Enantioselective Bromocyclization of Tryptamines Induced by Chiral

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Enantioselective Bromocyclization of Tryptamines Induced by Chiral Co(III)-complexes-templated Brønsted Acids Under an Air Atmosphere Kun Liu, Hua-Jie Jiang, Na Li, Hui Li, Jing Wang, Zheng-Zhu Zhang, and Jie Yu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01196 • Publication Date (Web): 17 May 2018 Downloaded from http://pubs.acs.org on May 17, 2018

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The Journal of Organic Chemistry

Kun Liu,† Hua-Jie Jiang,§ Na Li,† Hui Li,‡ Jing Wang,† Zheng-Zhu Zhang,† and Jie Yu*,† †

State Key Laboratory of Tea Plant Biology and Utilization and Department of Applied Chemistry, Anhui Agricultural University, Hefei, Anhui 230036, P. R. China

‡

Anhui Supervision Institute of Veterinary Drug and Feed, Hefei, Anhui 230091, P. R. China

§

Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China

Supporting Information Placeholder

A BSTRA CT: The chiral Co(III)-complex-templated Brønsted acids were found to be efficient bifunctional phase-transfer catalysts for the highly enantioselective bromocyclization of protected tryptamines with readily available N-bromosuccinimide (NBS) under an air atmosphere. The 3-bromohexahydropyrrolo[2,3-b]indoles, which are key building blocks of cyclotryptamine alkaloids, were thus obtained in up to 95% yield and 93.5:6.5 er.

Chiral anionic phase-transfer catalysis has seen increasing application as an effective strategy in the burgeoning field of asymmetric catalysis.1 Tremendous progress has been made on the chiral counteranion catalysis in the course of developing catalysts2 involving chiral phosphate anions2a-2c and anion-binding (thio)ureas2d,2e. With respect to chiral phosphate anion catalysis, although such catalysts have been found to act as one of the most efficient catalysts in both transition-metal-catalyzed 2c,3 and metal-free reactions4, the major drawback is the lengthy and expensive protocol required for the syntheses of such catalysts as well as a few precursors, especially BINOL, VAPOL5 and SPINOL6 derivatives. Clearly, catalysts with novel chiral anion templates in principal distinct from traditional platforms are still desirable to provide new opportunities for the development of enantioselective transformations. We recently introduced easily prepared octahedral chiral Co(III) complexes as inert templates for the design of enantiopure anion based ion-pair catalysts.7 In particular, the chiral Co(III)-complex-templated Brønsted acids (Λ-1f and Δ-1f) have been proven to be efficient bifunctional phase-transfer catalysts to shuttle the less soluble brominating reagent to reaction solution and also control stereoselectivity (Scheme 1a), enabling an enantioselective bromoaminocyclization of olefins to afford 2-substituted pyrrolidines with excellent enantioselectivities (Scheme 1b).7b This feature should be able to make anionic chiral Co(III) complexes, in which the metal center does not activate substrates directly but just offers the central chiral environment, hold unique privilege in chiral counteranion catalysis.8 Thus, we envisioned that the asymmetric bromocyclization9, 10 of tryptamines 2 employing the alternative chiral phasetransfer catalysts might afford 3-bromohexahydropyrrolo[2,3-b]indoles 3 (Scheme 1c), which are key building blocks of cyclotryptamine alkaloids with fascinating biological activities, and thereby are of highly synthetic importance.11

Scheme 1. A pplication of Chiral Co(III)-complex-templated A nionic Phase-Transfer Catalysis

In 2011, Gouverneur et al. established asymmetric fluorocyclization of tryptamines with moderate to good enantioselectivities using (DHQ)2PHAL as the catalyst.12 Since the enantioselective halogenation of olefins involving the chiral anionic phase-transfer catalysts was pioneered by Toste and cowork-

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ers,1e,13 the catalytic halocyclization of tryptamines has much less been studied due to the limitations which are posed by the background reaction.14 Ma and co-workers made a landmark contribution on the asymmetric bromocyclization of protected tryptamines with excellent enantioselectivities in the presence of 8H-R-TRIP and DABCO-derived bromide salt (4).15a Despite those advances, the development of novel catalytic systems for the enantioselective halocyclization is still necessary for the further improved activity and applicability. Herein, we present the highly enantioselective bromocyclization of protected tryptamines (2) catalyzed by Brønsted acid of anionic chiral Co(III) complexes, using N-bromosuccinimide (NBS) as the convenient and air-stable “bromo cation” source.10,16 Chiral Co(III)-complex-templated Brønsted acids (Λ-1f) were found to be efficient catalysts for the enantioselective synthesis of 3-bromohexahydropyrrolo-[2,3-b]indoles (3) with up to 95% yield and 93.5:6.5 er.

Table 1. Optimization of the reaction conditions a

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oselectivity in the presence of NaHCO315a (75:25 er, entry 2). Various brominating reagents, such as NBS, NBP, DBDMH and DABCO-derived trihalide salt 4 15a were then tested, and NBS turned out to be the optimal bromine source for this transformation (entry 2 vs entries 5-7). Interestingly, the addition of molecular sieves (M. S.) obviously improved the enantioselectivity (entries 8-10) and 4 Å M.S. were the best additives, affording the desired product 3a in 67% yield and 82.5:17.5 er (entry 9). It is worth mentioning that the absence of NaHCO3 resulted in enhanced yield with maintained enantioselectivity (entry 11) and the corresponding sodium salt of chiral Co(III)complexes (Λ-1b) exerted low yield and enantioselectivity (entry 12). Among chiral Co(III)-complex-templated Brønsted acids (Λ-1c-Λ-1f and Δ-1f) screened, Brønsted acid Λ-1f which exhibited excellent catalytic effect on previously published asymmetric bromoaminocyclization of olefins,7b provided the best enantiomeric ratio of 92.5:7.5 (entries 13-17). Additionally, raising the temperature to -30 ºC slightly improved the enantioselectivity (93.5:6.5 er, entry 18).

