Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Asymmetric Diels−Alder Reaction of 3‑Vinylindoles and Nitroolefins Promoted by Multiple Hydrogen Bonds Xi Yang,† Yu-Hao Zhou,† Han Yang,† Shan-Shan Wang,† Qin Ouyang,‡ Qun-Li Luo,† and Qi-Xiang Guo*,†
Org. Lett. Downloaded from pubs.acs.org by AUCKLAND UNIV OF TECHNOLOGY on 01/30/19. For personal use only.
†
Key Laboratory of Applied Chemistry of Chongqing Municipality and Chongqing Key Laboratory of Soft-Matter Material Chemistry and Function Manufacturing, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China ‡ College of Pharmacy, Third Military Medical University, Chongqing 400038, China S Supporting Information *
ABSTRACT: The first catalytic asymmetric Diels−Alder reaction of 3-vinylindole and nitroolefin is described. In the promotion of organocatalyst 3j, structurally diverse 1-nitrohydrocarbazoles are produced in moderate-to-good yields and high-to-excellent enantioselectivities. All of these products are obtained as a single diastereoisomer. The 1-nitro-hydrocarbazole compounds can be converted into 1-aminohydrocarbazole derivatives and structurally complex ringfused indoles enantioseletively. Possible transition states were investigated by control experiments and DFT calculations.
N
the construction of chiral indole compounds with complex molecular structures.10 For example, 3-vinylindoles have been successfully applied as dienes in the preparation of ring-fused chiral indole compounds,11 as nucleophiles to react with imines and carbonyl compounds,12 and as dipolarophiles,13 electrophiles,14 and dienophiles15 for the construction of chiral 3-substituted indoles. Among these reactions, the cycloaddition of 3-vinylindole with various dienophiles is an excellent strategy for the construction of hydrocarbazole skeletons. Many studies have investigated this type of transformation using catalytic asymmetric methods. α,βUnsaturated carbonyl derivatives, including conjugated enones, enals, imides, and quinones, have been the most commonly used dienophiles. Nitroolefins, which are highly important electrophiles and dienophiles, have been applied in numerous catalytic asymmetric organic reactions but have not been reacted as dienophiles with 3-vinylindoles, no matter by organo- or organometallic catalysis. Nitroolefins are ideal sources of nitrogen, making them suitable reagents for the construction of 1-amino-hydrocarbazole precursors (Figure 2).
atural products provide synthetic chemists with much inspiration for the design and preparation of new biologically active compounds. Preparing compounds containing core frameworks that are the same as or similar to those of natural products is among the most important synthetic approaches to drug candidate discovery. 1-Amino-hydrocarbazole is an important structural unit frequently found in the akuammiline alkaloids.1 Examples include aspidophylline A,2 lonicerine,3 picrinine,4 aspidodasycarpine,5 strictamine,1a scholarisine,6 cathafoline,2c lanciferine,7 and akuammigine8 (Figure 1). As many akuammiline alkaloids exhibit exciting biological activities,9 the preparation of chiral 1-aminohydrocarbazole derivatives has attracted interest for the discovery of akuammiline analogues with potentially good biological profiles. 3-Vinylindole is an important 3-functionalized indole reagent with derivatives that are versatile building blocks for
Figure 2. Our strategy for construction of the 1-amino-hydrocarbazole skeleton. Figure 1. Representative natural products containing 1-aminohydrocarbazole units. © XXXX American Chemical Society
Received: January 9, 2019
A
DOI: 10.1021/acs.orglett.9b00104 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Herein, we disclose the first Diels−Alder reaction of 3vinylindoles and nitroolefins. Various 1-nitro-tetrahydrocarbazoles were prepared in good-to-high yields with good-toexcellent enantioselectivities and converted into structurally diverse ring-fused chiral indole compounds. Initially, the catalytic asymmetric reaction of 3-vinylindole 1a and nitroolefin 2a was evaluated. Numerous studies have indicated that nitroolefins can be activated using a hydrogenbond donor catalyst,16 while the nucleophilic ability of 3vinylindoles can be enhanced by a hydrogen-bond acceptor catalyst.11−13 Therefore, a chiral tertiary amine thiourea catalyst was a suitable choice for this reaction. In the presence of catalyst 3a, 1-nitro-tetrahydracarbazole 4a was generated in moderate yield, but with very low enantioselectivity (Table 1,
