Highly Enantioselective Copper- and Iron-Catalyzed Intramolecular

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Highly Enantioselective Copper- and Iron-Catalyzed Intramolecular Cyclopropanation of Indoles Huan Xu,†,§ Yi-Pan Li,†,§ Yan Cai,†,§ Guo-Peng Wang,† Shou-Fei Zhu,*,† and Qi-Lin Zhou*,†,‡ †

State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China

‡

S Supporting Information *

achieved with catalysis by copper or iron complexes bearing chiral spiro bisoxazoline ligands. We began by investigating the intramolecular cyclopropanation reaction of diazo compound 1a in chloroform at 25 °C with catalysis by 5 mol% of a copper complex generated in situ from Cu(OTf)2, ligand (Ra,S,S)-3a,7c and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBAr F ) (Table 1, entry 1). The reaction was completed within 10 min, and desired intramolecular cyclopropanation product 2a, which has a [4.1.0] bicyclic ring system, was isolated as a single diastereomer in 87% yield with 99.1% ee. The structure and absolute configuration of (S,S,S)-2a were determined by X-ray diffraction analysis of a single crystal. 8 The use of diastereomeric ligand (Sa,S,S)-3a resulted in lower yield and enantioselectivity (entry 2). The substituent on the oxazoline ring of the ligand markedly affected the reaction outcome, and a phenyl substituent afforded the best results in terms of both yield and enantioselectivity (entries 1 and 3−5). Copper salts other than Cu(OTf)2 could also serve as catalyst precursors, giving essentially equivalent ee values (entries 6−9); however, salts with a triflate anion showed the highest activity (entry 8). The Cu-BOX complex, a standard catalyst for asymmetric cyclopropanation,3,9 also exhibited satisfactory results but requested relatively longer reaction time for full conversion (entry 10). To our delight, a chiral iron complex also catalyzed the reaction, affording the desired product in 74% yield and 96% ee (entry 11). Several other transition metals that are commonly used in cyclopropanation reactions were also examined. Cobalt, silver, and gold catalysts gave lower yields and enantioselectivities than the copper or iron catalyst (entries 12−14). Dirhodium catalysts preferentially gave the C−H bond insertion product rather than the desired cyclopropanation product (entries 15 and 16; see Supporting Information for details). Using the optimal reaction conditions, we evaluated various α-aryl-α-diazoesters (1, R = aryl) in the intramolecular cyclopropanation reaction with a copper or an iron catalyst (Scheme 1). Substrates with an electron-withdrawing group at the ortho-, meta-, or para-position of the phenyl ring (2b, 2c, 2f, and 2h−2k) gave good to high yields and excellent enantioselectivities with 5 mol% of a copper catalyst (conditions A) or 10 mol% of an iron catalyst (conditions B). Substrates with an electron-donating group (e.g., MeO, 2g) at the meta-position of the phenyl ring also gave high enantioselectivities. However,

ABSTRACT: We report the first intramolecular enantioselective cyclopropanation of indoles, which was accomplished in good to high yield (up to 94%) with excellent enantioselectivity (up to >99.9% ee) by using copper or iron complexes of chiral spiro bisoxazolines as catalysts. This reaction is a straightforward, efficient method for constructing polycyclic compounds with an all-carbon quaternary stereogenic center at the 3-position of the indole skeleton, a core structure shared by numerous natural products and bioactive compounds.

B

ecause the indole ring is a ubiquitous heterocycle in natural products,1 the development of methods for constructing chiral polycyclic systems with indole skeletons would facilitate the efficient synthesis of indole-containing natural products and pharmaceuticals and thus has recently drawn considerable attention.2 Transition-metal-catalyzed asymmetric intramolecular cyclopropanation of olefins is a powerful tool for constructing fused ring systems from simple linear substrates,3 and non-enantioselective intramolecular cyclopropanation of indoles has been used for the synthesis of indole-containing polycyclic compounds4 and indole alkaloids,5 such as communesin F,5b,c minfiensine,5d aspidofractinine,5e and lundurines5f−h (Figure 1). However, enantioselective versions of this reaction remain unexplored.6 As part of our ongoing work on transition-metal-catalyzed asymmetric carbene transformations,7 we herein report the first enantioselective intramolecular cyclopropanation of indoles, which was

Figure 1. Selected indole alkaloids having an all-carbon quaternary stereogenic center at the 3-position of the indole skeleton. © 2017 American Chemical Society

