Tetrahedron: Asymmetry 23 (2012) 1332–1337

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Tetrahedron: Asymmetry

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Enhanced efficiency of recyclable C3-symmetric cinchonine-squaramides inthe asymmetric Friedel–Crafts reaction of indoles with alkyl trifluoropyruvate

Xin Han a,�, Bin Liu a,�, Hai-Bing Zhou a,b, Chune Dong a,⇑a State Key Laboratory of Virology, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, Chinab Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, China

a r t i c l e i n f o a b s t r a c t

Article history:Received 28 June 2012Accepted 21 August 2012

0957-4166/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetasy.2012.08.015

⇑ Corresponding author. Tel.: +86 27 68759586; faxE-mail address: cdong@whu.edu.cn (C. Dong).

� These two authors contributed equally to this wor

The highly enantioselective Friedel–Crafts reaction of indoles with trifluoropyruvate catalyzed by a C3-symmetric cinchonine-squaramide is reported. A wide variety of trifluoromethylated indole derivativeswere obtained in high yields and with excellent enantioselectivities (99% and up to >99% ee). Moreoverthe C3 catalyst can be easily recovered and was used five times.

� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Enantiomerically pure indoles are important structural motifs inmany natural products and pharmaceutically promising com-pounds.1 As such, the development of asymmetric synthesis towardthese indole derivatives has generated considerable interest.2 Theenantioselective Friedel–Crafts alkylation reaction of indoles repre-sents one of the most convenient and straightforward approaches toobtain chiral indole compounds. Over the last two decades, this so-called F–C alkylation reaction has attracted much attention.3

Various chiral transition–metal complexes, such as chiral copper,platinum and gold complexes and so on, were found to be effectivein catalyzing the enantioselective Friedel–Crafts alkylation reac-tions of indoles with various classes of electrophiles.4 Nowadays,organocatalyzed Friedel–Crafts reactions are becoming increasinglyimportant. Pioneered by Macmillan’s imidazolidinones,5 a largenumber of organocatalytic examples have been reported. For exam-ple, diarylprolinol ethers,6 phosphoric acids,7 thioureas,8 sulfonyldiamines, and so on, have been developed as efficient catalysts forthis asymmetric functionalization (Fig. 1).9,10 Among these, cin-chona alkaloids and their derivatives, which are broadly used aseffective organocatalysts in many asymmetric transformations11

were introduced by Török et al. as organocatalysts to accomplishthe hydroxyalkylation of heteroaromatics with trifluoropyruvateproviding the corresponding products in high yields and ee values(up to 92%).12 Very recently, Feng et al. reported chiral N,N0-dioxidezinc(II) complexes that could successfully catalyze the Friedel–Crafts alkylation of indoles with trifluoropyruvate (up to 98% ee).13

However, despite these recent advances in this research area,effective organocatalysts for the asymmetric Friedel–Crafts alkyl-

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k.

ation of indoles with carbonyls, in particular trifluoromethylatedcarbonyl compounds, which exhibit unique biological properties,14

are still very rare. Furthermore, due to the difficulty in catalystrecycling, the application of these catalytic systems in pharmaceuti-cal production has been limited. Therefore, new strategies to designefficient, recyclable chiral organocatalysts for asymmetric Friedel–Crafts reactions are highly desirable. To the best of our knowledge,no chiral C3-symmetrical squaramide has been developed for theasymmetric Friedel–Crafts alkylation of indoles withtrifluoropyruvate.

Squaramides comprising a conformationally rigid square-shaped structure, have recently made their entrance in organoca-talysis as very efficient bifunctional catalysts for a number ofimportant enantioselective organic transformations.15,16 Moreover,C3-symmetric organocatalysts have provided a powerful tool for thesynthesis of chiral complex molecules with increased efficiency.17

Our group is currently designing and synthesizing novel C3-symmetric chiral squaramides and studying their application inasymmetric transformations,18 we envisioned that this C3-symmet-ric catalyst, which has advantages in stability, efficiency, and recov-ery, would enhance the enantioselectivity and enable its recycling.Since C3-symmetric cinchonine-squaramide L1 (CSCS) has shownexcellent behavior in asymmetric Michael addition reactions, in or-der to expand our C3-catalyst’s application in other asymmetrictransformations, we decided to explore the application of C3-sym-metric squaramides in the enantioselective Friedel–Craftsalkylation reaction.

