Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Gold(I)-Catalyzed Heterocyclization− Intermolecular Exo [4 + 3]-Cycloaddition Reactions for the Synthesis of Chiral Oxa-Bridged Benzocycloheptanes Xiaoyu Di,† Yidong Wang,† Lizuo Wu,† Zhan-Ming Zhang,† Qiang Dai,† Wenbo Li,*,† and Junliang Zhang*,†,‡ Org. Lett. Downloaded from pubs.acs.org by UNIV AUTONOMA DE COAHUILA on 04/17/19. For personal use only.
†
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P.R. China ‡ Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 2000438, P.R. China S Supporting Information *
ABSTRACT: The highly exo- and enantioselective goldcatalyzed tandem heterocyclization/[4 + 3] cycloaddition of 2(1-alkynyl)-2-alken-1-ones and 1,3-diphenylisobenzofuran was implemented by utilizing Ming-Phos, which provides a facile access to chiral seven-membered oxa-bridged rings in 80−98% yield with high exo selectivity (exo/endo up to 50:1) and up to 97% ee.
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Scheme 1. Asymmetric Cycloaddition for the Enantioselective Synthesis of the Seven-Membered OxaBridged Ring
he oxa-bridged ring, especially the seven-membered oxabridged ring, has attracted a great deal of interest in past few years because it is ubiquitous in a large number of natural products, synthetic molecules, and versatile intermediates with important biological activity (Figure 1).1 Many cycloadditions
Figure 1. Selected natural products and bioactive compounds containing a chiral oxa-bridged ring.
have been developed for their synthesis in racemic versions, i.e., the [4 + 3] cycloaddition between allyl cations and furans,2 [4 + 3] cycloaddition of 1,4-dicarbonyl compounds with 1,3bis(trimethylsilyl)oxy dienes,3 [5 + 2] annulations between oxidopyrylium and alkenes,4 and so on.5 Despite much progress, the way to efficiently construct a single configuration oxa-bridged ring from readily accessible precursors still remains a significant challenge and is in great demand.2f,6 To address this issue, the Lautens and Davies groups independently reported chiral auxiliary approaches in 1996.7,8 In 2003, Harmata’s group documented the first example of the asymmetric organocatalysis method to construct a sevenmembered oxa-bridged ring.9 In 2004, Hsung’s group reported a Cu(I)/bisoxazoline-catalyzed asymmetric [4 + 3] cycloaddition of furan with nitrogen-stabilized oxyallyl cations (Scheme 1a).10 In 2010, Iwasawa’s group developed a Ptcatalyzed highly enantioselective reaction for the synthesis of © XXXX American Chemical Society
enantioenriched seven-membered oxa-bridged ring via a formal [5 + 2] cycloaddition reaction (Scheme 1b).11 Mascareñas and López’s group demonstrated an elegant gold(I)-catalyzed tandem cyclization and formal [5 + 2]cycloaddition to furnish an optically active oxa-bridged ring (Scheme 1c).12 Received: February 12, 2019
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DOI: 10.1021/acs.orglett.9b00537 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization Reaction Conditionsa
entry
L
AgX
solvent
temp (°C)
yieldb,c (%)
exo/endo
ee (exo/endo)d (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17e 18e 19e 20e
L1 L2 PC1 S,Rs-M1 R,Rs-M1 M2 M3 M4 M4 M4 M4 M4 M4 M4 M4 M4 M4 M4 M4 M4
AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgOMs AgOTf AgPF6 AgBF4 AgBF4 AgBF4 AgBF4 AgBF4 AgBF4 AgBF4 AgBF4 AgBF4
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH3CN DCE THF toluene toluene toluene toluene toluene
rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt 0 −20 −30 −40
77 56 81 87 80 70 92 82 50 75 60 90 41 79 26 80 92 93 98 trace
1:2.5 1:1 1.5:1 3:1 2.3:1 1.5:1 3:1 3:1 1.5:1 3:1 3:1 3:1 1:1.3 6.5:1 4:1 6:1 9:1 11:1 12.5:1
−35/8 −15/44 11/20 56/16 28/6 54/20 58/28 62/39 61/26 62/15 62/12 63/11 80/30 73/31 83/29 78/25 88/21 93/47 96/43
a Reaction conditions: 1a (0.1 mmol), 2 (1.2 equiv), 5 mol % of catalyst, 2 mL of solvent under an atmosphere of nitrogen. bDetermined by 1H NMR analysis using C2H2Cl4 as the internal reference. cThe total yield of exo plus endo. dee value of product is determined by HPLC analysis on a chiral stationary phase. eActivated 4 Å MS was added.
