Catalytic Asymmetric Conjugate Addition of Indoles to para-Quinone

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Catalytic Asymmetric Conjugate Addition of Indoles to para-Quinone Methide Derivatives Jin-Rong Wang, Xiao-Li Jiang, Qing-Qing Hang, Shu Zhang, Guang-Jian Mei, and Feng Shi J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2019 Downloaded from http://pubs.acs.org on May 24, 2019

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The Journal of Organic Chemistry

Catalytic Asymmetric Conjugate Addition of Indoles to para-Quinone Methide Derivatives

Jin-Rong Wang,‡,a Xiao-Li Jiang,‡,a Qing-Qing Hang,a Shu Zhang,*,b Guang-Jian Mei*,a and Feng Shi*,a aSchool

of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, China

bDepartment

of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

E-mail: [email protected]; [email protected]; [email protected] ‡These

authors contributed equally to the work. OH

O t-Bu

t-Bu

t-Bu

G

t-Bu

O

OH R N H

10 mol% CPA, acetone

+ R

MgSO4, -30 oC

1

R1

H

O

NH

OH R 20 examples 54%-97%, 90:10 to 96:4 er

P

O OH

G G = 9-anthracenyl CPA

Abstract: A catalytic asymmetric conjugate addition of indoles to o-hydroxyphenyl substituted p-quinone methides has been established in the presence of chiral phosphoric acid, which afforded chiral indole-containing triarylmethanes in generally high yields (54%-97%) and good enantioselectivities (90:10 to 96:4 er). The control experiments indicated that o-hydroxyphenyl substituted p-quinone methides had a high possibility to transform into o-quinone methides in the presence of chiral phosphoric acid, and the formation of o-quinone methides might be a necessity for the reaction. This reaction will not only contribute to the research field of catalytic asymmetric transformations of p-quinone methides and o-quinone methides, but also provide a useful method for the construction of enantioenriched triarylmethane frameworks.

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Introduction In recent years, quinone methides (QMs) such as para-quinone methides (p-QMs)1-4 and ortho-quinone methides (o-QMs)5-8 have been recognized as versatile reactants or intermediates for catalytic asymmetric reactions. As a result, rapid developments have been achieved in this research field, and chemists have devised a variety of p-QMs and o-QMs or their precursors. Among them, o-hydroxyphenyl substituted p-QMs have been widely utilized in catalytic asymmetric (4+n) cyclizations including (4+1), (4+2) and (4+3) cyclizations (Scheme 1, eq. 1).9-11 However, in sharp contrast, catalytic asymmetric conjugate addition of o-hydroxyphenyl substituted p-QMs has rarely been reported (eq. 2). Until recently, Li and co-workers established an organocatalytic asymmetric conjugate addition of 5H-thiazol-4-ones to o-hydroxyphenyl substituted p-QMs in a diastereodivergent mode (eq. 3).12a In addition, Lu, Weng and coworkers reported a catalytic asymmetric conjugate addition of arylboronic acids to this class of p-QMs in the presence of BINOL-catalyst (eq. 4).12b In spite of these elegant work, the catalytic asymmetric conjugate addition of o-hydroxyphenyl substituted p-QMs is rather limited, which requires rapid development in this research field.


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OH R1

Nu E

Cat.* O R1

R1

R1

(4+n) cyclization

Well-established (1)

* Nu

R

O E OH R1

R OH

Cat.*

R1

Nu Rarely reported

conjugate addition R

(2)

* Nu OH

Two examples of catalytic asymmetric conjugate additions: O R1

OH

R1

R1 O

R2 + R

Organo-Cat.* S

R2 O

N

*

R

Ar

OH

OH

O R1

R OH

* S

(3)

N Ar

OH

R1

+

R1

R1

HO

OH B

R1

BINOL-Cat.* R

3

R

(4)

* OH

R3

Scheme 1. Profile of catalytic asymmetric reactions involving o-hydroxyphenyl substituted p-QMs

In order to fulfil this task and based on our long-lasting interests in synthesizing indole derivatives,13 we designed a chiral phosphoric acid14 (CPA)-catalyzed asymmetric conjugate addition of indoles15 to o-hydroxyphenyl substituted p-QMs. As illustrated in Scheme 2, in the presence of CPA, o-hydroxyphenyl substituted p-QMs could transform into o-QMs because of the low isomerization energy (6.7 kcal/mol).10d Then, CPA could form two hydrogen bonds with both o-QMs and indoles, thus promoting an enantioselective conjugate addition between them to generate chiral triarylmethane products. Notably, the analogues of this class of indole-containing triarylmethane frameworks exist in lots of biologically active compounds.16



O R1

Page 4 of 40

OH

R1

R1

R1 R2

R2

+

R

CPA N H

OH

*

R

NH

OH

p-QM

CPA 6.7 kcal/mol

OH R1

OH R1

R1

R2

R2 N H CPA

R o-QM

O

R1

N H

R O

O

H O P *

Scheme 2. Design of catalytic asymmetric conjugate addition of indoles to o-hydroxyphenyl substituted p-QMs

Results and Discussion Based on this design, we tried the reaction of indole 1a with o-hydroxyphenyl substituted p-QM 2a in the presence of CPA 4a (Table 1, entry 1). As expected, the conjugate addition smoothly occurred to give triarylmethane product 3aa in a high yield of 97% albeit with an extremely low enantioselectivity of 54:46 er. Nevertheless, this preliminary result demonstrated the feasibility of our design. To improve the enantioselectivity, a series of CPAs 4 were screened (entries 1-7), which found that CPA 4e bearing two bulky 9-anthracenyl groups could facilitate the conjugate addition in the highest enantioselectivity of 76:24 er (entry 5). Then, in the presence of the optimal catalyst 4e, some representative solvents were screened (entries 8-12), which discovered that acetone could deliver the reaction in the best enantioselectivity of 89:11 er (entry 9). So, acetone was selected as the most suitable reaction media. Then, the effect of temperature on the reaction was investigated (entries 13-17). It was found that elevating the reaction temperature was detrimental to the enantioselectivity (entry 13 vs entry 9), while lowering the reaction temperature could improve the enantioselectivity to some extent (entries 14-17 vs entry