Herein we report the first highly efficient, recyclable robustorganocatalyst for the asymmetric Friedel–Crafts alkylation ofindoles with trifluoropyruvates, which affords valuable chiraltrifluoromethylated indoles in excellent yields (up to 99%) andenantioselectivities (up to >99% ee) (Scheme 1).

As part of our continuous efforts to design and synthesize novelC3-symmetric chiral squaramides and their application in

NH

MeNO

Bn

tBu

.HX

MacMillan's catalyst

R N

cinchona alkaloids

NH

Me2N

S

NH

CF3

CF3

thioureas

R'

R'

OP

OO

OH

phosphoric acid

Fig. 1. Representative organocatalyst in F–C reaction.

NH

N

N H

H

NH

O

O

NH

N

N

H

H

NH

OO

NH

N

N

H

H

HN

OO

NH

F3C CO2R3

O

NH

CO2R3

OHF3C

L1 (CSCS)

R1 R2R2+ R1

R1 = H, OMe, F, Br, ClR2 = H, MeR3 = H, Me

L1

Scheme 1. C3-symmetric squaramide catalyzed Friedel–Crafts reaction.

X. Han et al. / Tetrahedron: Asymmetry 23 (2012) 1332–1337 1333

asymmetric transformation,18 we decide to explore the applicationof C3-symmetric squaramide in the enantioselective Friedel–Craftsalkylation reaction. As C3-symmetric cinchonine-squaramide L1has shown excellent behavior in asymmetric Michael additionreaction, we employed the catalyst to investigate the F–C alkyl-ation of indoles with trifluoropyruvates (Scheme 1).

2. Result and discussion

On the basis of above concept, we synthesized catalyst L1according to the literature.17 Catalysts L2–L5 were also preparedfor the sake of comparison. With these squaramides in hand, theiractivity was examined in detail. Initially, using indole 1a and ethyltrifluoropyruvate 2a as the model substrates, we conducted theasymmetric Friedel–Crafts alkylation. The results are summarizedin Table 1. The chiral C3-symmetric cinchonine-squaramide (CSCS)L1 was found to be effective in this Friedel–Crafts alkylation. In thepresence of 5 mol % of L1 at �20 �C, the reaction worked well toafford the desired product 3a in 93% ee (entry 16). Encouragedby these positive results, we screened a variety of reaction condi-tions. The solvent screen was performed with 1a as the substrate.The solvent was found to significantly affect the enantioselectivityof the reaction. When changing the solvent from methylene chlo-ride to THF under the same reaction conditions, the enantioselec-tivity increased from 17% to 86% (entries 1–4). Xylene gave thehighest yield, albeit with the lowest enantioselectivity. Our resultsrevealed that dichloromethane was the optimum solvent. Subse-quent temperature screening revealed �20 �C was the optimalchoice (entries 15–21). Additionally, it was found that the catalystloading had an obvious effect on the ee values. When the catalystloading was reduced to 1 mol %, 40% ee was obtained (entry 11).

Comparable enantioselectivity (83% ee) was obtained in the pres-ence of 10 mol % L1 under the same reaction conditions (entry15). As expected, both mono- and C2-symmetric catalysts L4 andL5 led to inferior ees (entries 17 and 18). The absolute configura-tion of the major isomer was determined to be (S). Access to (R)-enantiomer was possible when C3-symmetric cinchonidine-squaramide L2 was used (entry 22). No reaction occurred whenthe C3-symmetric catalyst based on proline L3 was used (entry23). Attempts to compare published result concerning the use ofsimple cinchonidine12 as the catalyst under the same reaction con-ditions gave the product 3a in 81% ee. The catalyst screening uti-lized various catalysts such as L3, L4, and L5 indicated that C3-symmetric catalyst (CSCS) was superior in terms of yield andenantioselectivity.