(R,Rs)-M1, the diastereoisomer of (S,Rs)-M1, gave rise to a dramatic decrease in enantioselectivity (Table 1, entry 5). M2−M4 were then subjected to the reaction, and the ee was slightly increased (Table 1, entries 6−8). A quick survey of silver salts such as AgOMs, AgOTf, AgPF6, and AgBF4 showed that AgBF4 is the best salt (Table 1, entries 9−12). When CH3CN was used as the solvent, the reaction gave lower yield with the endo diastereoisomer as the major product. We assume that the CH3CN may bind to the cationic gold catalyst and thus affect the reactivity and selectivity. After further carefully screening the solvent, temperature, and additives (Table 1, entries 13−20), the best reaction conditions were found by using the M4 as the chiral ligand, AgBF4 as the salt, toluene as the solvent, and 4 Å molecular sieves as additives and running the reaction at −30 °C. Under the optimal reaction conditions, the scope of this gold(I)-catalyzed tandem heterocyclization/[4 + 3] cycloaddition was next investigated by variation of the enynones 1 (Scheme 2). Both electron-withdrawing groups and electrondonating group on the aromatic ring R1 were tolerable to afford the desired products 3a−g in good yields (80−98% yield) with good to excellent exo-selectivity (13:1 → 50:1) and 92−97% ee. It is noteworthy that substrates possessing an electron-withdrawing group on the phenyl ring performed better than those with an electron-donating group; for example, when the R1 was a stronger electron-donating group such as 4-methoxyphenyl, the reaction led to a slight decrease in enantioselectivity (3h). By replacing the parasubstituent on phenyl ring R1 with the ortho-substituent, it can also deliver the desired product 3i in good yield and high enantioselectivity (91% ee), with just a slightly lower exo/endo
In 2010, we reported a metal-catalyzed tandem heterocyclization/[4 + 3] cycloaddition of 2-(1-alkynyl)-2-alken-1ones and 1,3-diphenylisobenzofuran to afford the desired achiral oxa-bridged-ring products.13 Unfortunately, only moderate exo/endo ratio was obtained after the systematic screening of many kinds of known chiral ligands. Inspired by our recent success in the design, synthesis, and applications of chiral sulfinamide phosphine ligands such as Ming-Phos,14 PCPhos,15 and so on, we wonder if these chiral ligands could address the low exo/endo and enantioselectivity issue of the above reaction. Herein, we report the highly enantioselective and exo-selective synthesis of enantioenriched oxa-bridged-ring polyheterocycles enabled by gold/Ming-Phos (Scheme 1d). Commercially available chiral ligands such as BIPHEP ligand L1 and phosphoramidite L2 delivered low exo/endo selectivity and ee at the same time (Table 1, entries 1 and 2, and Figure 2). PC-Phos PC1 is not efficient either (Table 1, entry 3). With the use of Ming-Phos (S,Rs)-M1 as the chiral ligand, the reaction proceeded well to afford the exo cycloadduct 3a in good yield with 56% ee as the major isomer (Table 1, entry 4).
Figure 2. Chiral ligands employed in the reaction. B
DOI: 10.1021/acs.orglett.9b00537 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Exploration of Reaction Scopea
a Unless otherwise specified, all the reactions were carried out with 1a (0.1 mmol), 2 (1.1 equiv), 5 mol % of catalyst, and 2 mL of solvent under an atmosphere of nitrogen at −30 °C. The exo/endo ratio was determined by 1H NMR analysis. Isolated yield. bThe reactions were carried out at −20 °C. cThe regioselectivity was determined by HMBC and HSQC.
