this PhD thesis the use of allenes in intermolecular cycloadditions catalyzed by gold or any other carbophilic metal catalyst had not yet been described. While our work was ongoing Iwasawa reported a Platinum(II)-catalyzed intermolecular (3+2) cycloaddition of propadienyl silyl ethers and alkenyl ethers. In most cases a competitive (2+2) cycloaddition was also observed. The authors propose that the allene is initially activated by the Pt(II) catalyst to give the corresponding  complex XXVIII. Then a nucleophilic addition of the 2-methoxypropene to the nonsubstituted terminus give zwitterionic intermediate XXIV. Ring closure with electron flow from the anionic platinum to the oxonium carbon at the position  to the metal (path a) gives the cyclopentylidene Pt(II) carbene intermediate XXX, which finally undergoes a 1,2hydrogen shift to give the cyclopentene derivative 50. The methylenecyclobutane derivative is thought to be produced by the attack of the silyl enol ether at the oxonium carbon to give the cyclobutylplatinum(II) intermedate XXXI (path b), followed by elimination of the Pt (Scheme 47).82 Later the same group found that a Pt(II) catalyst and a hollow-shaped triethynylphosphine ligand (L1) generates the (2+2) cycloadducts 51 as major products.83 Scheme 47 - Pt(II)-catalyzed (3+2) and (2+2) cycloadditions of propadienyl silyl ethers and alkenyl ethers. 82 Kusama, H.; Ebisawa, M.; Funami, H.; Iwasawa, N. J. Am. Chem. Soc. 2009, 131, 16352–16353. 83 Ebisawa, M.; Kusama, H.; Iwasawa, N. Chem. Lett. 2012, 41, 786–788. Enantioselective Gold (I) catalysis 33 There are several ways of producing compounds as single enantiomers. The resolution of a mixture of enantiomers can often be the cheapest or the conversion of a enantiomerically pure starting material into another derivative represents another useful technique in some cases.84 However, asymmetric synthesis can provide a more general approach to the preparation of enantiomerically enriched compounds. Although there may still be cases where asymmetric synthesis doesn’t provide the best method for the preparation of a particular enantiomerically pure compound, it certainly allows for the preparation of a more diverse range of structures. Asymmetric catalysis is especially appealing.85 In this regard, the rapid rise in interest for gold catalysis has been accompanied by efforts to develop enantioselective variants of gold-catalyzed reactions to further increase the synthetic utility of these transformations.86,87 The linear nature of gold complexes make difficult the design of catalysts that can provide asymmetric transformations. As aforementioned, the first enantioselective gold (I) catalyzed reaction, consisting of an asymmetric aldol condensation in the presence of a chiral ferrocenylphosphine-gold(I) complex, was developed by Hayashi et al. in 1986 (Scheme 48).17 O R N+ -C CO2Me [Au(CyNC)2]+BF4-(1%) Fe PPh2 H N Me PPh2 NEt2 ON CO2Me R ON CO2Me R CH2Cl2, 25ºC 1% N+ CCyNC: R=Ph,iPr, Me 98-100% yield dr = 84:16 - 98:2 Scheme 48 - Reaction of aldehydes with isocyanoacetate catalyzed by a chiral Au(I) complex. Despite the relevance of this report it was not until very recently when gold enantioselective catalysis was again investigated.87 In 2005, A. M. Echavarren and J. C. Carretero reported the gold(I)-catalyzed enantioselective alkoxycyclization of 1,6-enynes to yield methylenecyclopentanes 9.28 The authors screened various chiral phosphorous ligands, and found that a chiral bis-gold complex derived from tol-binap Au10 (1.6%) / AgSbF6 (2%) gave the best result (Scheme 49). Although, in general, the asymmetric 84 Chiral Drugs: Chemistry and Biological Action; Lin, G.-Q.; You, Q.-D.; Cheng, J.-F., Eds.; 1st ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2011. 85 Catalysis in Asymmetric Synthesis; Caprio, V.; Williams, J., Eds.; 2nd ed.; Wiley-Blackwell: West Sussex, United Kingdom, 2009. 86 Wang, Y.; Lackner, A. D.; Toste, F. D. Acc. Chem. Res. 2014, 47, 889–901. 87 Reviews on enantioselective gold catalysis: a) Sengupta, S.; Shi, X. ChemCatChem 2010, 2, 609–619. b) Widenhoefer, R. A. Chem. Eur. J. 2008, 14, 5382–5391. c) Pradal, A.; Toullec, P.; Michelet, V. Synthesis 2011, 2011, 1501–1514. d) López, F.; Mascareñas, J. L. Beilstein J. Org. Chem. 2013, 9, 2250–2264. 17 Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405–6406. 28 Muñoz, M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Organometallics 2005, 24, 1293–1300. 2 2. .3 3 - - E En na an nt ti io os se el le ec ct ti iv ve e G Go ol ld d ( (I I) ) c ca at ta al ly ys si i s s Introduction 40 Scheme 57 –Chiral NHC–Au(I)-catalyzed cyclization of enyne. In the same year, P. Espinet reported a series of gold complexes containing acyclic diaminocarbene ligands (ADC), also known as nitrogen acyclic carbenes (NAC). These complexes were tested in the cyclopropanation of vinyl arenes with propargyl pivaloate and in the intramolecular hydroalkoxylation of allenes (55), providing moderate to good yields of the expected products, however, the enantioselectivities were only poor or modest, not exceeding the 24% (Scheme 58).105 Scheme 58 - Gold chiral nitrogen acyclic carbenes and gold hydrogen bonded heterocyclic carbenes in cyclopropanation of vinyl arenes and in intramolecular allene hydroalkoxylation. In 2011, F. D. Toste developed a variant of the chiral ADC gold complex Au30b, incorporating a p-CF3Ph substituent at the 3,3’ positions of the BINAM (binaphthyl-2,2’- diamine) moiety, and applied it to the enantioselective cyclization of propargyl pivalates like 58. The resulting chromenyl pivalates (59) were obtained in excellent yield and enantioselectivities ranging from 83 to 95% (Scheme 59).106 105 Bartolomé, C.; García-Cuadrado, D.; Ramiro, Z.; Espinet, P. Inorg. Chem. 2010, 49, 9758–9764. 106 Wang, Y. M.; Kuzniewski, C. N.; Rauniyar, V.; Hoong, C.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 12972–12975. Enantioselective Gold (I) catalysis 41 Scheme 59 - Synthesis of 2-substituted chromenyl pivalates. One year later, L. M. Slaughter reported the enantioselective cyclization of 2alkynylbenzaldehydes, catalyzed by a mononuclear ADC-gold complex (Scheme 60).107 Scheme 60 – alkynylbenzaldehyde cyclizations. Although the abovementioned examples are excellent contributions in enantioselective gold catalysis, there are still many challenges such as the extension to other fold catalyzed processes, the development of more general ligands and the gaining of a better understanding of the stereoinduction process.87a,62 107 Handa, S.; Slaughter, L. M. Angew. Chemie Int. Ed. 2012, 51, 2912–2915. 87a Sengupta, S.; Shi, X. ChemCatChem 2010, 2, 609–619. 62 López, F.; Mascareñas, J. L. Beilstein J. Org. Chem. 2013, 9, 2250–2264. Introduction 42 As previously shown, alenes are excellent partners in gold catalyzed processes, owing to the ready complexation to the gold salts and cations. The presence of heteroatoms can render allenes even more reactive in their reactivity with electrophilic atoms and metals while still being relatively stable. Among these type of allenyl derivatives, allenamines might have some advantages owing to the trivalent nature of the nitrogen atom, allowing, for instance the tethering of a chiral-inducing auxiliary. Unfortunately, allenamines are highly sensitive toward hydrolysis and show a great tendency to polymerize even at low temperatures, thereby creating serious difficulties in their preparation and experimental handling. In this context, allenamides are an attractive alternative, once the delocalization of the nitrogen lone-pair into the carbonyl group (giving an extra resonance form) diminish its donating ability toward the allenic moiety, enhancing the stability.108 Scheme 61 – Allenamide resonance forms. 3 3. .1 1 - - P Pr re ep pa ar ra at ti io on n o of f a al ll le en na am mi id de es s The first known preparation of an allenamide was reported by W.B. Dickinson and P.C. Lang in 1967.109 These authors coined the term allenamide to describe 1,2-propadienyl-2pyrrolidinone, which they had obtained as the major product by treatment of 2pyrrolidinone with NaH and propargyl bromide. The reaction proceeds by addition of the amide to the propargyl bromide and the resulting propargyl amide undergoes a base promoted prototropic isomerization to give the allenamide 60a (Scheme 62 top). This protocol was later improved by R. P. Hsung, by splitting in 2 steps the synthesis and using tBuOK at room temperature for the isomerization (Scheme 62 bottom). This protocol allowed the preparation of a variety of cyclic allenamides, some of them with chiral auxiliaries, even in a large scale.110,111 108 Lu, T.; Lu, Z.; Ma, Z.-X.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2013, 113, 4862–4904. 109 Dickinson, W. B.; Lang, P. C. Tetrahedron Lett. 1967, 8, 3035-3040 110 Wei, L.; Mulder, J. A.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459–466. 111 a) Tracey, M. R.; Grebe, T.; Mulder, J. A.; Hsung, R. P. Org. Synth. 2005, 81, 147–151. b) Xiong, H.; Tracey, M.; Grebe, T. Org. Synth. 2014, 91, 12–26. 3 3 – – A Al ll le en na am mi id de e s s Preparation of Allenamides 43 Scheme 62 - W.B. Dickinson and P.C. Lang preparation of 1,2-propadienyl-2-pyrrolidinone (top) and some examples of allenamides obtained from Hsung protocol (bottom). In 2005, the B. M. Trost and R. P. Hsung independently published another method to make allenamides, consisting of a copper-catalyzed coupling between allenyl halides and amides. Importantly if carbamates, ureas or tosylamines are used as reaction components the corresponding allenamides are also obtained in good yields.112,113 Hsung also observed that when optically enriched allenyl halides were used, the chirality was transferred to the allenamides. In general both protocols provide the desired allenamides in moderate to good yields and are particularly suitable for the preparation of terminal alkyl substituted allenamides (Scheme 63). Scheme 63 - Copper-catalyzed coupling of allenyl halides with amides. 112 Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117–2120. 113 Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett. 2005, 7, 3081–3084. Introduction 44 3 3. .2 2 - - C Cy yc cl lo oa ad dd di it ti io on ns s o of f a al ll le en na am mi id de es s The electron rich character of allenamides has allowed their use in several thermally induced cycloaddition reactions.108 For instance, Y. Tamaru reported a thermal (2+2) cycloaddition of allenamides like 61 with alkenes and alkynes to afford cyclobutanes 62. The reaction occurs at the terminal double bond of the allene and provides almost exclusively the Z isomer. The reaction is limited to terminal alkenes and alkynes and requires a large excess of these components (40-120 equiv), which are employed as solvent.114 Scheme 64 - Thermal (2+2) Cycloaddition Reaction of Allenes with Alkenes or Alkynes. Allenamides like 61 can work as a 2 carbon atom component in a inverse electrondemand hetero-(4+2) cycloaddition reaction with  ,  -unsaturated carbonyls under thermal conditions. The cycloadditions took place selectively at the internal double bond of the allene and provides spiro compounds of type 62 as a major product.114b,115 Later Hsung reported that allenamides of type 60 were also good partners for the same reaction, and the heterodiene scope could be expanded, tolerating aromatic rings at the ketone or even a bromine at the alkene (Scheme 65, right).116,117 Scheme 65 - Inverse electron-demand hetero-(4+2) cycloaddition reaction of allenamides. V. Vranken reported the first example of a normal electron demand (4+2) cycloaddition of allenamides. In particular they demonstrated that the terminal allenyl double bond of a N-allenylsulfenimide works as a dienophile and react thermally with cyclopentadiene.118 Later Mapp employed the same reaction, also using cyclopentadiene, to demonstrate the utility of N-phosporamidate-substituted allenamides.119 Unfortunately, despite the significance of the method, no other results on thermal 108 Lu, T.; Lu, Z.; Ma, Z.-X.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2013, 113, 4862–4904 114 a) Kimura, M.; Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru, Y. J. Am. Chem. Soc. 1997, 119, 10869–10870. b) Horino, Y.; Kimura, M.; Tanaka, S.; Okajima, T.; Tamaru, Y. Chem. Eur. J. 2003, 9, 2419–2438. 115 Kimura, M.; Wakamiya, Y.; Horino, Y.; Tamaru, Y. Tetrahedron Lett. 1997, 38, 3963–3966. 116 Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629–7636. 117 a) Wei, L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron Lett. 1999, 40, 6903–6907. b) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T. Org. Lett. 1999, 1, 2145–2148. 118 Bacci, J. P.; Greenman, K. L.; Van Vranken, D. L. J. Org. Chem. 2003, 68, 4955–4958. 119 Danowitz, A. M.; Taylor, C. E.; Shrikian, T. M.; Mapp, A. K. Org. Lett. 2010, 12, 2574-2577. Allenamides in catalysis by transition metals 45 intermolecular Diels-Alder reaction using a diene other than cyclopentadienehave been reported. Scheme 66 - Normal electron demand (4+2) cycloaddition of allenamides with cyclopentadiene. R. P. Hsung also reported a thermally-induced intramolecular (4+2) cycloaddition of allenamides tethered to furans or 1,3-butadiene (63). The reaction is highly stereoselective and tolerates different lengths of the connecting tether, allowing to obtain interesting bi or tricyles (64) (Scheme 67). Importantly, R. P. Hsung has also observed that AuCl was a good catalyst for this reaction providing up to 66% yield of 64a after only 10 min in 1,2-dichloroethane, however the thermal process gave better results.120 Scheme 67 - Thermal intramolecular (4+2) cycloadditions of allenamides. In 2001, Hsung and coworkers demonstrated that treatment of oxazolidinone-substituted allenamides such as 60b with dimethyldioxirane (DMDO) provides an allene oxide which subsequently opens to give a nitrogen-stabilized oxyallyl cation. This oxyallyl cationic species could be trapped by cyclic dienes such as furan or cyclopentadiene in a standard (4+3) annulation (Scheme 68).121 This cycloaddition chemistry has been extensively studied and optimized by Hsung during the last decade, and can be considered among the most versatile, selective and efficient (4+3) cycloaddition methodologies relying on allyl cation intermediates.122 120 Lohse, A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430–3433. 121 a) Xiong, H.; Hsung, R. P.; Berry, C. R.; Rameshkumar, C. J. Am. Chem. Soc. 2001, 123, 7174–7175. b) Antoline, J.; Hsung, R. P. Synlett 2008, 2008, 739–744. c) Antoline, J. E.; Krenske, E. H.; Lohse, A. G.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2011, 133, 14443–14451. d) Du, Y.; Krenske, E. H.; Antoline, J. E.; Lohse, A. G.; Houk, K. N.; Hsung, R. P. J. Org. Chem. 2013, 78, 1753–1759. 122 For a review see: Lohse, A. G.; Hsung, R. P. Chem. Eur. J. 2011, 17, 3812–3822 Introduction 46 Scheme 68 – (4+3) cycloadditions of nitrogen-stabilized oxyallyl cations with furan or cyclopentadiene. In their original report,121a the authors demonstrated that by incorporating chiral oxazolidinones in the allene moiety, the (4+3) cycloaddition with dienes can take place with good to high levels of diastereoselectivity, depending on the chiral oxazolidinone used (Scheme 69). The reactions were completely endo selective and the best results (dr up to 96:4) were obtained with allenamides that incorporate a phenyl group at the nitrogen -position, and using ZnCl2 (2.0 equiv) as additive. Notably, these intermolecular cycloadditions can also be carried out in good yields and selectivities using N-protected pyrroles as diene counterparts, which provides access to tropinone alkaloids.123 Scheme 69 - (4+3) Cycloadditions of allenamides with dienes. R. P. Hsung also unveiled an enantioselective version of this process by using catalytic CuOTf2 and a C2-symmetric bisoxazoline ligand that afforded the cycloadducts in good yields and up to 99% ee (Scheme 70). 124 123 Antoline, J. E.; Hsung, R. P.; Huang, J.; Song, Z.; Li, G. Org. Lett. 2007, 9, 1275–1278. 124 Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50-51. Allenamides in catalysis by transition metals 47 Scheme 70 - Enanteoselective (4+3) cycloadditions of nitrogen-stabilized oxyallyl cations with furans. Introduction 48 3 3. .3 3 - - G Go ol ld d c ca at ta al ly yz ze ed d r re ea ac ct ti io on ns s o of f A Al ll le en na am mi id de es s Given the affinity of Au(I) towards allenes, it was expected that allenamides could be even more susceptible to the nucleophilic addition to gold-cationic complexes. As shown by G. Broggini, allenamides like 67 readily undergo a gold(III)-catalyzed intramolecular hydroamination.125 The reaction produces cis-2-vinylimidazolidinones 68 as the major product, however in most cases the trans isomer was also detected. A possible mechanism proposed by the authors starts with the activation of the allene moiety by the gold complex, which triggers an intramolecular nucleophilic attack by the amino group that yield a cyclic vinyl-gold intermediate. A final protonolysis gives the imidazolidinone and regenerates the gold catalyst (Scheme 71). Scheme 71 - Gold(III)-catalyzed intramolecular hydroamination of -amino allenamides. In 2010 M. C. Kimber disclosed an intermolecular Au-catalyzed hydroamination of allenamides using arylamines. The method is highly efficient, and tolerates either electron-donating or electron-withdrawing groups at the arylamine moiety, and the corresponding allylamino E-enamides 69 are obtained stereoselectively and generally in high yield. The authors propose a mechanism involving the initial activation of the allenamide by the Au(I) catalyst to give a stabilized allyl cation intermediate XXXII. The aniline derivatives then undergo 1,2-addition giving XXXIII, followed by protodemetalation to yield the observed E-enamide 69. Scheme 72 – Gold(I)-catalyzed intermolecular hydroamination of allenamides with arylamines. It is also possible to use carbon instead heteroatom nucleophiles, such as electron-rich aromatics or heteroaromatics.126 Therefore N. Fujii, and H. Ohno reported a Aucatalyzed intramolecular hydroarylation of allenamides 70 for the formation of dihydroquinolines 71.127 The mechanism involves the allene activation by the gold 125 Manzo, A. M.; Perboni, A. D.; Broggini, G.; Rigamonti, M. Tetrahedron Lett. 2009, 50, 4696–4699. 126 For a review covering these type of reaction see: Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994–2009. 127 Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007, 9, 4821–4824. Cycloadditions of Allenamides 49 catalyst, a subsequent electrophilic aromatic substitution with the electron-rich arene to give a vinyl-gold complex intermediate that leads to the product 71 by rearomatization and protodeauration (Scheme 73). The use of allenamides allows the C−C bond to be formed exclusively at the terminal allenic carbon atom, in a 6-endo-trig manner. Scheme 73 - Gold-catalyzed intramolecular hydroarylation of allenamides. In 2012, M. C. Kimber reported a related intramolecular hydroarylation using allenamides of type 72, that do not incorporate the aromatic ring directly linked to the N atom. In contrast to the process described by N. Fujii (Scheme 73), these substrates undergo a 6-exo-trig cyclization, affording -vinyl-substituted tetrahydro isoquinolines (73) (Scheme 74).128 Scheme 74 - Gold-catalyzed intramolecular hydroarylation of allenamides. M. C. Kimber also developed an intermolecular gold-catalyzed hydroarylation of allenenamides. In particular, the group demonstrated that Ph3PAuNTf2 is an excellent catalyst for the addition of electron-rich aromatics and heteroaromatics to allenamides in a regioselective manner and under mild conditions. The proposed mechanism involves the formation of the key acyliminium intermediate XXXIV that undergoes a 1,4-addition of the nucleophile to give intermediate XXXV. A subsequent protodemetalation yields the E-enamide 74.129 128 Singh, S.; Elsegood, M.; Kimber, M. Synlett 2012, 23, 565–568. 