Letter pubs.acs.org/OrgLett
Catalytic Asymmetric Construction of the Tryptanthrin Skeleton via an Enantioselective Decarboxylative [4 + 2] Cyclization Guang-Jian Mei,* Chen-Yu Bian, Guo-Hao Li, Shao-Li Xu, Wen-Qin Zheng, and Feng Shi* School of Chemistry and Material Science, Jiangsu Normal University, Xuzhou 221116, China S Supporting Information *
ABSTRACT: The first catalytic asymmetric construction of the tryptanthrin skeleton has been established, taking advantage of a palladium(0)/chiral ligand-catalyzed enantioselective decarboxylative [4 + 2] cyclization of vinyl benzoxazinanones with isatins. This reaction has not only provided a direct and efficient method for constructing chiral tryptanthrin skeleta in high yields and excellent enantioselectivities (up to 97% yield, >99% ee) but also represents the first catalytic asymmetric decarboxylative cyclization of vinyl benzoxazinanones with isatins.
T
Pd(0) and ligand (L),5,6 which can then act as four-atom building blocks for tandem cyclizations with other reagents (Scheme 1).7−9 As a result, this type of reactant has been successfully
ryptanthrin (I) skeleta belong to a class of privileged scaffolds, which are widely found in bioactive natural alkaloids and synthetic compounds (Figure 1).1 In particular,
Scheme 1. Profile of Vinyl Benzoxazinanone-Involved Catalytic Asymmetric Cyclizations
Figure 1. Bioactive alkaloids containing the tryptanthrin scaffold.
employed in catalytic enantioselective [4 + 1],7a [4 + 2],8 and [4 + 3]9 cyclizations with sulfur ylides, electron-deficient alkenes, and enals (eq 1−3), respectively, in the presence of a chiral ligand (L*) or a chiral N-heterocyclic carbene (NHC*), which efficiently constructed five- to seven-membered nitrogenous heterocycles with enantiopurity. The successful applications of vinyl benzoxazinanones in catalytic asymmetric cyclizations triggered us to envision whether this class of reactants could be used for constructing tryptanthrin skeleta in an enantioselective mode. Based on our previous experiences in constructing chiral heterocyclic frameworks via catalytic asymmetric reactions,10 we designed a palladium(0)/chiral ligand-catalyzed asymmetric decarboxylative cyclization of vinyl benzoxazinanones 1 with
alkaloids II−VIII with one or two stereocenters possess a broad range of bioactivities such as antibacterial, antiparasitic, antitubercular, antimalarial, and antitumor properties.1 Stimulated by the unique structure and biological significance of tryptanthrin skeleta, the construction of this type of nucleus has received increasing attention from the chemistry community.2−4 Yet, nearly all of the methods have been focused on the construction of achiral or racemic tryptanthrin skeleta,2,3 and no catalytic asymmetric methods have been devised for the direct construction of enantioenriched tryptanthrin scaffolds.4 So, it has become an urgent task to develop a direct and catalytic asymmetric strategy for the construction of tryptanthrin skeleta in an enantioselective fashion. In recent years, vinyl benzoxazinanones have been recognized as a class of competent reactants for catalytic asymmetric cyclizations because they can easily transform into Pd-stabilized zwitterionic intermediates via decarboxylation in the presence of © 2017 American Chemical Society
Received: May 3, 2017 Published: May 25, 2017 3219
DOI: 10.1021/acs.orglett.7b01336 Org. Lett. 2017, 19, 3219−3222
Letter
Organic Letters isatins 2 for the construction of chiral tryptanthrin skeleta 3 in an enantioselective style. As illustrated in Scheme 2, vinyl
Table 1. Ligands and Model Reaction Employed for Condition Optimizationa
Scheme 2. Design of Catalytic Asymmetric Cyclization for the Construction of Chiral Tryptanthrin Skeleton
benzoxazinanones 1 could convert into Pd-stabilized zwitterionic intermediates A via decarboxylation under the catalysis of a palladium(0)/chiral ligand. Then, the amide N−H group of isatins 2 would attack the intermediates A to carry out an enantioselective allylic amination with branched selectivity, which would give rise to another intermediates B with the formation of the stereogenic center. Finally, an intramolecular condensation of the intermediates B would lead to the construction of the desired chiral tryptanthrin skeleta 3. Although this strategy sounds feasible, there are still some challenges embedded in this design. The first one is controlling the chemoselectivity of the reaction because the carbonyl group (CO) of isatins in most cases exhibits high reactivity which, in principle, can undergo a decarboxylative [4 + 2] cyclization with vinyl benzoxazinanones 1 to generate the byproducts 4.11 The second challenge is controlling the branch/linear selectivity in the allylic amination step;12−14 otherwise, byproducts 5 from ring opening would be generated. The final challenge is controlling the enantioselectivity of the reaction. In spite of these challenges, we decided to try the designed reaction and overcome these difficulties to realize the catalytic asymmetric construction of tryptanthrin skeleta. Initially, the catalytic asymmetric decarboxylative [4 + 2] cyclization of vinyl benzoxazinanone 1a with isatin 2a was employed as a model reaction to test our hypothesis (Table 1). First, we carried out an investigation to find an effective chiral ligand (entries 1−9). The desired product 3aa was successfully obtained in the presence of the axially chiral phosphoramidite L1, but in a low yield and with a low enantioselectivity of 20% ee (entry 1). Although the other axially chiral phosphoramidites L2−L5 could improve the yields to a high level, they all failed to improve the enantioselectivities (entries 2−5). Besides, the bidentate ligand L6 only gave a racemic product (entry 6). Then, spiro-phosphoramidites L7−L8 were examined (entries 7−8), which revealed that L7, with less steric hindrance, could give the desired product 3aa in an excellent yield but with low enantioselectivity (entry 7), while L8, with larger steric hindrance, failed to catalyze the reaction (entry 8). Gratifyingly, chiral monodentate spiro-phosphine L9, which was developed by the Zhou group,15 furnished the desired product in a high yield of 80% with the best enantioselectivity of 64% ee (entry 8 vs 1−7).
