Angewandte Communications Chemie International Edition: DOI: 10.1002/anie.201915895 German Edition: DOI: 10.1002/ange.201915895 Gold Catalysis Acetylene as a Dicarbene Equivalent for Gold(I) Catalysis: Total Synthesis of Waitziacuminone in One Step Dagmar Scharnagel, Imma Escofet, Helena Armengol-Relats, M. Elena de Orbe, J. Nepomuk Korber, and Antonio M. Echavarren* Abstract: The gold(I)-catalyzed reaction of acetylene gas with alkenes leads to (Z,Z)-1,4-disubstituted 1,3-butadienes and biscyclopropanes depending on the donor ligand on gold(I). Acetylene was generated in situ from calcium carbide and water in a user-friendly procedure. Reaction of acetylene with 1,5-dienes gives rise stereoselectively to tricyclo[5.1.0.02,4]octanes. This novel double cyclopropanation has been applied to the one step total synthesis of the natural product waitziacuminone from acetylene and geranyl acetone. The last decade has witnessed the impact of gold(I) catalysis for the construction of complex organic frameworks,[1] particularly in the realm of the total synthesis of natural products.[2] However, while gold(I)-catalyzed intramolecular transformations usually perform outstandingly, their intermolecular versions are more challenging.[3] Our group demonstrated that the intermolecular reaction between terminal alkynes and alkenes 1 leads selectively to cyclobutenes 3, although 1,3-dienes 4 were also formed with ortho-substituted aryl alkynes (Scheme 1).[4] These two transformations proceed via cyclopropyl gold carbenes 2 that undergo ring expansion or formal 1,3-C migration to afford cyclobutenes 3 or 1,3-dienes 4, respectively.[4c] The synthesis of cyclobutenes by [2+2] cycloaddition is a general reaction that can be carried out enantioselectively,[5] although alkyl-substituted alkynes are poorly reactive partners. Acetylene is a commodity feedstock for the production of vinyl chloride and other products.[6] In stark contrast, its use in homogeneous gold catalysis, especially for the assembly of complex structures, is very limited. So far, acetylene has not been used for the preparation of cyclobutenes 3 or dienes 4. [*] D. Scharnagel, I. Escofet, H. Armengol-Relats, M. E. de Orbe, J. N. Korber, Prof. A. M. Echavarren Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology Av. Països Catalans 16, 43007 Tarragona (Spain) and Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili C/ Marcel·lí Domingo s/n, 43007 Tarragona (Spain) E-mail: aechavarren@iciq.es Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201915895.  2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Interestingly, cyclopropyl gold carbenes 2 with R1 = H, which formally correspond to those that would be generated by reaction of acetylene with an alkene, were shown to be intermediates in the decarbenation of a cyclopropyl-substituted cycloheptatriene.[4c, 7] Herein, we report the use of acetylene gas in intermolecular gold(I)-catalyzed reactions leading, stereoselectively, to Z,Z-dienes 4, biscyclopropanes 5, and tricyclo[5.1.0.02,4]octanes 6 (Scheme 1). Acetylene was conveniently produced in situ in small quantities from calcium carbide and water[8] using a Y shaped two-chamber flask.[9] Several gold(I) catalysts were initially tested in the reaction of acetylene with trans-stilbene (1 a) (Table 1). Gold(I) complexes A and B with JohnPhos as the ligand (Table 1, entries 1 and 2) led to mixtures of 1,3-diene 4 a and biscyclopropane 5 a. While complexes C and D with tBuXPhos as ligand delivered selectively Z,Z-diene 4 a (Table 1, entries 3 and 4), IPr gold(I) complexes E and F favored the formation of 5 a (Table 1, entries 5 and 6).