Received: March 28, 2017 Published: May 26, 2017 7697

DOI: 10.1021/jacs.7b03086 J. Am. Chem. Soc. 2017, 139, 7697−7700

Communication

Journal of the American Chemical Society Table 1. Transition-Metal-Catalyzed Asymmetric Intramolecular Cyclopropanation of 1a: Optimization of Reaction Conditionsa

entry

[M]

ligand

time (h)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11d 12d 13d 14d 15e 16e

Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(OTf)2 Cu(acac)2 CuCl CuOTf·(toluene)0.5 [Cu(MeCN)4]PF6 Cu(OTf)2 Fe(ClO4)2·xH2O CoCl2 AgClO4.H2O AuCl Rh2(R-PTAD)4 Rh2(S-DOSP)4

(Ra,S,S)-3a (Sa,S,S)-3a (Ra)-3b (Ra,S,S)-3c (Ra,S,S)-3d (Ra,S,S)-3a (Ra,S,S)-3a (Ra,S,S)-3a (Ra,S,S)-3a (S,S)-BOX (Ra,S,S)-3a (Ra,S,S)-3a (Ra,S,S)-3a (Ra,S,S)-3a − −

0.2 0.1 0.3 1 18 12 12 0.4 3 8 24 30 4 0.3 0.2 0.2

87 86 86 53 48 87 87 86 77 91 74 37 28 27 − 10

99.1 86 42 68 7 98 99 98 97 98 96 90 7 70 − 78

Scheme 1. Copper- or Iron-Catalyzed Asymmetric Intramolecular Cyclopropanation of 1a

a Conditions A: Cu(OTf)2/(Ra,S,S)-3a/NaBArF/1 = 0.01/0.012/ 0.012/0.2 (mmol), in 3 mL of CHCl3 at 25 °C. Conditions B: Fe(ClO4)2·xH2O/(Ra,S,S)-3a/NaBArF/1 = 0.03/0.036/0.036/0.3 (mmol), in 6 mL of CHCl3 at 60 °C. Conditions C: Cu(OTf)2/ (Sa,S,S)-3a/NaBArF/1 = 0.01/0.012/0.012/0.2 (mmol), in 3 mL of CHCl3 at 25 °C. Isolated yields are given. The ee values were determined by SFC or HPLC.

a

Reaction conditions: [Cu]/ligand/NaBArF/1a = 0.01/0.012/0.012/ 0.2 (mmol), in 3 mL of CHCl3 at 25 °C. bIsolated yield. cDetermined by SFC or HPLC using Chiralpak AS-H column. dReaction conditions: [M]/ligand/NaBArF/1a = 0.03/0.036/0.036/0.3 (mmol), in 6 mL of CHCl3 at 60 °C. eReaction conditions: [Rh]/1a = 0.002:0.2 (mmol), in 1.5 mL of CHCl3 at 25 °C.

enoate almost quantitatively as a Z/E mixture (Z/E = 2.3:1). In addition, the cyclopropanation product could not be obtained when the R group of the diazo substrate was changed to H. The intramolecular cyclopropanation reaction could be used to prepare a [3.1.0] bicyclic ring system (Scheme 2). Although Boc-protected substrate 4a gave only moderate enantioselectivities (77% and 78% ee, respectively) in the copperand iron-catalyzed reactions, Ts-protected substrates 4b−4d afforded much higher enantioselectivities (85−93% ee). The iron catalyst exhibited slightly higher enantioselectivity than the corresponding copper catalyst. The structure and absolute configuration of cyclopropanation product (S,S,S)-5a were determined by X-ray diffraction analysis of a single crystal.8 Under the standard reaction conditions, other substrates with different tethers were also briefly evaluated (Scheme 3). The cyclopropanation of amide-tethered indole substrate 6 gave a complicated product mixture and the desired cyclopropanation product 7 was obtained in 16% yield with 32% ee (eq 1). Similarly, the substrate 8 having a tether at 2-position of indole could also afford corresponding cyclopropanation product 9 albeit with very modest enantioselectivity (eq 2). The highly active donor−acceptor-type cyclopropane structure of products 2 and 5 provides many possibilities for further transformations (Scheme 4).10 For example, product 5b