entry
ligand
solvent
t (h)
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15e 16f 17e
L1 L2 L3 L4 L5 L6 L7 L8 L9 L9 L9 L9 L9 L9 L9 L9 L10
DCM DCM DCM DCM DCM DCM DCM DCM DCM CHCl3 toluene THF 1,4-dioxane 1,4-dioxane 1,4-dioxane/toluene = 1:1 1,4-dioxane/toluene = 1:1 1,4-dioxane/toluene = 1:1
3.5 3.5 2.5 3.5 8.0 8.0 2.5 8.0 8.0 8.0 8.0 8.0 8.0 30 30 30 30
20 98 97 98 65 40 96 0 80 78 86 95 97 97 96 68 95
20 0 8 16 34 0 4 − 64 60 84 84 84 86 88 88 95
a
Unless otherwise indicated, the reaction was carried out at 0.05 mmol scale and catalyzed by 5 mmol % Pd2(dba)3·HCl3 with 10 mmol % ligand in a solvent (1 mL) at 25 °C, and the molar ratio of 1a:2a was 1:1.2. bIsolated yield. cThe ee value was determined by HPLC. d Performed at 10 °C. ePerformed at 0 °C. fPerformed at −10 °C.
Encouraged by this result, the solvent effect was investigated (entries 9−13). It was found that changing the solvent from dichloromethane to 1,4-dioxane led to a great increase in the enantioselectivity (entry 9 vs 13). In addition, the enantioselectivity could be further improved at a lower temperature, although a prolonged reaction time was needed (entries 14−16). Finally, the best reaction conditions were established to be those found in entry 15, which could deliver the reaction in an excellent yield of 96% with a high enantioselectivity of 88% ee in a mixed solvent of 1,4-dioxane and toluene at 0 °C. Notably, when L10 bearing a similar structure with L9 was employed in the reaction under the optimal conditions, a higher enantioselectivity of 95% ee was obtained (entry 17). After establishing the optimal reaction conditions for our process, we investigated the substrate scope of isatins 2 for the construction of chiral tryptanthrin skeleta. As shown in Figure 2, this decarboxylative [4 + 2] cyclization could be applicable to a variety of isatins 2 bearing various substituents on the different positions of the phenyl ring, affording chiral tryptanthrin 3220
DOI: 10.1021/acs.orglett.7b01336 Org. Lett. 2017, 19, 3219−3222
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Organic Letters
Figure 2. Substrate scope of isatins 2. Unless otherwise indicated, the reaction was carried out at 0.1 mmol scale and catalyzed by 5 mmol % Pd2(dba)3·HCl3 with 10 mmol % L9 in 2 mL of toluene/1,4-dioxane (1:1) at 0 °C for 30 h, and the molar ratio of 1:2 was 1:1.2. The yield referred to the isolated yield, and the ee value was determined by HPLC. Products 3ab, 3ae, 3ah, and 3ai were synthesized in the presence of 10 mmol % L10 instead of L9.