amine and thiourea units of 3a to afford catalysts 3b−3f. As expected, catalyst 3b greatly increased the yield and enantioselectivity of 4a (Table 1, entry 2). Catalysts 3c−3f were also screened in this reaction, with tertiary leucinederived catalyst 3e increasing the enantioselectivity of 4a to 83% ee (Table 1, entry 5). Next, we replaced the quinine unit of 3e with a 1,2-diphenylethane-1,2-diamine skeleton to give catalysts 3g−3i, among which 3g, 3i, and 3j gave comparable experimental outcomes to 3e. Lowering the reaction temperature also enhanced the enantioselectivity (Table 1, entries 11−17), but only catalyst 3j gave a satisfactory yield under these conditions (Table 1, entry 14). Solvent screening indicated that xylene gave both the best yield and enantioselectivity (Table 1, entries 14 and 18−23). Reaction additives were also investigated. Adding H2O (20 μL) gave product 4a in 63% yield and 91% ee (Table 1, entry 25). The optimal reaction conditions were thus determined from these results. With optimal reaction conditions in hand, we next examined the substrate scope of this reaction. First, substituted phenyl groups were introduced at the β-position of nitroolefin 2. Nitroolefins bearing para-, meta-, or ortho-substituted phenyls gave corresponding products in good yields and excellent enantioselectivities (Table 2, entries 1−8). Nitroolefins having
Table 1. Catalyst Screening and Reaction Condition Optimizationa
entry
3
solvent
T (°C)
t (h)
y (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3j 3j 3j 3j 3e 3g 3i 3j 3j 3j 3j 3j 3j 3j 3j
xylene xylene xylene xylene xylene xylene xylene xylene xylene xylene xylene xylene xylene xylene xylene xylene xylene DCM hexane PhCl CHCl3 PhF toluene THF xylene
50 50 50 50 50 50 50 50 50 50 40 30 20 0 0 0 0 0 0 0 0 0 0 0 0
48 24 24 24 24 24 24 24 24 24 36 48 48 72 72 72 72 72 72 72 72 72 72 72 48
48 71 58 74 68 67 60 65 61 58 52 51 54 55 41 41 51 53 29 55 66 50 54 trace 63
6 75 72 68 83 75 83 76 83 83 85 87 89 91 86 92 90 75 66 89 75 88 91 − 91d
Table 2. Substrate Scope of Nitroolefinsa
entry
4
R1
t (h)
y (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4a
4-ClC6H5 4-CF3C6H5 4-OMeC6H5 3-BrC6H5 3-NO2C6H5 3-OMeC6H5 2-BrC6H5 2-CF3C6H5 3,4−2MeC6H5 2,4−2ClC6H5 1-naphthyl 2-naphthyl 2-furyl 2-thienyl n-propyl n-butyl c-hexyl C6H5
48 48 72 48 48 72 48 48 72 60 72 48 72 72 72 72 72 48
66 68 52 53 65 55 60 70 62 57 69 62 49 60 57 44 56 62
92 90 91 91 89 91 87 86 91 90 91 92 90 92 89 88 90 84d
a
Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), 3j (0.01 mmol), and xylene (1 mL). bIsolated yield. cDetermined by chiral HPLC. dAt a 1 mmol scale.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), 3 (0.01 mmol), and solvent (1 mL). bIsolated yield. cDetermined by chiral HPLC. d 20 μL of H2O was added.
two substituents were also good reaction partners in this reaction, giving products 4j and 4k in good experimental outcomes (Table 2, entries 9−10). For all phenyl-substituted nitroolefin substrates, substituent electronic effects had no obvious influence on the yields and stereoselectivities. Other aryl-substituted nitroolefins were also examined in this reaction. Naphthyl, furyl, and thienyl-substituted dienophiles showed good reaction activity and gave the corresponding products in good yields and excellent enantioselectivities
entry 1). Notably, a single diastereomer was obtained in this reaction. Multiple-hydrogen bond catalysis has proven to be a good strategy for many organic transformations, especially for asymmetric reactions involving nitro compounds.17 We expected increasing the amount of hydrogen donor sites to enhance the enantioselectivity of this reaction. Inspired by Jiang’s work,18 an amino acid unit was inserted into the tertiary B
DOI: 10.1021/acs.orglett.9b00104 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (Table 2, entries 11−14). Alkyl-substituted nitroolefins were also good reaction partners, as exemplified by n-propyl, n-butyl, and cyclohexyl-substituted substrates 2, which participated smoothly in the reaction to give the corresponding products in satisfactory yields and high enantioselectivities (Table 2, entries 15−17). Next, the substrate scope of 3-vinylindoles was investigated. The position and electronic properties of substituents had clear effects on the yield and enantioselectivity. 3-Vinylindoles bearing an electron-withdrawing group at the 5-position generated the corresponding products in satisfactory yields and high enantioselectivities (Table 3, entries 1 and 2).
