Letter Cite This: Org. Lett. 2018, 20, 4453−4457
pubs.acs.org/OrgLett
Organocatalytic Asymmetric [3 + 2] Cycloaddition of N‑2,2,2Trifluoroethylisatin Ketimines with β‑Trifluoromethyl ElectronDeficient Alkenes: Access to Vicinally Bis(trifluoromethyl)Substituted 3,2′-Pyrrolidinyl Spirooxindoles Yong You,† Wen-Ya Lu,§ Zhen-Hua Wang,† Yong-Zheng Chen,*,‡ Xiao-Ying Xu,§ Xiao-Mei Zhang,§ and Wei-Cheng Yuan*,§ Org. Lett. 2018.20:4453-4457. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 08/04/18. For personal use only.
†
Institute for Advanced Study, Chengdu University, Chengdu 610106, China School of Pharmacy, Zunyi Medical University, Zunyi, 563000, China § Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China ‡
S Supporting Information *
ABSTRACT: N-2,2,2-Trifluoroethylisatin ketimines with βtrifluoromethyl enones, 3-trifluoroethylidene oxindole, and 3trifluoroethylidene benzofuranone can undergo asymmetric [3 + 2] cycloaddition, catalyzed by chiral bifunctional squaramide-tertiary amine catalysts, affording a wide spectrum of 3,2′-pyrrolidinyl spirooxindoles. The significance of this protocol is highlighted by its extremely high efficiency in the construction of the structurally diverse spirocyclic oxindoles, bearing a vicinally bis(trifluoromethyl)-substituted pyrrolidine moiety, including four contiguous stereocenters, in high yields with excellent stereocontrol. he introduction of fluorine-containing groups into organic molecules can often enhance their chemical or original biological performances.1 In particular, the addition of trifluoromethyl (CF3) group has been proven to promote the metabolic stability and bioavailability of many bioactive compounds.2 Numerous methods have been developed for the installation of the CF3 group into a variety of organic molecular structures.3 However, reports on the construction of molecular fragments containing two CF3 groups on vicinal carbon atoms are extremely rare,4 despite their potential usefulness in medicinal chemistry and advanced materials.5 Nevertheless, the catalytic enantioselective preparation of the vicinally bis(trifluoromethylated) compounds still remains mysterious, although a CF3-containing chiral center is found in many optically active pharmaceutical molecules.6 In this context, the development of creative approaches to access the vicinally bis(trifluoromethyl)-substituted structures in an enantioseletive manner remains an important, as well as challenging, goal in the area of organic synthesis. In the various types of spirocyclic oxindole structures, the 3,2′-pyrrolidinyl spirooxindole scaffold has been considered the characteristic structural centerpiece of a large number of natural or synthetic compounds with strong bioactivity profiles (Figure 1).7 The defined three-dimensional shape of spirooxindoles greatly influences their biological activity in drug discovery programs. In the past few years, extensive effort has been devoted to the development of efficient catalytic asymmetric methodologies for the preparation of various optically active 3,2′-pyrrolidinyl spirooxindoles.8 Despite the
T
© 2018 American Chemical Society
Figure 1. Biologically active compounds featuring a 3,2′-pyrrolidinyl spirooxindole skeleton.
substantial progress that has been made, N-2,2,2-trifluoroethylisatin ketimines were first used for the synthesis of CF3substituted 3,2′-pyrrolidinyl spirooxindoles until 2015.9 Of particular importance is the fact that this type of reagent can act as azomethine ylide precursors undergoing cycloaddition reaction with electron-deficient alkenes, thus directly generating 3,2′-pyrrolidinyl spirooxindole compounds bearing a CF3 group.10,11 This advantage and characteristic has provided the impetus to explore a new synthetic strategy to access structurally diverse 3,2′-pyrrolidinyl spirooxindoles with high diastereoselectivities and enantioselectivities. Structural modification in prototype compounds that are known to possess pharmacological activity has attracted enormous attention, because of its potential impact on the Received: June 3, 2018 Published: July 25, 2018 4453
DOI: 10.1021/acs.orglett.8b01730 Org. Lett. 2018, 20, 4453−4457
Letter
Organic Letters development of new drugs.12 Taking this into account, we can assume that the installation of CF3 group into various 3,2′pyrrolidinyl spirooxindole scaffolds has very good prospects in the discovery of biologically active compounds. In addition, we noticed that some CF3-containing electron-deficient alkenes could be used efficiently for the cycloaddition reactions.13 Based on our long-standing research on the asymmetric synthesis of spirocyclic oxindoles, we envisaged that a catalytic asymmetric [3 + 2] cycloaddition between N-2,2,2-trifluoroethylisatin ketimines and β-trifluoromethyl electron-deficient alkenes would open a straightforward approach access to 3,2′pyrrolidinyl spirooxindole derivatives with four contiguous stereocenters, particularly those containing vicinally bis(trifluoromethyl)-substituted pyrrolidine, which are promising in research connected to new drug discovery programs (see Scheme 1). Herein, we wish to report our research on this subject.