Table 2 Substrate Scope of A symmetric Bromocyclization a

Entry

3

R1

R2

PG

PG’

yield (%)b

erc

Entry

1

Br+ source

yield (%)b

erc

1

3a

H

H

Boc

Boc

89

93.5:6.5

1d, e

Λ-1a

NBS

86

67.5:32.5

2

3b

H

H

Boc

Cbz

91

90:10

2e

Λ-1a

NBS

67

75:25

3

3c

H

H

Boc

Troc

88

85:15

3e,f

Λ-1a

NBS

80

53:47

4

3d

H

H

Boc

Fmoc

99

90:10

51.5:48.5

5

3e

H

H

Boc

CO2Me

80

91.5:8.5

d

3f

H

H

Fmoc

Boc

42

85.5:14.5

d

e,g

4

5e

Λ-1a Λ-1a

NBS NBP

80 54

73.5:26.5

6

56:44

7

3g

H

H

CO2Me

Boc

71

82.5:17.5

20

51:49

8

3h

5-Me

H

Boc

Boc

95

91:9

NBS

57

78.5:21.5

9

3i

H

Boc

Boc

71

92.5:7.5

Λ-1a

NBS

67

82.5:17.5

5OMe

10e,j

Λ-1a

NBS

69

82:18

11i

Λ-1a

NBS

78

82.5:17.5

12 i

Λ-1b

NBS

12

62:38

13i

Λ-1c

NBS

31

52:48

14i

Λ-1d

NBS

39

57:43

15i

Λ-1e

NBS

40

54:46

16i

Λ-1f

NBS

85

92.5:7.5

i

Δ-1f

NBS

96

41.5:58.5

i,k

Λ-1f

NBS

89

93.5:6.5

6e

Λ-1a

DBDMH

e

7

Λ-1a

4

8e,h

Λ-1a

9e,i

17 18

74

10e

3j

5-Br

H

Boc

Boc

74

89.5:10.5

e

3k

5-Cl

H

Boc

Boc

72

89.5:10.5

f

12

3l

5-F

H

Boc

Boc

78

90:10

13

3m

7-Me

H

Boc

Boc

95

88.5:11.5

14d

3n

H

Me

Boc

Boc

68

59:41

11

a

a

Unless otherwise noted, the reaction was performed with 2a (0.1 mmol), Br+ source (0.12 mmol), catalyst 1 (0.01 mmol) in toluene (1 mL) at -40 °C under an air atmosphere in the absence of light for 60 h. b Yield of isolated product. c Determined by HPLC analysis on a chiral stationary phase. d The reaction was carried out at -20 °C for 36 h. e NaHCO3 (0.4 mmol) was used. f MTBE (t-Butyl methyl ether) was used as solvent. g Et2O was used as solvent. h 3 Å M. S. (100 mg) was used. i 4 Å M. S. (100 mg) was used. j 5 Å M. S. (100 mg) was used. k The reaction was carried out at -30 °C for 36 h. The reaction of Boc-protected tryptamine 2a with NBS was initially examined in the presence of 10 mol% of Brønsted acid of anionic chiral Co(III)complexes (Λ-1a), which are derived from 3,5-di-tert-butylsalicylaldehyde and L-tert-leucine (Table 1, entries 1-4). The screening of reaction parameters, including temperature and solvents, indicated that the reaction performed in lower temperature (-40 ºC) and nonpolar solvent toluene gave higher enanti-

Unless otherwise noted, the reaction was performed with 2 (0.1 mmol), NBS (0.12 mmol), Λ-1f (0.01 mmol) in toluene (1 mL) at -30 °C under an air atmosphere in the absence of light for 36 h. b Yield of isolated product. c Determined by HPLC analysis on a chiral stationary phase. d The reaction was carried out at -20 °C for 36 h, see the Supporting Information for details of optimization about temperature.e The reaction was carried out at -40 °C for 60 h.f The reaction was carried out at -35 °C for 60 h. With optimal reaction conditions established, we next explored the substrate scope of the asymmetric bromocyclization with respect to the substituted tryptamines 2.17 As shown in Table 2, a variety of carbamate protected tryptamines 2 were well tolerated, giving the corresponding 3bromohexahydropyrrolo[2,3-b]indoles 3b-3g in up to 99% yield and 91.5:8.5 er (entries 2-7). The substituent on the indole moiety of di-Boc-protected tryptamines 2h-2m was then evaluated. The electronic feature of 5-substituted tryptamines 2h-2l had little influence on the enantioselectivities (entries 8-12), and the highest enantiomeric ratio of 92.5:7.5 was obtained for the 5-methoxysubstituted product 3i with 71% yield (entry 9). However, slightly lower enantioselectivity was observed in the case of 7-methyl-substituted product 3m, which could be attributed to the steric interaction between the substituent and anionic chiral Co(III) complexes (entry 13). Although 2-methyl-substituted


2

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The Journal of Organic Chemistry tryptamine 2n participated in the reaction smoothly in -20 ºC, only low enantioselectivity (59:41 er) was obtained (entry 14). When the reaction in the absence of light was carried out under a nitrogen atmosphere in order to improve the enantioseletivity, only low yield and enantioselectivity (34% yield, 64:36 er) were obtained. Interestingly, replacing nitrogen with oxygen resulted in a better yield and similar enantioselectivity (99% yield, 93:7 er) compared to that observed for the reaction under an air atmosphere. Preliminarily kinetic studies on the Λ-1f catalyzed bromocyclization under O2 or N2 atmosphere were then performed. As shown in Scheme 2, during the beginning of the reaction under a nitrogen or oxygen atmosphere (the reactions are being run to about 12% conversion in 6 hours), similar reaction rates were observed in both cases. With increasing reaction time, the oxygen atmosphere showed a much higher activity than the nitrogen atmosphere. These results suggested that the involvement of a change in the overall mechanistic complexity of the process under an oxygen atmosphere. It is possible that the presence of oxygen promotes the initiation of a new catalytic cycle, considering the background reaction with NBS14, 18 and the structural and stereochemical stability of chiral Co(III)-complexes.19 Despite these observations, the unambiguous role of molecular oxygen in these reactions remains unresolved.

Scheme 2. The Effect of A tmosphere and Preliminarily Kinetic Studies on the A symmetric Bromocyclization

substrate 2a (Figure 1b). The NMR spectra of the mixture of NBP or DBDMH and the catalyst indicated that the catalyst could also react with the brominating reagents (NBP or DBDMH).20 According to the similarity between NBS and NBP, it is believed that these two Br+ reagents could give the similar results: 67% yield, 75:25 er for NBS and 54% yield, 73.5:27.5 er for NBP catalyzed by Λ-(S,S)-1a (see Table 1, entry 2 vs. entry 5). Moreover, the absolute configuration of the 3-bromopyrroloindoline 3a was determined to be (3aR, 8aR) by X-ray crystallographic analysis.21 According to these experimental data, we propose a catalytic cycle based on our previous work7b and Danishefsky’s finding22 (Scheme 3). The Brønsted acid 1 could render an exchange reaction with NBS to give the covalent CO2Br species 5 7b and succinimide in toluene, and the unstable 5 leads to the formation of the chiral ion-pair 6. The generated chiral brominating reagent 6 is soluble in the nonpolar solvent, thus might undergo the enantioselective bromocyclization with tryptamine 2a to afford the product 3a via the transition states TS-I and regenerate the Brønsted acid 1. As illustrated in transition states TS-I and TSII, the C-3 position on the indole moiety of 2 attacks the bromiranium ion of the ion-pair 6, meanwhile the hydrogen-binding interaction between the carbamate group and the anion complex might enhance the nucleophilicity of the carbamate group.7b, 10b Then the bromocyclization could favorably occur on the Re face in TS-I, as the Si face might be disfavored due to the steric repulsion between the indole ring as well as the Boc group of the substrate and the tertbutyl of the Schiff base (TS-II). The stereocontrol outcomes were not excellent may be posed by the background reaction of NBS.