129 Kimber, M. C. Org. Lett. 2010, 12, 1128–1131. Chapter I – (4+2) cycloadditions 56 Scheme 79 – (4+3) Cycloaddition of a trimethylenemethane precursor. S. Saito described an interesting Ni-catalysed (4+3) cycloaddition reactions of ethyl cyclopropylideneacetate with 1,3-dienes, which provided the corresponding cycloheptene derivatives 80 with both moderate yields and regioselectivities (Scheme 80). 134 Scheme 80 – Ni catalyzed intermolecular (4+3) cycloaddition. An interesting alternative way of rapidly assembling seven membered rings consists of the (5+2) cycloaddition of vinylcyclopropanes and alkynes or alkenes, first reported by P. A. Wender in 1998.135,136 This group showed that the treatment of the siloxycyclopropane with an alkyne in the presence of [Rh(CO)2Cl]2 produces cycloadducts of type 81, that are hydrolyzed during workup to the ketone. The proposed catalytic cycle begins with the coordination of the Rh-complex to the vinylcyclopropane, followed by opening of the cyclopropane ring to give a rhodium coordinated -allyl system (XXXVI). Subsequent alkyne coordination followed by insertion delivered intermediate XXXVII, which gives the observed cycloadduct through a reductive elimination (Scheme 81).137 Scheme 81 – Rh-catalyzed Intermolecular (5+2) Cycloaddition. 134 Saito, S.; Takeuchi, K. Tetrahedron Lett. 2007, 48, 595–598. 135 For reviews on 5+2 cycloadditions see: a) Pellissier, H. Adv. Synth. Catal. 2011, 353, 189–218. b) Ylijoki, K. E. O.; Stryker, J. M. Chem. Rev. 2013, 113, 2244–2266. 136 Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc. 1998, 120, 10976–10977. 137 Liu, P.; Cheong, P. H.-Y.; Yu, Z.-X.; Wender, P. a; Houk, K. N. Angew. Chemie Int. Ed. 2008, 47, 3939–3941. Foreword 57 P. A. Wender also studied the feasibility of the intermolecular process with allenes. The introduction of an additional conjugated coordinating group, such as an alkynyl, or cyano substituent, allowed a smooth cycloaddition at the distal double bond of the allene, providing substituted alkylidenecycloheptanones 82 as mixtures of Eand Zisomers (Scheme 82).138 Scheme 82 – Rh-catalyzed intermolecular (5+2) cycloadditions of allenes and vinylcyclopropanes. The group of Barluenga developed a formal (3+2+2) cyclization of chromium alkenyl- (methoxy)carbene complexes (83) with two unities of allenes in the presence of Ni(0) or Rh(I) catalysts. The Ni(0)-mediated (3+2+2) reaction affords 84, that after chromatographic purification led to the 3,4-diisopropylidenecycloheptanone 85 (Scheme 83, left). While using [Rh(COD)Cl]2 as catalyst, the reaction yielded 3,5bis(alkylidene)cycloheptenes 86, which upon protonolysis afforded 2,4bis(alkylidene)cycloheptanones 87 (Scheme 83 right). Thus 1,2and 1,3-dialkylidenecycloheptane derivatives can be chemo-, regio-, and diastereoselectively obtained depending upon the choice of the catalyst.139 Scheme 83 – (3+2+2) cycloaddition of alkenyl Fischer carbene complexes and allenes. S Si ix x- -m me em mb be er re ed d r ri in ng gs s With regard to the construction of cyclohexanyl adducts using metal catalyzed intermolecular cycloadditions, the examples are mainly reduced to Lewis acid promoted Diels Alder reactions.31 Some of these reactions involve the use of allenes,140 such as in 138 Wegner, H. A.; de Meijere, A.; Wender, P. A. J. Am. Chem. Soc. 2005, 127, 6530–6531. 139 Barluenga, J.; Vicente, R.; Barrio, P.; López, L. A.; Tomás, M.; Borge, J. J. Am. Chem. Soc. 2004, 126, 14354–143545. 31 a) Vollhardt, K. P. C.; Schore, N. E. Organic Chemistry; 3rd ed.; W.H.Freeman & Co Ltd, 1998. b) Fringuelli, F.; Taticchi, A. The Diels-Alder Reaction: Selected Practical Methods; Wiley: Chichester, U.K., 2002. c) Miller, J. P. Advances in Chemistry Research. Volume 18 - Recent Advances in Asymmetric Diels-Alder Reactions; Taylor, J. C., Ed.; Nova Science Publishers, Inc., Chapter I – (4+2) cycloadditions 58 the reaction of 88 with cyclopentadiene to give the two (4+2) cycloadducts endo and exo89. The use of a Lewis acid lowers the reaction temperature and improves the yield and endo selectivity (Scheme 84).141 Scheme 84 – (4+2) cycloaddition of allenic ester with cyclopentadiene. M. Murakami developed a highly regioselective (4+2) cycloaddition of vinylallene derivatives like 90 and alkynes for the synthesis of substituted benzenes, catalyzed by a Rh(I) complex.142 The resulting benzene derivatives (91) are obtained with excellent regioselectivities and very good yields. A plausible mechanism proposed by the authors involves the initial formation of a five-membered rhodacycle intermediate. Coordination of the alkyne, followed by a carbometallation step would provide a seven-membered rhodacycle. A final reductive elimination followed by isomerization to gain aromaticity delivers the benzene product 91. Scheme 85 - Rh-catalyzed (4+2) cycloaddition of vinyl allene and a terminal alkyne. The same authors also demonstrated that related (4+2) cycloadditions between vinylallenes 90 and unactivated 1,3-dienes could also be efficiently promoted by a Pd catalyst (Scheme 86), affording a cyclohexene derivative (92) in a highly regioand stereoselective manner.143 The proposed mechanism involves the participation of the - allyl complex XXXVIII, which explains the observed regioand stereochemical outcome of the process. 2013; 18, 179–220. d) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2002, 41, 1668–1698. e) Takao, K.-I.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779–4807. 140 Murakami, M.; Matsuda, T. Cycloadditions of Allenes, in Modern Allene Chemistry; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH Verlag GmbH: Weinheim, Germany, 2004.141 Ismail, Z. M.; Hoffmann, H. M. R. J. Org. Chem. 1981, 46, 3549– 3550. 141 Ismail, Z. M.; Hoffmann, H. M. R. J. Org. Chem. 1981, 46, 3549–3550. 142 Murakami, M.; Ubukata, M.; Itami, K.; Ito, Y. Angew. Chemie Int. Ed. 1998, 37, 2248–2250. 143 Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc. 1997, 119, 7163–7164. Foreword 59 Scheme 86 - Intermolecular directed (4+2) cycloaddition of vinylallenes with 1,3-dienes. Chapter I – (4+2) cycloadditions 60 3 3. .1 1 P Pr re el li im mi in na ar ry y s st tu ud di ie es s Initially we tested the feasibility of the reaction of allenes with pyrroles, because in case of a (4+3) cycloaddition the methodology would afford a straighforward way of assembling tropane systems. This type of structure is common to a wide variety of natural products and pharmaceutical agents. Therefore, finding methods for their synthesis is highly appealing.144 To test the feasibility of the process we mixed phenyl(1H-pyrrol-1-yl)methanone with different type of allenes in presence of catalytic amounts of PtCl2 or of the cationic gold complex resulting from mixing the phosphite derivative Au6 with AgSbF6. The results of the reactions tested are summarized in the Table 1. As can be deduced, the reactions led either to low conversions or to the formation of complex mixtures of products. The only products that could be identified, albeit in low yields, are enamides 93, that arise from an intermolecular hydroarylation reaction between the allene and the pyrrole. The best result, shown in entry 5, is obtained with an allene having an oxazolidinone group as substituent, and Au6/AgSbF6 as catalyst, whih in any case gave only a 12% yield of 93. In none of the cases we could identify the (4+3) or a (4+2) cycloaddition products. 144 a) Vaccinine B: Zanolari, B.; Guilet, D.; Marston, A.; Queiroz, E. F.; Paulo, M. D. Q.; Hostettmann, K. J. Nat. Prod. 2005, 68, 1153–1158. b) 2,7-dihydroxynortropane: Asano, N.; Yokoyama, K.; Sakurai, M.; Ikeda, K.; Kizu, H.; Kato, A.; Arisawa, M.; Höke, D.; Dräger, B.; Watson, A. A.; Nash, R. J. Phytochemistry 2001, 57, 721–726. b) Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10312–10313. 3 3. . R Re es su ul lt ts s a an nd d d di is sc cu us ss si io o n n Preliminary studies 61 Table 1 - Reaction of pyrrole and allenes in the presence of a Pt or a Au catalyst. Entry R1 R 2 [M] (5 mol%) Time Yield (%) 1 OMe H Au6 / AgSbF6 10 min -a 2 OMe H PtCl2 7h - a 3 Me Me Au6 / AgSbF6 5h 93a, 5% 4 Me Me PtCl2 7h No reaction 5 O N O H Au6 / AgSbF6 2h 93b, 12% 6 PtCl2 21h No reaction 7b Si-t-BuPh2 H A 3h No reaction a) Allene degradation. b) Using Ethyl acetate as solvent at 76ºC, A = [PtCl2C2H4]2/p-o-tolyl Given the poor results obtained with pyrroles as dienes, we turned our attention to other types of dienes. In this case we obtained interesting results when using allenamides as allene cycloaddition partners, as described in the next article published in the journal Chemical Science.145 The mechanistic aspects of this chemistry, result of collaboration with theoretical colleagues, are described in the second article included in the sections (Chem. Eur. J.).146 An appendix to this chapter includes notes on the development of an enantioselective version. 145 Faustino, H.; López, F.; Castedo, L.; Mascareñas, J. L. Chem. Sci. 2011, 2, 633-637. 146 Montserrat, S.; Faustino, H.; Lledós, A.; Mascareñas, J. L.; López, F.; Ujaque, G. Chem. Eur. J. 2013, 19, 15248–15260. 3 3. .2 2 P Pu ub bl li is sh he ed d m ma an nu us sc cr ri ip pt ts s Faustino, H.; López, F.; Castedo, L.; Mascareñas, J. L. Chem. Sci. 2011, 2, 633-637. Author contributions J.L.M and F.L. directed and conceived the research. H.F. performed the experiments with exception to those presented in table 3, entry 1-3, performed by F.L.. F.L. and J.L wrote the manuscript with inputs from all authors. All authors discussed the results and revised the manuscript. A Ar rt ti ic cl le e 1 1 - - G Go ol ld d( (I I) )- -c ca at ta al ly yz ze ed d i in nt te er rm mo ol le ec cu ul la ar r ( (4 4+ +2 2) ) c cy yc cl lo oa ad dd di it ti io on n o o f f a al ll le en na am mi id de es s a an nd d a ac cy yc cl li ic c d di ie en ne es s Gold(I)-catalyzed intermolecular (4 + 2) cycloaddition of allenamides and acyclic dienes† H elio Faustino, a Fernando L opez,* b Luis Castedo a and Jos e L. Mascare~ nas* a Received 15th December 2010, Accepted 13th January 2011 DOI: 10.1039/c0sc00630k A new type of intermolecular (4 + 2) cycloaddition, based on a gold-catalyzed reaction between allenamides and acyclic conjugated dienes, is reported. The annulation, which fails under standard Diels–Alder conditions, provides a straight entry to a variety of differently substituted cyclohexenes, and takes place with excellent regioand diastereoselectivity. Intermolecular (4 + 2) Diels–Alder cycloadditions are among the most powerful synthetic transformations so far described; 1 however, their effectiveness is usually restricted to the use of properly biased dienes and dienophiles. The development of methods that allow us to perform (4 + 2) cycloaddition of Diels– Alder-inactive substrates would significantly expand the scope and potential of this ring assembly strategy. We and others have recently described gold-catalyzed intramolecular (4 + 2) cycloadditions of allene-tethered-dienes, 2 reactions that efficiently afford trans-fused bicyclic systems under very mild conditions. Conversely, more challenging, intermolecular versions of these cycloadditions have remained elusive. Herein, we report the discovery and implementation of such intermolecular process, namely a highly selective goldcatalyzed (4 + 2) cycloaddition between non-activated 1,3-dienes and allenamides, a particularly accessible and versatile type of allenic scaffold. 3 To the best of our knowledge, this methodology constitutes the first transition metal-catalyzed intermolecular (4 + 2) cycloaddition between allenes (2C) and 1,3-dienes (4C), 4 as well as one of the very few types of intermolecular cycloadditions of allenes promoted by gold or platinum catalysts. 5,6 A preliminary reactivity screening using isoprene (2a) revealed that its treatment with electronically neutral allenes, such as 3methylbuta-1,2-diene (1a, Fig. 1), in the presence of different sources of Pt or Au catalysts, leads to intractable mixtures of products. These results confirmed that the development of intermolecular variants of this type of annulations between allenes and dienes is not straightforward. 7 Electronically rich allenes such as 1b or 1c also led to complex reaction mixtures. 8 Gratifyingly, treatment of isoprene with the allenamide 1d in the presence of PPh 3 AuCl/AgSbF 6 ,at15 C, produced the (4 + 2) cycloadduct 3da in 33% yield together with the (2 + 2) cycloadduct 4da, which was isolated in 19% yield. (Table 1, entry 1). 9 As shown in entries 1–4, this reaction could also be promoted by several other cationic Au-catalysts (B-D). In all the cases, in addition to the (4 + 2) adduct, we also isolated variable amounts of the (2 + 2) cyclobutane derivative 4da (14–20% yield). 10 Remarkably, neutral gold chloride catalysts turned out to be less active but more selective in favor of the (4 + 2) process (Table 1, entries 5–7), with AuCl being the most effective as we observed only traces of the side (2 + 2) adduct (Table 1, entry 7). Thus, treatment of 1d with 5 mol% of AuCl in presence of isoprene (6 equiv) at rt afforded, in a completely regioand highly stereoselective manner, the (4 + 2) cycloadduct 3da in a 65% isolated yield. Importantly, reducing the amount of isoprene from six to three equivalents did not influence the efficiency of the process (Table 1, entry 8), whereas the use of just 2 equivalents provided a slightly lower reaction yield (Table 1, entry 9). Remarkably, Pt catalysts that had been previously found useful for inducing intermolecular (3 + 2) cycloadditions 5 gave very poor results in this process (Table 1, entries 10–11). On the other hand, control experiments with Brønsted acids or silver salts revealed that neither of them are able to promote the annulation (Table 1, entries 13–15), which, as expected, is also unfeasible under thermal conditions (Table 1, entries 16–17). This result confirms the Au-catalyzed nature of the process, as opposed to the recent thermal intramolecular cycloadditions of furan-tethered allenamides. 9g Fig. 1 a Departamento de Qu ımica Org anica, Centro Singular de Investigaci on en Qu ımica Biol ogica y Materiales Moleculares, y Unidad Asociada al CSIC. Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain. E-mail: [email protected]; Fax: +34 981 595012; Tel: +34 881814405 b Instituto de Qu ımica Org anica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain. E-mail: [email protected]; Fax: +34 915644853; Tel: +34 915622900 † Electronic supplementary information (ESI) available: Experimental procedures, characterization data, crystallographic data. CCDC reference numbers 804843–804850. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0sc00630k This journal is ªThe Royal Society of Chemistry 2011 Chem. Sci., 2011, 2, 633–637 | 633 Dynamic Article LinksC < Chemical Science Cite this: Chem. Sci., 2011, 2, 633 www.rsc.org/chemicalscience EDGE ARTICLE Downloaded on 22 March 2011 Published on 14 February 2011 on http://pubs.rsc.org | doi:10.1039/C0SC00630K View Online DOI: 10.1002/chem.201302330 Mechanistic Intricacies of Gold-Catalyzed Intermolecular Cycloadditions between Allenamides and Dienes Sergi Montserrat,[a] Hlio Faustino,[b] Agust Lleds,*[a] Jose L. MascareÇas,*[b] Fernando Lpez,*[b, c] and Gregori Ujaque*[a] Dedicated to Professor Maria Jos Calhorda on the occasion of her 65th birthday Introduction Along the last decade, research in homogeneous gold catalysis has experienced an extraordinary growth.[1] The singular characteristics of gold catalysts, such as their high carbophilicity, has allowed the development of a variety of powerful and unique transformations. Particularly relevant in terms of versatility and synthetic potential are the cycloadditions between allenes and p-unsaturated systems, such as dienes or alkenes.[2–8] Several intramolecular versions of this type of reaction have already been described[3–6] and, more recently, challenging intermolecular variants have also been successfully addressed.[7,8] In this context, we recently disclosed a gold-catalyzed intermolecular [4 + 2] cycloaddition of 1,3dienes (4C) and allenamides (2C),[7a,b,9] which takes place with good yield and high regioand diastereoselectivity, by using AuCl or the cationic gold(I) complex [IPrAuCl]/ AgSbF6(IPr=1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene) as catalysts.[7a] In a number of cases, and depending on the catalyst and diene employed, in addition to the [4 + 2] adducts of type 3, we also observed cyclobutane side products arising from a competitive [2 + 2] cycloaddition between the allene and one of the C=C double bonds of the diene (Scheme 1).[8] Scheme 1. Gold-catalyzed [4 + 2] cycloadditions of the allenamide 1and the dienes 2.[7a] Abstract: The mechanism of the goldcatalyzed intermolecular cycloaddition between allenamides and 1,3-dienes has been explored by means of a combined experimental and computational approach. The formation of the major [4 + 2] cycloaddition products can be explained by invoking different pathways, the preferred ones being determined by the nature of the diene (electron neutral vs. electron rich) and the type of the gold catalyst (AuCl vs. [IPrAu] + ,IPr=1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene). Therefore, in reactions catalyzed by AuCl, electron-neutral dienes favor a concerted [4 + 3] cycloaddition followed by a ring contraction event, whereas electron-rich dienes prefer a stepwise cationic pathway to give the same type of formal [4 + 2] products. On the other hand, the theoretical data suggest that by using a cationic gold catalyst, such as [IPrAuCl]/AgSbF6, the mechanism involves a direct [4 + 2] cycloaddition between the diene and the gold-activated allenamide. The theoretical data are also consistent with the observed regioselectivity as well as with the high selectivity towards the formation of the enamide products with a Zconfiguration. Finally, our data also explain the formation of the minor [2 + 2] products that are obtained in certain cases. Keywords: allenamides ·cycloaddition ·density functional calculations ·gold ·reaction mechanisms [a] Dr. S. Montserrat, Prof. Dr. A. Lleds, Dr. G. Ujaque Departament de Qumica Universitat Autnoma de Barcelona 08193 Bellaterra, Barcelona (Spain) E-mail: [email protected]ab.es [email protected] [b] H. Faustino, Prof. Dr. J. L. MascareÇas, Dr. F. Lpez Centro Singular de Investigacin en Qumica Biolgica y Materiales Moleculares (CIQUS) and Departamento de Qumica Orgnica Universidade de Santiago de Compostela C/Jenaro de la Fuente, s/n, 15782 Santiago de Compostela (Spain) Fax : ( + 34)981563100 Fax : ( + 34)981595012 E-mail: [email protected] [email protected] [c] Dr. F. Lpez Instituto de Qumica Orgnica General (CSIC) Juan de la Cierva, 3, 28006, Madrid (Spain) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302330.  2013 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Chem. Eur. J. 2013,19, 15248 –15260 15248 From a mechanistic point of view, we preliminary proposed that the activation of the allene by the gold catalyst could generate a gold–allyl cation species of type I (Scheme 2), which could be intercepted by a nucleophilic diene. This attack would trigger a stepwise cationic process such as that depicted in Scheme 2, to give either [4 + 2] or [2 + 2] adducts, depending on the site selectivity at the ring closure in intermediate II. Interestingly, when the AuCl-catalyzed reaction of the allenamide 1and 2,3-dimethyl butadiene (2b) was performed in the presence of exogenous MeOH (3 equiv), small amounts of the allyl ether 5b (12% yield) could be isolated together with the [4 + 2] cycloaddition product 3b, which was also obtained in 40% yield.[7a] The formation of small amounts of 5b supports a stepwise pathway like that shown in Scheme 2, but does not rule out the existence of parallel alternative pathways leading to the [4 + 2] cycloaddition products of type 3. In particular, the formation of the products 3could also be explained by invoking either a [4 + 3] cycloaddition of Iand the diene, followed by a ring contraction in the resulting gold–carbene species III (Scheme 3, upper pathway), or a concerted [4 + 2] cycloaddition between intermediate Iand the diene (Scheme 3, lower pathway). Indeed, the former pathway has been demonstrated for the intramolecular [4 + 2] cycloadditions of allenedienes,[4] whereas the second one has been proposed to operate in the [Ph3PAu] + -catalyzed [4 + 2] cycloaddition between allenyl ethers and dienes.