Organocatalytic Highly Enantioselective Monofluoroalkylation of 3

Mar 18, 2014 - ... a wide range of pre-electrophiles (3-bromooxindoles) and prenucleophiles ... Construction of Vicinal All-Carbon Quaternary Stereoce...
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Organocatalytic Highly Enantioselective Monofluoroalkylation of 3‑Bromooxindoles: Construction of Fluorinated 3,3′-Disubstituted Oxindoles and Their Derivatives Chongyang Wu,† Guofeng Li,† Wangsheng Sun,† Ming Zhang,† Liang Hong,*,† and Rui Wang*,†,‡ †

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, P.R. China ‡ State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P.R. China S Supporting Information *

ABSTRACT: A new practical organocatalytic asymmetric protocol for the introduction of a monofluoroalkyl group into the oxindole framework has been successfully developed. Excellent diastereoselectivities (>20:1 dr) and enantioselectivities (93−99% ee) of the products were obtained with a wide range of pre-electrophiles (3-bromooxindoles) and prenucleophiles (α-fluorinated β-keto gem-diols). The obtained products themselves and their derivatives may significantly benefit drug discovery. hile natural fluorinated organic compounds are rare, synthetic fluoro-organic chemistry has not evoked adequate attention from medicinal chemists until recent decades.1 Actually, the incorporation of a fluorine-containing substituent could improve metabolic stability, affect the molecular physicochemical properties, play an important role in combining the protein and ligand, and thereby improve the biological activity profile.2 Therefore, fluorinated organic compounds, particularly optically active organofluorine compounds, have become attractive synthetic targets in pharmaceuticals and agrochemicals. Catalytic enantioselective fluoroalkylation has been one of the most efficient strategies for the construction of those compounds.3−6 Until now, great advances have been made in enantioselective trifluoromethylation reactions, and methodolgies are still springing up.4 In comparison with multiple important asymmetric synthetic methods involving a trifluoromethyl group, fewer asymmetric catalytic strategies are available to install a monofluoroalkyl group, especially in the nonaromatic position.3c,d,5,6 3,3′-Disubstituted oxindoles having a chiral all-carbon quaternary center at the C3 position are frequently found in many natural products, pharmaceuticals, and biologically active compounds (Figure 1), and the C3 substituents often greatly impact their biological activities.7 Thus, the substitution of a hydrogen atom in biologically active oxindoles with a fluorine atom in a nonaromatic position might improve their physiological properties. An example worth noting is the monofluorinated oxindole BMS-204352, a promising agent for the treatment of stroke. 7f However, the synthesis of

W

© 2014 American Chemical Society

Figure 1. Representative synthetic biologically active oxindole derivatives.

enantioenriched 3-monofluoroalkyl oxindoles has been less studied. Only very recently, Fang, Wu and co-workers reported an aldol reaction of trifluoromethyl α-fluorinated gem-diols8 with N-benzyl isatins.6d On the other hand, in the past few years, many methods have been developed for the synthesis of 3,3′-disubstituted oxindoles. Among them, the most important and efficient approaches involve the use of electrophilic isatins/isatinimines and nucleophilic 3-monosubstituted oxindoles (Figure 2).9 Despite these advances, the use of indol-2-ones (generated in situ from 3-halooxindoles) as electrophiles has been limited.10 Recently, we reported the asymmetric addition of indoles to the indol-2-ones for the construction of indolenines.10g Based on these results and our continuous interest in the construction of oxindoles,11 we sought to develop a catalytic Received: February 18, 2014 Published: March 18, 2014 1960

dx.doi.org/10.1021/ol500517d | Org. Lett. 2014, 16, 1960−1963

Organic Letters

Letter

organocatalysts derived from different chiral sources for the reaction (Table 1, entries 1−7) and found that Takemoto’s catalyst 3b12 was the most promising for the model reaction, providing the 4aa in 56% yield, >20:1 dr and 59% ee (Table 1, entry 2). Subsequent examination on the solvent effect revealed that the choice of solvent impacted the yield, diastereoselectivity, and enantioselectivity greatly (Table 1, entries 2 and 8− 13) and that MTBE (methyl tert-butyl ether) was the most ideal for the reaction, affording 4aa in 63% yield, 19:1 dr and 91% ee (Table 1, entry 9). We then turned our attention to the investigation of the base effect and found that it also had great influence on the yield, diastereoselectivity, and enantioselectivity (Table 1, entries 9 and 14−18), and DIPEA afforded the best results (57% yield, >20:1 dr and 96% ee) (Table 1, entry 18). Increasing the utility amount of the base to 2.5 equiv could slightly improve the reaction yield (Table 1, entries 19 and 20). Finally, we chose 3b as the catalyst, DIPEA as the base, and MTBE as the reaction medium in the following investigation. Having the optimum reaction conditions established, we next investigated the substrate scope of the reaction orthogonally. In general, the reaction proceeded well in the presence of catalyst 3b (20 mol %) and DIPEA (2.5 equiv) andafforded the desired products in satisfactory yields, with excellent diastereoselectivities and enantioselectivities (Scheme 1). For the reaction with 3-methyl-3-bromooxindole 1a, a range of trifluoromethyl αfluorinated β-keto gem-diols 2a−e were examined. The results showed that excellent diastereoselectivities (>20:1 dr) and enantioselectivities (93−96% ee) were obtained in all cases, while the yields were relevant to the electronic properties of the