Scheme 3. Possible Catalytic Cycle and Transition States

Figure 1. 1H-N M R A nalysis of the M ixture of Brominating Reagents or Substrate 2a and the Catalyst In summary, we have demonstrated that the chiral Co(III)-complextemplated Brønsted acids are efficient bifunctional phase-transfer catalysts for highly enantioselective bromocyclization of protected tryptamines with NBS, furnishing the 3-bromohexahydropyrrolo[2,3-b]indoles with up to 95% yield and 93.5:6.5 er. The preliminary data may indicate the involvement of molecular oxygen in the catalytic cycle. The consequences of the atmosphere effects on asymmetric bromocyclization and other halogenation reactions are currently under investigation. Further studies will also focus on the exploration of the potential of the anionic chiral Co(III)-complexes.

1

H-NMR spectral analysis of the mixture of NBS and Brønsted acid Δ-(S,S)1f in deuterated toluene was then carried out at room temperature under either nitrogen or air atmosphere.7b The occurence of N-succinimide in both cases clearly disclosed that Δ-(S,S)-1f reacted with NBS to produce a new complex,7b thereby leading to the formation of N-succinimide (Figure 1a). 1HNMR analysis of the mixture of substrate 2a, NBP, or DBDMH and the catalyst Λ-(S,S)-1f was also carried out under an air atmosphere. No evidence showed that there is an interaction between the catalyst Λ-(S,S)-1f and the

NMR spectra were recorded on Bruker-400 MHz spectrometer and Bruker-600 MHz spectrometer. FT-ICRMS spectra were recorded on P-SIMS-Gly of Bruker Daltonics Inc. Infrared spectra were recorded on a Nicolet MX-1E FT-IR spectrometer. HPLC analysis was performed on Waters-Breeze (2998 Dual λ Absorbance Detector and 1525 Binary HPLC Pump, UV detection monitored at 254nm and 214nm). Chiralpak ADH, IC and ID columns were purchased from Daicel Chemical Industries, Ltd. Optical rotations were determined at 589 nm (sodium D line) by using the Anton Paar-MCP-100 polarimeter. The absolute configuration of 3a was assigned by the X-ray analysis.


3


Analytic grade solvents for the column chromatography and commercially available reagents were used as received. CH2Cl2 was dried over CaH2 and distilled prior to use. Toluene, THF, MTBE and Et2O were dried over Na and distilled prior to use. The catalysts (Λ-1a to Λ-1f, Δ-1f) were synthesized according to the literature.7 The substrates 2a, 2e, 2i, 2m and 2n are known compounds and they are synthesized according to related literature.15a tert-Butyl 3-(2-(((benzyloxy)carbonyl)amino)ethyl)-1H-indole-1-carboxylate (2b): Benzyl chloroformate (410 mg, 2.4 mmol) was added in one portion to a solution of tert-butyl 3-(2-aminoethyl)-1H-indole-1-carboxylate (520 mg, 2.0 mmol) and Et3N (0.31 mL, 2.2 mmol) in CH2Cl2 (10 mL) at 0 ℃. Two hours later, the reaction mixture was treated with 1 M HCl, 5% NaOH and brine. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by chromatography on silica gel (EA/PE 1:5) afforded the title compound 2b as pale yellow oil (583 mg, 74%). 1H NMR (600 MHz, CDCl3) δ 8.13 (brs, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 7.38-7.29 (m, 5H), 7.25-7.23 (m, 2H), 5.11 (s, 2H), 4.86 (s, 1H), 3.55 (d, J = 5.8 Hz, 2H), 2.94-2.91 (m, 2H), 1.67 (s, 9H); 13C NMR (101MHz, CDCl3) δ 156.4, 149.7, 136.5, 135.6, 130.3, 128.6, 128.2, 128.1, 124.5, 123.3, 122.5, 118.9, 117.5, 115.4, 83.6, 66.7, 40.7, 28.2, 25.6; IR (KBr): ν 3426, 2922, 1729, 1456, 1372, 1259, 1161, 1091, 741, 692 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C23H26N2NaO4: 417.1790; Found 417.1783. tert-Butyl 3-(2-(((2,2,2-trichloroethoxy)carbonyl)amino)ethyl)-1H-indole-1carboxylate (2c). Following the procedure of synthesizing 2b, 2c was prepared similarly from 2,2,2-trichloroethyl chloroformate and tert-butyl 3-(2aminoethyl)-1H- indole-1-carboxylate. Chromatographic purification (EA/PE 1:5) gave 591 mg (68%) of a white foam. 1H NMR (600 MHz, CDCl3) δ 8.14 (brs, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.43 (s, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.257.23 (m, 1H), 5.07 (s, 1H), 4.74 (s, 2H), 3.60-3.56 (m, 2H), 2.96 (t, J = 6.5 Hz, 2H), 1.67 (s, 9H); 13C NMR (101MHz, CDCl3) δ 153.5, 148.6, 134.6, 129.2, 123.6, 122.4, 121.6, 117.8, 116.1, 114.4, 94.6, 82.7, 73.5, 39.8, 27.2, 24.4; IR (KBr): ν 3370, 2929, 1723, 1526, 1386, 1267, 1147, 1091, 818, 767, 723 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C18H21Cl3N2NaO4: 457.0465; Found 457.0459. tert-Butyl 3-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-1H-indole1-carboxylate (2d). Following the procedure of synthesizing 2b, 2d was prepared similarly from 9-fluorenylmethyl chloroformate and tert-butyl 3-(2aminoethyl)-1H- indole-1-carboxylate. Chromatographic purification (EA/PE 1:5) gave 618 mg (64%) of a white solid. mp 123.8-125.3 ºC; 1H NMR (600 MHz, CDCl3) δ 8.13 (brs, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.61-7.52 (m, 3H), 7.44 (brs, 1H), 7.40 (t, J = 7.4 Hz, 2H), 7.36-7.28 (m, 3H), 7.25-7.22 (m, 1H), 4.89 (s, 1H), 4.40 (d, J = 7.0 Hz, 2H), 4.22 (t, J = 6.9 Hz, 1H), 3.58-3.53 (m, 2H), 2.93 (t, J = 6.8 Hz, 2H), 1.66 (s, 9H); 13C NMR (101MHz, CDCl3) δ 156.4, 149.7, 144.0, 141.3, 135.6, 130.4, 127.7, 127.1, 125.1, 124.6, 123.3, 122.6, 120.0, 118.9, 117.6, 115.4, 83.6, 66.7, 47.3,40.7, 28.3, 25.7; IR (KBr): ν 3413, 2929, 2361, 1723, 1538, 1450, 1380, 1253, 1158, 759, 741 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C30H30N2NaO4: 505.2103; Found 505.2108. (9H-Fluoren-9-yl)methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indole-1carboxylate (2f). Finely grounded NaOH (0.50 g, 15 mmol) and TBAHS (0.085 g, 1 mmol) were added to a solution of tert-butyl (2-(1H-indol-3yl)ethyl)carbamate (1.30 g, 5 mmol) in CH2Cl2 (50 mL), and the resulting suspension was stirred for 10 minutes. A solution of 9-fluorenylmethyl chloroformate (2.58 g, 10 mmol) in CH2Cl2 (5.0 mL) was added via syringe, and the mixture was stirred for 3 h. H2O (50 mL) was then added, and the reaction was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The organic extracts were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by chromatography on silica gel (EA/PE 1:5) afforded the title compound 2f as an white solid (1.95 g, 81%). mp 152.8-154.3 ºC; 1H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.52 (brs, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.39 (brs, 1H), 7.33 (t, J = 7.4 Hz, 2H), 7.25-7.23 (m, 3H), 4.81 (brs, 2H), 4.61 (brs, 1H), 4.43 (t, J = 5.9 Hz, 1H),