[7c] Owing to these open mechanistic questions, we were challenged to perform additional studies that could shed further light on these gold-catalyzed cycloadditions as well as on the reasons behind their high stereoand regioselectivity.[7a] Relying on a combined experimental and computational study, we report herein the results of such a study, which not only confirm that there are several mechanistic pathways that account for the experimentally observed products, but also that their respective prevalence is quite dependent on the particular characteristics of the diene and the catalyst employed. Results and Discussion Our first mechanistic incursions addressed the possibility of experimentally trapping reaction intermediates of the type II and III in the AuCl-catalyzed cycloadditions of allenamide 1with neutral dienes, like isoprene (2a) or 2,3-dimethyl butadiene (2b). As mentioned above, the reaction with 2,3-dimethyl butadiene (2b), in the presence of exogenous MeOH allowed the isolation of the allyl methyl ether 5b with 12% yield, which must arise from the interception of a cationic intermediate such as IIb (Scheme 2, R2,3 =Me, R1,4 =H; Table 1, entry 2). Carrying out the same reaction with isoprene (2a) provided a complex mixture of products containing only traces of the [4 + 2] cycloaddition product 3a (Table 1, entry 4). These ambiguous results led us to explore other nucleophilic reagents as trapping agents. In particular, we tested several pyridine oxides and aryl sulfoxides, previously shown effective in the interception of carbocationic species, or in the oxidation of gold carbenes into their corresponding carbonyl derivatives.[10] As can be seen in Table 1 (entries 5–13), all reactions promoted by AuCl (5 mol%) between allenamide 1and the dienes 2a or 2b in the presence of these external additives provided, in addition to adducts of the type 3, the sevenmembered [4 + 3] cycloaddition products 6a or 6b, respectively, which presumably arise from the oxidative interception of the gold carbenoid intermediates of the type III.[10a,11] In the case of isoprene (2a, Table 1, entries 5–8), product 6a was obtained in a maximum yield of 18% when the reaction was performed in the presence of 3,5-dichloropyridine oxide (3 equiv) as external oxidant (Table 1, entry 5). In this reaction, the [4 + 2] adduct 3a was also isolated in 28% yield. For 2,3-dimethyl butadiene (2b), a higher yield of 6b (20%) was observed when using 4-nitropyridine oxide (3 equiv) and the reaction also provided the [4 + 2] adduct 3b in 52% yield (Table 1, entry 11). Overall, and although the yields of 6a or 6b were modest, the formation of these cycloheptenones points out to the participation of intermediates of the type III, which should evolve to the six-membered carbocycles 3a or 3b by means of a 1,2-ring contraction process.[4] In the presence of the external oxidant, this ring contraction competes with the carbene Scheme 3. Alternative mechanistic pathways that could render the [4 + 2] cycloaddition product 3. Scheme 2. Preliminary mechanistic proposal based on a stepwise cationic pathway. Chem. Eur. J. 2013,19, 15248 –15260  2013 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim www.chemeurj.org 15249 FULL PAPER oxidation process and therefore we observe mixtures of the seven-membered ketone 6a or 6b and the six-membered cycloaddition product 3a or 3b. Importantly, by using these oxide additives we never detected putative products resulting from interception of intermediates of type II (Scheme 2).[12] Because the [4 + 2] cycloadditions can also be performed with cationic gold complexes (Scheme 1),[7a,b] we also tried to trap intermediates in the cycloadditions between allenamide 1and the dienes 2a or 2b, carried out in the presence of 5 mol% of [IPrAuCl]/AgSbF6. In this case, we did not observe products other than the [4 + 2] and the [2 + 2] cycloaddition products 3and 4(Table 1, entries 14–17). These data suggest that for this cationic catalyst, a concerted [4 + 2] cycloaddition,[7c] and/or a cationic stepwise pathway could be operative. The [4 + 2] cycloaddition of allenamides can also be performed with electron-rich dienes, such as 1-methoxy-1,3-butadiene (2c) (Table 2, entry 1).[7a] To assess which of the pathways could be operative in this case, we performed the cycloaddition of allenamide 1and diene 2c in the presence of trapping agents (Table 2). The reaction between 1and 2c, in the presence of MeOH (3 equiv) led to a complex mixture of products, from which the aldehyde 7c was the only one that could be isolated, in a modest 20% yield (Table 2, entry 2). The employment of non-protic additives, such as pyridine oxides or diaryl sulfoxides, allowed to increase the efficiency of the reaction, providing aldehyde 7c and the hemiketal 7c’in good combined yields. Thus, by using simple pyridine oxide (3 equiv), 48% yield of the aldehyde 7c was isolated together with 25% yield of its hemiketal precursor 7c’(Table 2, entry 3). Similarly, the bis(pchlorophenyl) sulfoxide led to 43% yield of 7c and traces (2% yield) of the [4 + 2] cycloaddition product 3c (Table 2, entry 4). The formation of the acyclic products 7c and 7c’suggests a stepwise mechanism involving the species IIc (Table 2), which is trapped by the external nucleophile. The [2 + 2] cycloaddition product 4c, as well as other products such as the sevenmembered derivative 6c, potentially arising from the oxidative interception of the cycloheptyl–carbene intermediates IIIc, were never detected. Although the above-described experimental data do not allow to extract definitive mechanistic conclusions, they suggest that different mechanistic pathways might be operating depending on the type of the diene (electron neutral vs. electron rich), and also on the type of the gold catalyst (AuCl vs. [IPrAu] + ). The use of electron-rich dienes, such as 2c, favors a stepwise cationic pathway, whereas more neutral dienes, such as 2a or 2b, prefer pathways involving concerted cycloadditions, albeit competitive stepwise processes could be simultaneously operative. Table 1. Assays for capturing reaction intermediates in the cycloadditions of allenamide 1and the dienes 2a and 2b. Entry Diene Additive[a] [Au] 3([%])[b] 4([%])[b] 5([%])[b] 6([%])[b] 12b – AuCl 3b (76) – – – 22b MeOH AuCl 3b (40) – 5b (12) – 32a – AuCl 3a (66) 2 – – 42a MeOH AuCl 3a (2) – – – 52a ACHTUNGTRENNUNG(3,5-Cl2)-Py-O[c] AuCl 3a (28) – – 6a (18) 62a ACHTUNGTRENNUNG(4-NO2)-Py-O AuCl 3a (38) – – 6a (16) 72a Ph2S=O AuCl 3a (13) – – 6a (16) 82a Ar2S=O[d] AuCl 3a (24) – – 6a (14) 92b Py-O AuCl 3b (32) – – 6b (9) 10 2b ACHTUNGTRENNUNG(3,5-Cl2)-Py-O AuCl 3b (51) – – 6b(18) 11 2b ACHTUNGTRENNUNG(4-NO2)-Py-O AuCl 3b (52) – – 6b(20) 12 2b Ph2S=O AuCl 3b (44) – – 6b (15) 13 2b Ar2S=O[d] AuCl 3b (35) – – 6b (15) 14 2a –[e] ACHTUNGTRENNUNG[IPrAuCl]/AgSbF63a (41) 4a (16) – – 15 2a ACHTUNGTRENNUNG(3,5-Cl2)-Py-O[e] ACHTUNGTRENNUNG[IPrAuCl]/AgSbF63a (27) 4a (7) – – 16 2a MeOH[e] ACHTUNGTRENNUNG[IPrAuCl]/AgSbF63a (4) ––– 17 2b ACHTUNGTRENNUNG(3,5-Cl2)-Py-O[e] ACHTUNGTRENNUNG[IPrAuCl]/AgSbF63b (44) – – – [a] Reactions carried out in the presence of three equivalents of the additive in CH2Cl2at RT for 1–6 h, unless otherwise noted. Results from entries 1–3 and 14 were taken from reference [7a]. [b] Yield of isolated product. [c] Py=pyridine. [d] Ar=p-Cl-C6H4. [e] Reaction carried out at 15 8 C. Table 2. Interception of reaction intermediates in the cycloaddition of allenamide 1and diene 2c. Entry Additive[a] T[ 8 C] 3c[%][b] 7c [%][b] 7c’[%][b] 1– RT76 – – 2 MeOH 15 – 20 – 3 Py-O 15 – 48 25 4Ar 2S=O15 2 43 – [a] Reactions carried out in the presence of three equivalents of the additive in CH2Cl2for 1–6 h. [b] Yield of isolated products. www.chemeurj.org  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013,19, 15248 – 15260 15250 A. Lleds, J. L. MascareÇas, F. Lpez, G. Ujaque et al. To further clarify the mechanistic scenario, we performed DFT calculations by using the allenamide 1, the dienes 2a and 2c as model substrates, and AuCl and [NHCAu] + as gold catalysts.[13] We first evaluated the conformations of allenamide 1and its behavior with the gold complexes (Scheme 4). Of the two preferred conformers considering the dihedral angle C3-N-C-O, conformation 1is the most stable one (Scheme 4).[14] The calculations indicate that this initial h2-coordination by using AuCl takes place through the internal C2=C3 double bond of 1, with a preference over the alternative C1=C2 counterpart of 1.6 kcalmol1. The resulting intermediate (Int-1) evolves to the s-coordinated metal allyl cation intermediate Int-2 (Scheme 4). This process is accessible with an energy barrier of 4.2 kcalmol1, and the resultant zwitterionic species Int-2 is just 0.8 kcal mol1less stable than its precursor Int-1. An analogue step was found by using [NHCAu] + as catalyst, with quite similar energy values and an energy barrier of 4.6 kcalmol1.The calculated data indicate that the C2=C3 bond is longer than the C1=C2 bond and that the C3N bond is shorter than those of their immediate precursor Int-1, which confirms that the amide group contributes to the stability of this key intermediate. Alternative conformations of this type of zwitterions, such as Int-2Icould not be located, probably due to a higher allylic strain. Metal allyl cation intermediates of the type Int-2 are reactive species susceptible of being attacked by the diene through an exo or an endo mode (Scheme 5). s-cis Dienes Exo approach: The energy profile for the exo approach of isoprene (2a)toInt-2 by using AuCl as catalyst is shown in Figure 1. As energy reference we chose the allenamide h2coordinated to the metal complex (Int-1) in the presence of the diene 2a arranged in an s-cis conformation (Int-1 + 2a). The first step, as previously commented, involves the formation of the metal allyl cation (Int-2) through an energy barrier of 3.5 kcalmol1(TS1).[15] The reaction between the diene 2a and the metal allyl cation moiety was explored trying to identify the three previously proposed alternatives, namely a stepwise process involving an allyl cation of the type II (Scheme 2), a concerted [4 + 2] cycloaddition (Scheme 3, lower pathway), or a concerted [4 + 3] annulation (Scheme 3, upper pathway). Despite an intensive search, only the latter pathway could be computationally located. As shown in Figure 2, the transition state for the [4 + 3] cycloaddition TS2, is significantly asynchronous, with a CC bond lengths of 2.186 (C1C4) and 2.986  (C3C7).[16] A visual inspection of the imaginary frequency motion suggests Scheme 4. Initial gold activation of allenamide 1(distances are given in [], DGvalues are given in [kcalmol1]). Scheme 5. Exo and endo approaches exemplified for isoprene (2a)(L= Cl or NHC). Figure 1. Energy profile for the exo approach of isoprene (2a)toInt-2 (DGvalues are given in [kcalmol1]). Chem. Eur. J. 2013,19, 15248 –15260  2013 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim www.chemeurj.org 15251 FULL PAPER Gold-Catalyzed Cycloadditions between Allenamides and Dienes that the driving force for the transformation is the nucleophilic attack of the diene (C4) to the former terminal allene carbon atom (C1), thereby generating the corresponding C1C4 bond. The cycloaddition process has a relative energy barrier of 5.2 kcalmol1, and the heptacyclic intermediate Int-3 has an energy of 7.6 kcalmol1.Int-3 is characterized by a chair-like conformation with a pseudoequatorial disposition of the oxazolidinone moiety. The participation of the species Int-3 in the cycloaddition is consistent with the experimental isolation of the seven-membered ketone 6a when the AuCl-catalyzed reaction of allenamide 1and diene 2a was carried out in the presence of gold–carbene oxidants (Table 1, entries 5–8). The carbene species Int-3 might evolve through different 1,2-hydrogen-atom migrations or 1,2-alkyl shifts, as previously demonstrated in the context of [4 + 3] intramolecular cycloadditions between allenes and dienes.[3,4] The calculations indicate that the ring contraction to give the cyclohexene adducts is clearly favored over the 1,2-hydrogen-atom migrations, which would generate cycloheptadienes of the type 8 (never observed experimentally). The energy profile of these pathways and the structure of the key stationary points can be found in Figures 1 and 2. The stereospecific formation of the Z-enamide moiety is a consequence of the pseudoequatorial disposition of the oxazolidinone group, which determines the stereochemistry of the alkene resulting from the ring contraction. Indeed, exploration of the same ring contraction on conformer Int-3I, which displays the oxazolidinone group in a pseudoaxial disposition, led to the isomeric E-enamide cycloadduct, (E)-3a, through an energy barrier of 6.1 kcalmol1(TS3I, Figure 3).[17] The energy barrier for the conversion of Int-3 into Int-3Iturned out to be of 8.1 kcalmol1, with Int-3I being 4.8 kcalmol1less stable than Int-3. Thus, the global energy barrier for the formation of E-3a from Int-3 is 10.9 kcalmol1.[18,19] These results explain the high selectivity towards the Z-enamide cycloadduct Z-3a, which is the major product in the cycloaddition between allenamide 1and neutral dienes like 2a (Scheme 1, Z/Eratios93:7, by using AuCl as catalyst).[7a] We also explored the pathway leading to the regioisomeric product 9a (Figure 4). We located the transition state for the corresponding regiocomplementary exo [4 + 3] cycloaddition between Int-2 and 2a (regio-TS2) and found that it exhibits a higher relative energy than the alternative TS2 [DACHTUNGTRENNUNG(DG°)=1.6 kcalmol1].[19] Although the difference is not high, the result is qualitatively in agreement with the experimental observation of 3a instead of 9a. Figure 2. Structures of the key stationary points leading to Z-3a-(AuCl) (distances are given in []). Figure 3. Formation of (E)-3a by conversion of Int-3 into Int-3I(DGvalues are given in [kcalmol1]). Figure 4. Regiocomplementary approach between Int-2 and 2a. www.chemeurj.org  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013,19, 15248 – 15260 15252 A. Lleds, J. L. MascareÇas, F. Lpez, G. Ujaque et al. In conclusion, the formation of the [4 + 2] product 3a (and other related adducts like 3b) in the AuCl-catalyzed cycloadditions of allenamide 1with diene 2a (or related neutral dienes like 2b),[7a] as well as the observed regioselectivity (with diene 2a) and the Zselectivity (typically Z/E93:7) is consistent with the mechanistic profile outlined in Figure 1.[20] Endo approach: In contrast to the exo approach, when the diene approaches the allyl cation in an endo mode, a transition state analogous to TS2, leading to a seven-membered carbene intermediate of the type Int-3 was not found. Instead, we located a related transition state, TS2-endo, corresponding to a direct [4 + 2] cycloaddition between Int-2 and 2a (Figures 5 and 6) that leads to the same product (Z)-3a. The new transition state is highly asynchronous (TS2-endo: dACHTUNGTRENNUNG(C1C4)=2.141 and dACHTUNGTRENNUNG(C2C7)=3.395 ), and the driving force for the reaction is also the nucleophilic attack of 2a to the metal allyl cation intermediate Int-2 to make the C1C4 bond (Figure 6). The reason for the preferred closure of the cycle by the C2 atom, leading to the cyclohexene product, instead of the C3 atom, which would generate the cycloheptene ring, is not evident. However, it is important to note that in TS2 the C7 atom is nearest to the C3 atom than to the C2 atom (dACHTUNGTRENNUNG(C2C7)=3.144 and dACHTUNGTRENNUNG(C3C7)=2.986 ), whereas in TS2-endo C2C7 is the shortest distance (dACHTUNGTRENNUNG(C2 C7)=3.395 and dACHTUNGTRENNUNG(C3C7)=3.419 ) (Figure 6). Importantly, TS2-endo is of higher energy than TS2, with a difference of 1.7 kcalmol1(8.3 vs. 6.6 kcalmol1). Analysis of both transition states shows that this difference is mainly produced by the higher distortion energy of the allenyl–gold moiety in TS2-endo (Edistortion-allenyl moiety =7.5 kcalmol1) than in TS2 (Edistortion-allenyl moiety =6.0 kcalmol1). Analysis of the natural orbitals of the reactants showed that the HOMO2 and the LUMO are the orbitals that interact in this step, with the energy difference between the HOMO2 and the LUMO being slightly higher for the TS2-endo species. In summary, we have found different mechanistic paths for the cycloaddition of isoprene (2a), depending on considering an exo or an endo approach; although both give rise to the same six-membered ring product (Z)-3a.Theexo pathway, proceeding through the seven-membered carbene species Int-3, is favored by 1.7 kcalmol1, though both pathways might similarly contribute to the product formation. s-trans Dienes: In the above-described cases, in which we considered an s-cis conformation of the diene, stepwise cationic processes like that drawn in the Scheme 2 could not be located. However, such a stepwise mechanism was computationally captured when considering an s-trans conformation of the diene (Figures 7 and 8). When the s-trans-configured diene 2a, which is more stable than the s-cis conformer,[21] Figure 5. Energy profile for the endo approach with isoprene (2a)(DG values are given in [kcalmol1]). Figure 6. Comparison of the exo (TS2) and the endo (TS2-endo) approach. Figure 7. Energy profile for the exo approach with the s-trans-configured diene 2a (DGvalues are given in [kcalmol1]). Chem. Eur. J. 2013,19, 15248 –15260  2013 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim www.chemeurj.org 15253 FULL PAPER Gold-Catalyzed Cycloadditions between Allenamides and Dienes attacks the electrophilic species Int-2, a new intermediate, Int-4, which features an allyl cation moiety (dACHTUNGTRENNUNG(C5C6)= 1.430 and dACHTUNGTRENNUNG(C6C7)=1.356 ) is detected. This process exhibits a relative energy barrier of 9.8 kcalmol1and Int-4 is 7.4 kcalmol1less stable than its precursor. At this point, Int-4 may evolve by attacking the C2 atom of the vinyl gold species to the allyl cation moiety at the C5 atom to give the [2 + 2] product (Z)-4a. This step, which proceeds through TS5 (dACHTUNGTRENNUNG(C2C5)=2.102 ), has a relative energy barrier of 4.9 kcalmol1, with an overall energy barrier for the formation of (Z)-4a of 13.5 kcalmol1. The formation of the cisenamide adduct, (Z)-4a, can be understood by analyzing the structures of Int-4 and the corresponding transition state leading to the cyclobutane (TS5). It can be observed that the preferred conformation of Int-2, displaying the Au atom and the oxazolidinone in a cis arrangement is conserved in TS2-(s-trans), Int-4, and through TS5. Int-4 can also evolve to the formal [4 + 2] cyclohexene adduct (Z)-3a. In this case the preferred path involves the formation of Int-5 (dACHTUNGTRENNUNG(C5Au) = 2.238 ), in which the electron density of the metal partially neutralizes the positive charge of the allyl cation.[22] This stabilizing interaction is also reflected in the energy values, because Int-5 is 5.9 kcalmol1 more stable than Int-4.Accordingly, the dACHTUNGTRENNUNG(C5C6) value has now been increased up to 1.475  and the length of the C6C7 bond is closer to that of a double bond (dACHTUNGTRENNUNG(C6C7)= 1.343 ) (Figure 8). Interestingly, Int-5 can be readily converted through an energy barrier of 7.2 kcalmol1to the rotamer Int-6 (rotation around the C5C6 sbond). This new intermediate has the appropriate orientation to evolve to the [4 + 2] product (Z)-3a through transition state TS8 (5.6 kcal mol1, Figure 7).[23] The whole stepwise process leading to the [4 + 2] adduct (Z)-3a exhibits an overall energy barrier of 11.4 kcalmol1thereby being more favorACHTUNGTRENNUNGable than that leading the [2 + 2] product (Z)-4a (overall energy barrier of 13.5 kcalmol1).