Under the optimal reaction conditions, a series of indoles wereexplored to examine the substrate scope (Table 2). In general, in-doles bearing electron-rich or electron-deficient groups on thephenyl ring reacted smoothly with trifluoropyruvate, providingthe adducts in excellent yields and enantioselectivities. As illus-trated in Table 2, the 5-fluoroindole 1b reacted with methyl tri-fluoro-pyruvate exclusively to afford the corresponding productin 91% yield and >99% ee, which clearly demonstrated that thisC3 catalyst indeed enhances the enantioselectivity for this transfor-mation. To the best of our knowledge, this is the highest ee valueever achieved (entry 2). It is noteworthy that substitution on thepyrrole ring had little effect on the enantioselectivity. For example,the indole with a methyl group at the 2-position 1g reacted withethyl trifluoropyruvate to form the product in 91% ee (entry 7).We also found that with respect to electron-deficient group substi-tuted indoles, ethyltrifluoropyruvate generally gave a higher eethan methyl trifluoropyruvate in this kind of asymmetric

Table 1Optimization and catalyst screening for hydroxyalkylation of indole 1a with ethyl 3,3,3-trifluoro pyruvate 2aa

L1 (CSCS)

NH

N

O

O

NH

NO

O

NH

NO

O

Ph

HOPh

Ph

Ph OH

Ph

Ph

OH

L2

L3 L4 L5

NH

N

N

H

H

HN

O O

NH

N

NH

HNH

O

O

HN

N

NH

H

HN

O

O

NH

N

N

H

H

HN

O O HN

N NH H

HN

O

O

NHN

N

H

H

NH

O

O

NH

N

N

H

H

N

O O

NH

N

NH

HNH

O

O

HN

N

NH

H

HN

O

O

NH

F3C CO2Et

O

NH

CO2Et

OHF3C

1a 2a 3a

Cat.

Entry Catalyst (mol %) Solvent T (�C) Yieldb (%) eec (%)

1 L1, 2 CH2Cl2 �8 >99 172 L1, 2 Xylene �8 99 243 L1, 2 Toluene �8 99 764 L1, 2 THF �8 98 865 L1, 2 Ether �8 97 576 L1, 2 Benzene �8 96 727 L1, 2 CHCl3 �8 96 788 L1, 2 CH2Cl2/ether = 1:1 �8 95 819 L1, 2 Ether/hexane = 1:1 �8 99 4710 L1, 2 CHCl3/toluene = 1:1 �8 93 7011 L1, 1 THF �8 79 4012 L1, 3 THF �8 90 8913 L1, 5 THF �8 96 92

1334 X. Han et al. / Tetrahedron: Asymmetry 23 (2012) 1332–1337

Table 2C3-symmetric cinchonine-squaramide catalyzed Friedel–Crafts reactiona

5 mol% L1

-20oC, 12hNH

F3C CO2R3

O

NH

CO2R3

OHF3C

R1R2R2

+ R1

Entry R1 R2 R3 Yieldb (%) eec (%)

1 H H Et 3a 99 932 5-F H Me 3b 91 >993 5-Cl H Me 3c 80 964 5-Br H Me 3d 83 925 5-F H Et 3e 90 926 7-Me H Et 3f 77 927 H Me Et 3g 96 918 H H Me 3h 97 909 4-CO2Me H Et 3i 85 8610 5-Br H Et 3j 85 8611 H Me Me 3k 96 8312 5-CO2Me H Me 3l 75 8313 5-Cl H Et 3m 87 8014 7-Me H Me 3n 91 80

a Reaction was carried out on a 0.2 mmol scale in 2 mL of THF at �20 �C for 12 h.b Isolated yield by column chromatography.c Determined by HPLC analysis using a Daicel Chiralcel column, configuration (S) was assigned by the sign of the specific

rotation with that reported in the literature4h–j or by analogy.

Table 1 (continued)

Entry Catalyst (mol %) Solvent T (�C) Yieldb (%) eec (%)

14 L1, 7 .5 THF �8 95 8115 L1, 10 THF �8 97 8316 L1, 5 THF �20 88 9317 L4, 15 THF �20 85 8018 L5, 7.5 THF �20 84 8319 L1, 5 THF �40 83 8020 L1, 5 THF �78 80 3421 L1, 5 THF rt 99 7322d L2, 5 THF �20 90 8723 L3, 5 THF �20 — —

a Reaction was carried out on a 0.2 mmol scale in 2 mL of solvent for 12 h.b Isolated yield by column chromatography.c Determined by HPLC analysis using an OJ–H column.d The opposite configuration was obtained.