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9). Thus, -30 oC was chosen as the optimal reaction temperature (entry 16). Subsequently, the reagents ratio was carefully modulated (entries 18-22), and the molar ratio of 1.2:1 was set as the suitable reagents ratio (entry 20). Finally, some additives such as molecular sieves (MS) and anhydrous sulfate were tentatively added to the reaction (entries 23-27), which found that the addition of magnesium sulfate could enhance the enantioselectivity to the highest level of 95:5 er (entry 26). In addition, we also utilized magnesium phosphate of 4e as a catalyst in this reaction in the absence or presence of magnesium sulfate (entries 28-29). It was found that product 3aa could be generated in a high yield of 98% and a considerable enantioselectivity (85:15 er and 89:11 er, respectively). But in these cases, the enantioselectivities were lower than those of the reactions catalyzed by phosphoric acid 4e (entry 28 vs entry 20, entry 29 vs entry 26). These results suggested that magnesium phosphate of 4e could also catalyze the reaction, but it was inferior to phosphoric acid 4e in terms of controlling the enantioselectivity. Because the addition of magnesium sulfate to the reaction system might have a possibility to convert the free phosphoric acid 4e into the corresponding Mg-phosphate salt, a Lewis acid-catalyzed process could not be excluded in this reaction. Table 1. Screening of catalysts and optimization of reaction conditionsa G

G

4a, G = 4-ClC6H4 4b, G = 2-naphthyl 4c, G = 1-naphthyl 4d, G = 9-phenanthrenyl 4e, G = 9-anthracenyl 4f, G = 2,4,6-(i-Pr)3C6H2 4g,G = SiPh3

O

t-Bu

O O (S)-4

P

t-Bu

O OH

OH t-Bu

t-Bu

OH N H

10 mol% Cat.

+

*

solvent, T oC

NH

OH 2a

1a

entry

Cat.

solvent

3aa

T (oC)

1a:2a

additives


yield (%)b

erc


Page 6 of 40

1

4a

ClCH2CH2Cl

25

1:1.2

-

97

54:46

2

4b

ClCH2CH2Cl

25

1:1.2

-

90

55:45

3 4 5 6 7 8

4c 4d 4e 4f 4g 4e

1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2

-

75:25 61:39 76:24 52:48 57:43 88:12

4e

25 25 25 25 25 25 25

98 97 95 97 98 98

9

ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl EtOAc acetone

97

89:11

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e Mg[4e]2 Mg[4e]2

1,4-dioxane CH3CN toluene acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone

25 25 25 50 0 -15 -30 -40 -30 -30 -30 -30 -30 -30 -30 -30 -30 -30 -30 -30

1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 3:1 2:1 1.2:1 1:2 1:3 1.2:1 1.2:1 1.2:1 1.2:1 1.2:1 1.2:1 1.2:1

3Å MS 4Å MS 5Å MS MgSO4 Na2SO4 MgSO4

98 97 98 94 90 88 94 94 96 95 97 97 98 94 93 95 97 95 98 98

85:15 84:16 68:32 83:17 90:10 92:8 92:8 91:9 92:8 92:8 92:8 87:13 88:12 68:32 65:35 75:25 95:5 92:8 85:15 89:11

aUnless

otherwise indicated, the reaction was carried out at the 0.05 mmol scale in a solvent (1 mL) with or

without additives (50 mg) for 12 h. bIsolated yield. cThe enantiomeric ratio (er) was determined by HPLC.

After establishing the optimal reaction conditions, we then investigated the substrate scope of indoles 1 in the conjugate addition with o-hydroxyphenyl substituted p-QM 2a. As summarized in Table 2, this catalytic asymmetric conjugate addition reaction could be applicable to a wide range of indoles 1 bearing either electron-donating or electron-withdrawing groups at different positions of the phenyl ring (C4-C7), which successfully participated in the reaction to give products 3 in good yields (71%-97%) and high enantioselectivities (90:10 to 96:4 er). It seems that the


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electronic nature of the substituents exerted some effect on the enantioselectivity because the electron-withdrawing

groups

generally

showed

higher

capacity

in

controlling

the

enantioselectivity than electron-donating groups at the same position of the indole ring (entries 4-8 vs entry 3; entries 11-14 vs entries 9-10). However, in most cases, the position of the substituents did not show evident influence on the enantioselectivity. For example, C5- and C6-methyl substituted indoles 1c and 1i afforded products 3ca and 3ia in the same enantioselectivity of 90:10 er (entry 3 vs entry 9). The similar phenomena could be found in the cases of C5- and C6- fluoro or chloro-substituted indoles (entry 4 vs 11, entry 5 vs 12). Table 2. Substrate scope of indoles 1a OH

O t-Bu 5

t-Bu

4

t-Bu

OH

R 6

t-Bu

N H

7

10 mol% 4e, acetone

+

2a

1

NH

H

MgSO4, -30 oC OH 3

yield

R

entry

R (1)

3

1

H (1a)

3aa

97

95:5

2

4-OMe (1b)

3ba

87

90:10

3

5-Me (1c)

3ca

91

90:10

4

5-F (1d)

3da

97

95:5

5

5-Cl (1e)

3ea

6

5-Br (1f)

3fa

7

5-I (1g)

3ga

8

5-CN (1h)

3ha

93 90 85 71

93:7 93:7 95:5 90:10

9

6-Me (1i)

3ia

10

6-OMe (1j)

3ja

11d

6-F (1k)

3ka

12

6-Cl (1l)

3la

13

6-Br (1m)

3ma

14

6-CN (1n)

3na

15

7-F (1o)

3oa

98 92 79 82 95 75 83

90:10 90:10 96:4 92:8 90:10 93:7 95:5

aUnless

(%)b

erc

indicated otherwise, the reaction was carried out in 0.1 mmol scale in acetone (2 mL) with MgSO4 (100 mg) at -30 oC for 12 h, and the molar ratio of 1:2a was 1.2:1. bIsolated yield. cThe enantiomeric ratio (er) was determined by HPLC. dWhen the reaction was performed with 50 mg of MgSO4, the yield was 75% and the enantioselectivity was 91:9 er.