[24] The overall energy barriers leading to the cyclohexene, (Z)-3a, and the cyclobutane, (Z)-4a, through either mechanistic pathway are indicated in the Table 3. Taking as reference the energy of Int-1 + 2a-(s-trans) (Figure 7), which corresponds to the less energetic initial intermediate, it can be observed that in all cases the formation of the [4 + 2] product (Z)-3a is preferred. Moreover, and despite the requirement of an initial s-trans-to-s-cis conformational rearrangement, the pathway involving a [4 + 3] cycloaddition followed by Figure 8. Structures of the key stationary points for the exo approach with the s-trans-configured diene 2a (distances are given in []). www.chemeurj.org  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013,19, 15248 – 15260 15254 A. Lleds, J. L. MascareÇas, F. Lpez, G. Ujaque et al. a ring contraction process is the most favored (9.9 kcal mol1). The experimental observation of minor amounts of the [2 + 2] product (Z)-4a can be explained according to the pathway indicated in Figure 7, which begins from species Int-1 + 2a-(s-trans), and presents an overall energy barrier of 13.5 kcalmol1. Overall, the energy barriers are in qualitative agreement with the experimental results, because only a 2% yield of the [2 + 2] product (Z)-4a was isolated in the reaction between the allenamide 1and isoprene (2a)by using AuCl as catalyst. Reactions with 1-methoxy-1,3-butadiene (2c): We have also computationally explored the behavior of the methoxydiene 2c assuming an exo approach and an s-cis conformation (Figures 9 and 10).[25] After the formation of the gold allyl cation intermediate, the reaction proceeds by the nucleophilic attack of the diene to its terminal unsubstituted C1 atom (TS2OMe; energy barrier of 2.3 kcalmol1), which leads to the quite stable oxonium intermediate Int-4OMe (7.2 kcal mol1). In contrast to the case of isoprene, transition states for concerted [4 + 3] or [4 + 2] cycloaddition processes could not be located. Compared to diene 2a, the higher ability of the methoxy group of 2cto stabilize the positive charge generated in this nucleophilic attack seems to disfavor a concerted processes. Int-4OMe easily evolves to the formal [4 + 2] product (Z)-3c through TS3OMe, with an energy barrier of 8.2 kcalmol1.Int-4OMe can also be converted to the [2 + 2] cycloaddition product (Z)-4c through TS4OMe, although this step presents a significantly higher energy barrier (12.4 kcal mol1). Similarly to the formation of the cyclobutane (Z)-4a from Int-4 (Figure 7), the stereospecific formation of the cyclohexene (Z)-3c (and (Z)-4c) is determined by the conformation of the enamide moiety in Int-4OMe. Intermediate Int4OMe might also give the seven-membered carbene species Int-3OMe through transition state TS5OMe but the energy barrier is also higher than that leading to product 3c. Overall, the calculated stepwise pathway through Int-4OMe nicely fits with the experimental results given in Table 2, and with the interception of this species by nucleophilic external agents to afford the aldehyde and hemiketal products 7cand 7c ’ . Reactions catalyzed by [NHCAu] + : As exemplified in Scheme 1, [IPrAuCl]/AgSbF6performs differently than AuCl in the reaction of allenamide 1with neutral dienes like 2a or 2b, as in addition to the [4 + 2] adducts we observed significant amounts of the cyclobutane products (5– 16% yield, Scheme 1).[7a] Therefore, we also decided to computationally explore the different scenarios with this catalyst, considering both an exo and an endo approach of the Table 3. Overall DG°values for the AuCl-catalyzed cycloadditions of allenamide 1and the diene 2a.[a] Entry Approach[b] (Z)-3a (Z)-4a 1Int-1 + 2a[d] 9.9 –[c] 2Int-1 + 2a-ACHTUNGTRENNUNG(endo)[e] 11.6 –[c] 3Int-1 + 2a-ACHTUNGTRENNUNG(s-trans)[f] 11.4 13.5 [a] DG°values are given in [kcalmol1]. [b] Represented by the initial intermediate of the process. [c] A pathway leading to (Z)-4a could not be located. [d] See Figure 1. [e] See Figure 4. [f] See Figure 7. Figure 9. Energy profile for the exo approach with diene 2c (DGvalues are given in [kcalmol1]). Figure 10. Structures of the key stationary points for the exo approach with the s-cis-configured diene 2c. Chem. Eur. J. 2013,19, 15248 –15260  2013 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim www.chemeurj.org 15255 FULL PAPER Gold-Catalyzed Cycloadditions between Allenamides and Dienes diene, and an s-cis and an s-trans conformation of the diene 2a. Although, the potential energy surfaces revealed similar mechanistic pathways to those previously found for AuCl, there are some interesting differences. Analysis of the exo and the endo approach of the diene 2a in an s-cis conformation revealed that in both cases the formation of the cyclohexene product involves a direct cycloaddition between this diene and the gold allyl cation Int2NHC. In contrast to that observed with AuCl, the [4 + 3] cycloaddition pathway could not be located. Figure 11 compares the structure of TS2NHC and that of its analogue with AuCl (TS2). Both are very close in geometry, and exhibit a shorter C7C3 distance than C7C2,suggesting that a [4 + 3] cycloaddition could be feasible (TS2: dACHTUNGTRENNUNG(C2 C7)=3.144 and dACHTUNGTRENNUNG(C3C7)=2.986 ; TS2NHC:dACHTUNGTRENNUNG(C2C7)= 3.276 and dACHTUNGTRENNUNG(C3C7)=3.048 ). The preference of the sixmembered rather than the seven-membered closure could be related to the subtle differences in the electron density of the C2 and C3 atoms in these transition states, which is directly influenced by the electronic properties of the ligand at the gold atom. However, a definitive conclusion cannot yet be extracted from the computational data.[26] In any case, both transition states eventually give rise to the same final and experimentally observed product, and both catalysts presents very similar overall energy profiles (Figure 12). With [NHCAu] + , the energy barrier for the allyl cation formation is of 3.4 kcalmol1(TS1NHC) and that of the subsequent [4 + 2] cycloaddition is of 7.6 kcalmol1 (TS2NHC). On the other hand, as above described with AuCl (Figure 1), the first step through TS1 involves an energy barrier of 3.5 kcalmol1, whereas the [4 + 3] cycloaddition (TS2) and the ring contraction process (TS3) present energy barriers of 6.6 and 5.9 kcalmol1, respectively. The endo approach with [NHCAu] + also leads to a direct [4 + 2] cycloaddition mechanism, with a global energy barrier of 9.7 kcalmol1(TS2NHC-(endo)).[19] Thus, like with AuCl, the endo approach is less accessible than the exo approach (7.6 kcalmol1,TS2 NHC). The second major difference between the reaction profiles with AuCl and [NHCAu] + is relevant to understand the formation of a higher amount of the cyclobutane (Z)-4a when [IPrAuCl]/AgSbF6is used as catalyst. The energy profile for the reaction of diene 2a considering an s-trans disposition is shown in Figure 13. In contrast to the results with AuCl, the pathway giving rise to the cyclobutane product (Figure 13, solid line) is now the less costly, with a global energy barrier of 14.5 kcalmol1(through TS10NHC), meanwhile, the route to the [4 + 2] product (Figure 13, dashed line) features a maximum energy barrier of 19.9 kcalmol1(through TS8NHC). Other than the energetic difference, the pathways are quite similar to those obtained with AuCl (Figure 6). The first step is the formation of the metal allyl cation, followed by a nucleophilic attack to form the allyl cation intermediate Int-4NHC (energy barrier of 12.2 kcalmol1through TS2NHC- (s-trans)). Alternative conformations of similar energy to Int-4NHC, such as Int-5NHC and Int-6NHC, but exhibiting the allyl cation moiety closer to the metal center could also be localized (Figures 13 and 14). However, in comparison with the same intermediate with AuCl (Int-5), the distance between the metal and the allyl cation in these conformations is higher (dACHTUNGTRENNUNG(C5Au) =2.238 (Int-5), 3.935 (Int-5NHC), and 3.755  (Int-6NHC)). Thus, the stabilizing interaction between the allyl cation and the metal center seems stronger with AuCl than with [NHCAu] + . This fact is also reflected by the higher relative energy of these intermediates (Int-5NHC and Int-6NHC) compared to Int-5 (Figure 7). As in the AuCl system, the formation of the formal [4 + 2] product from Int6NHC requires a conformational change through rotation around the C5C6 bond; the energy barrier for this rotation turned out to be significantly higher than with AuCl (9.8 (TS8NHC) vs. 5.6 kcalmol1(TS8)), which is in consonance with the lower interaction between the metal center and the allyl cation moiety. Indeed, the structure of TS8NHC shows Figure 11. Comparison between TS2 and TS2NHC (distances are given in []). Figure 12. Comparison between exo approaches with AuCl and [NHCAu] + (DGvalues are given in [kcalmol1]). www.chemeurj.org  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013,19, 15248 – 15260 15256 A. Lleds, J. L. MascareÇas, F. Lpez, G. Ujaque et al. Chapter I – (4+2) cycloadditions 88 performed with Au40, which incorporates a cyclohexyl group instead of a Me in the ortho position, an ee value of 90% was obtained. Scheme 87 - Preliminary screening of chiral Au(I) catalysts. This ee could be improved by using AgNTf2 as a silver salt (up to 94%). As shown in the Scheme 88, a great variety of dienes participate in this process, leading to the desired cycloadducts in moderate to good yields, excellent ee’s and good diastereoselectivities. A remarkable example of the robustness of this method is illustrated in the cycloaddition of 60c with 1-phenyl-4-methyl-1,3-butadiene, which provided the cyclohexenyl adduct, including three new stereogenic centers with complete regioand diastereoselectivity as well as with an excellent 91% ee (Scheme 88).148 148 Francos, J.; Grande-Carmona, F.; Faustino, H.; Iglesias-Sigüenza, J.; Díez, E.; Alonso, I.; Fernández, R.; Lassaletta, J. M.; López, F.; Mascareñas, J. L. J. Am. Chem. Soc. 2012, 134, 14322–14325. Enantioselective version 89 Scheme 88 – Scope of the Au(I)-catalyzed asymmetric intermolecular (4+2) cycloadditions of allenamides and dienes. The X-ray structures of of the major enateomer of 94a (Figure 5, left) show the S configuration for the stereogenic center. Furtermore the X-ray structures of complex (R)- Au40 (Figure 5, right) was used for the assignment of the absolute configuration of the chiral axis. The analysis of these structures confirmed that there might be substantial differences in the accessibility of either prochiral face of the allyl-cation gold intermediate that is presumably formed by activation of the allenamide.146 Figure 5 – Right, X-ray structure of (R)-Au40. H-atoms are omitted for clarity. Left, X-Ray structure of 94a. . 146 Montserrat, S.; Faustino, H.; Lledós, A.; Mascareñas, J. L.; López, F.; Ujaque, G. Chem. Eur. J. 2013, 19, 15248–15260. Chapter I – (4+2) cycloadditions - Conclusion 90 Shortly after our publication on the Au(I)-catalyzed intermolecular (4+2) cycloadditions of allenamides,150 a related article by A. Goeke appeared in the literature. This work describes a cationic gold(I)-catalyzed intermolecular (4+2) cycloaddition between dienes and allenyl ethers 95.151 The scope of the reaction with respect to the allenyl ethers is quite narrow, and for instance the reactivity of substituted allenes is not described. The reported scope for dienes is also limited, with only three cyclopentadienes and two acyclic dienes tested. The reaction has an excellent Z selectivity for all dienes (99:1 or higher), except for the unsubstituted cyclopentadiene (from 77:23 to 99:1). Therefore it seems that the allenamides, probably owing to presenting a more equilibrated reactivity, provide much better results. Scheme 89 - Au(I)-catalyzed intermolecular (4+2) cycloaddition between dienes and allenyl ethers. Based on DFT calculations the authors proposed that the cycloaddition occurs through an initial coordination of the gold catalyst to the allenyl ether to generate a zwitterionic metal intermediate of type XXXIX. This species undergo a (4+2) concerted cycloaddition with the diene, directly leading to the observed carbocycles (96). Depending on the conformation of species XXXIX, two different transition states (TS1 and TS2), respectively leading to the Z and E isomers, were identified. Transition state TS1, leading to the Z isomer turned out to be more favorable, by 2.0 Kcal.mol-1, in qualitative agreement with Z-selectivity observed with acyclic dienes (Scheme 90). 150 Faustino, H.; López, F.; Castedo, L.; Mascareñas, J. L. Chem. Sci. 2011, 2, 633-637. 151 Wang, G.; Zou, Y.; Li, Z.; Wang, Q.; Goeke, A. Adv. Synth. Catal. 2011, 353, 550–556. 4 4. . S Su ub bs se eq qu ue en nt t w wo or rk k b by y o ot th he er r a au ut th ho or rs s Enantioselective version 91 Scheme 90 – Proposed mechanism for the Au(I)-catalyzed intermolecular (4+2) 5 5. . C Co on nc cl lu us si io on n In conclusion, we have developed a new Au(I)-catalyzed (4+2) cycloaddition reaction between a variety of conjugated dienes and allenamides. For the racemic version, AuCl turned out to be a more selective catalyst, however in the cases where AuCl was less active, the catalytic system [IPrAuCl]/AgSbF6 was a good alternative. The method provides synthetically appealing cyclohexene derivatives in a highly or completely selective manner and shows a wide scope and generality. Experimental data and computational calculations showed that the mechanism of the reaction can diverge depending on the nature of the diene and the type of the gold catalyst. In reactions catalyzed by AuCl, electron-neutral dienes favored a concerted (4+3) cycloaddition followed by a ring contraction event, whereas electron-rich dienes preferred a stepwise cationic pathway to give the same type of formal (4+2) products. On the other hand, the theoretical data suggests that by using a cationic gold catalyst, such as [IPrAuCl]/AgSbF6, the mechanism involves a direct (4+2) cycloaddition between the diene and the gold-activated allenamide. Finally, in a separated record, the first examples of a highly enantioselective version of this process were described, which also represents the first asymmetric intermolecular (4+2) cycloaddition promoted by a chiral carbophilic metal complex. The success in the asymmetric induction relies on the development of a novel class of designed Nheterocyclic carbene ligands (developed by Lassaleta and Fernandez’s group), featuring a triazole unit embedded in a rigid axially chiral cyclic frame. C Ch ha ap pt te er r I II I – – G Go ol ld d( (I I) )- -C Ca at ta al ly yz ze ed d I In nt te er rm mo ol le ec cu ul la ar r ( (2 2+ +2 2) ) C Cy yc cl lo oa ad dd di it ti io on ns s b be et tw we ee en n A Al ll le en na am mi id de es s a an nd d a al lk ke en ne es s Objective - Foreword 95 In the previous chapter we described the first gold-catalyzed intermolecular cycloaddition of non-activated 1,3-dienes (4C) and allenamides (2C). In some cases a cyclobutane side product, resulting from a (2+2) cycloaddition of the allenamide with one of the double bonds of the diene was also observed. Given the synthetic and structural relevance of cyclobutane rings we decided to explore the feasibility of achieving the intermolecular (2+2) process in a selective manner. In case of success this methodology might represent a rapid and simple manner to construct highly functionalized cyclobutanes. Scheme 91 - (2+2) cycloaddition. 1 1. . O Ob bj je ec ct ti iv v e e Chapter II – (2+2) cycloadditions 96 Cyclobutanes are widely spread among natural and biologically active products, such as antibiotics, terpenes, steroids, fatty acids, or cyctotoxic to cancer cells.152 In many cases they constitute the sole ring of the product, while in other they are fused to other cycles. Owing to their intrinsic strain, the stereoselective assembly of cyclobutane rings, particularly those which present several substitutents, is challenging.153 The main strategies for the formation of the four-carbon ring system involve (2+2) cycloadditions, 1,4-cyclizations of acyclic precursors or ring expansion of cyclopropanes.153,154 The ring expansion methodology needs a previous assembly of the required cyclopropane precursors, which necessarily involves the introduction of additional steps in the synthetic process. In the context of gold catalysis, it is interesting to comment the work by Toste and co-workers on the ring expansion of 1-allenylcyclopropanols like 97 to cyclobutanones in the presence of chiral gold-phosphine complexes.155 The method provides synthetically valuable cyclobutanones of type 98, with a vinyl-substituted quaternary stereogenic center in high enantioselectivities and yields. The authors proposed a mechanism involving a initial external coordination of the Au(I) complex to the allene, followed by a ring expansion that results in the formation of cationic vinylgold(I) species XL. A subsequent protodemetalation liberates the catalyst and releases the product (Scheme 92). 152 a) Sergeiko, A.; Poroikov, V. V; Hanus, L. O.; Dembitsky, V. M. Open Med. Chem. J. 2008, 2, 26–37. b) Dembitsky, V. M. J. Nat. Med. 2008, 62, 1–33. c) Hansen, T.; Strenstrøm, Y. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; Elsevier Science Ltd, 2001; pp. 1–38. d) Terpenes; Breitmaier, E., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2006. 153 a) The Chemistry of Cyclobutanes; Rappoport, Z.; Liebman, J. F., Eds.; Patai Series: The Chemistry of Functional Groups; John Wiley & Sons, Ltd: Chichester, UK, 2005. b) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485–1537. c) Mack, D. J.; Njardarson, J. T. ACS Catal. 2013, 3, 272–286. d) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chemie Int. Ed. 2011, 50, 7740–7752. 154 a) Secci, F.; Frongia, A.; Piras, P. P. Molecules 2013, 18, 15541–15572. b) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1483. 155 Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 9178–9179. Previously the same group had reported a related rearrangement of 1-alkynylcyclopropanols: Markham, J. P.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 9708– 9709. 2 2. . C Cy yc cl lo ob bu ut ta an ne es s: : r re el le ev va an nc ce e a an nd d s sy yn nt th he et ti ic c a ac cc ce es ss si ib bi il li it t y y Foreword 97 Scheme 92 - Gold(I)-catalyzed ring expansion of a allenylcyclopropanol. Probably the most attractive method to make a cyclobutane ring relies on the use of a (2+2) cycloaddition, since two C−C bonds and up to four stereogenic centers can be formed in a single step, and the precursors can be simple alkenes or derivatives. These reactions can be thermal, photochemical or promoted by metal catalysts. While thermal processes are relatively scarce, (2+2) photochemical cycloaddions have been widely used, but they are limited to specific type of activated alkenyl precursors, and only work efficiently for homodimerization processes. Therefore there is a great interest on the use of transition metals to induce new type of catalytic (2+2) cycloadditions that can have a much larger scope than the thermal or the photochemical processes. Some succesful metal catalyzed (2+2) cycloadditions require that both reacting partners are tethered, and therefore the reaction generates fused cyclobutanes, such as the (2+2) annulations of propargylic indole-3-acetates catalyzed by Ph3PAuCl/AgSbF6 (Scheme 28, page 23),57 or the intramolecular (2+2) cycloadditions of enynes catalyzed by a gold (I) phosphine catalyst (Scheme 20, page 19).47,48 Allenes have also been used as reaction partners in metal catalyzed intramolecular reactions.156156,41 For instance, our group, in collabration with M. A. Esteruelas, has developed a fully diastereoselective (2+2) cycloaddition of allenenes or allenedienes (99).157 The proposed mechanism, supported with DFT calculations involves the participation of a complex like XLI, which evolves into the ruthenabicycle XLII by oxidative cyclometalation. A  to -allyl isomerization affords XLIII, which eventually afford the bicyclo[3.2.0]heptane products like 100. 