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3.45 (s, 2H), 2.85-2.93 (m, 2H), 1.44 (s, 9H); 13C NMR (151MHz, CDCl3) δ 155.8, 143.3, 141.5, 128.0, 127.3, 124.8, 122.9, 120.2, 119.0, 115.3, 68.6, 46.9, 40.1, 28.4, 25.7; IR (KBr): ν 3434, 2922, 1728, 1504, 1456, 1399, 1250, 1168, 757, 740 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C30H30N2NaO4: 505.2103; Found 505.2097. Methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indole-1-carboxylate (2g). Following the procedure of synthesizing 2f, 2g was prepared similarly from methyl chloroformate and tert-butyl (2-(1H-indol-3-yl)ethyl)carbamate. Chromatographic purification (EA/PE 1:5) gave 1.27 g (80%) of a white solid. mp 114.7-115.9 ºC; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.44 (brs, 1H), 7.38-7.31 (m, 1H), 7.29-7.24 (m, 1H), 4.63 (brs, 1H), 4.03 (s, 3H), 3.48-3.46 (m, 2H), 2.90 (t, J = 6.7 Hz, 2H), 1.44 (s, 9H); 13C NMR (151MHz, CDCl3) δ 155.8, 130.4, 124.7, 122.8, 122.7, 119.0, 118.7, 115.2, 79.3, 53.7, 40.0, 28.4, 25.6; IR (KBr): ν 3362, 2924, 1723, 1629, 1450, 1384, 1257, 1168, 744 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C17H22N2NaO4: 341.1477; Found 341.1465. To a solution of substituted tryptamines (2.00 mmol) in CH2Cl2 (5 mL) were added (Boc)2O (917 mg, 4.20 mmol) and DMAP (14 mg, 0.11 mmol) at 0 °C. The mixture was warmed to room temperature and stirred overnight. After the starting material was completely consumed as monitored by TLC, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, and washed with 1 M HCl and brine. The organic layer was dried over Na2SO4, and concentrated in vacuo to give yellow oil, which was purified by column chromatography (EA/PE 1:7) to afford 2h and 2j-2l. tert-Butyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-methyl-1H-indole-1carboxylate (2h). white solid; yield: 71%; mp 77.1-79.0 ºC; 1H-NMR (600 MHz, CDCl3) δ 7.99 (brs, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.61 (brs, 1H), 3.46-3.45 (m, 2H), 2.88-2.85 (m, 2H), 2.45 (s, 3H), 1.66 (s, 9H), 1.44 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 155.9, 149.8, 133.8, 131.9, 130.6, 125.8, 123.3, 118.9, 117.5, 114.9, 83.3, 79.3, 40.2, 28.4, 28.2, 25.6, 21.4; IR (KBr): ν 3433, 2929, 1723, 1449, 1378, 1154, 1077, 798, 764 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C21H30N2NaO4: 397.2103; Found 397.2090. tert-Butyl 5-bromo-3-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-indole-1carboxylate (2j). white solid; yield: 75%; mp 78.8-80.4 ºC; 1H-NMR (600 MHz, CDCl3) δ 8.00 (brs, 1H), 7.64 (s, 1H), 7.41-7.39 (m, 2H), 4.61 (brs, 1H), 3.47-3.40 (m, 2H), 2.86-2.82 (m, 2H), 1.66 (s, 9H), 1.44 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 155.8, 149.3, 134.3, 132.2, 127.3, 124.3, 121.7, 117.2, 116.8, 115.9, 84.0, 79.4, 40.3, 28.4, 28.2, 25.5; IR (KBr): ν 3395, 2977, 1736, 1508, 1377, 1255, 1158, 1099, 856, 764 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C20H27BrN2NaO4: 461.1052; Found 461.1048. tert-Butyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-chloro-1H-indole-1carboxylate (2k). white solid; yield: 72%; mp 92.8-93.9 ºC; 1H-NMR (600 MHz, CDCl3) δ 8.06 (brs, 1H), 7.49 (s, 1H), 7.42 (brs, 1H), 7.28-7.26 (m, 1H), 4.62 (brs, 1H), 3.47-3.39(m, 2H), 2.86-2.83 (m, 2H), 1.66 (s, 9H), 1.45 (s, 9H); 13 C-NMR (101 MHz, CDCl3) δ 154.8, 148.3, 132.9, 130.7, 127.2, 123.6, 123.4, 117.6, 116.3, 115.3, 82.9, 78.4, 39.3, 27.4, 27.2, 24.5; IR (KBr): ν 3400, 2980, 1730, 1510, 1460, 1375, 1258, 1087, 859, 754 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C20H27ClN2NaO4: 417.1557; Found 417.1550. tert-Butyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-fluoro-1H-indole-1carboxylate (2l). white solid; yield: 77%; mp 131.6-133.4 ºC; 1H-NMR (600 MHz, CDCl3) δ 8.07 (brs, 1H), 7.44 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 9.0 Hz, 1H), 4.61 (brs, 1H), 3.44-3.37 (m, 2H), 2.87-2.82 (m, 2H), 1.66 (s, 9H), 1.44 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 160.4, 158.0, 155.8, 149.4, 131.9, 131.5, 124.7, 117.6, 116.2 (d, J = 8.8 Hz), 112.2 (d, J = 25.1 Hz), 104.6 (d, J = 23.2 Hz), 83.8, 79.4, 40.2, 28.4, 28.2, 25.5; IR (KBr): ν 3426, 2985, 2631, 2332, 1729, 1470, 1386, 1260, 1161, 860, 670 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C20H27FN2NaO4: 401.1853; Found 401.1846. A 10-mL oven-dried vial was charged with tryptamines 2 (0.10 mmol),