Page 8 of 40

Then, the substrate scope of o-hydroxyphenyl substituted p-QMs 2 was studied by the conjugate addition with indoles 1a and 1k. As listed in Table 3, several p-QMs 2a-2f bearing C5 or C4-substituents on the phenyl ring could be utilized as suitable substrates in the reaction, affording products 3 in moderate to high yields (54%-97%) with good enantioselectivities (90:10 to 95:5 er). The electronic nature of the substituents seems to have no obvious effect on the enantioselectivity due to the fact that substrates 2b-2e bearing either electron-withdrawing groups or electron-donating groups delivered the products in the same enantioselectivity of 90:10 er (entries 2-5). Table 3. Substrate scope of o-hydroxyphenyl substituted p-QMs 2a OH t-Bu

O t-Bu

t-Bu

t-Bu OH

N H

R

1a, R = H 1k, R = F

+

6

5

R

10 mol% 4e, acetone MgSO4, -30 oC

1

4

3

OH 2

NH

H R1 3

R

entry

1

R1 (2)

3

yield (%)b

erc

1

1a

H (2a)

3aa

97

95:5

2

1a

5-F (2b)

3ab

81

90:10

3

1k

5-Cl (2c)

3kc

4

1k

5-Me (2d)

3kd

97 97

90:10 90:10

5

1k

5-OMe (2e)

3ke

6

1k

4-Br (2f)

3kf

60 54

90:10 90:10

aUnless

indicated otherwise, the reaction was carried out in 0.1 mmol scale in acetone (2 mL) with MgSO4 (100 mg) at -30 oC for 12 h, and the molar ratio of 1:2 was 1.2:1. bIsolated yield. cThe enantiomeric ratio (er) was determined by HPLC.

The absolute configuration of product 3ba was determined to be (R)-configuration via its single-crystal X-ray analysis (97:3 er after recrystallization).17 Thus, the absolute configuration of other products 3 was deduced to be (R) by analogy. In order to investigate the possible activation mode of chiral catalyst 4e on substrates 1 and 2, we performed some control experiments (Scheme


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3). First, N-methyl-protect indole 1p was used as a substrate instead of N-unprotected indoles under the standard conditions (eq. 5). In this case, indole 1p could undergo conjugate addition with p-QM 2a to give product 3pa in a good yield of 79%. However, nearly no enantio-control was observed during the formation of product 3pa (52:48 er). This result demonstrated that the N-H group of indoles played an important role in controlling the enantioselectivity possibly via forming a hydrogen bond with chiral catalyst 4e. Second, o-methoxyphenyl substituted p-QM 2g and phenyl substituted p-QM 2h were employed as substrates instead of o-hydroxyphenyl substituted p-QMs 2 in the conjugate addition under the standard conditions (eq. 6-7). In the two cases, no reaction occurred, which indicate that the OH group of phenyl-substituted p-QMs played a crucial role in controlling the reactivity via the hydrogen-bonding interaction with catalyst 4e. Moreover, ortho-hydroxybenzyl alcohol 2i as a precursor of o-QM was utilized as a substrate in the reaction. It was found that no reaction occurred under the standard conditions (eq. 8). However, elevating the reaction temperature and changing the solvent led to the generation of desired product 3ai in a high yield of 98% and a considerable enantioselectivity of 87:13 er (eq. 9). These results implied that the reactivity of ortho-hydroxybenzyl alcohols is lower than o-hydroxyphenyl substituted p-QMs 2 in the conjugate addition at low temperature, and the conjugate addition of p-QMs 2 might occur via the formation of o-QM intermediates. Finally, tetrasubstituted p-QM 2j was tentatively employed to the reaction under the standard conditions or at a higher temperature. However, no reaction occurred either at lower temperature or at higher temperature (eq. 10). This result indicated that the reactivity of tetrasubstituted p-QMs is much lower than commonly used trisubstituted p-QMs 2, which still remains to be a challenge in the chemistry of p-QMs.



Page 10 of 40

OH t-Bu

O t-Bu

t-Bu

t-Bu OH

N Me

10 mol% 4e, acetone

+

*

o

MgSO4, -30 C

N Me (5)

OH

1p

3pa 79%, 52:48 er

2a O t-Bu

N H

t-Bu 10 mol% 4e, acetone

+

(6)

No reaction

MgSO4, -30 oC OMe 2g

1a

O t-Bu

N H


+

No Reaction

MgSO4, -30 oC

1a

2h

H

10 mol% 4e, acetone Ph MeO N H

No Reaction

OH

Ph 10 mol% 4e, DCE

2i

MeO

o

MgSO4, 50 C O t-Bu N H

(8)

MgSO4, -30 oC

OH

+

1a

(7)

*

(9)

OH NH 3ai 98%, 87:13 er


+

MgSO4, -30 oC or 50 oC

No Reaction

(10)

1a OH 2j

OMe

Scheme 3. Control experiments

Based on the experimental results, we suggested two possible reaction pathways and activation modes of the catalyst to the substrates (Scheme 4). In pathway A, it is suggested that o-hydroxyphenyl substituted p-QMs 2 transformed into o-QMs 2’ in the presence of CPA 4e. Then, CPA 4e simultaneously formed two hydrogen bonds with the N-H group of indoles 1 and the carbonyl group of o-QMs 2’, thus facilitating an enantioselective 1,4-addition of indoles 1 to o-QMs 2’ and giving rise to products 3 with observed (R)-configuration. In pathway B, it is suggested that o-hydroxyphenyl substituted p-QMs 2 were directly attacked by indoles 1 in the