Figure 3. Substrate scope of vinyl benzoxazinanones 1. Unless otherwise indicated, the reaction was carried out at 0.1 mmol scale and catalyzed by 5 mmol % Pd2(dba)3·HCl3 with 10 mmol % L9 in 2 mL of toluene/1,4dioxane (1:1) at 0 °C for 30 h, and the molar ratio of 1:2 was 1:1.2. The yield referred to the isolated yield, and the ee value was determined by HPLC. Products 3ba, 3da, 3ea, 3ga, 3ha, and 3ia were synthesized in the presence of 10 mmol % L10 instead of L9.
derivatives 3 in generally good yields (55% to 82%) and excellent enantioselectivities (80% to >99% ee). It seems that the position of the substituents exerts some effect on the enantioselectivity, because a C4-bromo-substituted substrate generated the product 3af with a much higher enantioselectivity than C5- and C6bromo-substituted counterparts (3af vs 3ac and 3ae). In addition, disubstituted isatins could also be applied to the reaction, which delivered the corresponding products 3ah and 3bh in good-toexcellent enantioselectivities. Next, the substrate scope of the vinyl benzoxazinanones 1 was studied by reactions with isatin 2a or 2f (Figure 3). Obviously, this catalytic asymmetric decarboxylative [4 + 2] cyclization was amenable to a wide range of vinyl benzoxazinanones 1 with electronically distinct substituents at different positions of the phenyl ring, which constructed the chiral tryptanthrin scaffolds 3 in overall good yields with high enantioselectivities (up to 97% yield, 96% ee). The electronic nature of the substituents seems to have some influence on the enantioselectivity. For instance, C6methoxy- or C6-methyl-substituted vinyl benzoxazinanones afford the products 3fa and 3da with much better enantioselectivity than C6-chloro- or C6-bromo-substituted analogues (3fa and 3da vs 3ea and 3ha). Besides, the positions of the substituents also impose a delicate effect on controlling the reactivity and enantioselectivity. For example, a C8-methyl-substituted substrate was superior to the C6-methyl-substituted counterpart in terms of the yield and enantioselectivity (3ba vs 3da). A C7chloro-substituted substrate delivered the product 3ca in a much better yield with higher enantioselectivity than the product 3ea, which was generated from the C6-chloro-substituted substrate. In addition, C7,C8-dimethyl-substituted benzoxazinanone could serve as a competent substrate, which generated products 3ga and 3gf in good-to-excellent yields with high enantioselectivities. Notably, all of the reactions proceeded in an exclusively chemoselective and branch-selective manner. No byproducts 4 and 5 were observed. The absolute configuration of product 3aa (99% ee after recrystallization) was unambiguously determined by single crystal X-ray diffraction analysis (see the Supporting
Information (SI) for details).16 The (S)-absolute configuration of other products 3 were assigned by analogy. To demonstrate the utility of this catalytic asymmetric decarboxylative [4 + 2] cyclization, a preparative scale synthesis of the product 3aa was performed under standard conditions (see the SI for details). Compared with the small scale reaction (Table 1, entry 17), this larger scale reaction was able to deliver 3aa in a maintained, excellent yield of 90% with a high enantioselectivity of 94% ee. This result indicated that this reaction could be scaled up for the construction of chiral tryptanthrin skeleta. Moreover, 3aa could be quantitatively transformed into chiral tryptanthrin derivative 6 with retained enantioselectivity (see the SI for details). In summary, the first catalytic asymmetric construction of tryptanthrin skeleta has been established, which takes advantage of a Pd(0)/chiral ligand-catalyzed enantioselective decarboxylative [4 + 2] cyclization of vinyl benzoxazinanones with isatins. This reaction not only has provided a direct and efficient method for constructing chiral tryptanthrin skeleta in high yields with excellent enantioselectivities (up to 97% yield, >99% ee) but also represents the first catalytic asymmetric decarboxylative cyclization of vinyl benzoxazinanones with isatins. In addition, in this reaction, the C−N bond of isatins has been utilized to perform enantioselective cyclizations rather than the commonly more reactive CO bond, which will allow for further development of isatin-involved catalytic enantioselective transformations and will greatly enrich the research content for decarboxylative cyclization of vinyl benzoxazinanones.