57 Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804–16805. 47 Nieto-Oberhuber, C.; López, S.; Muñoz, M. P.; Cárdenas, D. J.; Buñuel, E.; Nevado, C.; Echavarren, A. M. Angew. Chemie Int. Ed. 2005, 44, 6146–6148 48 Nieto-Oberhuber, C.; Pérez-Galan, P.; Herrero-Gómez, E.; Lauterbach, T.; Rodríguez, C.; López, S.; Bour, C.; Rosellón, A.; Cardenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2008, 130, 269–279. 156 Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Soc. Rev. 2010, 39, 783–816. 41 Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49–92. 157 Gulías, M.; Collado, A.; Trillo, B.; López, F.; Oñate, E.; Esteruelas, M. A; Mascareñas, J. L. J. Am. Chem. Soc. 2011, 133, 7660–7663. On this basis, and considering the synthetic and medicinal relevance of the cyclobutane framework,[11] we decided to specifically pursue the development of a gold-catalyzed intermolecular [2 + 2]cycloaddition.[12] Herein, we demonstrate that the allenamide 1participates in a variety of [2 + 2]cycloadditions with different type of alkenes, in particular with enamides and styrene derivatives, to provide excellent yields of [2 + 2]adducts of type 6, with complete regio-, chemoand stereoselectivity. Our technology represents a significant addition to the armoury of catalytic cycloaddition methods and provides a particularly practical, powerful and versatile manner to construct highly functionalized cyclobutanes. In order to assess the viability of a robust and selective [2 + 2]process, we decided to check the reaction conditions using as cycloaddition partners the allenACHTUNGTRENNUNGamide 1and a challenging 1,2-disubstituted alkene, namely trans-methylstyrene 5a (Table 1). Unfortunately, using the optimal conditions developed for the [4 + 2]cycloaddition, we observed the formation of a relatively complex mixture of products (Table 1, entries 1 and 2). Nonetheless, in this mixture we could identify traces of the desired [2 + 2]adduct 6a, together with the homodimer 7and the acyclic hydroalkenylation product 8a.[13] The picolinic acid goldACHTUNGTRENNUNG(III) derivative Au3 or the biaryl phosphine-based catalyst Au4/ AgSbF6, also failed to give the desired adduct, but selectively produced the allene homodimer 7in 64% and 34% yields, respectively (Table 1, entries 3 and 4).[14] Conversely, the p-acidic cationic phosphite gold(I) catalyst Au2/AgSbF6selectively provided the desired [2 + 2]cycloadduct 6a in a moderate 51% yield (Table 1, entry 5). Gratifyingly, running the reaction in the presence of 4  molecular sieves, and adding the allenamide to the reaction mixture over a period of one hour, led to a significant increase in the efficiency of the process, which now provided 6a in a good 80% yield (Table 1, entry 6). Moreover, the catalyst loading could be reduced without affecting the rate and efficiency of the reaction (Table 1, entry 7). It is important to note that the cycloaddition process took place with complete selectivity, since no other regioor stereoisomers could be detected by 1H NMR analysis of the crude reaction mixtures. Once having established an optimum catalytic system, the versatility and scope of the process was evaluated. As shown in Scheme 2, allenamide 1also undergoes the cycloaddition reaction with styrene to provide, after just 5 min, the corresponding ACHTUNGTRENNUNG[2 + 2]adduct 6b in 81% yield. Methyl substituents at the para,meta, and ortho positions of the phenyl ring of 5were perfectly tolerated, so the corresponding ACHTUNGTRENNUNG[2 + 2]adducts (6c–6e) could be isolated in good to excellent yields (80–96%). The presence of a bromine atom at the aromatic ring is also compatible with the Table 1. Preliminary screening of catalytic activity between 1and 5a.[a] Entry [Au] Temperature [ 8 C] 6a ([%] yield) 7([%] yield) 8a ([%] yield) 1 AuCl r.t. – – – 2Au1/AgSbF615 – – – 3Au3 r.t. 4 64 8 4Au4/AgSbF65340 5Au2/AgSbF615 51 0 0 6[b] Au2/AgSbF615 80 0 0 7[b,c] Au2/AgSbF615 79 0 0 [a] Allene 1(1 equiv.) was added dropwise to a mixture of 5a (3 equiv.) and the gold(I) catalyst (5 mol%) in CH2Cl2(0.1M) at 15 8 C, unless otherwise noted; >99% conversions (1H NMR). Yields indicated correspond to isolated products. [b] Allenamide 1was added dropwise over 1 h. [c] Reaction carried out with 2 mol% catalyst. Adv. Synth. Catal. 2012,354, 1658 –1664  2012 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim asc.wiley-vch.de 1659 Gold(I)-Catalyzed Intermolecular [2 + 2]Cycloadditions between Allenamides and Alkenes reaction conditions, although the adduct 6f was isolated in a modest 42% yield. Importantly, the cycloaddition also proceeded with 1,1-disubstituted alkenes such as 1-phenyl-1-cyclohexene and a-methyl styrene to selectively afford, in 74 and 77% yields, the [2 + 2]cycloadducts 6g and 6h, which incorporate one quaternary stereocenter. Interestingly, the cycloaddition with the cis-styrene (Z)-5a led to a 15% yield of a 1:1.2 mixture of 6a and its syn isomer 6a ’ .[15] However, the cycloaddition with 1Hindene provided the [2 + 2]adduct 6i in an excellent 82% yield. The stereochemical identity of all these adducts (6a–6i) was determined by NMR analysis. Additionally, the structure of 6a and 6i could be further confirmed by X-ray diffraction analysis (Figure 1).[16] The requirement of an aromatic substituent at the alkene was next investigated. Initially, we tested the feasibility of the cycloaddition of 1with methylenecyclohexene (Table 2, entry 1). Unfortunately, although the desired cycloadduct 6j was detected, the major product of the reaction was the acyclic compound 8j, formally resulting from the hydrofunctionalization of the allenamide unit with the alkene.[13] Both 6j and 8j were isolated as an inseparable 1:6 mixture in a global 78% yield. The observation of allenamide cyclodimerization side reactions (to 7) suggested the possibility of using enamides as alkene components. Gratifyingly, enamides 5k–5n are excellent cycloaddition partners, providing the corresponding cyclobutanic adducts with complete selectivity and excellent yields (entries 2– 7).[17] Remarkably, as can be deduced from entries 3– 6, both (E) and (Z) isomers of enamides 5l and 5m provided, with comparable efficiencies, a single stereoisomer of the cycloadducts 6l and 6m, both featuring a trans disposition of the methyl and carbamoyl groups. These results clearly point out to a reaction mechanism involving carbocationic intermediates, as this could explain the observed loss of stereochemical information of the starting Z-enamides. Finally, the phenylenamide derivative 5n also participated in the reaction, leading to cycloadduct 6n, which was obtained with complete regioand stereoselectivity and good yield (entry 7). Scheme 2. ACHTUNGTRENNUNG[2 + 2]Cycloaddition of allenamide 1and styrene derivatives. Figure 1. X-ray structures of adducts 6a and 6i.[16] 1660 asc.wiley-vch.de  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2012,354, 1658– 1664 COMMUNICATIONS Hlio Faustino et al. It was recently reported that indoles react with alACHTUNGTRENNUNGlenamides such as 1in the presence of [Ph3PAu] + complexes to provide hydrofunctionalization products of type 8o and p.[13b] In consonance, under our catalytic conditions, indole 5o reacted to provide the hydrofunctionalization product 8o in 75% yield. However, the reaction of its N-Boc analogue 5p afforded a low but promising 33% yield of the desired [2 + 2]cycloadduct 6p. On the other hand, the reaction with a cyclic enamide such as 5q proceeded with excellent yield Table 2. Scope of the cycloaddition with other alkenes.[a] Entry Alkene 5Products Yield [%][b] 15j 6j + 8j:78 25k 6k:76 3(E)-5l 6l:91 4(Z)-5l 6l:96 5(E)-5m 6m:73 6(Z)-5m 6m:71 75n 6n:78 85o,R=H6o:0;8o:75 95p,R=Boc 6p:33;8p:21 10 5q 6q:94 [a] Allene 1(1 equiv.) was added dropwise over 1 h to a mixture of 5(3 equiv.) and the gold(I) catalyst (2 mol%) in CH2Cl2 (0.1M) at 15 8 C, unless otherwise noted; >99% conversions (1H NMR). [b] Isolated yields. Adv. Synth. Catal. 2012,354, 1658 –1664  2012 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim asc.wiley-vch.de 1661 Gold(I)-Catalyzed Intermolecular [2 + 2]Cycloadditions between Allenamides and Alkenes and complete selectivity to provide the 4,6-fused bicyclic system 6q in 94% yield. The stereochemical assignment of 6k as well as that of 6q could be successfully confirmed by X-ray analysis (Figure 2).[18] From a mechanistic perspective the reaction might proceed through a stepwise cationic pathway such as that shown in Scheme 3, at least in the case of the enamide partners. Thus, activation of the allene by the Au catalyst would afford an Au-allyl cation species of type I.[3,4,7] Nucleophilic intermolecular interception of Iby the alkene would provide a second cationic intermediate II. This would be the regioselectivity-determining step, with the formation of the more stabilized bencylic or imonium cation being favoured. At this point, rotation around the sigma CC bond results in the loss of the stereochemical information coming from the alkene. Finally, a ring closing process through attack of the vinyl gold species to the stabilized cation, and elimination of the Au complex, would yield the final [2 + 2] adduct of type 6. Alternatively, when the metal allyl cation intermediate Iis attacked by another unit of allenamide 1, a second cationic intermediate of type III could be formed. After a ring closing process, this intermediate could give rise the homodimer adduct 7, observed in certain cases. We are currently further investigating the mechanistic aspects of the cycloaddition by theoretical and experimental means, and seeking an explanation for the different behaviour of (Z) and (E)-5a. In conclusion, we have developed an efficient catalytic [2 + 2]cycloaddition methodology that provides synthetically appealing cyclobutane derivatives in a highly or completely selective manner. Work to deFigure 2. X-ray structures of adducts 6k and 6q.[18] Scheme 3. Mechanistic rationale for the [2 + 2]cycloadditions of allenamide 1and alkenes. 1662 asc.wiley-vch.de  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2012,354, 1658– 1664 COMMUNICATIONS Hlio Faustino et al. velop enantioselective variants and to gain a deeper mechanistic understanding is underway. Experimental Section Representative Procedure for the [2 + 2]Cycloaddition of 1 with 5a To a cooled solution (15 8 C) of trans-b-methylstyrene (5a, 162 mL, 1.25 mmol), AgSbF6(2.86 mg, 8.31 mmol) and Au2 (7.31 mg, 8.31 mmol) in a dried Schlenk tube, was slowly added a solution of allenamide 1(52 mg, 0.426 mmol) in CH2Cl2(1 mL), over 1 hour. The mixture was additionally stirred at 15 8 C for 5 min and filtered through a short pad of florisil, eluting with Et2O. The solvent was evaporated and the crude mixture was chromatographed to give 6a; yield: 80 mg (0.30 mmol, 79%). Acknowledgements This work was supported by the Spanish MEC (SAF200761015, SAF2010-20822-C02) and Consolider-Ingenio 2010 (CSD2007-00006), the ERDF, CSIC and Xunta de Galicia (INCITE09 209 122 PR and GRC2010/12). HF and PB acknowledge the Fundażo para a CiÞncia e a Tecnologia-Portugal for a PhD Grant SFRH/BD/60214/2009 and the Spanish MICINN for a FPI fellowship, respectively. Ana Gimeno is gratefully acknowledged for preliminary experiments with other type of alkenes. Johnson-Matthey is acknowledged for a gift of metals. References [1] For recent reviews, see: a) A. S. K. Hashmi, Chem. Rev. 2007,107, 3180–3211; b) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008,108, 3351–3378; c) A. Arcadi, Chem. Rev. 2008,108, 3266–3325; d) A. Frstner, Chem. Soc. Rev. 2009,38, 3208–3221; e) A. Corma, A. Leyva-Prez, M. J. Sabater, Chem. Rev. 2011,111, 1657–1712; f) E. Jimnez-NfflÇez, A. M. Echavarren, Chem. Rev. 2008,108, 3326–3350; g) N. Krause, C. Winter, Chem. Rev. 2011,111, 1994–2009; h) B.-L. Lu, L. Dai, M. Shi, Chem. Soc. Rev. 2012,41, 3318–3339. [2] For reviews including gold-catalyzed cycloadditions of allenes, see: a) F. Lpez, J. L. MascareÇas, Beilstein J. Org. 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T. Craft, L. N. Bailey, K. Kirschbaum, Chem. Eur. J. 2010,16, 639–644; f) S. Montserrat, G. Ujaque, F. Lpez, J. L. MascareÇas, A. Lleds, Top. Curr. Chem. 2011,302, 225–248; g) S. Montserrat, I. Alonso, F. Lpez, J. L. MascareÇas, A. Lleds, G. Ujaque, Dalton Trans. 2011,40, 11095–11105; h) I. Fernndez, J. L. MascareÇas, Org. Biomol. Chem. 2012,10, 699–704; i) I. Fernndez, F. P. Cossio, A. de Czar, A. Lleds, J. L. MascareÇas, Chem. Eur. J. 2010,16, 12147–12157; j) see also ref.[4a] [4] For intramolecular [4 + 2] examples, see: a) P. Maulen, R. M. Zeldin, A. Z. Gonzlez, F. D. Toste, J. Am. Chem. Soc. 2009,131, 6348–6349; b) I. Alonso, B. Trillo, F. Lpez, S. Montserrat, G. Ujaque, L. Castedo, A. Lleds, J. L. MascareÇas, J. Am. Chem. Soc. 2009, 131, 13020–13030; c) A. Z. Gonzlez, F. D. Toste, Org. Lett. 2010,12, 200–203; d) D. Benitez, E. Tkatchouk, A. Z. Gonzlez, W. A. Goddard, F. D. Toste, Org. Lett. 2009,11, 4798–4801. [5] For intramolecular [3 + 2] examples, see: a) X. Huang, L. Zhang, J. Am. Chem. Soc. 2007,129, 6398–6399; b) A. Buzas, F. Gagosz, J. Am. Chem. Soc. 2006,128, 12614–12615. For a Pt-catalyzed intramolecular [3 + 2]cycloaddition, see: c) G. Zhang, V. J. Catalano, L. Zhang, J. Am. Chem. Soc. 2007,129, 11358–11359. [6] For intramolecular [2 + 2] examples, see: a) M. R. Luzung, P. Maulen, F. D. Toste, J. Am. Chem. Soc. 2007,129, 12402–12403; b) L. Zhang, J. Am. Chem. Soc. 2005,127, 16804–16805; c) H. Teller, S. Flugge, R. Goddard, A. Frstner, Angew. Chem. 2010,122, 1993– 1997; Angew. Chem. Int. Ed. 2010,49, 1949–1953; d) M. Alcarazo, T. Stork, A. Anoop, W. Thiel, A. Frstner, Angew. Chem. 2010,122, 2596–2600; Angew. Chem. Int. Ed. 2010,49, 2542–2546; e) A. Z. Gonzlez, D. Benitez, E. Tkatchouk, W. A. Goddard, F. D. Toste, J. Am. Chem. Soc. 2011,133, 5500–5507. [7] a) H. Faustino, F. Lpez, L. Castedo, J. L. MascareÇas, Chem. Sci. 2011,2, 633–637. For related [4 + 2]cycloadditions with allenyl ethers, see: b) G. Wang, Y. Zou, Z. Li, Q. Wang, A. Goeke. Adv. Synth. Catal. 2011,353, 550–556. For a thermal [4 + 2]cycloaddition of tosyl allenamides and dienes, see: c) A. G. Lohse, R. P. Hsung, Org. Lett. 2009,11, 3430–3433. [8] For a relevant intermolecular platinum-catalyzed [3 + 2]cycloaddition between allenyl silyl ethers and alkenes, in which [2 + 2]adducts were also detected as minor side products, see: H. Kusama, M. Ebisawa, H. Funami, N. Iwasawa, J. Am. Chem. Soc. 2009,131, 16352–16353. [9] For a review on the synthetic utility of allenamides, see: L.-L. Wei, H. Xiong, R. P. Hsung, Acc. Chem. Res. 2003,36, 773. [10] For other types of [2 + 2]cycloadditions employing different types of allenamides, see: a) M. Kimura, Y. Horino, Y. Wakamiya, T. Okayima, Y. Tamaru, J. Am. Chem. Soc. 1997,119, 10869. For a relevant gold-cataAdv. Synth. Catal. 2012,354, 1658 –1664  2012 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim asc.wiley-vch.de 1663 Gold(I)-Catalyzed Intermolecular [2 + 2]Cycloadditions between Allenamides and Alkenes lyzed [2 + 2]cycloaddition of alkynes and alkenes, see: b) V. Lpez-Carrillo, A. M. Echavarren J. Am. Chem. Soc. 2010,132, 9292–9294. For a review on [2 + 2]cycloadditions of allenes, see: c) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Soc. Rev. 2010,39, 783–816. For a[2 + 2]cycloaddition of allenes to alkenes promoted by Ru complexes, see: d) M. Gulas, A. Collado, B. Trillo, F. Lpez, E. OÇate, E.; M. A. Esteruelas, J. L. MascareÇas J. Am. Chem. Soc. 2011,133, 7660–7663. [11] a) J. C. Namyslo, D. E. Kaufmann, Chem. Rev. 2003, 103, 1485–1538. For a review on bioactive cyclobutane alkaloids, see: b) V. M. Dembitsky, J. Nat. Med. 2008, 62, 1–33. [12] While refining this work, Chen et al. reported a goldcatalyzed intermolecular cycloaddition of tosyl allenamides. This publication urged us to disclose our own results in this area, see: X.-X. Li, L.-L. Zhu, W. Zhou, Z. Chen, Org. Lett. 2011,14, 436–439. [13] The gold-catalyzed hydrofunctionalization of allenamides with indoles, aromatic nucleophiles or amines provides products related to 8: a) A. W. Hill, M. R. J. Elsegood, M. C. Kimber, J. Org. Chem. 2010,75, 5406; b) M. C. Kimber, Org. Lett. 2010,12, 1128. [14] ACHTUNGTRENNUNG[2 + 2]Homodimer 7could be further characterized by X-ray analysis. CCDC 863035 contains the supplementary crystallographic data for this compound. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [15] This reaction provided a complex mixture of products together with a 15% yield of a 1:1.2 mixture of 6a and 6a ’ . [16] CCDC 863034 (6a) and CCDC 863036 (6i) contain supplementary crystallographic data for these compounds. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. [17] Cycloaddition of allenamide 5k could be carried out using 1.5 equiv. of enamide, albeit 6k is isolated in a slightly lower yield (56%). Additionally, performing the addition of the enamide in one portion did not significantly affect the efficiency of the reaction, since 6k could be isolated in a comparable 63% yield. [18] CCDC 863038 (6k) and CCDC 863037 (6q) contain supplementary crystallographic data for these compounds. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 1664 asc.wiley-vch.de  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2012,354, 1658– 1664 COMMUNICATIONS Hlio Faustino et al. Addendum 111 Considering the importance of highly substituted cyclobutanes we also attempted the cycloaddition of an allenamide equipped with a methyl group at the distal position (60c) with trans-  -methylstyrene. Unfortunately this reaction does not give the desired product (107). However the dimerization (2+2) cycloadduct 108, which itself is a cyclobutane substituted in all carbons of the cycle was obtained in a 52% yield and a dr = 1.25:1 (Scheme 98). Scheme 98 Despite the significance of the previous result, a (2+2) cycloaddition between 2 different components to obtain a tetrasubtituted cyclobutane could be more interesting. Encouraged by the previous result, we use the  -subtituted enamide 109 and the - methyl-allenamide 60d in this process in the presence the benzonitrile stabilized cationic Au-Complex Au43. Fortunately these components afford the desired tetrasubstitued cyclobutane 107b in a 46% yield (dr = 2.4:1), alongside with the allenamide dimer 108 in a 16% yield (Scheme 99). Scheme 99 4 4. . A Ad dd de en nd du u m m Chapter II – (2+2) cycloadditions 112 While the previous manuscript was in preparation,162 a related work by Z. Chen appeared in the literature.163 This work describes the gold catalyzed intermolecular (2+2) cycloaddition of allenamides with electron-rich olefins, such as vinyl ethers/amides and electron-rich styrenes to afford cyclobutanes of type 110. Products coming from homodimerization processes (111) were also included in the discussion. As in our case, the cycloaddition was completely regioand stereoselective for most cases, although - or -substituted allenamides did not give the desired products. NRTs R1 R2 NRTs NRTs •NRTs R1 R2 [Au]/AgSbF6(5%) MS4Å,CH2Cl2,rt N O CH2-p-C6H4F Ts 87%1 N CH2-p-C6H4F Ts NBoc 87%1 N CH2-p-C6H4F Ts 69%1 N CH2-p-C6H4F Ts 84%1 syn/anti =1/2 OEt Me N CH2-p-C6H4F Ts 85%1 Me OMe N NTs nBu Ts nBu 76%2 N NTs Bn Ts Bn 67%2 N NTs Ph Ts Ph 67%2 PAuCl tBu tBu Au44 1-[Au]= ;2- [Au] = PPh3AuCl and without the addition of alkene 110 111 OMe Scheme 100 – Chen’s gold catalyzed (2+2) cycloaddition of allenamides with electron-rich olefins, and allenamide dimerization. Before submitting our publication we became aware that the group of J. M. González was also working in a (2+2) intermolecular cycloaddition of enol ethers with Nallenylsulfonamides. Despite the similitude of the reaction, the scope of allenes and alkenes in this report is complementary to ours, and for this reason both papers were published as “back to back” articles.164 Although many of the examples described by the group of González overlap with those of Zili Chen, the use of a different catalyst, in this case a gold(I)-phosphite Au43 allowed to decrease the catalyst loading to an impressive 0.5% and more importantly, a -ethyl-allenamide was also tolerated and generate a tetrasubtituted cycloadduct (Scheme 101). 