substrates with an electron-donating group at the ortho- or para-position required the use of ligand (Sa,S,S)-3a to obtain high ee values (conditions C; 2d, 2e, and 2l). The iron catalyst could also improve the enantioselectivity through changing (Ra,S,S)-3a to its diastereomer (e.g., from 2% ee to 78% ee for the reaction of 1e); however, the improvement is inferior to those of copper catalyst. The mechanism of the enhancement of the enantioselectivity is unclear at current stage. Both electron-withdrawing and electron-donating substituents on the indole ring of the diazo substrates were tolerated, and such substrates gave satisfactory results under the optimal conditions (2m−2o). The copper-catalyzed reaction could readily be scaled up to gram scale. For instance, the reaction of 1k proceeded smoothly on a gram scale to afford 1.35 g of 2k in 69% yield with 99.5% ee under the optimal conditions. The αaryl group of diazo substrates 1 was critical for high yields and enantioselectivities; the reaction of α-diazo propionate 1p (R = Me) gave a complicated product mixture and only a low yield of desired cyclopropanation product 2p, albeit with 98% ee. When R is an ethyl, a rapid β-H migration occurred under standard reaction conditions to afford corresponding but-27698

DOI: 10.1021/jacs.7b03086 J. Am. Chem. Soc. 2017, 139, 7697−7700

Communication

Journal of the American Chemical Society Scheme 2. Copper- or Iron-Catalyzed Asymmetric Intramolecular Cyclopropanation of 4a

Scheme 4. Transformations of the Products to Polycyclic Compounds Having an All-Carbon Quaternary Stereogenic Center at the 3-Position of the Indole Skeleton

a Reaction conditions: [M]/(Ra,S,S)-3a/NaBArF/4 = 0.01/0.012/ 0.012/0.2 (mmol), in 3 mL of CHCl3 at specified temperature. [Cu] = Cu(OTf)2; [Fe] = Fe(ClO4)2.xH2O. Isolated yields are given. The ee values were determined by SFC or HPLC.

Scheme 3. Copper-Catalyzed Asymmetric Intramolecular Cyclopropanation of 6 and 8a

us to synthesize several complex polycyclic products with high stereospecificity.

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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/jacs.7b03086. Experimental procedures and spectral data for all new compounds (PDF) CIF files for 2a, 5a, 10−13 (ZIP)

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could be transformed to more-complex fused-ring compound 10 or 11 with retained ee values by means of a TMSOTfpromoted Friedel−Crafts reaction (eq 1) or a Sc(OTf)3promoted formal [3+2] cycloaddition with benzaldehyde (eq 2), respectively. Moreover, product 2k underwent stereospecific ring opening in the presence of trifluoroacetic acid to afford chiral spiro compound 12 in 91% yield (eq 3). Hexahydropyrrolo[2,3-b]indole 13, which is the core structure of a number of indole alkaloids,1f was prepared in high yield by condensation of 12 with benzylamine (eq 4). The structures and absolute configurations of products 10−13 were confirmed by single-crystal X-ray diffraction analysis.8 In summary, we accomplished enantioselective intramolecular cyclopropanation of indoles catalyzed by copper or iron complexes of chiral spiro bisoxazolines. Chiral polycyclic compounds bearing donor−acceptor-type cyclopropane moieties were prepared in good to high yields (up to 94%) with excellent enantioselectivities (up to >99.9% ee) under mild reaction conditions. The donor−acceptor-type cyclopropane moiety enabled numerous additional transformations, allowing

AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Shou-Fei Zhu: 0000-0002-6055-3139 Qi-Lin Zhou: 0000-0002-4700-3765 Author Contributions §

H.X., Y.-P.L., and Y.C. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21625204, 21290182, 21532003, 21421062), the National Basic Research Program of China (2012CB821600), the “111” project (B06005) of the Ministry of Education of China, and the National Program for Support of Top-notch Young Professionals for financial support. 7699

DOI: 10.1021/jacs.7b03086 J. Am. Chem. Soc. 2017, 139, 7697−7700

Communication

Journal of the American Chemical Society

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(h) Yang, J.-M.; Li, Z.-Q.; Li, M.-L.; He, Q.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2017, 139, 3784. (8) CCDC 1536623, 1536830, 1536832, 1536831, 1536598, and 1536617 contain the supplementary crystallographic data for compounds 2a, 5a, 10−13. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif. The CIF files are also available, along with additional X-ray crystallographic details, in the Supporting Information. (9) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726. (10) For recent reviews on the plentiful transformations of donor− acceptor-type cyclopropanes, see: (a) Cavitt, M. A.; Phun, L. H.; France, S. Chem. Soc. Rev. 2014, 43, 804. (b) Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew. Chem., Int. Ed. 2014, 53, 5504.

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DOI: 10.1021/jacs.7b03086 J. Am. Chem. Soc. 2017, 139, 7697−7700