X. Han et al. / Tetrahedron: Asymmetry 23 (2012) 1332–1337 1335

transformation. For electron-rich group substituted indoles,methyl trifluoropyruvate gave results than ethyltrifluoropyruvate.For example, in the case of 7-methylated indole 1f, changing theelectrophile from methyl trifluoropyruvate to ethyl trfluoropyru-vate resulted in an obvious improvement in enantioselectivity(entries 6 vs 14). Furthermore, comparable excellent results wereachieved for indoles containing an electron-withdrawing groupon the phenyl ring compared to those with an electron-donatinggroup in terms of enantioselectivity and reactivity. With respectto the indole with the CO2Me group at the 5-position, it reactedwell with methyl trifluoropyruvate, and was obtained with 83%ee (entry 12).

The poor solubility of the C3-symmetric squaramide in organicsolvents allows its recycling. To obtain the information on therecycling ability of the catalyst, L1 was recovered and reused inthe Friedel–Crafts alkylation of 1a and 2a (Table 3). As shown inTable 3, our results indicated this C3 catalyst could be reused fivetimes without losing activity or selectivity.

3. Conclusion

In conclusion, a C3-symmetric cinchonine-squaramide (CSCS)L1 was identified as the best catalyst for the enantioselective

Friedel–Crafts reaction of indoles with trifluoropyruvates. A num-ber of chiral trifluoromethylated indoles were prepared in excel-lent yields (up to 99%) and enantioselectivities (up to >99%). Inaddition, this C3 catalyst can also be reused five times. Furtherapplication of the C3-symmetric squaramide to other asymmetrictransformations is currently underway.

4. Experimental

4.1. Materials and methods

Unless otherwise noted, reagents and materials were obtainedfrom commercial suppliers and used without further purification.All solvents were purified according to reported procedures. Reac-tions were run in oven dried glassware under an Ar atmosphere.Reactions were monitored by thin layer chromatography (TLC) andcolumn chromatography purifications were performed using 230–400 mesh silica gel. 1H and 13C NMR spectra were measured on Bru-ker DRX and DMX spectrometers at 400 MHz for 1H NMR spectra and100 MHz for 13C NMR spectra and calibrated from residual solventsignal. Enantiomeric excesses (ee) were determined by HPLC analy-sis using an SHIMADZU Series instrument with Daicel Chiralpak AD-H or Chiralcel OD-H columns, as indicated. The racemic samples

Table 3Recycling experiments of C3 squaramide L1 in the Friedel–Crafts alkylation of 1a with 2aa

5 mol % L1-20 °C, 12hN

HF3C CO2Et

O

NH

CO2EtOHF3C

1a 2a 3aCycle No. Yieldb (%) eec (%) Recovery rate (%)

0 90 92 921 91 92 922 90 91 893 90 90 884 85 89 895 87 90 856 75 67 80

a Reaction was carried out on a 1.0 mmol scale in 5 mL of THF at �20 �C for 12 h.b Isolated yield by column chromatography.c Determined by HPLC analysis using an AD-H column.

1336 X. Han et al. / Tetrahedron: Asymmetry 23 (2012) 1332–1337

were prepared with AlCl3 as the catalyst. The catalysts L1–L5 wereprepared according to our previous work.18a

4.1.1. General procedure for the asymmetric Friedel–Craftsreaction of indoles with alkyl trifluoropyruvates

Under an argon atmosphere, indole (0.2 mmol, 23.2 mg) andcatalyst L1 (0.01 mmol, 12.8 mg) were dissolved in 2 mL of THFat �20 �C. The mixture was stirred at �20 �C for 30 min. Ethyl3,3,3-trifluoropyruvate (0.3 mmol) was then added. The mixturewas stirred at �20 �C for 12 h and then progress was monitoredby TLC. After the reaction was completed, the solvents wereremoved. Next, the crude product was purified by columnchromatography (petroleum ether/ethyl acetate = 4:1).