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The Journal of Organic Chemistry catalyst Λ-1f (7.2 mg, 0.01 mmol), activated 4 Å molecular sieves (100 mg) and distilled toluene (1 mL) at room temperature in the absence of light. The mixture was cooled to -30 ºC (for 2a-2e, 2h, 2i, 2m and 2n), -20 ºC (for 2f, 2g, and 2o), -40 ºC (for 2j and 2k), or -35 ºC (for 2l) and stirred for 15 min. The NBS (0.12 mmol) was added and the resulting solution was stirred vigorously under an air atmosphere until the reaction was complete (monitored by TLC). The reaction was then quenched with NEt3 (140 μL, 1.0 mmol) and saturated aqueous Na2S2O3 (0.2 mL). The mixture was purified by flash column chromatography (silica gel, petrol ether/EtOAc = 7:1) to give the enantioenriched 3-bromohexahydropyrrolo[2,3-b]indoles 3. Di-tert-butyl (3aR,8aR)-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,8dicarboxylate (3a).15a yield: 89%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 89.6-91.1 ºC; [α]D20 -139.60 (c 0.415, CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 7.51 (brs, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.25-7.17 (m, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.37 (s, 1H), 3.70-3.61 (m, 1H), 2.77-2.64 (m, 3H), 1.51 (s, 9H), 1.42 (s,9H); 13C-NMR (101 MHz, CDCl3) δ 153.4, 152.1, 142.1, 132.7, 130.3, 124.0, 123.8, 117.4, 83.9, 82.1, 80.8, 62.2, 46.2, 28.4, 28.3; HRMS (ESI) m/z: [M+Na]+ Calcd for C20H27BrN2NaO4: 461.1052; Found 461.1048. Enantiomeric ratio: 93.5:6.5, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 4.54 min, tmin = 5.33 min. 1-Benzyl 8-(tert-butyl) (3aR,8aR)-3a-bromo-2,3,3a,8a-tetrahydropyrrolo [2,3b]indole-1,8-dicarboxylate (3b). yield: 91%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 65.4-66.9 ºC; [α]D20 -128.07 (c 0.456, CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 7.62 (brs, 1H), 7.36-7.28 (m, 7H), 7.10 (t, J = 7.5 Hz, 1H), 6.46 (s, 1H), 5.20-5.16 (m, 2H), 3.81-3.77 (m, 1H), 2.93-2.70 (m, 3H), 1.54 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 154.0, 152.1, 142.0, 136.5, 132.4, 130.5, 128.4, 128.0, 127.9, 124.2, 123.7, 117.4, 84.0, 82.2, 67.2, 62.0 46.3, 28.2; IR (KBr): ν 2917, 1708, 1627, 1471, 1262, 1020, 804, 745, 702 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C23H25BrN2NaO4: 495.0895; Found 495.0890. Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 80/20, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 5.54 min, tmin = 6.78 min. 8-(tert-Butyl) 1-(2,2,2-trichloroethyl) (3aR,8aR)-3a-bromo-2,3,3a,8atetrahydropyrrolo [2,3-b]indole-1,8-dicarboxylate (3c). yield: 88%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); pale yellow oil; [α]D20 -63.53 (c 0.489, CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 7.61 (brs, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.43 (s, 1H), 4.76-4.57 (m, 2H), 3.85-3.80 (m, 1H), 2.91 (td, J = 11.5, 5.1 Hz, 1H), 2.83-2.69 (m, 2H), 1.52 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 152.0, 141.9, 132.0, 130.6, 124.2, 123.8, 117.1, 95.4, 84.3, 82.5, 75.0, 61.6, 46.5, 41.7, 28.2; IR (KBr): ν 2960, 2853, 1710, 1473, 1339, 1258, 1150, 1080, 805, 757 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C18H20BrCl3N2NaO4: 534.9570; Found 534.9565. Enantiomeric ratio: 85:15, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 3.94 min, tmin = 4.34 min. 1-((9H-Fluoren-9-yl)methyl) 8-(tert-butyl) (3aR,8aR)-3a-bromo-2,3,3a,8atetrahydropyrrolo [2,3-b]indole-1,8-dicarboxylate (3d). yield: 99%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 91.8-93.4 ºC; [α]D20 -136.40 (c 0.554, CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ 7.75 (d, J = 7.4 Hz, 2H), 7.72-7.51 (m, 3H), 7.43-7.26 (m, 6H), 7.12 (t, J = 7.4 Hz, 1H), 6.50 (s, 1H), 4.50-4.38 (m, 3H), 3.74 (brs, 1H), 3.00-2.61 (m, 3H), 1.51 (s, 9H); 13C-NMR (151 MHz, CDCl3) δ 155.8, 130.4, 124.7, 122.8, 122.7, 119.0, 118.7, 115.2, 79.3, 53.7, 40.1, 28.4, 25.6; IR (KBr): ν 2922, 1717, 1471, 1329, 1258, 1148, 737 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C30H29BrN2NaO4: 583.1208; Found 583.1217. Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chirapak AD, hexane / isopropanol = 95/5, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 16.21 min, tmin = 12.31 min. 8-(tert-Butyl) 1-methyl (3aR,8aR)-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylate (3e).15a yield: 80%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 81.4-84.2 ºC;