162 Faustino, H.; Bernal, P.; Castedo, L.; López, F.; Mascareñas, J. L. Adv. Synth. Catal. 2012, 354, 1658–1664. 163 Li, X.-X.; Zhu, L.-L.; Zhou, W.; Chen, Z. Org. Lett. 2012, 14, 436–439. Correction: Li, X.-X.; Zhu, L.-L.; Zhou, W.; Chen, Z. Org. Lett. 2012, 14, 1185–1185. 164 Suárez-Pantiga, S.; Hernández-Díaz, C.; Piedrafita, M.; Rubio, E.; González, J. M. Adv. Synth. Catal. 2012, 354, 1651–1657. 5 5. . S Si im mu ul lt ta an ne eo ou us s a an nd d s su ub bs se eq qu ue en nt t r re el la at te ed d w wo or rk k b by y o ot th he er r g gr ro ou up ps s Related works 113 Scheme 101 - González Phosphite-Gold(I)-catalyzed (2+2) intermolecular cycloaddition of enol ethers with N-allenylsulfonamides. More recently, J. M. González accomplished the enantioselective version of these type annulations between sulfonyl allenamides and vinylarenes, providing optically active cyclobutanes.165 Several chiral phosphoramidite gold complexes derived from Siphos, Binol and Vanol gave excellent enantioselectivities. However the performance of  - substituted styrenes, enamides or enol ethers and of -substituted allenamides was not commented in this article. Importantly, the method also allowed the preparation of cyclobutanes containing challenging quaternary carbon centers (Scheme 102). Scheme 102 - Enantioselective Gold(I)-catalyzed synthesis of cyclobutane derivatives. Z. Chen has further explored the potential of allenamides in Au(I) catalysis and used them as two carbon atom component in (3+2) cycloadditions with azomethine imines or nitrones providing the first examples of the assembly of heterocycles using gold catalyzed intermolecular cycloadditions of allenes.166,167 The intermolecular (3+2) cycloaddition of azomethine imines with allenes was already known by thermal or Phosphine-catalyzed proceses,168 however the regiochemistry in 165 Suárez-Pantiga, S.; Hernández-Díaz, C.; Rubio, E.; González, J. M. Angew. Chemie Int. Ed. 2012, 11552–11555. 166 Zhou, W.; Li, X.-X.; Li, G.-H.; Wu, Y.; Chen, Z. Chem. Commun. 2013, 49, 3552–3554. 167 Li, G.-H.; Zhou, W.; Li, X.-X.; Bi, Q.-W.; Wang, Z.; Zhao, Z.-G.; Hu, W.-X.; Chen, Z. Chem. Commun. 2013, 49, 4770–4772. 168 a) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Guo, H.; Kwon, O. J. Am. Chem. Soc. 2011, 133, 13337–48. b) Jing, C.; Na, R.; Wang, B.; Liu, H.; Zhang, L.; Liu, J.; Wang, M.; Zhong, J.; Kwon, O.; Guo, H. Adv. Synth. Catal. 2012, 354, 1023–1034. c) Na, R.; Liu, H.; Li, Z.; Wang, B.; Liu, J.; Wang, M.-A.; Wang, M.; Zhong, J.; Guo, H. Tetrahedron 2012, 68, 2349–2356. Chapter III – Cascade cycloadditions 120 Assembling these medium-sized carbocycles, which are present in a large number of relevant products, continues to be a major challenge in organic synthesis.174,175 Indeed, despite the importance of this oxa-bridged medium-sized carbocycles, practical catalytic access to these carbocycles are extremely scarce.176 An attractive approach for the preparation of these systems involves cascade processes which generate several bonds in a single operational step.177 In 1987 G. A. Molander reported a versatile approach to oxabridged seven and eight membered rings involving the combination of dicarbonyl compounds (119) with 3-iodo2-[(trimethylsilyl)methyl]propene (118) as a trimethylenemethane dianion synthon.178 The process is promoted by SnF2, which generates the allylstannane from 118 (Scheme 106). Carbonyl allylation is then followed by hemiacetal formation and allylsilane cyclization, to provide the oxa-bridged carbocycles 120 in moderate to excellent yields. Albeit the method is interesting it needs stoichiometric reagents and is very poor from the atom economy point of view. 174 a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95–102. b) Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 2000, 3117–3125. 175 For a review on diverse methods for medium ring synthesis see: Molander, G. A. Acc. Chem. Res. 1998, 31, 603–609. 176 a) Molander, G. A. Acc. Chem. Res. 1998, 31, 603–609. b) López, F.; Mascareñas, J. L. Chem. Eur. J. 2007, 13, 2172–2178. 177 Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chemie Int. Ed. 2006, 45, 7134–7186. 178 a) Molander, G. A.; Shubert, D. C. J. Am. Chem. Soc. 1987, 109, 6877–6878. b) Later a related Indium-mediated annulation in aqueos medium was reported, see: Minehan, T.; Allatabakhsh, A.; Pham, M. Heterocycles 2007, 72, 115-122. Foreword 121 Scheme 106 – SnF2-promoted [m+n] annulations. As shown in the Scheme 14, page 14, interesting oxabridged cycloheptane derivatives, that allowed a relatively short synthesis of englerine A, 179 have been obtained by means of a gold-catalyzed cycloisomerization reaction of designed enynes with pendant carbonyl groups.30 C. H. Oh and S.-H. Han have shown that AuCl3 or gold nanoparticles efficiently promote the cyclization of 1,6-allenynebenzaldehyde 121 to produce oxabridged ketone 122 as product.180 The first step of the proposed mechanism consists of a nucleophilic attack of the aldehyde oxygen onto the activated triple bond, thus giving rise to a zwitterionic intermediate which rearranges into a oxabridged polycyclic carbene through a (3+2) dipolar cycloaddition. The latter undergoes the attack of water to afford compound 122 (Scheme 107). Scheme 107 – AuCl3 catalysed (3+2) dipolar cycloaddition of an 1,6-allenynebenzaldehyde. Oxabridged eight membered carbocycles were also prepared using gold catalysis. In 2010 R.-S. Liu reported a highly stereoselective Au-catalyzed synthesis of 9oxabicyclo[3.3.1]nona-4,7-dienes 124 from 1-oxo-4-oxy-5-ynes 123 and a vinyl ether.181 The proposed mechanism starts with an 6-exo-dig cyclization of the carbonyl moiety 179 Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chemie Int. Ed. 2010, 49, 3517–3519. 30 Jiménez-Núñez, E.; Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chemie 2006, 45, 5578–5581. 180 Gupta, A. K.; Rhim, C. Y.; Oh, C. H.; Mane, R. S.; Han, S.-H. Green Chem. 2006, 8, 25–28. 181 Teng, T.-M.; Das, A.; Huple, D. B.; Liu, R.-S. J. Am. Chem. Soc. 2010, 132, 12565–12567. Chapter III – Cascade cycloadditions 122 onto the alkyne affording the 1,4-dipole XLVII, which is in resonance with the goldcarbene intermediate XLVIII. A subsequent (3+2) cycloaddition between the carbonyl ylide XLVIII and an external olefin, followed by a ring expansion (1,2-alkyl migration) that is assisted by the MOM group generates the oxonium intermediate XLIX (Scheme 108). A final elimination process affords the oxacyclic product 124 and regenerates the catalyst. Scheme 108 - Synthesis of 9-oxabicyclo[3.3.1]nona-4,7-dienes from 1-oxo-4-oxy-5-ynes and a vinyl ether. Recently Z. Wang reported a Au-catalyzed intramolecular (4+2) cross-cycloaddition of alkynylcyclopropane ketones with carbonyl compounds.182 This method provides a stereoselective construction of oxa-bridged seven and eight membered carbocycles (126) fused with a furan ring from alkynylcyclopropane ketones with carbonyl compounds 125. The authors suggests that the gold complex promote the formation of a 1,4-dipole equivalent, that undergo a (4+2) annulation with the aldehyde. Scheme 109 - Au-catalyzed intramolecular (4+2) cross-cycloaddition of alkynylcyclopropane ketones with carbonyl compounds. All the above mentioned methods have been developed exclusively in a racemic fashion. 182 Bai, Y.; Tao, W.; Ren, J.; Wang, Z. Angew. Chemie Int. Ed. 2012, 51, 4112–4116. Foreword 123 There are some methods for the asymmetric preparation of 8-oxabicyclo[3.2.1]octanes based on the use of chiral-auxiliaries.183 One of the more efficient examples has been recently disclosed by T.-P. Loh and involves a cationic cascade cyclization reaction of alkenes-tethered acetals like 127 and silyl enol ethers in the presence of TiCl4.184 The acetal 127 derived from (2R,3R)-2,3-butanediol gave 128 with the highest enantioselectivity. The proposed mechanism consists of a Mukaiyama aldol reaction between the acetal and the silyl enol ether. Subsequently, the olefin attacks the silylated oxocarbenium via a transition state with the R1 and OTIPS groups adopt pseudoequatorial positions to yield the anti-configured product 128 (Scheme 110). O O TIPSO O OTIPS TiCl4(1.2 equiv.) CH2Cl2,-78ºC OTIPS RO H OTIPS H RO Ph Ph Ph Ph 128, 88%, 97% ee 127 H H Scheme 110 – TiCl4 promoted cationic cascade cyclization reaction of alkenes-tethered acetals and silyl enol ethers. With regard to catalytic asymmetric processes, in 2011 E. N. Jacobsen reported an interesting highly enantioselective of thiourea-catalyzed intramolecular cycloaddition of alkenes or allenes 129 to give seven membered oxabridged carbocycles like 130 (Scheme 111).185 A cooperative catalyst effect has been observed wherein the combination of both achiral (T1) and chiral (T2) thiourea catalysts lead to optimal results. The authors propose that the achiral thiourea T1 catalyst acts as a carboxylate-binding agent assisting in the benzoate abstraction. While the amine functionality of T2 binds to the substrate, simultaneously assisting oxidopyrylium formation and holding the substrate in the chiral catalyst environment. 183 For a review see: a) Hartung, I. V; Hoffmann, H. M. R. Angew. Chemie Int. Ed. 2004, 43, 1934–1949. For a review with examples based of asymmetric catalytic (4+3) cycloaddition reactions see: b) Harmata, M. Adv. Synth. Catal. 2006, 348, 2297–2306. 184 Li, B.; Zhao, Y.-J.; Lai, Y.-C.; Loh, T.-P. Angew. Chemie Int. Ed. 2012, 51, 8041–8045. 185 Burns, N. Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 14578–14581. Chapter III – Cascade cycloadditions 124 Scheme 111 - Dual thiourea catalyst system in intramolecular oxidopyrylium (5+2) cycloadditions. In 2010 N. Iwasawa reported a Pt-catalyzed asymmetric synthesis of 8oxabicyclo[3.2.1]octane derivatives 132, based on the (3+2)-cycloaddition between platinum-containing carbonyl ylides generated from acyclic ,-ynones 131 and vinyl ethers.186 The active chiral cationic catalyst was generated in situ from the addition of AgSbF6 to a PtCl2-L complex (Scheme 112). Scheme 112 – Enateoselective Pt-catalyzed 8-oxabicyclo[3.2.1]octane synthesis from ,-ynones. Another interesting method for the enantioselective preparation of oxabicyclo[3.2.1]octane derivatives reported by R. P. Hsung using allenamides and furans was mentioned previously (Scheme 70, page 47).124 In 2003 M. Harmata reported the first organocatalytic asymmetric (4+3) cycloaddition.187 The reaction of pentadienal 133 with 2,5-disubstituted furans in the presence of 20 mol% of the chiral amine catalyst and trifluoroacetic acid afforded the cycloadducts 134 with good yields and up to 89% enantiomeric excess. 186 a) Ishida, K.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2010, 132, 8842–8843. b) The racemic version of this reaction was previously reported, see: Kusama, H.; Ishida, K.; Funami, H.; Iwasawa, N. Angew. Chemie Int. Ed. 2008, 47, 4903– 4905. 124 Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50-51. 187 Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058–2059. Foreword 125 Scheme 113 - Intermolecular, organocatalytic asymmetric (4+3) cycloaddition. To the best of our knowledge, direct, catalytic, and enantioselective approaches to oxabridged eight membered rings are unknown. However, some enantioselective approaches based on two-step methods have been reported. In 2002 C.-M. Yu reported a very efficient method to prepare oxygen-bridged mediumsized carbocycles based on a Lewis acid catalyzed intramolecular allylsilane addition to a carbonium cation generated from a 1,5or 1,6-hydroxyketone derivative 135 (Scheme 114).188 The enantioenriched precursors 135 in the presence of of Sn(OTf)2 and Me3SiSPh led to the formation of the corresponding oxabridged systems 136 as sole products. Scheme 114 - Intramolecular allylic transfer reaction for the formation of 8 and 9 membered oxa-bridged carbocycles. In 2005 our group reported an asymmetric approach to the assembly of enantiopure, oxa-bridged, medium-sized carbocyclic systems from readily accessible 1-alkyn-3ketones (Scheme 115).189 The catalytic asymmetric hydrogen transfer reduction of ketones 137 with Noyori's ruthenium complex in iPrOH provided the desired alkynols 138 with excellent yields and ee. Treatment of the chiral alcohols with allyl ethyl ether in the presence of [CpRu(MeCN)3]PF6, followed by in situ acid-catalyzed acetalization with MeOH gave pyrans 139. Finally, FriedelCrafts cyclization of the acetals under SnCl4 promotion furnished the tricycles 140. 188 Yu, C.-M.; Lee, J.-Y.; So, B.; Hong, J. Angew. Chemie Int. Ed. 2002, 41, 161–163. 189 a) López, F.; Castedo, L.; Mascareñas, J. L. Org. Lett. 2005, 7, 287–290. For a related previous work see: b) López, F.; Castedo, L.; Mascareñas, J. L. J. Am. Chem. Soc. 2002, 124, 4218–4219. Chapter III – Cascade cycloadditions 126 Scheme 115 - Medium-sized carbocyclic systems from 1-alkyn-3-ketones. While catalytic asymmetric entries to oxabridged eigh membered rings are not known, related approaches to any type of eight-membered ring are also very scarce.190 In 2007 S. R. Gilbertson reported a Rh-catalyzed (4+2+2) cycloadditon of dienynes and terminal alkynes.191 They found that the cycloaddition reaction catalyzed by [Rh(nbd)Cl]2 and AgSbF6 in the presence of (S,S)-Me-DuPhos at 60 ºC gave the final cycloadducts in good to excellent yields. However, the highest enantioselectivity was 41% ee. Scheme 116 - Rh-catalyzed (4+2+2) cycloadditon of dienynes and terminal alkynes. F. D. Toste demonstrated that it is possible to assemble sevento nine-membered carbocycles using gold catalyzed olefin cyclopropanations.192 High enantioselectivities were achieved for sevenand eight-membered ring products employing chiral gold(I) complexes (Scheme 117). 190 For a review on transition-metal-catalyzed cycloadditions for the synthesis of eight-membered carbocycles see: Yu, Z.- X.; Wang, Y.; Wang, Y. Chem. Asian J. 2010, 5, 1072–1088. 191 a) DeBoef, B.; Counts, W. R.; Gilbertson, S. R. J. Org. Chem. 2007, 72, 799–804. b) Gilbertson, S. R.; DeBoef, B. J. Am. Chem. Soc. 2002, 124, 8784–8785. 192 Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056–2057. Foreword 127 Scheme 117 - Asymmetric synthesis of medium-sized rings by intramolecular Au(I)-catalyzed cyclopropanation. In summary, despite the importance of oxabridged medium size carbocycles, catalytic methods for their preparation are still scarce and require relatively long synthetic protocols. Furthermore, catalytic enantioselective approaches are only reported for the preparation of seven membered rings. For the asymmetric preparation of oxacyclic eight membered rings only chiral-auxiliary or chiral pool approaches have been reported. These precedents reinforce the relevance of developing new practical, rapid, efficient, versatile and if possible enantioselective methodologies to construct these frameworks. Faustino, H.; Alonso, I.; Mascareñas, J. L.; López, F. Angew. Chemie Int. Ed. 2013, 52, 6526– 6530. Author contributions J.L.M and F.L. directed and conceived the research. H.F. performed the screening of substrates and conditions and catalysts for the racemic version. I.A. performed the screening of chiral gold complexes and explored the manipulability of the oxa-bridged carbocycles. H.F. and I.A. prepared and explored the scope of the substrates. (In table 2 entries 1,5,6,8,9,10 and 12 by were performed by H.F. and 2,3,4,7,11 and 13 by I.A.. In scheme 3 products 6am, 6ap, 6aq, 6ar and 6bm by H.F. and products 6an and 6ao by I.A.. H.F. and I.A. prepared the subtrates.). F.L. and J.L wrote the manuscript with input from all authors. All authors discussed the results and revised the manuscript. 3 3. . A Ar rt ti ic cl le e 4 4 - - G Go ol ld d( (I I) )- -c ca at ta al ly yz ze ed d c ca as sc ca ad de e c cy yc cl lo oa ad dd di it ti io on ns s b be et tw we ee en n a al ll le en na am mi id de es s a an nd d c ca ar rb bo on ny yl l- -t te et th he er re ed d a al lk ke en ne es s: : a an n e en na an nt ti io os se el le ec ct ti iv ve e a ap pp pr ro oa ac ch h t to o o ox xa a- -b br ri id dg ge ed d m me ed di iu um m- -s si iz ze ed d c ca ar rb bo oc cy yc cl le es s. . Related works 137 4 4. . R Re el la at te ed d s si im mu ul lt ta an ne eo ou us s w wo or rk k b by y o ot th he er r a au ut th ho or rs s While preparing the above manuscript, a related paper by the group of A. M. Echavarren appeared in the literature.193 This article describes the intermolecular gold(I)-catalyzed reaction of terminal alkynes with oxoalkenes of type 115 in the presence of gold catalyst Au47, que contains a bulky biphenylphosphine ligand, to afford 8-oxabicyclo-[3.2.1]oct-3-enes 141. However, the technology is restricted to the use of arylalkynes. Methyl or phenyl groups were well tolerated at the -position of the alkene and in the ketone, however, aldehydes gave a modest 16% yield. The mechanistic proposal based on DFT calculations revealed a stepwise formation of the C-C and C-O bonds (Scheme 118). The nucleophilic attack of alkene 115 to complex L takes place with both regioand stereoselectively and forms intermediate LI. Regioselective attack of the carbonyl group at the most substituted position then leads to oxonium cation LII, which undergoes a Prins reaction to close the seven-membered ring. Finally, 141 is obtained by metal elimination. Scheme 118 - Intermolecular gold-catalyzed cycloaddition of alkynes with oxoalkenes. The only reported example with substituents at the -position of the alkene led to the 8cyclobutene 142 as the major product, along with 143 (Scheme 119). Oxoalkenes featuring longer carbon tethers that could eventually allow to prepare eight or ninemembered carbocycles were not reported. 193 Obradors, C.; Echavarren, A. M. Chem. Eur. J. 2013, 19, 3547–351. Chapter III – Cascade cycloadditions 138 Scheme 119 - Intermolecular gold-catalyzed cycloaddition of phenylacetylene with a  -subtitued alkene. Addendum – Multicomponent cascade cycloadditions - Foreword 139 5 5. .1 1 O Ob bj je ec ct ti iv ve e The aforementioned Au-catalyzed cycloadditions between allenamides and carbonyltethered alkenes suggest that this reaction proceed through a stepwise mechanism in which the cation in intermediate XLVI is intercepted by a carbonyl moiety (Scheme 120).194 Scheme 120 – Proposed mechanism for Au(I)-catalyzed cascade cycloadditions between allenamides and carbonyl-tethered alkenes. In light of this mechanism, we wondered whether the same reaction could be achieved in a fully intermolecular way, by using using external carbonyl derivatives. This strategy would constitute a very simple methodology for the assembly of tetrahydropyrans from commercial available alkenes, carbonyl derivatives and easy accessible allenamides that can be prepared on a multigram scale.110,111 Of course, getting all the components to react in a synchronized manner is not trivial. Scheme 121 - Proposed mechanism for Au-catalyzed multicomponent cycloaddition between allenamides, alkenes and aldehydes. 194 Faustino, H.; Alonso, I.; Mascareñas, J. L.; López, F. Angew. Chemie Int. Ed. 2013, 52, 6526–6530. 110 Wei, L.; Mulder, J. A.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459–466. 111 a) Tracey, M. R.; Grebe, T.; Mulder, J. A.; Hsung, R. P. Org. Synth. 2005, 81, 147–151. b) Xiong, H.; Tracey, M.; Grebe, T. Org. Synth. 2014, 91, 12–26. 5 5. . A Ad dd de en nd du um m: : G Go ol ld d( (I I) )- -c ca at ta al ly yz ze ed d m mu ul lt ti ic co om mp po on ne en nt t c ca as sc ca ad de e c cy yc cl lo oa ad dd di it ti io on n b be et tw we ee en n a al ll le en na am mi id de es s, , a al lk ke en ne es s a an nd d a al ld de eh hy yd de es s Chapter III – Cascade cycloadditions 140 The requirement for a high level of synchronization becomes evident when considering the possible side products that could arise from these components, such as allenamide dimers,162-165 hydrofuncionalization products,162,128,129 or (2+2) cycloaddition between the allene and the alkene (Scheme 122).162-165 Other competitive processes include a (2+2) cycloaddition with the aldehydes to give oxetanes or a carbocationic polymerization process.195 Scheme 122 - Possible secondary products for Au-catalyzed multicomponent cycloaddition between allenamides, alkenes and aldehydes. 