[10] As we have observed before,[4c, 11] complexes D and F with BArF4À as the anion outperform those with SbF6À . The catalytic system based on complex tBuXPhos-gold(I) complex D was further optimized delivering the diene 4 a in 27 % yield (Scheme 2). Substrates with a methyl or tert-butyl group in para position of the stilbene aryl group lead to products 4 b and 4 c with similar results. Noteworthy, the yield with stilbene 1 d with ortho-methyl groups was significantly higher. This is in line with our observations in the reactions of alkenes with aryl alkynes bearing ortho-substituents.[4c] The transformation of 1-naphtyl derivative 1 e gave also small 1  2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Ü Ü Angew. Chem. Int. Ed. 2020, 59, 1 – 5 Scheme 1. General pathways for the reaction of alkynes with alkenes catalyzed by gold(I) catalysts and transformation of acetylene into Z,Zdienes 4, biscyclopropanes 5, or tricyclo[5.1.0.02,4]octanes 6. These are not the final page numbers! Angewandte Communications Table 1: Gold(I) catalyzed reaction of acetylene with stilbene 1 a. Entry [Au] 4 a Yield [%][a] 5 a Yield [%][a] 1 2 3 4 5 6 A B[b] C D E F 24 15 7 25 <1 1 11 41 0 <1 6 56 [a] Yield determined by 1H NMR using diacetyl benzene as internal standard. [b] Reaction with equimolar amounts of B and NaBArF4. Chemie amounts of E,E-4 e in addition to the Z,Z-isomer, usually observed as the sole product. Stilbene 1 f with 3,5-disubstituted aryls afforded diene 4 f in moderate yield. The low to moderate yields result from the competing reaction of 1,3dienes 4 with acetylene leading to oligomerization. Thus, we detected products containing up to 4 units of acetylene by MALDI analysis of the crude reaction mixtures (Scheme 2).[12] Optimization of the catalytic system using complex F led to biscyclopropyl compounds 5 a–c and 5 f in good yields in a biscyclopropanation, in which acetylene behaves as a dicarbene equivalent (Scheme 2). Remarkably, only one diastereomer was observed by NMR, chiral supercritical fluid chromatography and reverse phase ultra-high-performance liquid chromatography. The relative configuration of 5 a was confirmed by X-ray diffraction.[13] The formation of biscyclopropyl derivatives 5 from acetylene is not only applicable to aryl-substituted alkenes but could be also carried out with cyclooctene to form 5 g (Scheme 3). In a competition experiment with equimolar amounts of stilbene 1 c and cyclooctene 1 g, the crossbiscyclopropane 5 h was obtained together with biscyclopropanes 5 c and 5 g. Scheme 3. Biscyclopropanation of cyclooctene. 2 Ü Ü Scheme 2. Synthesis of dienes 4 and biscyclopropyl compounds 5 from acetylene and stilbenes 1 a–f and oligomerization experiments. Yields of isolated products (yields determined by 1H NMR using diacetyl benzene as internal standard in parenthesis); 5 a is shown as a CYLview depiction of the X-ray crystal structure. [a] Isolated as a mixture with starting material. [b] Reaction carried out in chloroform, at 40 8C. [c] Reaction with equimolar amounts of tBuXPhosAuCl and NaBArF4. www.angewandte.org To understand the high selectivity on the formation of the meso-biscyclopropyl products 5 a–c and 5 f, we carried out a DFT study of the reaction of trans-stilbene (1 a) with (h2alkyne)gold(I) complex Int1 a (Scheme 4).