ratio (10:1). Next, the substituent effect of R2 was evaluated under the optimal conditions. The 4-FC6H4-, 4-ClC6H4-, 4BrC6H4-, 4-CF3C6H4-, 4-NO2C6H4-, 4-MeC6H4-, and 4MeOC6H4-substituted enynones worked well, furnishing the
desired products in 80−96% yields with good exo/endo selectivity and 91−97% ee (3j−x). When R3 was an aryl group, these reactions also smoothly proceeded to provide the C
DOI: 10.1021/acs.orglett.9b00537 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
would mediate the cyclization of enynone 1 to afford a furan gold carbocation intermediate B. The chiral ligand Ming-Phos M4 blocks the top face and thus makes the isobenzofuran more likely to undergo [4 + 3] cycloaddition from under the newly generated furan B. The π−π interaction between the furan and the benzofuran, and the steric demands of the naphthalene group result in the reaction proceeding via the favored transition state C1 to give the exo product 3. In summary, we developed a highly diastereoselective and enantioselective gold(I)/Mingphos-catalyzed tandem heterocyclization/[4 + 3] cycloaddition of 2-(1-alkynyl)-2-alken-1ones and 1,3-diphenylisobenzofuran, which provides a facile access to chiral oxa-bridged-ring polyheterocyclic compounds in good yields with high exo selectivity and up to 97% ee. A gram-scale reaction and a transformation of representative product 3d were investigated to demonstrate the potential synthetic applications of this method. Further explorations of applications in other asymmetric reactions are still ongoing in our group and will be reported in due course.
desired products (3y,z) in 81−83% yield with relatively lower ee value. When unsymmetrical 1-(4-methoxyphenyl)-3-phenylisobenzofuran) was subjected to the reaction, the desired product 3ab was obtained in 81% yield and 86% ee and the exo/endo = 9:1. It is noteworthy that the regioselectivity is very high (>20:1) as determined by crude NMR analysis. When the symmetrical, more electron-rich 1,3-bis(4-methoxyphenyl)isobenzofuran was used, the desired product 3ac could be obtained in good yield but with moderate selectivity. In addition, aliphatic enynones did not undergo enantioselective cycloaddition with the present catalytic system, and only 7% ee was obtained (3δ). Furthermore, a 3 mmol scale reaction was carried out, providing 1.6 g of 3d in 90% yield with 93% ee (eq 1). This
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00537. Experimental procedures, 1H and 13C NMR spectra, and HPLC data for all new products (PDF) Accession Codes
CCDC 1881153 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
result indicates there is no loss of efficiency and selectivity during the scale-up operation. The absolute configuration of the product 3d (4R,9S,10R) was determined by single-crystal X-ray analysis. Compound 3d can be efficiently converted into a useful functionalized oxabicyclic compound 516 in 80% yield with the same enantioselectivity by treatment with 3chloroperoxybenzoic acid (m-CPBA) under mild conditions (eq 2). A plausible reaction pathway for this gold(I)-catalyzed transformation is depicted in Scheme 3. The gold catalyst
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Scheme 3. Proposed Mechanism
Junliang Zhang: 0000-0002-4636-2846 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the Shanghai Sailing Program (16YF1402800), 973 Programs (2015CB856600), National Natural Science Foundation of China (21672067, 21702063), and Changjiang Scholars and Innovative Research Team in University (PCSIRT) for financial support.
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REFERENCES
(1) (a) Christy, M. E.; Boland, C. C.; Williams, J. G.; Engelhardt, E. L. J. Med. Chem. 1970, 13, 191. (b) Battaglia, R.; De Bernardi, M. D.; Mellerio, G. F. G.; Vidari, G.; Vita-Finsi, P. J. Nat. Prod. 1980, 43, 319. (c) Patel, M.; Hegde, P. V.; Horan, A.; Barrett, T.; Bishop, R.; King, A.; Marquez, J.; Hare, R.; Gullo, V. J. Antibiot. 1989, 42, 1063. (d) Huang, K.-S.; Lin, M.; Yu, L.-N.; Kong, M. Tetrahedron 2000, 56, 1321. (e) Jadulco, R. C.; Pond, C. D.; Van Wagoner, R. M.; Koch, M.; Gideon, O. G.; Matainaho, T. K.; Piskaut, P.; Barrows, L. R. J. Nat. Prod. 2014, 77, 183.