Scheme 1. Subsequent Product Transformations
The absolute configuration of the new generated chiral carbon center of 8a was determined by 2D NMR (see the Supporting Information). The possible reaction mechanism was then studied. We found the N-Me 1a could not react with 2a in the promotion of 3j, which maybe indicated that there existed a hydrogen bond interaction between the 3-vinylindole and catalyst (Figure 3, a). In principle, the thiourea group of 3j was to
Table 3. Substrate Scope of 3-Vinylindolesa
entry
5
R1/R2/R3
R4
t (h)
y (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10
5a 5b 5c 5d 5e 5f 5g 5h 5i 5j
5-Br/H/H 5-Cl/H/H 5-Me/H/H 6-Br/H/H 6-Me/H/H 4-Me/H/H H/H/H H/H/Me H/Ph/H H/H/He
H H H H H H Me H H 2be
72 72 48 72 48 48 72 48 48 48
61 53 41 38 30 29 16 NRd NRd NRd
93 90 84 88 78 86 93 − − −
a
Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), 3j (0.01 mmol), and xylene (1 mL). bIsolated yield. cDetermined by chiral HPLC. d NR = no reaction. e2b = N-Bn maleimide.
However, introducing an electron-donating substituent at the 5-position greatly decreased the yield, albeit with high enantioselectivity maintained (Table 3, entry 3). Installing an electron-donating or electron-withdrawing substituent at the 6position of 3-vinylindole resulted in decreased yields (Table 3, entries 4 and 5). 4-Methyl-3-vinylindole also gave product 5f in a low yield (Table 3, entry 6). A nitroolefin bearing a 2methyl group also reacted with 3-vinylindole but gave only a 16% yield (Table 3, entry 7). Fortunately, these products retained high enantioselectivities. The model reaction could be scaled up to 1 mmol, giving product 4a in 61% yield and 84% ee (Table 2, entry 18). The absolute configuration of 4a (S, S, S) was established by X-ray single-crystal analysis. The stereochemistry of compounds 4 and 5 was assigned by comparison with that of 4a (see the Accession Codes section). The resulting Diels−Alder products were readily converted into 1-amino-tetrahydrocarbazole derivatives. For example, the nitro group in compound 4a was reduced to the corresponding amino, affording product 6a in 70% yield. Subsequently, amino groups were protected with benzoyl groups to give compound 7a, which then underwent an ene-reaction with nitrosobenzene to give 1,4-diamino-tetrahydrocarbazole 8a in excellent yield (Scheme 1, a). Compound 4h bearing an O-Br phenyl group was first reduced to afford 1-amino-tetrahydrocarbazole 6b and then underwent an intramolecular Ullmann coupling to give chiral hexahydroindolo[2,3-a]carbazole 7b in high yield (Scheme 1, b). In both cases, final products 8a and 7b were generated in high yields and with good enantioselectivities.
Figure 3. Transition states study.
activate the nitroolefin via the formation of double hydrogen bonds.18 So, two possible transition states (TS I and TS II) were proposed to explain the observed stereoselectivities. DFT calculations showed that the energy of TS II was 6.7 kcal/mol higher than that of TS I. That is to say, catalyst 3j was preferably providing its carbonyl, not tertiary amine group, to activate the 3-vinylindole 1a via the formation of a hydrogen bond (Figure 3, b). Based on these results, a new, simple, chiral carbonyl−thiourea organocatalyst 3k was designed to promote this reaction, leading to product 4a in 46% yield and 34% ee (Figure 3, c), which was better that that obtained from catalyst 3a (48% yield, 6% ee) (Table 1, entry 1). To the best of our knowledge, it was the first example to reveal that the chiral carbonyl−thiourea catalyst could promote an asymmetric organic reaction. This was an interesting discovery for the development of novel chiral carbonyl−hydrogen bond organocatalysts. In conclusion, we have described the first Diels−Alder reaction of 3-vinylindoles and nitroolefins. Various structurally diverse 1-nitro-tetrahydrocarbazoles were produced in moderate-to-good yields with good-to-excellent enantioselectivities. C