[α]D20 -154.30 (c 0.426, CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.39 (s, 1H), 3.82-3.78 (m, 1H), 3.75(s, 3H), 2.90-2.74 (m, 3H), 1.60 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 154.7, 152.1, 141.9, 132.3, 130.5, 124.2, 123.7, 117.3, 84.0, 82.1, 62.0, 52.7, 46.2, 41.0, 28.2; HRMS (ESI) m/z: [M+Na]+ Calcd for C17H21BrN2NaO4: 419.0582; Found 419.0590. Enantiomeric ratio: 91.5:8.5, determined by HPLC (Daicel Chirapak AD, hexane / isopropanol = 95/5, flow rate 0.7 mL/min, T = 30 ºC, 254 nm): tmaj = 11.61min, tmin = 9.96 min. 8-((9H-fluoren-9-yl)methyl) 1-(tert-butyl) (3aR,8aR)-3a-bromo-2,3,3a,8atetrahydropyrrolo [2,3-b]indole-1,8-dicarboxylate (3f). yield: 42%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); pale yellow oil; [α]D20 -43.16 (c 0.234, CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H), 7.38-7.20 (m, 6H), 7.12-7.08 (m, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.37 (brs, 1H), 4.73 (brs, 1H), 4.46 (brs, 1H), 4.34 (t, J = 6.0 Hz, 1H), 3.66-3.62 (m, 1H), 2.79-2.68 (m, 3H), 1.34 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 153.2, 143.8, 141.4, 132.7, 130.4, 127.7, 127.28, 127.24, 125.0, 124.6, 123.6, 120.0, 117.6, 83.8, 81.0, 68.0, 62.1, 53.4, 47.0, 46.1, 28.3; IR (KBr): ν 2960, 1710, 1482, 1363, 1264, 1154, 1030, 801, 754, 741 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C30H29BrN2NaO4: 583.1208; Found 583.1201. Enantiomeric ratio: 85.5:14.5, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 5.42 min, tmin = 7.73 min. 1-(tert-Butyl) 8-methyl (3aR,8aR)-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylate (3g). yield: 71%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); pale yellow oil; [α]D20 -109.93 (c 0.302, CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.1 Hz, 1H), 7.397.37 (m, 1H), 7.35-7.30 (m, 1H), 7.13 (td, J = 7.6, 0.9 Hz, 1H), 6.41 (s, 1H), 3.89 (s, 3H), 3.80-3.74 (m, 1H), 2.88-2.72 (m, 3H), 1.48 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 153.8, 153.4, 141.6, 132.5, 130.5, 124.5, 123.8, 117.2, 84.1, 81.0, 62.4, 53.1, 46.1, 41.3, 28.4; IR (KBr): ν 2955, 1706, 1481, 1394, 1261, 1157, 804, 752 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C17H21BrN2NaO4: 419.0582; Found 419.0570. Enantiomeric ratio: 82.5: 17.5, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 5.88 min, tmin = 6.32 min. Di-tert-butyl (3aR,8aR)-3a-bromo-5-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylate (3h). yield: 95%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); pale yellow oil; [α]D20 -60.21 (c 0.431, CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ 7.44 (brs, 1H), 7.15 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.41 (s, 1H), 3.74-3.69 (m, 1H), 2.85-2.75 (m, 2H), 2.74-2.65 (m, 1H), 2.33 (s, 3H), 1.57 (s, 9H), 1.48 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 153.5, 152.2, 139.9, 133.8, 132.7, 131.1, 124.0, 117.3, 84.0, 81.9, 80.7, 62.5, 46.1, 29.6, 28.4, 28.3, 20.9; IR (KBr): ν 2977, 1716, 1494, 1362, 1258, 1154, 814 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C21H29BrN2NaO4: 475.1208; Found 475.1197. Enantiomeric ratio: 91: 9, determined by HPLC (Daicel Chirapak ID, hexane / isopropanol = 95/5, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 4.25 min, tmin = 4.62 min. Di-tert-butyl (3aR,8aR)-3a-bromo-5-methoxy-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylate (3i).15a yield: 71%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 38.2-40.7 ºC; [α]D20 -43.27 (c 0.302, CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ 7.49 (s, 1H), 6.92-6.82(m, 2H), 6.37 (d, J = 43.5 Hz, 1H), 3.80 (s, 3H), 3.73-3.70 (m, 1H), 2.87-2.54 (m, 3H), 1.56 (s, 9H), 1.48 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 156.7, 153.4, 152.4, 135.7, 133.8, 116.3, 108.5, 84.1, 81.8, 80.8, 62.4, 55.8, 46.0, 31.2, 28.4, 28.3; HRMS (ESI) m/z: [M+Na]+ Calcd for C21H29BrN2NaO5: 491.1158; Found 491.1149. Enantiomeric ratio: 92.5: 7.5, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 7.66 min, tmin = 10.73 min. Di-tert-butyl (3aR,8aR)-3a,5-dibromo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole1,8-dicarboxylate (3j). yield: 74%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 55.6-56.4 ºC; [α]D20 74.77 (c 0.333, CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ 7.60 -7.45(m, 2H),


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7.39-7.37 (m, 1H), 6.43 (s, 1H), 3.78-3.75 (m, 1H), 2.83 (td, J = 11.6, 5.1 Hz, 1H), 2.75-2.68 (m, 2H), 1.58 (s, 9H), 1.48 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 153.3, 151.8, 141.2, 134.7, 133.2, 126.9, 118.7, 116.2, 84.2, 82.5, 80.9, 61.1, 46.2, 41.7, 28.3, 28.2; IR (KBr): ν 2962, 1715, 1471, 1394, 1261, 1146, 1099, 854, 799 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C20H26Br2N2NaO4: 539.0157; Found 539.0163. Enantiomeric ratio: 89.5:10.5, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 3.88 min, tmin = 4.42 min.

light. The mixture was cooled to -30 ºC and stirred for 15 min. The NBS (0.12 mmol) was added and the resulting solution was stirred vigorously for 36h. The reaction was then quenched with NEt3 (140 μL, 1.0 mmol) and saturated aqueous Na2S2O3 (0.2 mL). The mixture was purified by flash column chromatography (silica gel, petrol ether/EtOAc = 7:1) to give the enantioenriched 3bromohexahydropyrrolo[2,3-b]indoles 3a.

Di-tert-butyl (3aR,8aR)-3a-bromo-5-chloro-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylate (3k). yield: 72%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 79.4-81.2 ºC; [α]D20 -48.86 (c 0.322, CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ 7.54 (brs, 1H), 7.32 (s, 1H), 7.28 -7.23 (m, 1H), 6.43 (s, 1H), 3.77-3.74 (m, 1H), 2.82 (td, J = 11.5, 5.1 Hz, 1H), 2.77-2.65 (m, 2H), 1.57 (s, 9H), 1.48 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 153.3, 151.8, 140.7, 134.3, 130.3, 128.9, 123.9, 118.3, 84.3, 82.4, 80.9, 61.1, 46.1, 41.7, 28.3, 28.2; IR (KBr): ν 2964, 1715, 1477, 1391, 1258, 1150, 1020, 857, 801 cm-1; HRMS (ESI) m/z: [M+Na]+ Calcd for C20H26BrClN2NaO4: 495.0662; Found 495.0657. Enantiomeric ratio: 89.5:10.5, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 3.90 min, tmin = 4.51 min.