D
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Organic Letters (2) (a) Kover, A.; Hoffmann, H. M. R. Tetrahedron 1988, 44, 6831. (b) Huang, H.; Kende, A. S. Tetrahedron Lett. 1997, 38, 3353. (c) Xiong, H.; Hsung, R. P.; Berry, C. R.; Rameshkumar, C. J. Am. Chem. Soc. 2001, 123, 7174. (d) Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058. (e) Lo, B.; Lam, S.; Wong, W.; Chiu, P. Angew. Chem., Int. Ed. 2012, 51, 12120. (f) For a review, see: Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2004, 43, 1934. (3) (a) Molander, G. A.; Cameron, K. O. J. Org. Chem. 1991, 56, 2617. (b) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993, 115, 830. (4) (a) Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001, 123, 5814. (b) Burns, N. Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 14578. (c) Witten, M. R.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2014, 53, 5912. (5) (a) Jiménez-Núñez, E.; Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5452. (b) Oh, C. H.; Lee, J. H.; Lee, S. J.; Kim, J. I.; Hong, C. S. Angew. Chem., Int. Ed. 2008, 47, 7505. (c) Oh, C. H.; Yi, H. J.; Lee, J. H.; Lim, D. H. Chem. Commun. 2010, 46, 3007. (d) Li, B.; Zhao, Y.; Lai, Y.; Loh, T. Angew. Chem., Int. Ed. 2012, 51, 8041. (e) Li, Y.; Dai, M. Angew. Chem., Int. Ed. 2017, 56, 11624. (6) (a) Stark, C. B. W.; Eggert, U.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 1998, 37, 1266. (b) Ivanova, O. A.; Budynina, E. M.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V. Angew. Chem., Int. Ed. 2008, 47, 1107. (c) Gerstner, N. C.; Adams, C. S.; Tretbar, M.; Schomaker, J. M. Angew. Chem., Int. Ed. 2016, 55, 13240. (d) Liang, R.; Ma, T.; Zhu, S. Org. Lett. 2014, 16, 4412. (7) Lautens, M.; Aspiotis, R.; Colucci, J. J. Am. Chem. Soc. 1996, 118, 10930. (8) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem. Soc. 1996, 118, 10774. (9) Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058. (10) Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50. (11) Ishida, K.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2010, 132, 8842. (12) Faustino, H.; Alonso, I.; Mascareñas, J. L.; López, F. Angew. Chem., Int. Ed. 2013, 52, 6526. (13) Gao, H.; Wu, X.; Zhang, J. Chem. Commun. 2009, 46, 8764. (14) For applications of Ming-Phos in asymmetric catalysis, see: (a) Chen, M.; Zhang, Z.-M.; Yu, Z.; Qiu, H.; Ma, B.; Wu, H.-H.; Zhang, J. ACS Catal. 2015, 5, 7488. (b) Zhang, Z.-M.; Xu, B.; Xu, S.; Wu, H.-H.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 6324. (c) Xu, B.; Zhang, Z.-M.; Xu, S.; Liu, B.; Xiao, Y.; Zhang, J. ACS Catal. 2017, 7, 210. (d) Wang, Y.; Zhang, Z.-M.; Liu, F.; He, Y.; Zhang, J. Org. Lett. 2018, 20, 6403. (e) For a review on the chiral ligand designed by Chinese chemists, see: Liu, Y.; Li, W.; Zhang, J. Natl. Sci. Rev. 2017, 4, 326. (15) For applications of PC-Phos in asymmetric catalysis, see: (a) Wang, Y.; Zhang, P.; Di, X.; Dai, Q.; Zhang, Z.-M.; Zhang, J. Angew. Chem., Int. Ed. 2017, 56, 15905. (b) Wang, L.; Chen, M.; Zhang, P.; Li, W.; Zhang, J. J. Am. Chem. Soc. 2018, 140, 3467. (16) (a) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48. (b) Hosomi, A.; Tominaga, Y. In Comprehensive Organic Synthesis; Trost, B., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5, Chapter 5.1, p 593. (c) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1. (d) Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163.
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DOI: 10.1021/acs.orglett.9b00537 Org. Lett. XXXX, XXX, XXX−XXX