quinine-derived thiourea catalyst C and squaramide catalyst D as catalysts, respectively, it was found that catalyst D gave the best results (entry 4). After a brief screening of solvents, CH2Cl2 was proven to be the best candidate (entry 4 vs entries 5−7). Decreasing the catalyst loading from 10 mol % to 5 mol %, 3a also could be obtained in excellent results, albeit a prolonged reaction time was needed (entry 8). Further decreasing to 2 mol %, the yield dropped to 88% (entry 9). Ultimately, lowering the temperature to 0 °C and with 5 mol % catalyst D, a set of excellent results were able to be obtained (entry 10). With the optimal reaction conditions established, the generality of the asymmetric [3 + 2] cycloaddition reaction was examined by using a series of N-2,2,2-trifluoroethylisatin ketimines. As shown in Table 2, different N-protecting groups in trifluoroethylisatin ketimine substrates were well-tolerated, furnishing adducts 3a−3e in 82%−98% yields with excellent dr values and 94%−99% ee (entries 1−5). The benzyl, allyl, and acetyl groups are valuable, as they can be easily removed to afford the unprotected spirocyclic oxindoles. Notably, the nitrogen-free substrate 1f could also smoothly react with 2a under the standard conditions, giving 3f in 86% yield with >20:1 dr and 92% ee (entry 6). Nevertheless, the reactions also proved to be almost unbiased toward either electron-donating or electron-withdrawing substituents on the C-5 position of oxindole aromatic ring; the corresponding products 3g−3l were obtained in excellent results (entries 7−12). The substituent on the C-6 or C-7 position of the oxindole aromatic ring also does not affect the reactivity and stereoselectivity (entries 13 and 14). When the substituent on the C-4 position, the reactivity was decreased but the stereoselectivity was not affected (entry 15). Further exploration of the substrate scope was focused on diverse (E)-β-trifluoromethyl enones 2b−2k by a reaction with 1a.14 As summarized in Table 3, for the substrates bearing different aryl substituents at the α′-position, the reactions gave the corresponding products with excellent yields, dr and ee
Scheme 1. Strategy for the Synthesis of Vicinally Bis(trifluoromethyl)-Substituted 3,2′-Pyrrolidinyl Spirooxindoles through Asymmetric [3 + 2] Cycloaddition
The initial reaction was performed by reacting N-2,2,2trifluoroethylisatin ketimine 1a with (E)-1,1,1-trifluoro-4phenylbut-3-en-2-one 2a using chiral thiourea catalyst A in CH2Cl2 at room temperature.14 As shown in Table 1, the cycloaddition product 3a could be obtained in 98% yield with >20:1 dr and 67% ee (entry 1). The chiral squaramide catalyst B gave disappointing enantioselectivity (entry 2). Then, with Table 1. Optimization of Reaction Conditionsa
entry
solvent
catalyst
x
yieldb (%)
diastereomeric ratio, drc
enantiomeric excess, eec (%)
1 2 3 4 5 6 7 8 9 10
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 THF toluene CH2Cl2 CH2Cl2 CH2Cl2
A B C D D D D D D D
10 10 10 10 10 10 10 5 2 5
98 97 85 96 72 83 87 95 88 98
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
67 54 77 97 97 53 96 97d 98e 98f
a
Unless otherwise noted, the reactions were conducted with 1a (0.10 mmol), 2a (0.12 mmol) and 10 mol % catalyst in 2.0 mL of solvent at room temperature for 3 h. bIsolated yields. cDetermined by chiral HPLC analysis. dRun for 12 h. eRun for 17 h. fRun at 0 °C for 14 h. 4454
DOI: 10.1021/acs.orglett.8b01730 Org. Lett. 2018, 20, 4453−4457
Letter
Organic Letters Table 2. Substrate Scope of N-2,2,2-Trifluoroethylisatin Ketiminesa
entry
R1/R2/1
time (h)
3/yield (%)b
diastereomeric ratio, drc
enantiomeric excess, eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Bn/H/1a Me/H/1b Et/H/1c Allyl/H/1d Ac/H/1e H/H/1f Bn/5-Me/1g Bn/5-MeO/1h Bn/5-F/1i Bn/5-Cl/1j Bn/5-Br/1k Bn/5-NO2/1l Bn/6-Cl/1m Bn/7-Cl/1n Bn/4-Cl/1o
14 20 15 15 15 20 15 15 15 15 15 15 15 15 48
3a/98 3b/85 3c/82 3d/86 3e/98 3f/86 3g/99 3h/99 3i/92 3j/98 3k/99 3l/96 3m/95 3n/87 3o/75
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1d
98 94 97 97 99 92 98 97 95 95 95 94 98 97 97
Unless otherwise noted, the reactions were conducted with 1 (0.10 mmol), 2a (0.12 mmol) and 5 mol % D in 2.0 mL of CH2Cl2 at 0 °C for the specified reaction time. bIsolated yields. cDetermined by chiral HPLC analysis. dDetermined by 1H NMR.