Page 11 of 40

presence CPA 4e to undergo an enantioselective 1,6-addition, thus generating (R)-3. However, in the control experiment (Scheme 3, eq. 6), o-methoxyphenyl substituted p-QM 2g failed to participate in the conjugate reaction. This result indicated that the formation of o-QMs 2’ might be a necessity for the reaction. As illustrated in Scheme 4, in the presence of CPA, o-hydroxyphenyl substituted p-QMs 2 could easily transform into o-QMs 2’ via the proton-transfer process, and CPA could serve as a shuttle for proton transfer. On the contrary, p-QM 2g could hardly transform into o-QMs 2g’ due to the absence of the OH group, which is crucial for proton transfer. So, based on the control experiment, we consider that pathway A has a higher possibility than pathway B, but pathway B should not be totally excluded. OH t-Bu

t-Bu OH

OH

t-Bu

H

1

R

O Pathway A 2' (o-QM)

9-An

O

P

ac hr

O

O

thrac

t-Bu

OH

nt

O

1

9-A

CPA 4e

R1

N H

H

R

t-Bu

en yl

t-Bu

O

H

CPA 4e

enyl

NH

R R1 (R)-3

1,4-addition CPA 4e

O t-Bu

9-Anthracenyl

t-Bu

O

H

H N 1

CPA 4e

R

nyl

H

R

(R)-3

race

OH 2 (p-QM)

O

t-Bu

t-Bu

1 Pathway B

O

nth

R

P

O

O

CPA 4e

9-A

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

OH 1,6-addition O

H

t-Bu

t-Bu

O *

O

OH

t-Bu

t-Bu

t-Bu

CPA 4e

P OR

O

H 2 (p-QM)

O

t-Bu

t-Bu

t-Bu

CPA 4e R O 2' (o-QM)

OMe 2g

Scheme 4. Possible reaction pathway


R 2g'

OMe


Page 12 of 40

Moreover, to examine the utility of this reaction, we performed two larger-scale reactions under the standard conditions (Scheme 5). To our satisfaction, the catalytic asymmetric conjugate addition reaction of indole 1k to 2a at the 0.5 mmol scale successfully afforded product 3ka in a nearly maintained good enantioselectivity of 94:6 er and an excellent yield of 93% (eq. 11), which is higher than the small-scale reaction (Table 2, entry 11). In addition, the catalytic asymmetric reaction between indole 1a and p-QM 2a at the 1 mmol scale also smoothly offered product 3aa in a quantitative yield and a high enantioselectivity of 93:7 er (eq. 12), which are similar to the results of small-scale reaction (Table 2, entry 1). These results demonstrated that the catalytic asymmetric conjugate addition reaction could be used as a practical tool for the synthesis of chiral indole-containing triarylmethanes. OH t-Bu

O t-Bu

t-Bu

OH

10 mol% 4e, acetone

+

N H

F

t-Bu

NH

H

(11)

MgSO4, -30 oC OH 3ka F 93% (207mg), 94:6 er

2a 0.5 mmol

1k 0.6 mmol

OH

O t-Bu

t-Bu

1.2 mmol

*

MgSO4, -30 oC

N H OH 2a 1.0 mmol

t-Bu

OH

10 mol% 4e, acetone

+

1a

t-Bu

NH

(12)

3aa 99% (423 mg), 93:7 er

Scheme 5. Larger-scale reactions. Finally, to do some preliminary derivation of products, we carried out a Suzuki coupling of product 3fa with 4-chlorophenylboronic acid, which generated product 5 in a good yield of 79% and a maintained high enantioselectivity of 94:6 er (Scheme 6).


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OH t-Bu

OH t-Bu

t-Bu

OH H

NH

t-Bu

OH 4-ClC6H4B(OH)2 (1.5 equiv.) Cs2CO3 (2 equiv.) Pd(OAc)2 (0.05 equiv.)

H

NH

Butyl di-1-adamantylphosphine (0.06 equiv.) DME (0.6 mL), 80 oC, 12 h

Br 3fa 93:7 er

Cl

5 79%, 94:6 er

Scheme 6. Preliminary derivation of product 3fa

Conclusions

In summary, we have established a catalytic asymmetric conjugate addition of indoles to o-hydroxyphenyl substituted p-QMs in the presence of chiral phosphoric acid, which afforded chiral indole-containing triarylmethanes in generally high yields (54%-97%) and good enantioselectivities (90:10 to 96:4 er). The control experiments indicated that o-hydroxyphenyl substituted p-QMs had a high possibility to transform into o-QMs in the presence of chiral phosphoric acid, and the formation of o-QMs might be a necessity for the reaction. The larger-scale reaction demonstrated that the catalytic asymmetric conjugate addition could be scaled up. This reaction will not only contribute to the research field of catalytic asymmetric transformations of p-QMs and o-QMs, but also provide a useful method for the construction of enantioenriched triarylmethane frameworks.

Experimental Section 1H

and

13C

NMR spectra were measured at 400 and 100 MHz, respectively. The solvents

used for NMR spectroscopy were DMSO-d6, CDCl3 and acetone-d6, using tetramethylsilane as the internal reference. HR MS (ESI) was determined by a HR MS/MS instrument. The X-ray source