5 5. .2 2 r re el le ev va an nc ce e o of f t th he e p py yr ra an ne e s sk ke el le et to on n Over the last few decades the number of biologically active natural products isolated which contain substituted tetratetrahydropyran units has increased dramatically. However, the study of their biological activity is oftentimes hampered by the lack of enough amounts of the natural products or their close derivatives.196 Some of these molecules have simple structures, such as Tubulexin A, a potential modulator of mitosis,197 (-)-Diospongin B with anti-osteoporotic activity,198 or (+)- and (-)- Centrolobines, with antiflammatory and antibacterial activities.199 Others are part of macrocycles, such as Leucascandrolide A, an extremely potent inhibitor of tumor cell proliferation and a antifungal,200 Phorboxazoles, which exhibit extraordinary cytotoxic activity,201 or Bryostatins, with anticancer activity (Scheme 123).202 162 Faustino, H.; Bernal, P.; Castedo, L.; López, F.; Mascareñas, J. L. Adv. Synth. Catal. 2012, 354, 1658–1664. 163 Li, X.-X.; Zhu, L.-L.; Zhou, W.; Chen, Z. Org. Lett. 2012, 14, 436–439. Correction: Li, X.-X.; Zhu, L.-L.; Zhou, W.; Chen, Z. Org. Lett. 2012, 14, 1185–1185. 164 Suárez-Pantiga, S.; Hernández-Díaz, C.; Piedrafita, M.; Rubio, E.; González, J. M. Adv. Synth. Catal. 2012, 354, 1651–1657 165 Suárez-Pantiga, S.; Hernández-Díaz, C.; Rubio, E.; González, J. M. Angew. Chemie Int. Ed. 2012, 11552–11555. 128 Singh, S.; Elsegood, M.; Kimber, M. Synlett 2012, 23, 565–568. 129 Kimber, M. C. Org. Lett. 2010, 12, 1128–1131. 195 a)Vogl, O. J. Polym. Sci. 1960, 46, 261–264. b) Vogl, O. J. Macromol. Sci. Part A 1992, 29, 1085–1113. 196 Clarke, P. A. Tetrahedron 2011, 67, 4959. 197 Voigt, T.; Gerding-Reimers, C.; Ngoc Tran, T. T.; Bergmann, S.; Lachance, H.; Schölermann, B.; Brockmeyer, A.; Janning, P.; Ziegler, S.; Waldmann, H. Angew. Chemie Int. Ed. 2013, 52, 410–414. 198 a) Yin, J.; Kouda, K.; Tezuka, Y.; Le Tran, Q.; Miyahara, T.; Chen, Y.; Kadota, S. Planta Med. 2004, 70, 54–58. Total synthesis: (1) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006, 71, 7911–7914. b) Hiebel, M.-A.; Pelotier, B.; Piva, O. Tetrahedron 2007, 63, 7874–7878. c) Sabitha, G.; Padmaja, P.; Yadav, J. S. Helv. Chim. Acta 2008, 91, 2235–2239. 199 For some recent total synthesis see: a) Zeng, J.; Tan, Y. J.; Ma, J.; Leow, M. L.; Tirtorahardjo, D.; Liu, X.-W. Chem. Eur. J. 2014, 20, 405–409. b) Nakata, K.; Tokumaru, T.; Iwamoto, H.; Nishigaichi, Y.; Shiina, I. Asian J. Org. Chem. 2013, 2, 920– 922. c) Fujioka, H.; Yahata, K.; Kubo, O.; Sawama, Y.; Hamada, T.; Maegawa, T. Angew. Chemie Int. Ed. 2011, 50, 12232– 12235. 200 For some relevant total synthesis see: a) Lee, K.; Kim, H.; Hong, J. Org. Lett. 2011, 13, 2722–2725. b) Fettes, A.; Carreira, E. M. Angew. Chemie Int. Ed. 2002, 41, 4098–4101. c) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894–12895. d) D’Ambrosio, M.; Guerriero, A.; Pietra, F.; Debitus, C. Helv. Chim. Acta 1996, 79, 51–60. 201 a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126–8131. b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996, 118, 9422–9423. For some recent total synthesis see: c) Wang, B.; Hansen, T. M.; Wang, T.; Wu, D.; Weyer, L.; Ying, L.; Engler, M. M.; Sanville, M.; Leitheiser, C.; Christmann, M.; Lu, Y.; Chen, J.; Zunker, N.; Cink, R. D.; Ahmed, F.; Lee, C.-S.; Forsyth, C. J. J. Am. Chem. Soc. 2011, 133, 1484–1505. d) Wang, B.; Hansen, T. M.; Weyer, L.; Wu, D.; Wang, T.; Christmann, M.; Lu, Y.; Ying, L.; Engler, M. M.; Cink, R. D.; Lee, C.-S.; Ahmed, F.; Forsyth, C. J. J. Am. Chem. Soc. 2011, 133, 1506–1516. 202 a) Hale, K. J.; Hummersone, M. G.; Manaviazar, S.; Frigerio, M. Nat. Prod. Rep. 2002, 19, 413–453. b) Mutter, R.; Wills, M. Bioorg. Med. Chem. 2000, 8, 1841–1860. c)Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.; Arnold, E.; Clardy, J. J. Am. Chem. Soc. 1982, 104, 6846–6848. For some relevant total synthesis see: d) Trost, B. M.; Dong, G. Nature 2008, 456, Addendum – Multicomponent cascade cycloadditions - Foreword 141 Scheme 123 - Biological active products containing tetrahydropyrans. One of the most popular methods for the preparation of tetrahypropyrans is based in the Prins cyclization,203,204 that normally involves a homoallylic alcohol (144), an aldehyde, and a Lewis acid to activate the carbonyl group (145). The Lewis acid, depending on experimental conditions, can also serve as a source of a nucleophilic anion. The generally accepted mechanism is initiated by complexation of the Lewis acid with the aldehyde, which activates the carbonyl carbon towards the attack by the hydroxyl group of the alcohol, generating the hemiacetal intermediate LIII. Loss of the Lewis acid fragment from the hemiacetal forms the key oxonium ion intermediate, LIV. Subsequent 6-endo cyclization of LIV selectively leads to secondary tetrahydropyranyl carbocation LV, which captures the halide or another nucleophile to afford to the tetratetrahydropyran product 146. 485–488. e) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540–7552. f) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407–7408. 203 Review in prins cyclization: a) Crane, E. A.; Scheidt, K. A. Angew. Chemie Int. Ed. 2010, 49, 8316–8326. b) Greco, S. J.; Fiorot, R. G.; Valdemar Lacerda, J.; Santos, R. B. dos Aldrichimica Acta 2013, 46, 59–67. 204 Review in tetrahydropyrans preparation: a) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2006, 2045–2053. b) Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron 2010, 66, 413–445. Chapter III – Cascade cycloadditions 142 Scheme 124 - General mechanism of the Prins cyclization. A number of others strategies for the construction of tetratetrahydropyrans have also been reported, including cyclizations involving oxocarbenium ions205 and epoxides,206 hetero-Diels–Alder reactions,207 intramolecular nucleophilic reactions,208 Michael reactions,209 reductions of cyclic hemiacetals,210 cyclizations involving nonactivated double bonds,211 or tandem processes.212 However the proposed cascade coupling would represent a simpler and more direct entry to this type of skeletons, and therefore we considered worthy to test its viability. 205 Morris, W. J.; Custar, D. W.; Scheidt, K. A. Org. Lett. 2005, 7, 1113–1116. 206 Smith, A. B.; Dong, S.; Brenneman, J. B.; Fox, R. J. J. Am. Chem. Soc. 2009, 131, 12109–12111. 207 Review: Jørgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558–3588. 208 Hilli, F.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6, 1289–92. 209 Paterson, I.; Chen, D. Y.-K.; Coster, M. J.; Aceña, J. L.; Bach, J.; Gibson, K. R.; Keown, L. E.; Oballa, R. M.; Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.; Norcross, R. D. Angew. Chemie Int. Ed. 2001, 40, 4055–4060. 210 Boulard, L.; BouzBouz, S.; Cossy, J.; Franck, X.; Figadère, B. Tetrahedron Lett. 2004, 45, 6603–6605. 211 Clarke, P. A.; Grist, M.; Ebden, M.; Wilson, C. Chem. Commun. 2003, 1560–1561. 212 Wang, L.; Li, P.; Menche, D. Angew. Chemie Int. Ed. 2010, 49, 9270–9273. Screening of conditions 143 5 5. .3 3 P Pr re el li im mi in na ar ry y s sc cr re ee en ni in ng gs s In order to assess the viability of a multicomponent, formal (2+2+2) process, we check the reaction between allenamide 60b, trans-methylstyrene and benzaldehyde (Table 1). To minimize the formation of allenamide homodimer 151, allenamide 60b was added dropwise, over 2h. Unfortunately, in presence of catalyst Ph3PAuNTf2 we only obtained traceable amounts of the desired product 149baa (over 2%). A biaryl phosphine-based catalyst Au8 also gave only a 2% of 149baa alongside with a 4% of 150ba. The major products was the allene homodimer 151 (44% yield). The cationic catalyst Au48, which features a Nheterocyclic carbene ligand provided 149baa in 15% yield, alongside with a mixture of other compounds. A catalyst prepared in situ from (PhO3)PAuCl (5%) and AgSbF6 (5%) afforded 149baa in a low 10% yield, together with 150ba (21%) and 151 (8%). The best result was obtained with phosphite gold(I) catalyst Au42, which afforded a 21% yield of the desired tetrahydropyran 149baa, alongside with 150ba (60%) and 151 (8%). Table 1 – Screening of catalysts Entry[a] [Au] T (ºC) Time Conv.[b] 149baa (%) 150ba (%) 151 (%) 1 Ph3PAuNTf2 (5%) -15 24 h 60 2 0 7 2 Au8 (5%) -15 5 h 99 2 4 44 3[c] Au48 (2%) -15 5 min 100 15 7 22 4 (PhO3)PAuCl (5%) /AgSbF6 (5%) -15 14 h 92 10 21 8 5 Au42 (2%) -15 3 h 100 21 60 8 [a] – 60b (1 equiv) added over two hours to a solution of 147a (2 equiv), 148a (10 equiv) and [Au] (mol%) in CH2Cl2 and 200 mg of 4Å molecular sieves. Yields determined by 1H-NMR analysis of the crude product using 1,3,5-trimethoxybenzene as internal standard. [b] – conversion of allenamide as determined by 1HNMR with internal standard. [c] – complex mixture of products. Although in a low yield, it is important to note that the (2+2+2) cycloaddition process took place with complete selectivity, since no other pyranyl regioor stereoisomers could be detected by 1H-NMR analysis of the crude reaction mixtures. The proposed relative stereochemistry for 149baa was based on nOe experiments as depicted in Figure 6. Chapter III – Cascade cycloadditions 144 Figure 6 – nOe assignment for 149baa Considering a possible influence of the solvent and temperature in the proportion of the products,213 we performed a small reaction screening by varying these parametrs (Table 2), using gold catalyst Au42. Unfortunately, the use of toluene, nitromethane or ,,- trifluorotoluene did not improve the results obtained with CH2Cl2 at -15 ºC. However at -45 ºC the yield of 149baa could be improved to 33%, alongside with a 37% of cyclobutane 150ba. Further decreasing of the temperature did not improve the yield of the process. Table 2 – Screening of solvents and temperature Entry[a] % [Au] Solvent T (ºC) Time Conv. 149baa (%) 150ba (%) 151 (%) 5 2% CH2Cl2 -15 3 h 100 21 60 8 6[b] 5% MeNO2 -15 30 min 100 16 30 8 7[b] 5% Tol -15 30 min 100 0 0 20 8[c] 5% TFT -15 30 min 94 19 20 14 9[d] 2% CH2Cl2 -45 1 h 100 33 37 0 10[b] 2% CH2Cl2 -78 20 h 83 28 30 0 [a] – 60b (1 equiv) added over two hours to a solution of 147a (2 equiv), 148a (10 equiv), Au42 (mol%) and 200 mg of 4Å molecular sieves. Yields determined by 1H-NMR analysis of the crude product using 1,3,5trimethoxybenzene as internal standard. [b] – complex mixture of products. [c] – TFT - ,, - Trifluorotoluene. [d] – isolated yields for 150ba and 149baa were 41% and 32% respectively. 5 5. .4 4 S Sc co op pe e o of f t th he e r re ea ac ct ti io on n Even though the results with trans-  -methylstyrene were not excellent, they show that the reaction is possible, and therefore we decided to check the viability of this intermolecular muticomponent cycloaddition with other alkenes (Table 3). As shown in Table 3, allenamide 60b undergoes the (2+2+2) cycloaddition reaction with -methylstyrene and benzaldehyde (Table 3, entry 2), in just 30 min, to provide an 213 Solvents and Solvent Effects in Organic Chemistry; Reichardt, C., Ed.; 3rd ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, FRG, 2002. Screening of conditions 145 excellent 98% yield of 149bba, which was isolated as a 2:1 mixture of diastereoisomers. 1,1-Diphenylethylene 147c afforded tetrahydropyran 149bca after only 10 min and in a good 85% yield (Table 3, entry 3). A small fraction of a hydrofunctionalization (5%) side product was also isolated. The use of 4-methyl-1,2-dihydronaphthalene 147d as alkene (Table 3, entry 4) led to the corresponding tricyclic product 149bda (57% yield of the major diastereoisomer). The crude also show some 1H-NMR characteristic signals of a (2+2) product and a minor diastereoisomer (dr=8.5:1), however these products could not be isolated and characterized. Unfortunately, alkyl substituted such as methylenecyclohexane 147e afford mainly hydrofunctionalization product (51%) and (2+2) cycloadduct (21%), alongside with a mixture of compounds that could not be characterized (Table 3, entry 5). On the contrary, 1-vinylpyrrolidin-2-one 147f participated in this reaction, affording the tetrahydropyran 149bfa as a single diastereoisomer, although in a modest 43% yield (Table 3, entry 6). Gratifyingly ethyl vinyl ether is an efficient cycloaddition partner and gives the corresponding tetrahydropyran 149bga in an excellent 94% yield, as a 1.5:1 mixture of diastereoisomers (Table 3, entry 7). The use of 3,4-dihydro-2H-pyran 147h allowed to isolate the interesting bicycle 149bha as a single diastereoisomer, although in a low yield (28%), together with the (2+2) product (40%) (Table 3, entry 8). The crude mixture also showed a complex mixture of other minor compounds that could not be identified. Supporting material for chapter 3, Addendum 249 The general procedures are those indicated in the Supporting material for chapter 3, article 4. In addition it should be mention the following: All the alkenes and aldehydes used were bought from Aldrich, Alfa Aesar, TCI or Acros and used without further purification, except 4-methyl-1,2-dihydronaphthalene, synthesized according to the reported procedure,214 in a 5 gram scale with 97% yield from Methylmagnesium bromide 3.0 M and 1-Tetralone. Representative procedure for the racemic multicomponent cycloaddition. (Exemplified for the reaction between 60b and trans-  -methylstyrene and benzaldehyde, Table 3, page 146, entry 1). To solution of trans-  -Methylstyrene (42 µl, 0,320 mmol), benzaldehyde (162 µl, 1,60 mmol) and Au42 (3,89 mg, 3,20 µmol) in CH2Cl2 (1 mL), at -45 °C in a dried Schlenk tube with 200 mg of powder MS, a solution of 3-(propa-1,2-dienyl)oxazolidin-2-one (20.0 mg, 0,160 mmol) in CH2Cl2 (0.5 mL) was slowly added over 2 hours. The mixture was stirred at -45 °C for 2 hours (the progress of the reaction was easily monitored by tlc) and filtered through a short pad of florisil eluting with EtOAc. The solvent was removed and the crude dissolved in 0.6 mL of a 1,3,5-trimethoxybenzene 0.266 M solution in CDCl3 for 1H-NMR analysis. The crude mixture was then purified on column chromatography (hexanes/EtOAc, 10-50%) to give 3-((Z)-(-3-methyl-2phenylcyclobutylidene)methyl)oxazolidin-2-one (150ba) (16 mg, 0,066 mmol, 41 % yield) and 3-((Z)-(-5-methyl-2,6-diphenyl-2H-pyran-3(4H,5H,6H)-ylidene)methyl)oxazolidin-2one (149baa) (18 mg, 0,052 mmol, 32 % yield). Representative procedure for the enantioselective multicomponent cycloaddition. (Exemplified for the reaction between 60b and -methylstyrene and benzaldehyde with (S,R,R)-Au24, Table 5, entry 13) To solution of -methylstyrene (42 µl, 0.32 mmol) and AgBF4 (1.6 mg, 8.0 µmol), (S,R,R)- Au24 (7.4 mg, 8.0 µmol) in CH2Cl2 (1.5 mL), at -94 °C (Hexane/N2 bath) in a dried Schlenk tube with 200 mg of powder MS, solid 60b (20 mg, 0.16 mmol) was added. The mixture was stirred at -94 °C for 30 min (the progress of the reaction was easily monitored by tlc) and filtered through a short pad of florisil eluting with EtOAc to provide a crude mixture which was purified on column chromatography (hexanes/EtOAc, 10-50%) to give (Z)-3-((6-methyl-2,6-diphenyl-2H-pyran-3(4H,5H,6H)- ylidene)methyl)oxazolidin-2-one 149bba (dr = 4:1) (51 mg, 0.15 mmol, 91 % yield). Enantioselectivity was determined by chiral HPLC analysis on Chiralpak IA3 at rt, (Hexane - iPrOH = 9:1, 0.5 ml/min). Racemic sample 149bba, 149bba:149bba’ = 1:1.2, Chiralpak IA3: 214 Silva, L. F.; Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.; Doriguetto, A. C. Org. Lett. 2007, 9, 1433–1436. Supporting material for chapter 3, Addendum 250 Racemic sample 149bba, 149bba:149bba’ = 13.7:1, Chiralpak IA3: Table 5, page 151, entry 13, ee 149bba = 74%, ee 149bba’ = 90%: Supporting material for chapter 3, Addendum 251 149baa - Racemic - 3-((Z)-((2R*,5S*,6R*)-5-methyl-2,6-diphenyldihydro-2H-pyran-3(4H)- ylidene)methyl)oxazolidin-2-one 1H NMR (500 MHz, CDCl3) δ 7.54 – 7.45 (m, 2H), 7.38 – 7.27 (m, 3H), 7.30 – 7.21 (m, 4H), 7.22 – 7.14 (m, 1H), 5.87 (d, J = 1.3 Hz, 1H), 5.41 (s, 1H), 4.87 (d, J = 3.7 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.58 (q, J = 8.3 Hz, 1H), 3.37 – 3.30 (m, 1H), 3.07 (td, J = 8.8, 5.2 Hz, 1H), 2.79 (ddd, J = 14.1, 6.0, 1.4 Hz, 1H), 2.33 (dd, J = 14.1, 5.0 Hz, 1H), 2.30 – 2.19 (m, 1H), 0.71 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 156.3 (C), 140.9 (C), 140.6 (C), 133.3 (C), 128.0 (CH), 127.9 (CH), 127.9 (CH), 127.4 (CH), 126.6 (CH), 125.6 (CH), 119.0 (CH), 79.5 (CH), 61.8 (CH2), 45.8 (CH2), 37.9 (CH2), 34.9 (CH), 14.0 (CH3). LRMS (m/z, ESI): 372.16 (M+Na)+, 332.16, 282.28, 263.14, 245.13, 117.07, 91.06. HRMS Calculated for C22H23NNaO3: 372.1570, found 372.1564. COSY between 4.87 (d, J = 3.7 Hz, 1H) and 2.30 – 2.19 (m, 1H). Irradiating 4.87 (d, J = 3.7 Hz, 1H) nOe with: 3.9% 2.30 – 2.19 (m, 1H); 6.2% 5.41 (s, 1H); 1.9% 2.79 (ddd, J = 14.1, 6.0, 1.4 Hz, 1H). Irradiating 5.41 (s, 1H) nOe with: 5.5% 4.87 (d, J = 3.7 Hz, 1H); 3.9% 7.54 – 7.45 (m, 2H); 1.1% 3.37 – 3.30 (m, 1H); 1.0% 3.07 (td, J = 8.8, 5.2 Hz, 1H); 1% 2.79 (ddd, J = 14.1, 6.0, 1.4 Hz, 1H). Irradiating 5.87 (d, J = 1.3 Hz, 1H) nOe with:1% 3.37 – 3.30 (m, 1H); 2% 2.79 (ddd, J = 14.1, 6.0, 1.4 Hz, 1H); 3% 2.33 (dd, J = 14.1, 5.0 Hz, 1H). Significant nOe’s observed. Supporting material for chapter 3, Addendum 252 149bba - Racemic - 3-((Z)-((2S*,6S*)-6-methyl-2,6-diphenyldihydro-2H-pyran-3(4H)- ylidene)methyl)oxazolidin-2-one 1H NMR (500 MHz, CDCl3) δ 7.51 – 7.46 (m, 4H), 7.37 – 7.32 (m, 3H), 7.31 – 7.27 (m, 2H), 7.19 (t, J = 7.7 Hz, 1H), 5.78 – 5.75 (m, 1H), 5.60 (s, 1H), 3.96 (td, J = 8.8, 5.3 Hz, 1H), 3.59 (q, J = 8.7 Hz, 1H), 3.31 (q, J = 8.6 Hz, 1H), 2.78 (td, J = 8.8, 5.3 Hz, 1H), 2.58 – 2.49 (m, 1H), 2.38 (dt, J = 14.3, 4.7 Hz, 1H), 2.25 (dt, J = 13.3, 5.0 Hz, 1H), 2.05 (ddd, J = 13.3, 11.5, 4.1 Hz, 1H), 1.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 155.7 (C), 148.7 (C), 141.2 (C), 139.0 (C), 128.2 (CH), 128.0 (CH), 127.9 (CH), 126.3 (CH), 124.7 (CH), 116.7 (CH), 75.7 (C), 73.0 (CH), 61.7 (CH2), 45.3 (CH2), 45.3 (CH2), 37.1 (CH2), 27.1 (CH3), 25.9 (CH2). Analysis on a 235bba:235bba’ 1:1 sample: LRMS (m/z, ESI): 372.16 (M+Na)+, 332.16, 263.14, 245.13, 143.11, 117.11. HRMS Calculated for C22H23NNaO3: 372.1570, found 372.1560. Irradiating 5.78 – 5.75 (m, 1H) nOe with: 1% 3.31 (q, J = 8.6 Hz, 1H); 1% 2.58 – 2.49 (m, 1H); 4% 2.38 (dt, J = 14.3, 4.7 Hz, 1H). Irradiating 5.60 (s, 1H) nOe with: 4% 1.67 (s, 3H), 1% 3.31 (q, J = 8.6 Hz, 1H), 1% 2.78 (td, J = 8.8, 5.3 Hz, 1H). Irradiating 1.67 (s, 3H) nOe with: 5% 5.60 (s, 1H) Significant nOe’s observed. 149bba’ - Racemic (Minor diastereoisomer, by exclusion of the 149bba spectra (in which 149bba was almost pure)- 3-((Z)-((2S*,6R*)-6-methyl-2,6-diphenyldihydro-2H-pyran3(4H)-ylidene)methyl)oxazolidin-2-one 1H NMR (300 MHz, CDCl3) δ 7.52 – 7.40 (m, 4H), 7.38 – 7.27 (m, 5H), 7.22 – 7.15 (m, 1H), 5.81 (q, J = 1.8 Hz, 1H), 5.15 (t, J = 1.6 Hz, 1H), 3.79 (ddd, J = 9.2, 8.4, 5.9 Hz, 1H), 3.55 – 3.46 (m, 1H), 3.20 (ddd, J = 9.2, 8.3, 7.6 Hz, 1H), 2.86 – 2.72 (m, 1H), 2.72 – 2.60 (m, 1H), 2.47 – 2.41 (m, 1H), 2.31 – 2.27 (m, 2H), 1.43 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 155.8 (C), 146.7 (C), 140.7 (C), 137.0 (C), 128.4 (CH), 128.3 (CH), 128.0 (CH), 127.9 (CH), 126.7 (CH), 125.3 (CH), 116.9 (CH), 76.7 (C), 73.9 (CH), 61.7 (CH2), 45.3 (CH2), 34.6 (CH2), 32.7 (CH3), 26.3 (CH2). LRMS (m/z, ESI): 372.16 (M+Na)+, 332.16, 263.14, 245.13, 143.11, 117.11. HRMS Calculated for C22H23NNaO3: 372.1570, found 372.1560. Irradiating 5.81 (q, J = 1.8 Hz, 1H) nOe with: 3% 2.47 – 2.41 (m, 1H); 1% 2.72 – 2.60 (m, 1H). Irradiating 5.15 (t, J = 1.6 Hz, 1H) nOe with: 1.4% 3.20 (ddd, J = 9.2, 8.3, 7.6 Hz, 1H); 1% 2.72 – 2.60 (m, 1H) Irradiating 1.43 (s, 3H) nOe with: 2% with 2.47 – 2.41 (m, 1H) Supporting material for chapter 3, Addendum 253 Significant nOe’s observed. 