a
Table 3. Substrate Scope of β-Trifluoromethyl Enonesa
entry
R/2
time (h)
3/yield (%)b
diastereomeric ratio, drc
enantiomeric excess, eec (%)
1 2 3 4 5 6 7 8 9 10
4-MeC6H4/2b 4-MeOC6H4/2c 3-MeOC6H4/2d 2-FC6H4/2e 4-ClC6H4/2f 3-BrC6H4/2g 4-BrC6H4/2h 2-naphthyl/2i 2-thienyl/2j 2-pyridyl/2k
18 18 20 24 20 16 20 20 20 12
3p/97 3q/96 3r/95 3s/90 3t/99 3u/99 3v/98 3w/98 3x/99 3y/92
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
99 99 98 94 98 98 98 99 99 98
Unless otherwise noted, the reactions were conducted with 1a (0.10 mmol), 2 (0.12 mmol) and 5 mol % D in 2.0 mL of CH2Cl2 at 0 °C for the specified reaction time. bIsolated yields. cDetermined by chiral HPLC analysis.
a
Inspired by the above results, we attempted to further investigate the asymmetric [3 + 2] cycloaddition reaction of N2,2,2-trifluoroethylisatin ketimines 1 with 3-trifluoroethylidene oxindole 4 and 3-trifluoroethylidene benzofuranone 5. As shown in Scheme 2, with 5 mol % B as catalyst in CH2Cl2 at −40 °C,15 the reactions of 1 with 4 proceeded smoothly and could be completed within 24−36 h, leading to the structurally complex bispirooxindoles 6a−6f in 78%−99% yields, >20:1 dr, and 87%−92% ee. The results are independent of the electronic and steric properties of the ketimines. The absolute configuration of 6a was determined to be (2S,10S,17R,18R) by X-ray analysis. Similarly, the reactions between 1 and 5 also occurred well at 0 °C and afforded the expected spirocyclic oxindoles 7a−7f in 86%−99% yields, >20:1 dr, and 93%−95% ee, regardless of the electronic nature or the positions of the substituents on the trifluoroethylisatin ketimine aromatic ring.
values, regardless of the nature or the position of the substituent on the aromatic ring (entries 1−7). Nevertheless, the sterically demanding naphthyl substitution was welltolerated in the asymmetric [3 + 2] cycloaddition with 1a (entry 8). The heteroaromatic groups, such as thienyl and pyridyl, were also compatible in the transformation (entries 9 and 10). Disappointingly, we found that the current reaction system was not suitable for the β-trifluoromethyl enones bearing an alkyl group (−Bn), alkoxy group (−OEt), or amide group (oxazolidin-2-one) at the α′-position (data not shown). These results suggest that an aromatic ring incorporating into the α′-position of the substrates is vital for the reactivity. The absolute configuration of 3t was determined as (7S,9S,10S,11S) by X-ray analysis. Assuming a common reaction pathway, the configuration of the other products 3 was assigned by analogy. 4455
DOI: 10.1021/acs.orglett.8b01730 Org. Lett. 2018, 20, 4453−4457
Letter
Organic Letters Scheme 2. Asymmetric [3 + 2] Cycloaddition of N-2,2,2Trifluoroethylisatin Ketimines with 3-Trifluoroethylidene Oxindole and 3-Trifluoroethylidene Benzofuranonea
literature reports,9−11 we propose a possible reaction mechanism for the asymmetric [3 + 2] cycloaddition reaction. The N-2,2,2-trifluoroethylisatin ketimines were combined with the tertiary N atom of the catalyst to form a five-membered ring; concurrently, the two squaramide N−H bonds of catalyst coordinated with the β-trifluoromethyl enones. The chiral catalyst makes the two substrates close to each other for a reaction with special stereocontrol. The two consecutive reface additions then deliver the corresponding products with the specific configurations.16 In summary, we have presented the asymmetric [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with diverse β-trifluoromethyl electron-deficient alkenes by employing a chiral bifunctional squaramide-tertiary amine catalyst. With β-trifluoromethyl enones as electron-deficient alkenes, the reaction provides a promising approach for the highly enantioselective construction of 3,2′-pyrrolidinyl spirooxindoles bearing a vicinally bis(trifluoromethyl)-substituted pyrrolidine moiety including four contiguous stereocenters. With 3-trifluoroethylidene oxindole and 3-trifluoroethylidene benzofuranone as substrates, the reaction generates a spectrum of enantiopure vicinally bis(trifluoromethyl)-substituted 3,2′pyrrolidinyl spirooxindoles with four contiguous stereocenters including two vicinal spiro-quaternary chiral center atoms. Significantly, the power of this method is highlighted by its extremely high efficiency in the construction of the spirocyclic oxindole skeletons possessing a vicinally bis(trifluoromethyl)substituted pyrrolidine moiety with excellent stereocontrol in one single operation.