[12] As we have shown before,[4c] cyclopropyl gold carbene Int2 a is formed in an exergonic process and it can react further with a second molecule of 1 a to form Int3 a or Int4 a. Formation of Int4 a through TSInt2a-Int4a, which leads to meso-5 a, is 2.7 kcal molÀ1 more favorable than formation of Int3 a, in agreement with the experimental results. Furthermore, 1,5-dienes 7 a–e react with acetylene to form tricyclo[5.1.0.02,4]octanes 6 a–e as single diastereomers in the presence of catalyst D (Scheme 5). The relative configuration of 6 a was assigned by X-ray diffraction.[13] This biscyclopropanation of 1,5-dienes was applied to the first total synthesis of waitziacuminone (9),[14, 15] a sesquiterpene isolated from the aerial parts of Waitzia acuminata, known as orange immortelle, an annual herb native to Australia (Scheme 6). With geranyl acetone (8) as the substrate and catalyst F, the natural product was produced  2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! Angew. Chem. Int. Ed. 2020, 59, 1 – 5 Angewandte Communications Chemie The different pathways for the reaction between acetylene and geranyl acetone (8) were studied computationally[12] (Scheme 7). In principle, four possible cyclopropyl gold carbenes can be formed by reaction of both alkenes of 8 with (h2-alkyne)gold(I) complex Int1 a. The most favorable cyclopropanation gives Int6 a, which immediately undergoes a second cyclopropanation through TSInt6a-Int7a to form Int7 a, and finally waitziacuminone (9). This pathway could compete Scheme 4. Calculated formation of different diastereomers of biscyclopropyl products. L = PMe3. DFT calculations performed with M06-D3/ 6-31G(d) (C, H, P) and SDD (Au) in CH2Cl2 (SMD). Free energies in Kcal molÀ1. Scheme 5. Synthesis of tricyclo[5.1.0.02,4]octanes 6. [a] Isolated as a mixture with various alkene side products [b]. Crude product resubmitted to reaction with acetylene and catalyst D two additional times (total 72 h reaction time). Scheme 6. One step total synthesis of (Æ)-waitziacuminone (9) and Xray crystal structure of its 2,4-dinitrophenylhydrazone 10 (CYLview depiction). Scheme 7. Different mechanistic pathways to form Int7 a,b by double cyclopropanation reactions. L = PMe3. DFT calculations performed with M06-D3/6-31G(d) (C, H, P, O) and SDD (Au) in CH2Cl2 (SMD). Free energies in kcal molÀ1. with the initial cyclopropanation of the internal alkene of 8 leading to Int5 a, which would similarly undergo an intramolecular cyclopropanation to form Int7 a. The two other alternative pathways have slightly higher activation energies and the corresponding intermediates Int5 b and Int6 b would be unproductive, since the second cyclopropanation would generate a highly strained tricyclo[5.1.0.02,4]octane bearing two trans-fused cyclopropanes, as shown by the high activation energies of these endergonic processes. In conclusion, we have developed catalytic systems for the incorporation of acetylene gas into complex frameworks by means of gold(I) catalysis under experimentally very simple conditions. Acetylene is activated by gold(I) as a dicarbene equivalent that allows for the stereoselective synthesis of Z,Zdienes 4, biscyclopropyl compounds 5, and tricyclo[5.1.0.02, 4]octanes 6. The latter transformation was applied to the first total synthesis of the sesquiterpene waitziacuminone (9) by the stereoselective formation of four CÀC bonds and three rings in a single step. as a racemate in only one step as a single diastereomer. The relative configuration of waitziacuminone (9) was confirmed by X-ray diffraction of its crystalline 2,4-dinitrophenylhydrazone 10.[13]  2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3 www.angewandte.org Ü Ü Angew. Chem. Int. Ed. 2020, 59, 1 – 5 These are not the final page numbers! Angewandte Communications Acknowledgements We thank the Agencia Estatal de Investigación (AEI)/ FEDER, UE (CTQ2016-75960-P, FPU predoctoral fellowship to H.A.