Page 14 of 40

used for the single crystal X-ray diffraction analysis of compound 3ba was GaKα (λ = 1.34139), and the thermal ellipsoid was drawn at the 30% probability level. Analytical grade solvents for the column chromatography were used after distillation, and commercially available reagents were used as received. Methods for the synthesis of substrates 2a-2g: p-QM derivatives 2 could be conveniently synthesized according to the known literature procedures.2a, 10a,18-20 Among them, 2a, 2c-2e10a, 2g18, 2h2a, 2i19 and 2j20 are known compounds. 2,6-di-tert-butyl-4-(2-hydroxybenzylidene)cyclohexa-2,5-dienone10a (2a): 78% yield (1.21 g); yellow solid; m.p. 158.6-159.8 oC; 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.60 (s, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.32 – 7.25 (m, 1H), 7.24 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.92 (m, 1H), 1.28 (s, 9H), 1.24 (s, 9H). 2,6-di-tert-butyl-4-(5-fluoro-2-hydroxybenzylidene)cyclohexa-2,5-dienone (2b): 70% yield (1.15 g); yellow solid; m.p. 160.1-161.4 oC; 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.50 (s, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.17 – 7.08 (m, 2H), 6.97 – 6.91 (m, 1H), 1.26 (s, 9H), 1.23 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 186.1, 155.5(J = 234 Hz), 153.6, 148.3, 146.8, 139.8, 135.8, 131.0, 128.3, 123.5 (J = 8 Hz), 118.0 (J = 23 Hz), 117.3, 117.2, 117.0, 79.6, 35.4, 35.1, 29.7, 29.5; IR (KBr): 3335, 2957, 1591, 1558, 1541, 1362, 1268, 1177, 737, 668 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H26FO2 329.1912, found 329.1907. 2,6-di-tert-butyl-4-(5-chloro-2-hydroxybenzylidene)cyclohexa-2,5-dienone10a

(2c):

75%

yield (1.29 g); yellow solid; m.p. 98.2-99.7 oC; 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 7.50 (s, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.24 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 1.27 (s, 9H), 1.24 (s, 9H).


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2,6-di-tert-butyl-4-(2-hydroxy-5-methylbenzylidene)cyclohexa-2,5-dienone10a

(2d):

71%

yield (1.15 g); yellow solid; m.p. 116.8-118.3 oC; 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.16 (s, 1H), 7.11 – 7.07 (m, 1H), 6.85 (d, J = 8.2 Hz, 1H), 2.24 (s, 3H), 1.27 (s, 9H), 1.24 (s, 9H). 2,6-di-tert-butyl-4-(2-hydroxy-5-methoxybenzylidene)cyclohexa-2,5-dienone10a (2e): 78% yield (1.33 g); orange solid; m.p. 81.7-83.2 oC; 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.58 (s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 6.93 – 6.88 (m, 3H), 3.72 (s, 3H), 1.28 (s, 9H), 1.25 (s, 9H). 4-(4-bromo-2-hydroxybenzylidene)-2,6-di-tert-butylcyclohexa-2,5-dienone (2f): 68% yield (1.32 g); yellow solid; m.p. 189.8-190.1 oC; 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.49 (s, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.14 – 7.07 (m, 2H), 1.26 (s, 9H), 1.23 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 186.2, 158.2, 148.2, 146.6, 140.1, 135.9, 133.2, 130.72, 128.4, 124.2, 122.6, 122.4, 119.0, 79.6, 35.4, 35.1, 29.7, 29.6; IR (KBr): 3566, 2956, 1683, 1558, 1456, 1256, 883, 749, 668, 517 cm-1; HRMS (ESI-TOF) m/z: [M H]- Calcd for C21H24BrO2 387.0965, found 387.0979. 2,6-di-tert-butyl-4-(2-methoxybenzylidene)cyclohexa-2,5-dienone18 (2g): 81% yield (1.31 g); yellow solid; m.p. 138.7-139.3 oC; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.2 Hz, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.08 (d, J = 2.3 Hz, 1H), 7.06 – 7.01 (m, 1H), 6.96 (d, J = 7.9 Hz, 1H), 3.89 (s, 3H), 1.34 (s, 9H), 1.29 (s, 9H). 4-benzylidene-2,6-di-tert-butylcyclohexa-2,5-dienone2a (2h): 71% yield (1.05 g); yellow solid; m.p. 75.7-76.2 oC; 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.49 – 7.35 (m, 5H), 7.20 (s, 1H), 7.03 (s, 1H), 1.35 (s, 9H), 1.31 (s, 9H).



Page 16 of 40

2-(hydroxy(phenyl)methyl)-4-methoxyphenol19 (2i): 85% yield (0.98 g); white solid; m.p. 105.6-106.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.41 – 7.28 (m, 5H), 6.79 (d, J = 8.8 Hz, 1H), 6.72 (dd, J = 8.8, 3.0 Hz, 1H), 6.44 (d, J = 3.0 Hz, 1H), 5.89 (s, 1H), 3.67 (s, 3H), 3.37 (s, 1H).

2,6-di-tert-butyl-4-((3-hydroxynaphthalen-2-yl)(4-methoxyphenyl)methylene)cyclohexa-2, 5-dienone20 (2j): 57% yield (1.32g); yellow solid; m.p. 92.6-93.5 oC; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.9 Hz, 1H), 7.83 – 7.76 (m, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.35 – 7.28 (m, 4H), 7.25 – 7.23 (m, 1H), 6.89 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 2.6 Hz, 1H), 5.23 (s, 1H), 3.83 (s, 3H), 1.33 (s, 9H), 1.05 (s, 9H).

General procedure for the synthesis of products 3 To the mixture of indoles 1 (0.12 mmol), p-QM derivatives 2 (0.1 mmol), chiral phosphoric acid 4e (0.01 mmol) and MgSO4 (100 mg) was added acetone (2 mL), which was stirred at -30 oC for 12 h. After the completion of the reaction which was indicated by TLC, the reaction mixture was directly purified by preparative thin layer chromatography to afford pure products 3.

(R)-2,6-di-tert-butyl-4-((2-hydroxyphenyl)(1H-indol-3-yl)methyl)phenol

(3aa):

Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 97% yield (41.4 mg); brown solid; m.p. 93.8-95.6 oC; [α]D20 = +41.9 (c 0.83, acetone); 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.38 – 7.29 (m, 2H), 7.23 – 7.13 (m, 2H), 7.11 (s, 2H), 7.06 – 7.00 (m, 2H), 6.90 – 6.82 (m, 2H), 6.72 – 6.66 (m, 1H), 5.70 (s, 1H), 5.41 – 5.15 (m, 1H), 5.15 (s, 1H), 1.38 (s, 18H); 13C{1H}

NMR (100 MHz, CDCl3) δ 154.3, 152.6, 136.9, 135.9, 132.3, 130.2, 130.1, 127.9, 126.9,

125.5, 123.9, 122.5, 120.7, 120.0, 119.7, 118.5, 116.5, 111.2, 43.9, 34.4, 30.4; IR (KBr): 3734, 3709, 3628, 2960, 1456, 742, 668, 649 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C29H32NO2 426.2438, found 426.2419; Enantiomeric ratio = 95:5, determined by HPLC (Daicel


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Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 11.217 min (minor), tR = 13.210 min (major).