149bca - (Z)-3-((2,6,6-triphenyldihydro-2H-pyran-3(4H)-ylidene)methyl)oxazolidin-2-one 1H NMR (300 MHz, CDCl3) δ 7.61 – 7.45 (m, 4H), 7.47 – 7.29 (m, 7H), 7.33 – 7.16 (m, 3H), 7.20 – 7.07 (m, 1H), 5.78 (d, J = 1.5 Hz, 1H), 5.24 (s, 1H), 3.88 – 3.69 (m, 1H), 3.48 (q, J = 8.2 Hz, 1H), 3.19 (q, J = 8.0 Hz, 1H), 2.88 – 2.65 (m, 2H), 2.69 – 2.42 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 156.0 (C), 148.1 (C), 144.1 (C), 140.6 (C), 136.9 (C), 128.4 (CH), 128.1 (CH), 127.9 (CH), 127.8 (CH), 127.8 (CH), 127.1 (CH), 127.0 (CH), 126.3 (CH), 125.2 (CH), 117.2 (CH), 80.0 (C), 73.8 (CH), 61.7 (CH2), 45.4 (CH2), 35.5 (CH2), 26.5 (CH2). LRMS (m/z, ESI): 434.17 (M+Na)+, 394.18, 325.26, 241.09, 193.10, 145.07, 117.07. HRMS Calculated for C27H25NNaO3: 434.1727, found 434.1721. (E)-3-(5,5-diphenylpenta-1,4-dien-1-yl)oxazolidin-2-one 1H NMR (300 MHz, CDCl3) δ 7.45 – 7.17 (m, 10H), 6.70 (dt, J = 14.3, 1.5 Hz, 1H), 6.08 (t, J = 7.6 Hz, 1H), 4.85 (dt, J = 14.3, 6.7 Hz, 1H), 4.46 – 4.37 (m, 2H), 3.72 – 3.65 (m, 2H), 2.94 – 2.86 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 155.27 (C), 142.56 (C), 142.20 (C), 139.53 (C), 129.62 (CH), 128.16 (CH), 128.02 (CH), 127.18 (CH), 127.08 (CH), 127.02 (CH), 126.64 (CH), 124.42 (CH), 109.20 (CH), 62.04 (CH2), 42.48 (CH2), 30.10 (CH2). LRMS (m/z, CI): 306 [M+ +1, 64], 235 (42), 209 (72), 183 (78), 128 (72), 116 (100), 88 (96). HRMS [M+ +1], Calculated for C20H20NO2: 306.1494, found 306.1482. 149bda - Racemic - 3-((Z)-((2S*,4aR*,10bS*)-10b-methyl-2-phenyl-4,4a,5,6-tetrahydro-2Hbenzo[h]chromen-3(10bH)-ylidene)methyl)oxazolidin-2-one 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 7.4 Hz, 2H), 7.34 – 7.24 (m, 3H), 7.17 – 7.07 (m, 2H), 7.04 (d, J = 7.1 Hz, 1H), 6.03 (s, 1H), 5.73 (s, 1H), 4.05 (q, J = 8.2, 7.8 Hz, 1H), 3.86 (q, J = 8.4 Hz, 1H), 3.38 (q, J = 8.5 Hz, 1H), 3.07 – 2.98 (m, 1H), 2.82 – 2.71 (m, 1H), 2.65 – 2.55 (m, 1H), 2.50 (t, J = 12.4 Hz, 1H), 2.42 (dd, J = 13.3, 4.9 Hz, 1H), 2.18 – 2.08 (m, 1H), 2.08 – 1.94 (m, 1H), 1.63 (s, 3H), 1.56 (dtd, J = 13.4, 9.4, 4.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 156.1 (C), 141.9 (C), 140.8 (C), 136.2 (C), 135.3 (C), 128.3 (CH), 127.9 (CH), 127.8 (CH), 127.6 (CH), 126.4 (CH), 126.3 (CH), 116.7 (CH), 74.6 (C), 72.9 (CH), 61.9 (CH2), 45.3 (CH2), 42.6 (CH), 33.9 (CH2), 30.3 (CH3), 28.3 (CH2), 27.8 (CH2). LRMS (m/z, ESI): 328.17 (M+Na)+, 358.18, 289.16, 214.09, 117.07. HRMS Calculated for C24H25NNaO3: 398.1727, found 398.1719. Irradiation at 6.03 (s, 1H) nOe with: 1% 3.38 (q, J = 8.5 Hz, 1H); 5% 2.42 (dd, J = 13.3, 4.9 Hz, 1H). Supporting material for chapter 3, Addendum 254 Irradiation at 5.73 (s, 1H) nOe with: 2% 3.38 (q, J = 8.5 Hz, 1H); 2% 3.07 – 2.98 (m, 1H) (these indicate Z geometry at the enamide); 1% 2.18 – 2.08 (m, 1H); 5% 1.63 (s, 3H). Irradiation at 1.63 (s, 3H) nOe with: 9% 5.73 (s, 1H); 8% 2.18 – 2.08 (m, 1H). Significant nOe’s observed. 149bfa - 3-((Z)-((2S*,6S*)-6-(2-oxopyrrolidin-1-yl)-2-phenyldihydro-2H-pyran-3(4H)- ylidene)methyl)oxazolidin-2-one 1H NMR (500 MHz, CDCl3) δ 7.42 – 7.37 (m, 2H), 7.36 – 7.26 (m, 3H), 6.07 (s, 1H), 5.57 (dd, J = 9.4, 4.8 Hz, 1H), 5.50 (s, 1H), 3.95 – 3.86 (m, 1H), 3.78 (q, J = 8.5 Hz, 1H), 3.47 (q, J = 8.1 Hz, 1H), 3.40 (q, J = 7.8 Hz, 1H), 3.32 (q, J = 8.2 Hz, 1H), 3.26 – 3.13 (m, 1H), 2.68 – 2.57 (m, 1H), 2.53 – 2.44 (m, 1H), 2.42 – 2.32 (m, 2H), 2.05 – 1.92 (m, 3H), 1.92 – 1.83 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 175.3 (C), 156.2 (C), 139.7 (C), 129.7 (C), 128.3 (CH), 128.2 (CH), 127.5 (CH), 119.1 (CH), 77.7 (CH), 77.2 (CH), 61.9 (CH2), 45.4 (CH2), 42.3 (CH2), 31.4 (CH2), 28.1 (CH2), 27.8 (CH2), 17.9 (CH2). LRMS (m/z, ESI): 365.15 (M+Na)+, 256.13, 238.12, 171.08, 117.07, 98.06. HRMS Calculated for C19H22N2NaO4: 365.1472, found 365.1474. Irradiating 5.50 (s, 1H) nOe with: 5% 5.57 (dd, J = 9.4, 4.8 Hz, 1H); 2% 3.32 (q, J = 8.2 Hz, 1H); 2% 3.26 – 3.13 (m, 1H), Irradiating 5.57 (dd, J = 9.4, 4.8 Hz, 1H) nOe with: 5% 5.50 (s, 1H). Significant nOe’s observed. 149bga + 149bga’ - (Z)-3-((6-ethoxy-2-phenyldihydro-2H-pyran-3(4H)- ylidene)methyl)oxazolidin-2-one 1H NMR (500 MHz, CDCl3) δ 7.47 – 7.26 (m, 5.0H), 6.32 (s, 0.4H), 6.30 (s, 0.6H), 5.80 (s, 0.4H), 5.60 (s, 0.6H), 4.83 (t, J = 4.0 Hz, 0.6H), 4.70 (dd, J = 8.0, 3.8 Hz, 0.4H), 4.17 – 4.01 (m, 2.0H), 3.95 (dq, J = 9.5, 7.0 Hz, 0.4H), 3.59 – 3.45 (m, 1.2H), 3.45 – 3.41 (m, 0.6H), 3.41 – 3.34 (m, 1.2H), 3.29 (dq, J = 9.3, 7.0 Hz, 0.6H), 2.84 – 2.75 (m, 0.6H), 2.41 (dd, J = 6.3, 4.1 Hz, 0.8H), 2.33 (dt, J = 14.1, 4.9 Hz, 0.6H), 2.04 – 1.92 (m, 1.0H), 1.92 – 1.82 (m, 0.6H), 1.77 – 1.65 (m, 0.4H), 1.24 (t, J = 7.1 Hz, 1.20H), 0.75 (t, J = 7.1 Hz, 1.80H). 13C NMR (75 MHz, CDCl3) δ 156.76 (C), 156.58 (C), 141.26 (C), Supporting material for chapter 3, Addendum 255 139.03 (C), 128.60 (CH), 128.07 (CH), 127.88 (CH), 127.52 (CH), 127.37 (CH), 127.16 (CH), 126.32 (C), 126.03 (C), 119.45 (CH), 119.39 (CH), 97.91 (CH), 96.49 (CH), 73.11 (CH), 72.27 (CH), 63.71 (CH2), 63.23 (CH2), 62.03 (CH2), 61.94 (CH2), 45.72 (CH2), 45.40 (CH2), 31.79 (CH2), 31.14 (CH2), 26.91 (CH2), 24.76 (CH2), 15.16 (CH3), 14.36 (CH3). Irradiation at 5.60 (s, 0.6H), major diastereoisomer, noe with: 4% 7.47 – 7.26 (m, 5.0H); 2% 4.83 (t, J = 4.0 Hz, 0.6H); 6% 3.41 – 3.34 (m, 1.2H). Irradiation at 4.83 (t, J = 4.0 Hz, 0.6H), major diastereoisomer, noe with: 2% 5.60 (s, 0.6H); 3.45 – 3.41 (m, 0.6H); 4% 2.33 (dt, J = 14.1, 4.9 Hz, 0.6H). 3% 2.04 – 1.92 (m, 1.0H), 2% 1.92 – 1.82 (m, 0.6H). Irradiation at 5.80 (s, 0.4H), minor diastereoisomer, noe with: 4% 7.47 – 7.26 (m, 5.0H); 6% 3.59 – 3.45 (m, 1.2H) 1H NMR (500 MHz, C6D6) δ 7.44 – 7.38 (m, 2.0H), 7.22 (t, J = 7.6 Hz, 0.8H), 7.19 – 7.10 (m, 1.6H), 7.07 (t, J = 7.3 Hz, 0.60H), 6.41 (s, 1.0H), 5.76 (s, 0.4H), 5.58 (s, 0.6H), 4.77 (t, J = 3.5 Hz, 0.6H), 4.52 (dd, J = 8.3, 3.6 Hz, 0.4H), 4.06 – 3.96 (m, 0.4H), 3.49 – 3.38 (m, 0.6H), 3.41 – 3.29 (m, 0.4H), 3.18 – 3.08 (m, 0.6H), 3.08 – 2.96 (m, 1.4H), 2.95 – 2.86 (m, 0.6H), 2.76 – 2.66 (m, 0.6H), 2.54 – 2.42 (m, 1.4H), 2.45 – 2.37 (m, 0.6H), 2.14 – 2.03 (m, 0.4H), 1.98 – 1.88 (m, 1.0H), 1.82 – 1.71 (m, 1.6H), 1.74 – 1.64 (m, 0.4H), 1.17 (t, J = 7.0 Hz, 1.2H), 0.66 (t, J = 7.0 Hz, 1.8H). Irradiation at 5.76 (s, 0.4H), minor diastereoisomers show noe with: 3% 7.44 – 7.38 (m, 2.0H); 7% 2.54 – 2.42 (m, 1.4H). This confirms the Z geometry at the enamide. In benzene the signals from the enamide do not overlap with those from the ethoxy group. (See HSQC) LRMS (m/z, ESI): 326.14 (M+Na)+, 258.11, 214.08, 171.08, 129.07, 88.04. HRMS Calculated for C17H21NNaO4: 326.1363, found 326.1370. Significant nOe’s observed. 149bha - 3-((Z)-((2S*,4aR*,8aS*)-2-phenyltetrahydro-2H,5H-pyrano[2,3-b]pyran-3(4H)- ylidene)methyl)oxazolidin-2-one 1H NMR (500 MHz, CDCl3) δ 7.49 – 7.43 (m, 2H), 7.37 – 7.27 (m, 3H), 6.01 (q, J = 1.4 Hz, 1H), 5.48 (s, 1H), 5.02 (d, J = 2.8 Hz, 1H), 3.97 (td, J = 8.8, 5.6 Hz, 1H), 3.88 – 3.79 (m, 1H), 3.79 – 3.70 (m, 1H), 3.58 – 3.50 (m, 1H), 3.40 – 3.31 (m, 1H), 3.24 (td, J = 8.7, 5.6 Hz, 1H), 2.51 – 2.40 (m, 2H), 2.07 – 1.97 (m, 1H), 1.84 – 1.73 (m, 1H), 1.71 – 1.62 (m, 1H), 1.62 – 1.47 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 156.48 (C), 140.43 (C), 129.15 (C), 127.95 (CH), 127.67 (CH), 127.20 (CH), 119.53 (CH), 97.27 (CH), 75.87 (CH), 63.18 (CH2), 61.90 (CH2), 45.79 (CH2), 35.36 (CH), 33.31 (CH2), 25.38 (CH2), Supporting material for chapter 3, Addendum 256 23.11 (CH2). LRMS (m/z, ESI): 338.14 (M+Na)+, 298.14, 229,12, 214.09, 183.12, 129.07. HRMS Calculated for C18H21NNaO4: 338.1363, found 338.1356. Irradiation at 5.48 (s, 1H) (alpha to oxigen and phenyl) noe with: 4% 7.49 – 7.43 (m, 2H); 3.5% 5.02 (d, J = 2.8 Hz, 1H); 1.4% 3.40 – 3.31 (m, 1H), 2.0% 3.24 (td, J = 8.7, 5.6 Hz, 1H). Irradiation at 5.02 (d, J = 2.8 Hz, 1H) (alpha to two oxigens) noe with: 3.6% 5.48 (s, 1H); 2% 3.58 – 3.50 (m, 1H); 1% 2.51 – 2.40 (m, 2H); 3.8% 2.07 – 1.97 (m, 1H). Significant nOe’s observed. 150bh - 3-((Z)-((1R*,6R*)-2-oxabicyclo[4.2.0]octan-8-ylidene)methyl)oxazolidin-2-one 1H NMR (500 MHz, CDCl3) δ 6.47 – 6.42 (m, 1H), 4.73 (dt, J = 7.0, 2.3 Hz, 1H), 4.36 (t, J = 8.1 Hz, 2H), 4.23 – 4.14 (m, 1H), 3.75 (q, J = 9.0 Hz, 1H), 3.72 – 3.63 (m, 1H), 3.60 – 3.52 (m, 1H), 2.51 – 2.42 (m, 1H), 2.46 – 2.37 (m, 1H), 2.29 – 2.22 (m, 1H), 2.03 – 1.92 (m, 1H), 1.66 – 1.57 (m, 1H), 1.59 – 1.43 (m, 2H). 13C NMR (75 MHz CDCl3) δ 156.15 (C), 121.52 (C), 118.53 (CH), 72.49 (CH), 63.24 (CH2), 62.34 (CH2), 44.30 (CH2), 30.45 (CH), 30.32 (CH2), 25.25 (CH2), 22.05 (CH2). LRMS (m/z, ESI): 232.09 (M+Na)+, 210.11, 173.10, 105.07HRMS Calculated for C11H15NNaO3: 232.0944, found 232.0937. Irradiation at 4.73 (dt, J = 7.0, 2.3 Hz, 1H), NOE with: 0.8% 4.23 – 4.14 (m, 1H); 1.5% 3.75 (q, J = 9.0 Hz, 1H); 2.7% 2.46 – 2.37 (m, 1H) Significant nOe’s observed. E-149dia - Racemic - N-((E)-((2S*,6R*)-6-methoxy-6-methyl-2-phenyldihydro-2H-pyran3(4H)-ylidene)methyl)-4-methyl-N-phenylbenzenesulfonamide (contaminated with the (2+2) cycloaduct) 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 1H), 7.38 (q, J = 7.0, 6.6 Hz, 4H), 7.28 – 7.18 (m, 3H), 7.17 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.96 (dd, J = 7.7, 1.8 Hz, 2H), 5.31 (t, J = 1.8 Hz, 1H), 5.11 (s, 1H), 3.22 (s, 3H), 2.52 (dt, J = 14.3, 4.2 Hz, 1H), 2.37 (s, 3H), 2.36 – 2.11 (m, 2H), 1.79 – 1.72 (m, 1H), 1.56 (td, J = 13.0, 5.0 Hz, 1H), 1.31 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 143.5 (C), 141.4 (C), 138.9 (C), 138.7 (C), 134.0 (C), 129.2 (CH), 128.8 (CH), 128.2 (CH), 128.1 (CH), 127.7 (CH), 126.8 (CH), 124.2 (CH), 98.7 (C), 73.9 (CH), 48.2 (CH3), 35.4 (CH2), 23.2 (CH3), 22.0 (CH2), 21.5 (CH3). LRMS (m/z, ESI): 486.17 (M+Na)+, 432.16, 380.13 Supporting material for chapter 3, Addendum 257 (probably from the (2+2) product, (M+Na)+), 326.12, 276.14, 218.10, 185.10, 119.06. HRMS Calculated for C27H29NNaO4S: 486.1710, found 486.1706. Irradiation at 5.31 (t, J = 1.8 Hz, 1H) nOe at: 10% 7.17 (d, J = 8.1 Hz, 2H); 1% 5.11 (s, 1H);. this nOe seems to indicate that we have the E isomer, however it is not a clear evidence. Irradiation at 5.11 (s, 1H) nOe at: 6% 7.38 (q, J = 7.0, 6.6 Hz, 4H); 1% 5.31 (t, J = 1.8 Hz, 1H); 4% 3.22 (s, 3H); 3% 2.36 – 2.11 (m, 2H). Irradiation at 3.22 (s, 3H) nOe at: 2% 5.11 (s, 1H); 2% 1.31 (s, 3H). Irradiation at 1.31 (s, 3H). nOe at: 3% 3.22 (s, 3H); 1% 1.79 – 1.72 (m, 1H), 2% 1.56 (td, J = 13.0, 5.0 Hz, 1H) Significant nOe’s observed. These nOes seems to indicate that we have the E isomer, however it is not a clear evidence. Z-149dia - Racemic - N-((Z)-((2S*,6R*)-6-methoxy-6-methyl-2-phenyldihydro-2H-pyran3(4H)-ylidene)methyl)-4-methyl-N-phenylbenzenesulfonamide 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 7.7 Hz, 2H), 7.63 (q, J = 7.8, 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.25 – 7.03 (m, 5H), 6.69 (d, J = 7.3 Hz, 2H), 6.17 (s, 1H), 4.96 (s, 1H), 2.98 (s, 3H), 2.49 – 2.41 (m, 1H), 2.40 (s, 3H), 2.29 (dt, J = 13.7, 4.8 Hz, 1H), 2.05 (td, J = 10.6, 9.5, 4.0 Hz, 1H), 1.70 (td, J = 12.6, 5.7 Hz, 1H), 1.30 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 143.6 (C), 139.9 (C), 139.4 (C), 138.3 (C), 134.4 (C), 133.7 (CH), 130.2 (CH), 129.3 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.8 (CH), 127.2 (CH), 127.2 (CH), 126.8 (CH), 120.5 (CH), 99.1 (C), 71.8 (CH), 48.5 (CH3), 36.4 (CH2), 25.8 (CH2), 23.8 (CH3), 21.5 (CH3). LRMS (m/z, ESI): 486.17 (M+Na)+, 472.15, 381.30, 353.27, 185.10. HRMS Calculated for C27H29NNaO4S, 486.1710 found 486.1706. Irradiation at 6.17 (s, 1H) nOe at: 3% 7.36 (d, J = 8.0 Hz, 2H); 4% 6.69 (d, J = 7.3 Hz, 2H); 5% 2.29 (dt, J = 13.7, 4.8 Hz, 1H). Irradiation at 4.96 (s, 1H) nOe at: 5% 7.25 – 7.03 (m, 5H); 2% 6.69 (d, J = 7.3 Hz, 2H); 3% 2.98 (s, 3H). Irradiation at 2.98 (s, 3H) nOe at: 1% 4.96 (s, 1H); 2% 1.30 (s, 3H). Irradiation at 1.30 (s, 3H).nOe at: 3% 2.98 (s, 3H); 2% 2.05 (td, J = 10.6, 9.5, 4.0 Hz, 1H). Significant nOe’s observed. A A r rt ti ic cl le e 1 1 - - G Go ol ld d( (I I) )- -c ca at ta al ly yz ze ed d i in nt te er rm mo ol le ec cu ul la ar r ( (4 4+ +2 2 ) ) c c y yc cl lo oa ad dd di it ti io on n o of f a al ll le en na am mi id de es s a an nd d a ac cy yc cl li ic c d di ie en ne es s Faustino, H.; López, F.; Castedo, L.; Mascareñas, J. L. Chem. Sci. 2011, 2, 633-637. 2 S14 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 S15 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 S16 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 S17 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 S18 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 S19 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 S20 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 S21 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 S22 Supplementary Material (ESI) for Chemical Science # This journal is (c) The Royal Society of Chemistry 2011 C Ch ha ap pt te er r I II I – – G Go ol ld d( (I I) )- -C Ca at ta al ly yz ze ed d I In nt te er rm mo ol le ec cu ul la ar r ( (2 2+ +2 2) ) C Cy yc cl lo oa ad dd di it ti io on ns s b be et tw we ee en n A Al ll le en na am mi id de es s a an nd d a al lk ke en ne es s 19 A A r rt ti ic cl le e 3 3 - - G Go ol ld d( (I I) )- -C Ca at ta al ly yz ze ed d I In nt te er rm mo ol le ec cu ul la ar r ( (2 2+ +2 2 ) ) C C y yc cl lo oa ad dd di it ti io on ns s b be et tw we ee en n A Al ll le en na am mi id de es s a an nd d A Al lk ke en ne es s Faustino, H.; Bernal, P.; Castedo, L.; López, F.; Mascareñas, J. L. Adv. Synth. Catal. 2012 , 354 , 1658–1664. 20 S13  S14  S15  S16  S17  S18  -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) -0. 5 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510. 0 f1 (ppm) S19  S26  -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) -0. 5 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510. 0 f1 (ppm) S27  -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) -0. 5 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510. 0 f1 (ppm) S28  -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) -0. 5 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510. 0 f1 (ppm) S29  -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510. 0 f1 (ppm) S30  S31  S32  -100102030405060708090100110120130140150160170180190200210220 f1 (ppm) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510. 0 f1 (ppm) S33  S34  A Ad dd de en nd du um m t to o - - C Ch ha ap pt te er r I II I – – G Go ol ld d( (I I) )- -C Ca at ta al ly yz ze ed d I In nt te er rm mo ol le ec cu ul la ar r ( (2 2+ +2 2) ) C Cy yc cl lo oa ad dd di it ti io on ns s b be et tw we ee en n A Al ll le en na am mi id de es s a an nd d a al lk ke en ne es s 43 A Ar rt ti ic cl le e 4 4 - - G Go ol ld d( (I I) )- -c ca at ta al ly yz ze ed d c ca as sc ca ad de e c cy yc cl lo oa ad dd di it ti io on ns s b be et tw we ee en n a al ll le en na am mi id de es s a an nd d c ca ar rb bo on ny yl l- -t te et th he er re ed d a al lk ke en ne es s: : a an n e en na an nt ti io os se el le ec ct ti iv ve e a ap pp pr ro oa ac ch h t to o o ox xa a- -b br ri id dg ge ed d m me ed di iu um m- -s si iz ze ed d c ca ar rb bo oc cy yc cl le es s. . Faustino, H.; Alonso, I.; Mascareñas, J. L.; López, F. Angew. Chemie Int. Ed. 2013, 52, 6526– 6530. 50 -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) - 1 010203040506070809010011012013014015016017018019020010 f1 (pp m ) 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 0 .0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) - 1 010203040506070809010011012013014015016017018019020010 f1 (pp m ) 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 0 .0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) * * * * - Ethyl acetate -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) - 1 010203040506070809010011012013014015016017018019020010 f1 (pp m ) 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 0 .0 f1 (ppm) - 1 010203040506070809010011012013014015016017018019020010 f1 (pp m ) 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 0 .0 f1 (ppm) 0102030405060708090100110120130140150160170180190 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) ** * - 2-propanol -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -20-100102030405060708090100110120130140150160170180190200210220 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) - 1 010203040506070809010011012013014015016017018019020010 f1 (pp m ) 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 0 .0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) 0. 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) - 1 010203040506070809010011012013014015016017018019020010 f1 (pp m ) 0 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 0 .0 f1 (ppm) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 f1 (ppm) -200-150-100-50050100150200 f1 (ppm) -1 0 0102030405060708090100110120130140150160170180190200210 f1 (ppm) * * * * * * - hexane A Ad dd de en nd du um m t to o - - C Ch ha ap pt te er r I II II I – – G Go ol ld d( (I I) )- -c ca at ta al ly yz ze ed d c ca as sc ca ad de e c cy yc cl lo oa ad dd di it ti io on ns s o of f a al ll le en na am mi id de es s, , a al lk ke en ne es s a an nd d c ca ar rb bo on ny yl ls s. . 103 -10010203040506070 80 90100110120130140150160170 180 190200210 f1 (ppm) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) 104 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 f2 (ppm) 1 2 3 4 5 6 7 f1 (ppm) COSY 105 1.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.0 f2 (ppm) 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 f1 (ppm) HSQC 106 -3.92 -1.87 100.00 -6.21 -4.19 -0.85 -1.04 -1.14 -5.46 100.00 -3.90 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) -3.24 -2.11 -0.92 100.00 nOe 107 1.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 f2 (ppm) 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 f1 (ppm) 114 -3.33 -1.35 -0.42 -1.12 100.00 -1.00 -0.50 -0.78 -1.43 100.00 -8.82 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.5 f1 (ppm) 100.00 -3.86 -2.18 -3.54 115 010203040506070 80 90100110120130140150160170 180 190200210 f1 (ppm) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) * * * * - Ethyl acetate 116 2.53.03.54.04.55.05.56.06.57.07.5 f2 (ppm) 30 40 50 60 70 80 90 100 110 120 130 140 150 160 f1 (ppm) HSQC 117 -0.89 -1.23 -1.02 100.00 -5.44 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) -14.45 100.00 -2.89 -1.40 -1.22 -0.54 118 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) * -10010203040506070 80 90100110120130140150160170 180 190200210 f1 (ppm) * * * - Ethyl acetate 119 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) -10010203040506070 80 90100110120130140150160170 180 190200210 f1 (ppm) 120 1.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 f2 (ppm) 30 40 50 60 70 80 90 100 110 120 130 140 150 160 f1 (ppm) 121 -0.05 -0.01 0.99 -0.05 -0.01 -0.02 -0.02 1.00 -0.05 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) 1.00 -0.07 -0.09 -0.06 122 -10010203040506070 80 90100110120130140150160170 180 190200210 f1 (ppm) 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) 123 -0.45 -0.35 -6.54 -0.59 -0.43 100.00 -0.24 -3.64 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) -0.54 -0.80 -3.13 -1.86 -4.39 -1.27 100.00 -0.47 -1.69 in CDCl 3 130 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) -10010203040506070 80 90100110120130140150160170 180 190200210 f1 (ppm) in C 6 H 6 131 0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 f2 (ppm) 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 f1 (ppm) in C 6 H 6 132 -6.99 100.00 -2.60 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.5 f1 (ppm) -3.27 -1.98 -3.48 -1.19 100.00 -1.56 in C 6 H 6 133 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) -10010203040506070 80 90100110120130140150160170 180 190200210 f1 (ppm) 134 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.0 f2 (ppm) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 f1 (ppm) 135 0.98 2.03 1.45 3.61 -100.00 4.00 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) 3.81 1.13 1.97 -100.00 3.63 136 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) -10010203040506070 80 90100110120130140150160170 180 190200210 f1 (ppm) 137 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 f2 (ppm) 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 f1 (ppm) 138 0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5 8.08.5 9.09.510.0 f1 (ppm) -2.74 -0.69 -1.45 -0.75 100.00 139