DOI: 10.1021/acs.orglett.9b00104 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(6) (a) Wang, D.; Hou, M.; Ji, Y.; Gao, S. Org. Lett. 2017, 19, 1922. (b) Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137, 6712. (c) Smith, M.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135, 12964. (d) Adams, G. L.; Carroll, P. J.; Smith, A. B. J. Am. Chem. Soc. 2012, 134, 4037. (e) Adams, G. L.; Carroll, P. J.; Smith, A. B. J. Am. Chem. Soc. 2013, 135, 519. (7) Beniddir, M. A.; Genta-Jouve, G.; Lewin, G. J. Nat. Prod. 2018, 81, 1075−1078. (8) (a) Laus, G.; Wurst, K. Helv. Chim. Acta 2008, 91, 831. (b) Robinson, R.; Thomas, A. F. J. Chem. Soc. 1954, 3479. (9) Ramirez, A.; Garcia-Rubio, S. Curr. Med. Chem. 2003, 10, 1891. (10) For review, see: (a) Rossi, E.; Abbiati, G.; Pirovano, V. Eur. J. Org. Chem. 2017, 2017, 4512. (b) Gioia, C.; Bernardi, L.; Ricci, A. Synthesis 2010, 2010, 161. (11) (a) Tan, B.; Hernández-Torres, G.; Barbas, C. F., III J. Am. Chem. Soc. 2011, 133, 12354. (b) Zheng, H.; Liu, X.; Xu, C.; Xia, Y.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2015, 54, 10958. (c) Wang, Y.; Zhang, P.; Liu, Y.; Xia, F.; Zhang, J. Chem. Sci. 2015, 6, 5564. (d) Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236. (e) Zheng, H.; He, P.; Liu, Y.; Zhang, Y.; Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2014, 50, 8794. (f) Enders, D.; Joie, C.; Deckers, K. Chem. - Eur. J. 2013, 19, 10818. (g) Harada, S.; Morikawa, T.; Nishida, A. Org. Lett. 2013, 15, 5314. (h) Pirovano, V.; Borri, M.; Abbiati, G.; Rizzato, S.; Rossi, E. Adv. Synth. Catal. 2017, 359, 1912. (i) Xiao, Y.-C.; Yue, C.-Z.; Chen, P.-Q.; Chen, Y.-C. Org. Lett. 2014, 16, 3208. (j) Cowell, J.; Harrington, R. W.; Probert, M. R.; Hall, M. J. Tetrahedron: Asymmetry 2015, 26, 1189. (k) Huang, Y.; Song, L.; Gong, L.; Meggers, E. Chem. - Asian J. 2015, 10, 2738. (12) (a) Xue, J.-H.; Shi, M.; Yu, F.; Li, X.-Y.; Ren, W.; Fu, L.-N.; Guo, Q.-X. Org. Lett. 2016, 18, 3874. (b) Li, X.-Y.; Yuan, W.-Q.; Tang, S.; Huang, Y.-W.; Xue, J.-H.; Fu, L.-N.; Guo, Q.-X. Org. Lett. 2017, 19, 1120. (13) (a) Zhang, C.; Zhang, L.-X.; Qiu, Y.; Xu, B.; Zong, Y.; Guo, Q.X. RSC Adv. 2014, 4, 6916. (b) Li, C.; Xu, D.-N.; Ma, C.; Mei, G.-J.; Shi, F. J. Org. Chem. 2018, 83, 9190. (c) Sun, X.-X.; Zhang, H.-H.; Li, G.-H.; Meng, L.; Shi, F. Chem. Commun. 2016, 52, 2968. (d) Fan, T.; Zhang, H.-H.; Li, C.; Shen, Y.; Shi, F. Adv. Synth. Catal. 2016, 358, 2017. (14) (a) Terada, M.; Moriya, K.; Kanomata, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2011, 50, 12586. (b) Wang, Z.; Ai, F.; Wang, Z.; Zhao, W.; Zhu, G.; Lin, Z.; Sun, J. J. Am. Chem. Soc. 2015, 137, 383. (c) Zhang, Y.; Zhang, S.-X.; Fu, L.-N.; Guo, Q.-X. ChemCatChem 2017, 9, 3107. (15) (a) Bergonzini, G.; Gramigna, L.; Mazzanti, A.; Fochi, M.; Bernardi, L.; Ricci, A. Chem. Commun. 2010, 46, 327. (b) Mao, Z.; Lin, A.; Shi, Y.; Mao, H.; Li, W.; Cheng, Y.; Zhu, C. J. Org. Chem. 2013, 78, 10233. (c) Zhang, H. H.; Sun, X. X.; Liang, J.; Wang, Y. M.; Zhao, C. C.; Shi, F. Org. Biomol. Chem. 2014, 12, 9539. (d) Mao, Z.; Lin, A.; Shi, Y.; Mao, H.; Li, W.; Cheng, Y.; Zhu, C. J. Org. Chem. 2013, 78, 10233. (16) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (17) (a) Fang, X.; Wang, C.