a
Reaction conditions: the reactions were conducted with 1 (0.10 mmol), 4 or 5 (0.12 mmol) and 5 mol % B in 2.0 mL of CH2Cl2 at −40 or 0 °C for the specified reaction time. The reported yields are the isolated yields of the sum of the diastereoisomers. The dr and ee values were determined by chiral HPLC analysis.
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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.8b01730.
Note that these [3 + 2] cycloaddition products 6a−6f and 7a− 7f have some significantly structural features, such as containing a vicinally bis(trifluoromethyl)-substituted pyrrolidine moiety, including four contiguous stereocenters and two vicinal spiro-quaternary chiral carbon atoms. The reaction can be scaled up to 2.0 mmol for 1a, which is 20-fold amplification as compared to the model reaction in Table 1, without any loss of the reactivity and stereoselectivity (see Scheme 3). Nevertheless, the reduction of 3a with NaBH4 led to the corresponding hydroxylation product 8 in quantitative yield by selectively reducing the carbonyl group. No changes occurred in the diastereoselectivity and enantioselectivity during this transformation (Scheme 3).16 In light of the dual-activation model of chiral bifunctional squaramide-tertiary amine catalyst17 and other relevant
Experimental details and characterization data for new compounds (PDF) Accession Codes
CCDC 1842919 and 1846199 contain 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, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (Y.-Z. Chen). *E-mail:
[email protected] (W.-C. Yuan).
Scheme 3. Scale-Up Experiment and the Reduction of 3a with NaBH4
ORCID
Wei-Cheng Yuan: 0000-0003-4850-8981 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National NSFC (Nos. 21572223 and 21572224), the Sichuan Youth Science and Technology Foundation (No. 2015JQ0041) and the Startup Fund of Chengdu University (No. 2081917041). 4456
DOI: 10.1021/acs.orglett.8b01730 Org. Lett. 2018, 20, 4453−4457
Letter
Organic Letters
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Long, X.-W.; Pan, W.-G.; Lu, G.; Chen, Q. Heterocycles 2017, 94, 879. (c) Gao, Y.-N.; Shi, M. Eur. J. Org. Chem. 2017, 2017, 1552. (12) Yale, H. L. J. Med. Pharm. Chem. 1959, 1, 121. (13) For selected examples, see: (a) Davies, A. T.; Taylor, J. E.; Douglas, J.; Collett, C. J.; Morrill, L. C.; Fallan, C.; Slawin, A. M. Z.; Churchill, G.; Smith, A. D. J. Org. Chem. 2013, 78, 9243. (b) Zhu, Y.; Li, X.; Chen, Q.; Su, J.; Jia, F.; Qiu, S.; Ma, M.; Sun, Q.; Yan, W.; Wang, K.; Wang, R. Org. Lett. 2015, 17, 3826. (c) Yuan, X.; Zhang, S.J.; Du, W.; Chen, Y.-C. Chem. - Eur. J. 2016, 22, 11048. (d) Xu, B.; Zhang, Z.-M.; Liu, B.; Xu, S.; Zhou, L.-J.; Zhang, J. Chem. Commun. 2017, 53, 8152. (e) Wang, H.; Lu, W.; Zhang, J. Chem. - Eur. J. 2017, 23, 13587. (14) The reaction did not work by using (Z)-1,1,1-trifluoro-4phenylbut-3-en-2-one as substrate with 1a. (15) See Supporting Information for the optimization of reaction conditions. (16) See Supporting Information for experimental details. (17) (a) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890. (b) Wurm, F. R.; Klok, H.-A. Chem. Soc. Rev. 2013, 42, 8220. (c) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253. (d) Held, F. E.; Tsogoeva, S. B. Catal. Sci. Technol. 2016, 6, 645.
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DOI: 10.1021/acs.orglett.8b01730 Org. Lett. 2018, 20, 4453−4457