(R)-2,6-di-tert-butyl-4-((2-hydroxyphenyl)(4-methoxy-1H-indol-3-yl)methyl)phenol (3ba): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 87% yield (39.8 mg); brown solid; m.p. 97.1–98.8 oC; [α]D20 = +47.3 (c 0.80, acetone); 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.16 – 7.03 (m, 4H), 7.00 – 6.91 (m, 2H), 6.89 – 6.75 (m, 2H), 6.62 – 6.54 (m, 1H), 6.44 (d, J = 7.7 Hz, 1H), 6.07 (s, 1H), 5.39 (s, 1H), 5.09 (s, 1H), 3.66 (s, 3H), 1.37 (s, 18H); 13C{1H}

NMR (100 MHz, CDCl3) δ 154.9, 153.9, 152.2, 138.3, 135.6, 133.2, 131.7, 129.9, 127.3,

125.7, 123.2, 122.5, 120.3, 119.2, 117.2, 116.1, 104.5, 100.3, 55.2, 43.9, 34.4, 30.4; IR (KBr): 3735, 3648, 3628, 3420, 2956, 1506, 1435, 1259, 1231, 1087 cm-1; HRMS (ESI-TOF) m/z: [M H]- Calcd for C30H34NO3 456.2544, found 456.2524; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 3.803 min (major), tR = 4.147 min (minor). (R)-2,6-di-tert-butyl-4-((2-hydroxyphenyl)(5-methyl-1H-indol-3-yl)methyl)phenol (3ca): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 91% yield (40.0 mg); brown solid; m.p. 180.0-181.9 oC; [α]D20 = +43.0 (c 0.80, acetone); 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.25 – 7.21 (m, 1H), 7.20 – 7.13 (m, 1H), 7.13 – 7.09 (m, 3H), 7.02 (d, J = 7.7 Hz, 2H), 6.92 – 6.80 (m, 2H), 6.66 (s, 1H), 5.66 (s, 1H), 5.22 (s, 1H), 5.14 (s, 1H), 2.36 (s, 3H), 1.38 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.3, 152.6, 135.9, 135.2, 132.3, 130.2, 130.1, 128.9, 127.9, 127.2, 125.5, 124.1, 124.0, 120.7, 119.5, 117.9, 116.5, 110.9, 43.9, 34.4, 30.4, 21.6; IR (KBr): 3648, 3629, 3420, 2957, 1456, 1435, 1232, 1154, 1090, 753 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H34NO2 440.2595, found 440.2586; Enantiomeric ratio = 90:10,



determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 10.723 min (minor), tR = 13.433 min (major). (R)-2,6-di-tert-butyl-4-((5-fluoro-1H-indol-3-yl)(2-hydroxyphenyl)methyl)phenol (3da): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 97% yield (43.2 mg); brown solid; m.p. 164.6-166.5 oC; [α]D20 = +28.9 (c 0.86, acetone); 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.33 (dd, J = 15.4, 8.1 Hz, 2H), 7.23 – 7.14 (m, 2H), 7.11 (s, 2H), 7.06 – 6.96 (m, 2H), 6.91 – 6.80 (m, 2H), 6.73 – 6.64 (m, 1H), 5.70 (s, 1H), 5.15 (s, 1H), 1.38 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.7 (J = 233 Hz), 154.1, 152.6, 136.0, 133.4, 132.0, 130.0, 129.8, 128.0, 127.3(J = 10 Hz), 125.6, 125.4, 120.8, 118.8 (J = 9 Hz), 118.7, 116.5, 111.9, 111.0, 110.7, 104.9 (J = 23 Hz), 43.6, 34.4, 30.4; 19F NMR (376 MHz, CDCl3) δ (ppm) 124.1; IR (KBr): 3854, 3735, 3629, 2959, 1559, 1540, 1507, 1457, 1165, 1089 cm-1; HRMS (ESI-TOF) m/z: [M - H]Calcd for C29H31FNO2 444.2344, found 444.2327; Enantiomeric ratio = 95:5, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 13.540 min (minor), tR = 17.560 min (major). (R)-2,6-di-tert-butyl-4-((5-chloro-1H-indol-3-yl)(2-hydroxyphenyl)methyl)phenol (3ea): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 93% yield (42.8 mg); brown solid; m.p. 114.7-116.5 oC; [α]D20 = +23.8 (c 0.86, acetone); 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.27 (s, 1H), 7.25 – 7.24 (m, 1H), 7.19 – 7.10 (m, 2H), 7.06 (s, 2H), 6.97 (d, J = 7.5 Hz, 1H), 6.89 – 6.80 (m, 2H), 6.73 – 6.65 (m, 1H), 5.65 (s, 1H), 5.14 (s, 1H), 5.02 (s, 1H), 1.36 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.0, 152.7, 136.0, 135.2, 131.9, 129.9, 129.8, 128.0, 125.4, 125.3, 125.2, 122.7, 120.8, 119.4, 118.5, 116.5, 112.2, 43.4, 34.4, 30.4; IR (KBr): 3725, 3648, 3628, 3420, 2958, 1558, 1540, 1506, 1457, 668 cm-1; HRMS (ESI-TOF) m/z: [M - H]-