A 10-mL oven-dried vial was charged with di-Boc-protected tryptamine 2a (36.0 mg, 0.10 mmol), Λ-(S,S)-1f (7.2 mg, 0.01 mmol), activated 4 Å molecular sieves (100 mg) and distilled toluene (1 mL) at room temperature in the absence of light. The mixture was cooled to -30 °C and stirred for 15 min under a nitrogen or oxygen atmosphere (purity > 99.99%). The NBS (0.12 mmol) was added and the resulting solution was stirred for a specific time (2h, 4h, 6h, 8h, 16h, 24h). The reaction was quenched with NEt3 (140 μL, 1.0 mmol) and saturated aqueous Na2S2O3 (0.1 mL). Then the mixture was filtered to remove molecular sieves, and the solid powder was washed with ethyl acetate (30 mL). After evaporation under the reduced pressure, the residue was resolved in CDCl3 (0.6 mL) and benzyl benzoate (21.2 mg, 0.1 mmol) was added as internal standard for 1H-NMR analysis.

Di-tert-butyl (3aR,8aR)-3a-bromo-5-fluoro-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole -1,8-dicarboxylate (3l). yield: 78%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 121.6-123.1 ºC; [α]D20 -37.86 (c 0.361, CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ 7.54 (brs, 1H), 7.04 (dd, J = 7.6, 2.4 Hz, 1H), 6.98 (td, J = 8.8, 2.4 Hz, 1H), 6.43 (s, 1H), 3.76-3.73 (m, 1H), 2.84-2.79 (m, 1H), 2.72-2.69 (m, 2H), 1.57 (s, 9H), 1.48 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 160.6, 158.2, 153.3, 152.1, 138.2, 134.3, 118.6, 117.2 (d, J = 23.3 Hz), 110.6 (d, J = 24.5 Hz), 84.3, 82.3, 80.9, 61.4, 46.1, 29.7, 28.4, 28.3; IR (KBr): ν 2966, 2852, 1714, 1486, 1367, 1257, 1024, 805 cm1 ; HRMS (ESI) m/z: [M+Na]+ Calcd for C20H26BrFN2NaO4: 479.0958; Found 479.0967. Enantiomeric ratio: 90:10, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 90/10, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 4.55 min, tmin = 5.62 min. Di-tert-butyl (3aR,8aR)-3a-bromo-7-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylate (3m).15a yield: 95%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 58.9-60.8 ºC; [α]D20 -97.66 (c 0.456, CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 7.21-7.18 (m, 1H), 7.14-7.10 (m, 2H), 6.25 (s, 1H), 3.58-3.49 (m, 1H), 2.84-2.67 (m, 3H), 2.30 (s, 3H), 1.54 (s, 9H), 1.50 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 153.6, 141.6, 135.1, 132.3, 130.9, 126.1, 120.2, 86.0, 81.9, 80.6, 62.1, 45.5, 38.0, 28.6, 28.2, 19.2; HRMS (ESI) m/z: [M+Na]+ Calcd for C21H29BrN2NaO4: 475.1208; Found 475.1199. Enantiomeric ratio: 88.5:11.5, determined by HPLC (Daicel Chirapak ID, hexane / isopropanol = 95/5, flow rate 1.0 mL/min, T = 30 ºC, 254 nm): tmaj = 4.58 min, tmin = 4.86 min. Di-tert-butyl (3aR,8aR)-3a-bromo-8a-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3b]indole-1,8-dicarboxylate (3n).15a yield: 68%; (Flash column chromatography eluent, petroleum ether/ethyl acetate = 7/1); white solid; mp 105.4-109.6 ºC; [α]D20 -27.35 (c 0.301, CH2Cl2); 1H-NMR (600 MHz, CDCl3) δ 7.71 (s, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 3.54 (t, J = 9.8 Hz, 1H), 2.83 (td, J = 11.2, 6.7 Hz, 1H), 2.34-2.31 (m, 1H), 2.25-2.19 (m, 1H), 1.94 (s, 3H), 1.58 (s,9H), 1.44 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ 152.9, 151.7, 142.5, 131.0, 130.1, 123.5, 122.9, 118.3, 88.4, 81.7, 80.3, 60.4, 45.3, 35.2, 28.5, 28.4, 22.2; HRMS (ESI) m/z: [M+Na]+ Calcd for C21H29BrN2NaO4: 475.1208; Found 475.1198. Enantiomeric ratio: 59:41, determined by HPLC (Daicel Chirapak IC, hexane / isopropanol = 99/1, flow rate 0.3 mL/min, T = 30 ºC, 214 nm): tmaj = 16.78 min, tmin = 19.07 min. A 10-mL oven-dried vial was charged with tryptamines 2a (0.10 mmol), Λ-(S,S)-1f (7.2 mg, 0.01 mmol), activated 4 Å molecular sieves (100 mg) and distilled toluene (1 mL) at room temperature under a nitrogen or oxygen atmosphere (purity > 99.99%) in the absence of

A 10-mL oven-dried tube was charged with the catalyst Λ-(S,S)-1f (7.2 mg, 0.01 mmol), N BS (1.8 mg, 0.01 mmol) and δ8-toluene (0.5 mL) at room temperature. The reaction mixture was stirred under either nitrogen or air atmosphere for 30 min, then transferred to a NMR tube and monitored by 1H-NMR analysis (Figure S1). A 10-mL oven-dried tube was charged with the catalyst Λ-(S,S)-1f (7.2 mg, 0.01 mmol), 2a (3.6 mg, 0.01 mmol) and δ8-toluene (0.5 mL) at room temperature. The reaction mixture was stirred under an air atmosphere for 30 min, then transferred to a NMR tube and monitored by 1H-NMR analysis (Figure S2). A 10-mL oven-dried tube was charged with the catalyst Λ-(S,S)-1f (7.2 mg, 0.01 mmol), N BP (2.3 mg, 0.01 mmol) or DBDM H (2.9 mg, 0.01 mmol) and δ8-toluene (0.5 mL) at room temperature. The reaction mixture was stirred under an air atmosphere for 30 min, then transferred to a NMR tube and monitored by 1H-NMR analysis (Figure S3).

The Supporting Information is available free of charge on the ACS Publications website. Screening of temperature of asymmetric bromocyclization, figures of 1H-NMR experiments, X-ray single crystal data for 3a and detailed 1H and 13C NMR spectra and chiral HPLC chromatogram data for compounds 2 and 3 (PDF) Crystallographic data for 3a (CIF)

* E-mail: [email protected] Jie Yu: 0000-0002-9968-1429

The authors declare no competing financial interests.