4.1.1.1. Compound 3a. 1H NMR (400 MHz, CDCl3) d 8.28 (s,1H), 7.89 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.34 (d,J = 8.1 Hz, 1H), 7.28–7.10 (m, 3H), 4.60–4.27 (m, 3H), 1.33 (t,J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 169.42, 136.35,125.13, 124.99, 124.44, 122.70, 121.15, 121.14, 120.53, 111.39,108.65, 64.25, 13.93. ½a�20

D ¼ þ18:5 (c 1.35, CHCl3), {Lit.4i

½a�22D ¼ þ16:6 (c 0.43, CHCl3)}, HPLC analysis on a chiralpack OJ-H

column (20% iPrOH in hexanes; flow rate = 1.0 mL/min;k = 220 nm; tmajor = 36.30 min, tminor = 41.94 min, ee = 93%).

4.1.1.2. Compound 3b. 1H NMR (400 MHz, Acetone-d6) d10.54 (s, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.42 (dd, J = 10.6, 2.1 Hz,1H), 7.32 (dd, J = 8.9, 4.6 Hz, 1H), 6.82 (td, J = 9.1, 2.5 Hz, 1H),3.77 (s, 3H). 13C NMR (100 MHz, Acetone-d6) d 169.63, 159.78,134.40, 127.77, 126.71, 123.77, 113.60, 111.23, 110.97, 106.44,78.25, 53.91. ½a�20

D ¼ þ12:1 (c 0.47, CHCl3), HPLC analysis on a Chi-ralpack AD-H column (10% iPrOH in hexanes; flow rate = 1.0 mL/min; k = 220 nm; tmajor = 21.37 min, tminor = 38.74 min, ee >99%)

4.1.1.3. Compound 3c. 1H NMR (400 MHz, Acetone-d6) d10.63 (s, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.33(d, J = 8.7 Hz, 1H), 7.01 (dd, J = 8.7, 2.0 Hz, 1H), 3.77 (s, 3H). 13CNMR (100 MHz, Acetone-d6) d 169.54, 136.21, 127.52, 126.53,125.95, 123.69, 122.96, 121.22, 113.99, 109.39, 78.25, 53.95.½a�20

D ¼ þ15:5 (c 0.87, CHCl3), {Lit.4i ½a�25D ¼ þ17:1 (c 0.82, CHCl3)},

HPLC analysis on a Chiralpack AD-H column (10% iPrOH in hex-anes; flow rate = 1.0 mL/min; k = 254 nm; tminor = 20.19 min, tma-

jor = 21.57 min, ee = 96%).

4.1.1.4. Compound 3d. 1H NMR (400 MHz, Acetone-d6) d10.64 (s, 1H), 7.95 (s, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.30 (d,

J = 8.7 Hz, 1H), 7.14 (dd, J = 8.7, 1.9 Hz, 1H), 3.77 (s, 3H). 13C NMR(100 MHz, Acetone-d6) d: 169.50, 136.45, 128.19, 127.39, 125.54,124.34, 123.96, 114.42, 113.58, 109.30, 78.26, 53.96. ½a�20

D ¼ þ1:8(c 0.55, CHCl3), HPLC analysis on a Chiralpack AD-H column (10%iPrOH in hexanes; flow rate = 1.0 mL/min; k = 254 nm; tmi-

nor = 16.25 min, tmajor = 18.45 min, ee = 92%).

4.1.1.5. Compound 3e. 1H NMR (400 MHz, CDCl3) d 8.38 (s,1H), 7.57 (d, J = 10.3 Hz, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 6.95 (t,J = 9.0 Hz, 1H), 4.40 (dq, J = 20.9 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H).13C NMR (100 MHz, CDCl3) d 169.19, 159.28, 132.90, 126.16,125.57, 125.47, 124.93, 122.08, 112.14, 112.04, 111.38, 111.12,108.67, 108.62, 106.40, 106.15, 64.42, 13.86. ½a�20

D ¼ þ16:5 (c1.04, CHCl3), {Lit.4i ½a�25

D ¼ þ18:3 (c 0.78, CHCl3)}, HPLC analysison a Chiralpack OJ-H column (10% iPrOH in hexanes; flowrate = 1.0 mL/min; k = 220 nm; tmajor = 24.67 min, tminor = 28.32 -min, ee = 92%).