Page 18 of 40

Page 19 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Calcd for C29H31ClNO2 460.2049, found 460.2040; [M - H]- Calcd for C29H31ClNO2 462.2019, found 462.2030; Enantiomeric ratio = 93:7, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 14.083 min (minor), tR = 18.713 min (major). (R)-4-((5-bromo-1H-indol-3-yl)(2-hydroxyphenyl)methyl)-2,6-di-tert-butylphenol (3fa): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 90% yield (45.5 mg); brown solid; m.p. 185.8-187.0 oC; [α]D20 = +41.5 (c 0.91, acetone); 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.43 – 7.40 (m, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.18 – 7.13 (m, 1H), 7.06 (s, 2H), 7.00 – 6.94 (m, 1H), 6.89 – 6.75 (m, 2H), 6.71 – 6.61 (m, 1H), 5.66 (s, 1H), 5.15 (s, 1H), 5.05 (s, 1H), 1.37 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.9, 152.7, 136.0, 135.5, 132.0, 130.0, 129.9, 128.7, 128.0, 125.4, 125.3, 125.1, 122.5, 120.9, 118.4, 116.5, 112.9, 112.7, 43.3, 34.4, 30.4; IR (KBr): 3735, 3675, 3648, 3628, 2957, 1457, 1233, 753, 668, 649 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C29H31BrNO2 504.1543, found 504.1525; [M - H]Calcd for C29H31BrNO2 506.1523, found 506.1527; Enantiomeric ratio = 93:7, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 3.933 min (minor), tR = 4.483 min (major). (R)-2,6-di-tert-butyl-4-((2-hydroxyphenyl)(5-iodo-1H-indol-3-yl)methyl)phenol

(3ga):

Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 85% yield (47.1 mg); brown solid; m.p. 203.4-204.7 oC; [α]D20 = +41.9 (c 0.94, acetone); 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.61 (s, 1H), 7.49 – 7.35 (m, 1H), 7.20 – 7.09 (m, 2H), 7.05 (s, 2H), 7.01 – 6.91 (m, 1H), 6.90 – 6.79 (m, 2H), 6.70 – 6.60 (m, 1H), 5.65 (s, 1H), 5.15 (s, 1H), 5.00 (s, 1H), 1.37 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.9, 152.6, 136.0, 135.8, 131.9, 130.7, 129.9, 129.8,



129.5, 128.8, 128.0, 125.1, 124.6, 120.8, 118.0, 116.4, 113.2, 83.1, 43.2, 34.4, 30.3; IR (KBr): 3419, 2959, 1456, 1435, 1261, 1234, 1092, 753, 668, 457 cm-1; HRMS (ESI-TOF) m/z: [M - H]Calcd for C29H31INO2 552.1405, found 552.1393; Enantiomeric ratio = 95:5, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 3.943 min (minor), tR = 5.063 min (major). (R)-3-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxyphenyl)methyl)-1H-indole-5-carbo nitrile (3ha): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 71% yield (32.3 mg); brown solid; m.p. 152.9-154.6 oC; [α]D20 = +17.0 (c 0.65, acetone); 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.61 (s, 1H), 7.43 – 7.36 (m, 2H), 7.20 – 7.08 (m, 1H), 7.03 (s, 2H), 6.94 (d, J = 7.5 Hz, 1H), 6.88 – 6.81 (m, 2H), 6.81 – 6.77 (m, 1H), 5.73 (s, 1H), 5.15 (s, 1H), 4.93 (s, 1H), 1.35 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.6, 152.7, 138.4, 136.0, 131.6, 129.8, 129.5, 128.1, 126.8, 125.9, 125.8, 125.3, 125.2, 120.9, 120.7, 120.2, 116.4, 112.0, 102.6, 42.7, 34.4, 30.3; IR (KBr): 3852, 3734, 3648, 3628, 2956, 1558, 1540, 1506, 668, 650 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H31N2O2 451.2391, found 451.2372; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 22.480 min (minor), tR = 28.243 min (major). (R)-2,6-di-tert-butyl-4-((2-hydroxyphenyl)(6-methyl-1H-indol-3-yl)methyl)phenol (3ia): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 98% yield (43.2 mg); brown solid; m.p. 81.8-82.4 oC; [α]D20 = +42.5 (c 0.86, acetone); 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.20 – 7.13 (m, 3H), 7.10 (s, 2H), 7.06 – 6.99 (m, 1H), 6.91 – 6.76 (m, 3H), 6.64 – 6.58 (m, 1H), 5.65 (s, 1H), 5.19 (s, 1H), 5.13 (s, 1H), 2.44 (s, 3H), 1.37 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.3, 152.5, 137.4, 135.8, 132.3, 132.2, 130.1, 130.0, 127.8, 125.4, 124.7,


Page 20 of 40

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123.1, 121.4, 120.6, 119.5, 118.3, 116.5, 111.1, 44.1, 34.4, 30.3, 21.7; IR (KBr): 3735, 3675, 3649, 3629, 2958, 1558, 1507, 668, 649, 472 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H34NO2 440.2595, found 440.2579; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 6.387 min (major), tR = 9.207 min (minor). (R)-2,6-di-tert-butyl-4-((2-hydroxyphenyl)(6-methoxy-1H-indol-3-yl)methyl)phenol (3ja): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 92% yield (42.2 mg); brown solid; m.p. 92.5-93.3 oC; [α]D20 = +35.3 (c 0.84, acetone); 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.19 – 7.12 (m, 2H), 7.09 (s, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.91 – 6.77 (m, 3H), 6.68 (d, J = 8.5 Hz, 1H), 6.58 (s, 1H), 5.63 (s, 1H), 5.25 (s, 1H), 5.13 (s, 1H), 3.82 (s, 3H), 1.37 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.7, 154.4, 152.5, 137.8, 135.9, 132.2, 130.1, 130.0, 127.9, 125.5, 122.6, 121.3, 120.7, 120.6, 118.5, 116.5, 109.7, 94.6, 55.6, 53.5, 44.2, 34.4, 30.4; IR (KBr): 3648, 3628, 3420, 2958, 1506, 1456, 1157, 802, 668, 649 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H34NO3 456.2544, found 456.2525; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 11.843 min (major), tR = 14.207 min (minor). (R)-2,6-di-tert-butyl-4-((6-fluoro-1H-indol-3-yl)(2-hydroxyphenyl)methyl)phenol (3ka): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 79% yield (35.1 mg); yellow solid; m.p. 209.0-210.6 oC; [α]D20 = +38.8 (c 0.70, acetone); 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.22 – 7.11 (m, 2H), 7.06 (s, 2H), 7.05 – 7.02 (m, 1H), 7.00 – 6.96 (m, 1H), 6.88 – 6.81 (m, 2H), 6.81 – 6.73 (m, 1H), 6.68 – 6.61 (m, 1H), 5.64 (s, 1H), 5.13 (s, 1H), 5.06 (s, 1H), 1.35 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1 (J = 236 Hz), 154.1, 152.5, 136.8 (J = 12