Figure 2. Strategies to the 3,3′-disubstituted oxindoles.

enantioselective synthesis of 3-monofluoroalkyloxindoles. We set up our investigation using various H-bond donor organocatalysts to conduct the reaction between racemic 3bromooxindole (1a) and trifluoromethyl α-fluorinated β-keto gem-diol (2a) in CH2Cl2 with potassium carbonate as base. In our initial experiments, we found a catalytic amount of 3a could promote the reaction with nearly full conversion of 2a in 24 h and good diastereoselectivity, albeit with poor enantioselectivity and moderate yield (Table 1, entry 1). Encouraged by this initial result, we then surveyed a variety of H-bond donor Table 1. Optimization of the Reaction Conditionsa

Scheme 1. Scope of the Reactiona

entry

cat. 3

solvent

base

yield (%)

drb

eec (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19d,e 20d,e,f

3a 3b 3c 3d 3e 3f 3g 3b 3b 3b 3b 3b 3b 3b 3b 3b 3b 3b 3b 3b

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF MTBE Toluene Xylene Dioxane CH3OH MTBE MTBE MTBE MTBE MTBE MTBE MTBE

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3 Et3N Na2CO3 K3PO4 DIPEA DIPEA DIPEA

58 56 42 33 55 37 63 60 63 58 60 54

16:1 >20:1 16:1 9:1 12:1 19:1 13:1 6:1 19:1 19:1 19:1 4:1 nd >20:1 >20:1 9:1 10:1 >20:1 >20:1 >20:1

39 59 5 23 52 5 52 44 91 75 80 77 nd 76 95 55 39 96 96 96

48 55 35 58 57 62 65

a Unless otherwise specified, the reaction was carried out with 1a (0.05 mmol), 2a (0.05 mmol), base (0.05 mmol), and catalyst 3 (0.01 mmol) in solvent (1.0 mL) at room temperature for 48 h. b Determined by 19F NMR spectroscopy of the crude mixture. c Determined by chiral HPLC on a Chiralcel OD-H column. d2.5 equiv base was used. eThe reaction was carried out with a 1/2 = 1:1.5 ratio. fThe reaction was carried out on a 0.1 mmol scale.

a

The reaction was carried out with 1 (0.10 mmol), 2 (0.15 mmol), catalyst 3b (0.02 mmol), and DIPEA (0.25 mmol) in MTBE (2.0 mL) at room temperature for 48 h. The yield of the isolated product is given in each case. The dr values were determined by 19F NMR spectroscopy of the crude mixture. The ee values were determined by HPLC on a chiral phase (Chiralcel column). 1961

dx.doi.org/10.1021/ol500517d | Org. Lett. 2014, 16, 1960−1963

Organic Letters

Letter

In conclusion, we have successfully developed a new practical organocatalytic asymmetric protocol for the introduction of a monofluoroalkyl group into the oxindole framework. Excellent diastereoselectivities and enantioselectivities of the products were obtained with a wide range of pre-electrophiles (3bromooxindoles) and prenucleophiles (α-fluorinated β-keto gem-diols). The obtained products themselves and their derivatives showed great potetial in biological activities, which may significantly benefit drug discovery. The further development of the methodology and biological evaluation of the products are underway in our laboratory.

substitution on substrate 2: electron-donating substituted substrates gave much higher yields than those with electronwithdrawing substitutions (Scheme 1, 4aa−ae). A variety of 3substituted-3-bromooxindoles 1 were then tested for the reaction with trifluoromethyl α-fluorinated β-keto gem-diol 2a. It appeared that different substitution patterns, regardless of the electronic nature, bulkiness, or position, of substituents at the 3-position of subatrate 1 could hardly impact the efficiency of the reaction, providing the corresponding adducts with moderate yields (51−70%) and excellent selectivities (>20:1 dr, 94−99% ee) (Scheme 1, 4ba−ja). It is particularly worth noting that both 3-allyl- and 3-azidoethyl-substituted products 4ia and 4ja, which can be easily transformed to medicinally valuable compounds, could be obtained in excellent selectivities. In addition, both electron-withdrawing and electrondonating substitutions on different positions of the phenyl ring of the oxindole core were fully compatible with this process (4ka−ma). The absolute configuration of the major diastereomer of 4ma was determined by X-ray analysis (Figure 3).13

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ASSOCIATED CONTENT

S Supporting Information *

Experimental details, characterization data for new compounds, copies of NMR and HPLC spectra, and X-ray crystal structure. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the NSFC (91213302, 21272102, 21202071) and the Fundamental Research Funds for the Central Universities (lzujbky-2013ct06, lzujbky-2013-77).

Figure 3. X-ray structure of product 4ma.

The synthetic utility of our methodology was further illustrated by the assembly of fluorinated 3,4′-piperidyl spirooxindoles and hexahydropyrrolo[2,3-b]indolines, which showed great potential in clinical efficiency in nervous system diseases.7g,14 5′-Fluorinated 3,4′-piperidyl spirooxindole 8 was obtained conveniently in 78% yield with 3.5:1 dr and 92% ee by the treatment of 4ja with Ph3P in THF/H2O under 50 °C (Scheme 2, eq a). Interestingly, after the carbonyl group of the product 4ja was protected by glycol, it could also be transformed to 3-fluoroalkyl tetrahydropyrrolo[2,3-b]indole 9, which is a precursor of fluoroalkyl modified natural product physostigmine (Scheme 2, eq b).

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