We are grateful for financial support from NSFC (Grants 21672002), Young Talent Program in Anhui Provincal University (gxyqZD2017017) and the Key


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The Journal of Organic Chemistry Project of Anhui Tabaco Company (20160551015). We also sincerely thank Prof. Liu-Zhu Gong (USTC) for his support.

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Gong, L.-Z. Switchable Stereoselectivity in Bromoaminocyclization of Olefins: Using Brønsted Acids of Anionic Chiral Cobalt(III) Complexes. Angew. Chem., Int. Ed. 2017, 56, 11931-11935. (c) Jiang, H.-J.; Liu, K.; Wang, J.; Li, N.; Yu, J. Brønsted Acids of Anionic Chiral Co(III) Complexes as Catalysts for the Stereoselective Synthesis of cis-4Aminofuranobenzopyrans. Org. Biomol. Chem. 2017, 15, 9077-9080. (8) For reviews on chiral-at-metal complexes in catalysis, see: (a) Brunner, H. Optically Active Organometallic Compounds of Transition Elements with Chiral Metal Atoms. Angew. Chem., Int. Ed. 1999, 38, 1194-1208. (b) Knight, P. D.; Scott, P. Predetermination of Chirality at Octahedral Centres with Tetradentate Ligands: Prospects for Enantioselective Catalysis. Coord. Chem. Rev. 2003, 242, 125-143. (c) Fontecave, M.; Hamelin, O.; Ménage, S. Chiral-at-Metal Complexes as Asymmetric Catalysts. Top. Organomet. Chem. 2005, 15, 271-288. (d) Bauer, E. B. 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Chem., Int. Ed. 2012, 51, 9684-9688. (e) Phipps, R. J.; Toste, F. D. Chiral Anion Phase-Transfer Catalysis Applied to the Direct Enantioselective Fluorinative Dearomatization of Phenols. J. Am.


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Chem. Soc. 2013, 135, 1268-1271. (f) Miles, D. H.; Veguillas, M.; Toste, F. D. Gold(I)Catalyzed Enantioselective Bromocyclization Reactions of Allenes. Chem. Sci. 2013, 4, 3427-3431. (g) Chen, T.; Foo, T. J. Y.; Yeung, Y.-Y. Indole-Catalyzed Bromolactonization in Lipophilic Solvent: A Solid−Liquid Phase Transfer Approach. ACS Catal. 2015, 5, 4751-4755. (14) For selected examples, see: (a) Espejo, V. R.; Rainier, J. D. An Expeditious Synthesis of C(3)-N(1’) Heterodimeric Indolines. J. Am. Chem. Soc. 2008, 130, 1289412895. (b) Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. Scalable Total Syntheses of N-Linked Tryptamine Dimers by Direct Indole-Aniline Coupling: Psychotrimine and Kapakahines B and F. J. Am. Chem. Soc. 2010, 132, 7119-7137. (c) Tu, D.; Ma, L.; Tong, X.; Deng, X.; Xia, C. Synthesis of Pyrrolo[2,3‑b]indole via Iodine(III)-Mediated Intramolecular Annulation. Org. Lett. 2012, 14, 4830-4833. (15) (a) Xie, W.; Jiang, G.; Liu, H.; Hu, J.; Pan, X.; Zhang, H.; Wan, X.; Lai, Y.; Ma, D. Highly Enantioselective Bromocyclization of Tryptamines and Its Application in the Synthesis of (-)-Chimonanthine. Angew. Chem., Int. Ed. 2013, 52, 12924-12927. (b) Liu, H.; Jiang, G.; Pan, X.; Wan, X.; Lai, Y.; Ma, D.; Xie, W. Highly Asymmetric Bromocyclization of Tryptophol: Unexpected Accelerating Effect of DABCO-Derived Bromine Complex. Org. Lett. 2014, 16, 1908-1911. (c) Feng, X.; Jiang, G.; Xia, Z.; Hu, J.; Wan, X.; Gao, J.-M.; Lai, Y.; Xie, W. Total Synthesis of (−)-Conolutinine. Org. Lett. 2015, 17, 4428-4431. (16) Tan, C. K.; Yeung, Y.-Y. Recent Advances in Stereoselective Bromofunctionalization of Alkenes Using N-bromoamide Reagents. Chem. Commun. 2013, 49, 79857996 and references cited therein. (17) See Section 1 of the Supporting Information for details. (18) For the effects of atmosphere in the aminobromination of olefins, see: (a) Yu, W. Z.; Chen, F.; Cheng, Y. A.; Yeung, Y.-Y. Catalyst-Free and Metal-Free Electrophilic Bromoamidation of Unactivated Olefins Using the N‑Bromosuccinimide/Sulfonamide Protocol. J. Org. Chem. 2015, 80, 2815-2821. (b) Yu, W. Z.; Cheng, Y. A.; Wong, M. W.; Yeung, Y. Y. Atmosphere- and Temperature-Controlled Regioselective Aminobromination of Olefins. Adv. Syn. Catal. 2017, 359, 234-239. (19) (a) Maleev, V. I.; Skrupskaya, T. V.; Yashkina, L. V.; Mkrtchyan, A. F.; Saghyan, A. S.; Il’in, M. M.; Chusov, D. A. Aza-Diels–Alder Reaction Catalyzed by Novel Chiral Metalocomplex Brønsted Acids. Tetrahedron: Asymmetry 2013, 24, 178-183. (b) Belokon, Y. N.; Belikov, V. M.; Vitt, S. V.; Saveleva, T. F.; Burbelo, V. M.; Bakhmutov, V. I.; Alexandrov, G. G.; Struchkov, Y. T. A Simple Stereochemical Model of PyridoxalDependent Aldolase: Asymmetric Conversions of the Amino Acid Fragment in Chiral Complexes of Potassium Λ and Δ bis-/N-Salicylideneaminoacidato/Cobaltate(III). Tetrahedron 1977, 33, 2551-2564. (20) See Section 2 of the Supporting Information for details. (21) CCDC 1573941 (3a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (22) (a) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. Stereoselective Total Syntheses of Amauromine and 5-N-Acetylardeemin. A Concise Route to the Family of "Reverse-Prenylated" Hexahydropyrroloindole Alkaloids. J. Am. Chem. Soc. 1994, 116, 11143-11144. (b) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. Total Synthesis of 5-N-Acetylardeemin and Amauromine: Practical Routes to Potential MDR Reversal Agents. J. Am. Chem. Soc. 1999, 121, 1195311963.


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Enantioselective Bromocyclization of Tryptamines Induced by Chiral

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