-J. Chem. Commun. 2015, 51, 1185. (b) Zhang, Z.-H.; Dong, X.-Q.; Tao, H.-Y.; Wang, C.-J. Asymmetric amination of cyclic β-keto esters catalyzed by amine-thiourea bearing multiple hydrogen bonding donors. ARKIVOC 2010, 2011 (2), 137− 150. (c) Dong, X.-Q.; Teng, H. L.; Wang, C.-J. Org. Lett. 2009, 11, 1265. (d) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008, 130, 8606. (e) Wang, C.-J.; Zhang, Z.H.; Dong, X.-Q.; Wu, X.-J. Chem. Commun. 2008, 12, 1431. (f) Zhang, Z.-H.; Dong, X.-Q.; Chen, D.; Wang, C.-J. Chem. - Eur. J. 2008, 14, 8780. (18) (a) Zhu, B.; Qiu, S.; Li, J.; Coote, M. L.; Lee, R.; Jiang, Z. Chem. Sci. 2016, 7, 6060. (b) Jiao, L.; Zhao, X.; Liu, H.; Ye, X.; Jiang, Z.; Li, Y. Org. Chem. Front. 2016, 3, 470. (c) Li, J.; Qiu, S.; Ye, X.; Zhu, B.; Liu, H.; Jiang, Z. J. Org. Chem. 2016, 81, 11916.
Notably, all products were generated as single diastereomers. Under mild reaction conditions, 1-nitro-tetrahydrocarbazoles could be converted into 1-amino-hydrocarbazoles and other ring-fused indole compounds in good yields with high enantioselectivities. Control experiments and DFT calculations showed that the amide group of 3j acted as a hydrogen bond acceptor to activate 3-vinylindole reactants.
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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.9b00104. Experimental procedures, analytical data, and NMR and HPLC spectra (PDF) Accession Codes
CCDC 1880243 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.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Qin Ouyang: 0000-0002-1161-5102 Qun-Li Luo: 0000-0002-9724-5674 Qi-Xiang Guo: 0000-0002-0405-7958 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21272002, 21472150, 21871223) and the Chongqing Science Technology Commission (cstccxljrc201701, cstc2018jcyjAX0548).
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REFERENCES
(1) For reviews, see: (a) Liu, X.; Xiao, T.; Qin, Y. Total Synthesis of the Akuammiline Alkaloid Strictamine. Progress in Chemistry 2018, 30, 578−585. (b) Smith, J. M.; Moreno, J.; Boal, B. W.; Garg, N. K. Angew. Chem., Int. Ed. 2014, 54, 400. (c) Adams, G. L.; Smith, A. B.; Knçlker, H.-J. The Alkaloids: Chemistry and Biology 2016, 76, 171− 257. (2) (a) Wang, T.; Duan, X.; Zhao, H.; Zhai, S.; Tao, C.; Wang, H.; Li, Y.; Cheng, B.; Zhai, H. Org. Lett. 2017, 19, 1650. (b) Jiang, S.-Z.; Zeng, X.-Y.; Liang, X.; Lei, T.; Wei, K.; Yang, Y.-R. Angew. Chem., Int. Ed. 2016, 55, 4044. (c) Moreno, J.; Picazo, E.; Morrill, L. A.; Smith, J. M.; Garg, N. K. J. Am. Chem. Soc. 2016, 138, 1162. (d) Teng, M.; Zi, W.; Ma, D. Angew. Chem., Int. Ed. 2014, 53, 1814. (e) Ren, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2014, 53, 1818. (f) Li, Q.; Li, G.; Ma, S.; Feng, P.; Shi, Y. Org. Lett. 2013, 15, 2601. (g) Zu, L.; Boal, B.; Garg, N. J. Am. Chem. Soc. 2011, 133, 8877. (3) Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982. (4) (a) Smith, J. M.; Moreno, J.; Boal, B. M.; Garg, N. K. J. Org. Chem. 2015, 80, 8954. (b) Smith, J. M.; Moreno, J.; Boal, B. M.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 4504. (c) Cai, X.-H.; Liu, Y.-P.; Feng, T.; Luo, X.-D. Chin. J. Nat. Med. 2008, 6, 20. (5) Ohashi, M.; Joule, J. A.; Djerassi, C. Tetrahedron Lett. 1964, 5, 3899. D
DOI: 10.1021/acs.orglett.9b00104 Org. Lett. XXXX, XXX, XXX−XXX