4.1.1.6. Compound 3f. 1H NMR (400 MHz, CDCl3) d 8.14 (s,1H), 7.64 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.00–6.96 (m,1H), 6.92 (d, J = 7.1 Hz, 1H), 4.37–4.30 (m, 2H), 4.26–4.19 (m,1H), 2.32 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)d 169.48, 135.97, 125.06, 124.70, 124.23, 123.18, 122.22, 120.73,120.64, 118.75, 109.08, 64.22, 16.40, 13.90. ½a�20

D ¼ þ5:0 (c 0.54,CHCl3), {Lit.4h ½a�20

D ¼ þ1:4 (c 0.40, CHCl3)}, HPLC analysis on a Chi-ralpack OD-H column (10% iPrOH in hexanes; flow rate = 0.5 mL/min; k = 220 nm; tmajor = 20.86 min, tminor = 33.43 min, ee = 92%).

4.1.1.7. Compound 3g. 1H NMR (400 MHz, CDCl3) d 8.02 (s,1H), 7.79 (d, J = 7.9 Hz, 1H), 7.21 (s, 1H), 7.11 (dd, J = 16.7, 7.8 Hz,2H), 4.37 (dd, J = 24.4, 7.2 Hz, 2H), 4.02 (s, 1H), 2.48 (s, 3H), 1.32(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 169.38, 135.30,134.66, 126.83, 125.40, 122.56, 121.61, 120.45, 120.23, 110.38,103.89, 63.58, 13.89, 13.74. ½a�20

D ¼ �4:65 (c 0.96, CHCl3), {Lit.4i

½a�20D ¼ �1:0 (c 0.40, CHCl3)}, HPLC analysis on a Chiralpack OD-H

column (10% iPrOH in hexanes; flow rate = 0.5 mL/min;k = 220 nm; tmajor = 26.48 min, tminor = 34.52 min, ee = 91%).

4.1.1.8. Compound 3h. 1H NMR (400 MHz, Acetone-d6) d10.39 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.30(d, J = 8.1 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H),3.73 (s, 3H). 13C NMR (100 MHz, Acetone-d6) d: 168.29, 136.25,125.91, 125.56, 124.36, 120.86, 120.45, 118.56, 111.02, 108.36,80.67, 51.47. ½a�20

D ¼ þ19:5 (c 0.88, CHCl3), {Lit.4j ½a�20D ¼ �24:1 (c

0.99, CHCl3)}, HPLC analysis on a Chiralpack AD-H column (10%

X. Han et al. / Tetrahedron: Asymmetry 23 (2012) 1332–1337 1337

iPrOH in hexanes; flow rate = 1.0 mL/min; k = 220 nm; tma-

jor = 18.92 min, tminor = 25.13 min, ee = 90%).

4.1.1.9. Compound 3i. 1H NMR (400 MHz, CDCl3) d 8.87 (s,1H), 7.59 (d, J = 7.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H),7.09 (t, J = 7.8 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.21 (q, J = 7.1 Hz,2H), 3.85 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)d 171.26, 169.07, 137.23, 127.02, 124.01, 123.38, 122.53, 122.23,121.57, 119.73, 116.53, 109.87, 63.13, 52.86, 13.78. ½a�20

D ¼ þ15:5(c 0.87, CHCl3), {Lit.4i, ½a�25

D ¼ þ17:1 (c 0.82, CHCl3)}, HPLC analysison a Chiralpack OD-H column (15% iPrOH in hexanes; flowrate = 1.0 mL/min; k = 220 nm; tmajor = 17.94 min, tminor = 24.73 -min, ee = 86%).