-R. and Severo Ochoa predoctoral fellowship to M.E.d.O.), the European Research Council (Advanced Grant No. 835080), the AGAUR (2017 SGR 1257), and CERCA Program/Generalitat de Catalunya for financial support. D.S. acknowledges the receipt of a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft. We also thank the ICIQ X-ray diffraction unit and Dr. RØmi Blieck for helpful discussions. Conflict of interest The authors declare no conflict of interest. Keywords: acetylene · cyclopropanation · gold catalysis · total synthesis 4 Ü Ü [1] a) A. M. Echavarren, M. N. Muratore, V. López-Carrillo, A. Escribano-Cuesta, A. Huguet, C. Obradors in Organic Reaction, Vol. 92 (Eds.: S. E. Denmark et al.), Wiley, 2017, pp. 1 – 288; b) R. Dorel, A. M. Echavarren, Chem. Rev. 2015, 115, 9028 – 9072; c) L. Fensterbank, M. Malacria, Acc. Chem. Res. 2014, 47, 953 – 965; d) A. Fürstner, Chem. Soc. Rev. 2009, 38, 3208 – 3221; e) J. W. Boyle, Y. Zhao, P. W. H. Chan, Synthesis 2018, 50, 1402 – 1416; f) D. P. Day, P. W. H. Chan, Adv. Synth. Catal. 2016, 358, 1368 – 1384; g) C. Chen, Y. Zhou, X. Chen, X. Zhang, W. Rao, P. W. H. Chan, Org. Lett. 2016, 18, 4730 – 4733. [2] a) R. Quach, D. P. Furkert, M. A. 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Rev. 2014, 114, ¸ 1761 – 1782. [7] C. R. Solorio-Alvarado, Y. Wang, A. M. Echavarren, J. Am. Chem. Soc. 2011, 133, 11952 – 11955. [8] K. S. Rodygin, G. Werner, F. A. Kucherov, V. P. Ananikov, Chem. Asian J. 2016, 11, 965 – 976. [9] V. V. Voronin, M. S. Ledovskaya, E. G. Gordeev, K. S. Rodygin, V. P. Ananikov, J. Org. Chem. 2018, 83, 3819 – 3828. [10] Several other gold(I) complexes and transition metal salts were screened, but did not show conversion or delivered only traces of 4 a and 5 a. See Supporting Information for details. [11] A. Homs, C. Obradors, D. Leboeuf, A. M. Echavarren, Adv. Synth. Catal. 2014, 356, 221 – 228. [12] See Supporting Information for details. A dataset collection of computational results is available in the ioChem-BD repository and can be accessed through https://doi.org/10.19061/iochem-bd1-148: M. lvarez-Moreno, C. de Graaf, N. Lopez, F. Maseras, J. M. Poblet, C. Bo, J. Chem. Inf. Model. 2015, 55, 95—103. [13] CCDC 1971217, 1971218, 1971429, and 1971216 (5 a, 6 a, 10, epi10) contain the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre. [14] J. Jakupovic, A. Schuster, F. Bohlmann, R. M. King, L. Haegi, Phytochemistry 1989, 28, 1943 – 1948. [15] The myliol family of natural products also contains an embedded tricyclo[5.1.0.02,4]octane, albeit with different relative configuration: S. H. von Reuss, C.-L. Wu, H. Muhle, W. A. Kçnig, Phytochemistry 2004, 65, 2277 – 2291, and references therein. Manuscript received: December 11, 2019 Accepted manuscript online: January 8, 2020 Version of record online: && &&, &&&&  2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! Chemie Angew. Chem. Int. Ed. 2020, 59, 1 – 5 Angewandte Communications Chemie Communications Gold Catalysis D. Scharnagel, I. Escofet, H. Armengol-Relats, M. E. de Orbe, J. N. Korber, A. M. Echavarren* &&&— &&& Acetylene gas behaves as a dicarbene equivalent in the presence of gold(I). This concept has been applied to the one step total synthesis of the natural product waitziacuminone from acetylene and geranyl acetone. Acetylene as a Dicarbene Equivalent for Gold(I) Catalysis: Total Synthesis of Waitziacuminone in One Step  2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5 www.angewandte.org Ü Ü Angew. Chem. Int. Ed. 2020, 59, 1 – 5 These are not the final page numbers!