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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.7b01336. 3221
DOI: 10.1021/acs.orglett.7b01336 Org. Lett. 2017, 19, 3219−3222
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Organic Letters
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Lu, L.-Q.; Li, M.-M.; Zhang, K.; Xiao, W.-J. J. Am. Chem. Soc. 2016, 138, 8360. (8) For catalytic asymmetric [4 + 2] cyclization: (a) Wang, C.; Tunge, J. A. J. Am. Chem. Soc. 2008, 130, 8118. (b) Wei, Y.; Lu, L.; Li, T.; Feng, B.; Wang, Q.; Xiao, W.-J.; Alper, H. Angew. Chem., Int. Ed. 2016, 55, 2200. (c) Leth, L. A.; Glaus, F.; Meazza, M.; Fu, L.; Thøgersen, M. K.; Bitsch, E. A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 15272. (9) For catalytic asymmetric [4 + 3] cyclization: Guo, C.; Fleige, M.; Janssen-Müller, D.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc. 2016, 138, 7840. (10) (a) Zhang, H.-H.; Wang, C.-S.; Li, C.; Mei, G.-J.; Li, Y.; Shi, F. Angew. Chem., Int. Ed. 2017, 56, 116. (b) Zhao, J.-J.; Sun, S.-B.; He, S.-H.; Wu, Q.; Shi, F. Angew. Chem., Int. Ed. 2015, 54, 5460. (c) Zhang, Y.-C.; Zhao, J.-J.; Jiang, F.; Sun, S.-B.; Shi, F. Angew. Chem., Int. Ed. 2014, 53, 13912. (11) (a) Shintani, R.; Hayashi, S.-Y.; Murakami, M.; Takeda, M.; Hayashi, T. Org. Lett. 2009, 11, 3754. (b) Shintani, R.; Tsuji, T.; Park, S.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 7508. (12) For some recent reviews on catalytic asymmetric allylic alkylations: (a) Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013, 2013, 2745. (b) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427. For some recent prominent examples: (c) James, J.; Guiry, P. J. ACS Catal. 2017, 7, 1397. (d) Nascimento de Oliveira, M.; Fournier, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2017, 19, 14. (e) Lin, H.-C.; Wang, P.-S.; Tao, Z.-L.; Chen, Y.-G.; Han, Z.-Y.; Gong, L.-Z. J. Am. Chem. Soc. 2016, 138, 14354. (f) Bai, D.-C.; Yu, F.-L.; Wang, W.-Y.; Chen, D.; Li, H.; Liu, Q.-R.; Ding, C.-H.; Chen, B.; Hou, X.-L. Nat. Commun. 2016, 7, 11806. (g) Yamamoto, K.; Qureshi, Z.; Tsoung, J.; Pisella, G.; Lautens, M. Org. Lett. 2016, 18, 4954. (h) Liu, W.-B.; Okamoto, N.; Alexy, E. J.; Hong, A. Y.; Tran, K.; Stoltz, B. M. J. Am. Chem. Soc. 2016, 138, 5234. (i) Kanbayashi, N.; Yamazawa, A.; Takii, K.; Okamura, T.; Onitsuka, K. Adv. Synth. Catal. 2016, 358, 555. (j) Kita, Y.; Kavthe, R. D.; Oda, H.; Mashima, K. Angew. Chem., Int. Ed. 2016, 55, 1098. (k) Zhang, X.; Liu, W.-B.; Tu, H.-F.; You, S.-L. Chem. Sci. 2015, 6, 4525. (l) Wei, X.; Liu, D.; An, Q.; Zhang, W. Org. Lett. 2015, 17, 5768. (m) Zhou, H.; Zhang, L.; Xu, C.; Luo, S. Angew. Chem., Int. Ed. 2015, 54, 12645. (n) Fananas-Mastral, M.; Vitale, R.; Perez, M.; Feringa, B. L. Chem. - Eur. J. 2015, 21, 4209. (13) For a recent review on asymmetric allylic aminations: (a) Grange, R. L.; Clizbe, E. A.; Evans, P. A. Synthesis 2016, 48, 2911. For some recent prominent examples: (b) Rajkumar, S.; Clarkson, G. J.; Shipman, M. Org. Lett. 2017, 19, 2058. (c) Zhuo, C.-X.; Zhang, X.; You, S.-L. ACS Catal. 2016, 6, 5307. (d) Ye, K.-Y.; Cheng, Q.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed. 2016, 55, 8113. (e) Soriano, S.; Escudero-Casao, M.; Matheu, M. I.; Diaz, Y.; Castillon, S. Adv. Synth. Catal. 2016, 358, 4057. (f) Wang, X.; Guo, P.; Han, Z.; Wang, X.; Wang, Z.; Ding, K. J. Am. Chem. Soc. 2014, 136, 405. (14) For a recent example with linear selectivity: Qi, Z.; Kong, L.; Li, X. Org. Lett. 2016, 18, 4392. (15) For a review, see: (a) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581. For selected examples, see: (b) Zhu, S.-F.; Yang, Y.; Wang, L.-X.; Liu, B.; Zhou, Q.-L. Org. Lett. 2005, 7, 2333. (c) Zhu, S.-F.; Qiao, X.-C.; Zhang, Y.-Z.; Wang, L.-X.; Zhou, Q.-L. Chem. Sci. 2011, 2, 1135. (16) CCDC 1525524 for 3aa; see the SI for details.
Experimental procedure and characterization data for substrates 1, experimental procedures, characterization data, NMR and HPLC spectra for 3 and 6 (PDF) Crystallographic data for 3aa (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Feng Shi: 0000-0003-3922-0708 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial supports from NSFC (21372002 and 21232007), PAPD, Natural Science Foundation of Jiangsu Province (BK20160003).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01336 Org. Lett. 2017, 19, 3219−3222