4.1.1.10. Compound 3j. 1H NMR (400 MHz, CDCl3) d 8.44 (s,1H), 7.90 (s, 1H), 7.40 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.14 (dd,J = 8.7, 1.7 Hz, 1H), 4.49 (d, J = 6.4 Hz, 1H), 4.44–4.38 (m, 1H),1.33 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 169.14,134.75, 126.27, 126.12, 125.87, 124.85, 123.05, 122.01, 120.71,112.44, 108.23, 64.51, 13.84. ½a�20

D ¼ þ14:8 (c 1.31, CHCl3), {Lit.4i

½a�22D ¼ þ14:5 (c 0.6, CHCl3)}, HPLC analysis on a Chiralpack OJ-H

column (10% iPrOH in hexanes; flow rate = 1.0 mL/min;k = 220 nm; tmajor = 29.31 min, tminor = 31.83 min, ee = 86%).

4.1.1.11. Compound 3k. 1H NMR (400 MHz, Acetone-d6) d10.15 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.86(tdd, J = 8.1, 7.6, 1.0 Hz, 2H), 3.66 (s, 3H), 2.38 (s, 3H). 13C NMR(100 MHz, Acetone-d6) d 169.94, 136.49, 128.11, 127.23, 124.40,121.72, 120.37, 120.28, 111.46, 104.91, 78.84, 53.07, 13.52.½a�20

D ¼ �6:8 (c 1.10, CHCl3), HPLC analysis on a Chiralpack IB col-umn (10% iPrOH in hexanes; flow rate = 1.0 mL/min; k = 254 nm;tmajor = 13.54 min, tminor = 18.43 min, ee = 83%).

4.1.1.12. Compound 3l. 1H NMR (400 MHz, Acetone-d6) d10.78 (s, 1H), 8.58 (s, 1H), 7.71 (dd, J = 8.6, 1.5 Hz, 1H), 7.55 (d,J = 2.4 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H).13C NMR (100 MHz, Acetone-d6) d 169.53, 168.20, 140.34, 139.72,127.63, 126.03, 124.88, 123.91, 122.92, 112.42, 111.05, 77.99,53.94, 51.98. ½a�20

D ¼ þ2:1 (c 0.33, CHCl3), HPLC analysis on a Chiral-pack AD-H column (10% iPrOH in hexanes; flow rate = 1.0 mL/min;k = 220 nm; tminor = 33.90 min, tmajor = 67.13 min, ee = 83%).

4.1.1.13. Compound 3m. 1H NMR (400 MHz, CDCl3) d 8.34 (s,1H), 8.00 (s, 1H), 7.35 (s, 1H), 7.18 (d, J = 10.3 Hz, 1H), 7.11 (d,J = 8.6 Hz, 1H), 4.40–4.27 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13CNMR (100 MHz, CDCl3) d 169.09, 135.03, 126.78, 125.70, 125.63,124.82, 123.90, 121.97, 113.91, 112.81, 108.28, 64.51, 13.89.½a�20

D ¼ þ12:5 (c 0.97, CHCl3), {Lit.4i ½a�20D ¼ þ17:2 (c 1.17, CHCl3)},

HPLC analysis on a Chiralpack OJ-H column (10% iPrOH in hexanes;flow rate = 1.0 mL/min; k = 220 nm; tmajor = 30.24 min, tmi-

nor = 33.49 min, ee = 80%).

4.1.1.14. Compound 3n. 1H NMR (400 MHz, Acetone-d6) d10.40 (s, OH), 7.54 (d, J = 7.1 Hz, 1H), 7.38 (s, 1H), 6.89–6.78 (m,2H), 3.72 (s, 3H), 2.35 (s, 3H). 13C NMR (100 MHz, Acetone-d6) d169.89, 137.22, 126.67, 126.07, 125.39, 123.31, 121.73, 120.84,119.37, 110.20, 78.34, 53.74, 16.87. ½a�20

D ¼ þ17:9 (c 0.53, CHCl3),HPLC analysis on a Chiralpack IB column (10% iPrOH in hexanes;flow rate = 1.0 mL/min; k = 254 nm; tminor = 11.83 min, tma-

jor = 13.21 min, ee = 80%).

Acknowledgments

We are grateful to the NSFC (Nos. 20872116, 20972121,91017005), the Program for New Century Excellent Talents in Uni-versity (NCET-10-0625), the National Mega Project on Major DrugDevelopment (2009ZX09301-014-1). Hubei Key Laboratory ofMolecular Imaging is also gratefully acknowledged.

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