Page 22 of 40

Hz), 135.9, 131.9, 130.0, 129.8, 127.9, 125.3, 124.2, 124.1, 123.5, 120.8 (J = 10 Hz), 120.7, 118.7, 116.4, 108.5 (J = 25 Hz), 97.5 (J = 26 Hz), 43.7, 34.4, 30.3; 19F NMR (376 MHz, DMSO-d6) δ (ppm) 122.3; IR (KBr): 3628, 3586, 3566, 3420, 2958, 1652, 668, 649, 472, 457 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C29H31FNO2 444.2344, found 444.2334; Enantiomeric ratio = 96:4, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 13.690 min (minor), tR = 15.607 min (major). (R)-2,6-di-tert-butyl-4-((6-chloro-1H-indol-3-yl)(2-hydroxyphenyl)methyl)phenol

(3la):

Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 82% yield (38.0 mg); brown solid; m.p. 89.5-91.0 oC; [α]D20 = +32.1 (c 0.76, acetone); 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.19 – 7.12 (m, 2H), 7.06 (s, 2H), 7.00 – 6.95 (m, 2H), 6.89 – 6.81 (m, 2H), 6.68 – 6.65 (m, 1H), 5.66 (s, 1H), 5.14 (s, 1H), 5.04 (s, 1H), 1.36 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.0, 152.6, 137.2, 136.0, 132.0, 130.0, 129.8, 128.3, 128.0, 125.6, 125.4, 124.5, 120.9, 120.8, 120.4, 118.9, 116.5, 111.1, 43.5, 34.4, 30.4; [M - H]- Calcd for C29H31ClNO2 462.2019, found 462.2032; IR (KBr): 3648, 3628, 3420, 2959, 1456, 1435, 1234, 804, 754, 472 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C29H31ClNO2 460.2049, found 460.2030; Enantiomeric ratio = 92:8, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 8.120 min (major), tR = 9.760 min (minor). (R)-4-((6-bromo-1H-indol-3-yl)(2-hydroxyphenyl)methyl)-2,6-di-tert-butylphenol (3ma): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 95% yield (47.9 mg); brown solid; m.p. 96.1-97.7 oC; [α]D20 = +12.8 (c 0.96, acetone); 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.50 (s, 1H), 7.19 – 7.08 (m, 3H), 7.06 (s, 2H), 6.99 – 6.95 (m, 1H), 6.89 – 6.80 (m,


Page 23 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2H), 6.67 – 6.64 (m, 1H), 5.66 (s, 1H), 5.14 (s, 1H), 5.03 (s, 1H), 1.36 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.0, 152.6, 137.6, 136.0, 132.0, 130.0, 129.8, 128.0, 125.9, 125.4, 124.5, 123.0, 121.3, 120.8, 119.0, 116.5, 116.0, 114.1, 43.5, 34.4, 30.4; IR (KBr): 3566, 3545, 3446, 2958, 1653, 1558, 1506, 668, 649, 457 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C29H31BrNO2 504.1543, found 504.1527; [M - H]- Calcd for C29H31BrNO2 506.1523, found 506.1525; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 8.440 min (major), tR = 9.900 min (minor). (R)-3-((3,5-di-tert-butyl-4-hydroxyphenyl)(2-hydroxyphenyl)methyl)-1H-indole-6-carbo nitrile (3na): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 75% yield (33.9 mg); brown solid; m.p. 220.5-220.8 oC; [α]D20 = +28.9 (c 0.68, acetone); 1H NMR (400 MHz, acetone-d6) δ 8.34 (s, 1H), 7.86 – 7.75 (m, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.20 – 7.16 (m, 1H), 7.15 (s, 2H), 7.07 – 6.97 (m, 3H), 6.92 – 6.88 (m, 1H), 6.76 – 6.70 (m, 1H), 6.06 (s, 1H), 5.90 (s, 1H), 2.93 (s, 1H), 1.36 (s, 18H); 13C{1H} NMR (100 MHz, acetone-d6) δ 154.5, 152.2, 137.0, 136.0, 134.1, 131.0, 130.2, 129.6, 128.5, 127.1, 125.4, 121.1, 120.7, 120.5, 120.4, 119.3, 116.2, 115.2, 103.5, 78.4, 40.7, 34.3, 29.9; IR (KBr): 3649, 3566, 3545, 3420, 2961, 1020, 798, 752, 668, 472 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H31N2O2 451.2391, found 451.2372; Enantiomeric ratio = 93:7, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 95:5, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 31.570 min (major), tR = 40.180 min (minor). (R)-2,6-di-tert-butyl-4-((7-fluoro-1H-indol-3-yl)(2-hydroxyphenyl)methyl)phenol (3oa): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 83% yield (37.1 mg);



yellow solid; m.p. 78.8-80.0 oC; [α]D20 = +29.3 (c 0.74, acetone); 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.19 – 7.12 (m, 1H), 7.06 (s, 2H), 7.05 – 7.02 (m, 1H), 7.00 – 6.95 (m, 1H), 6.94 – 6.87 (m, 2H), 6.87 – 6.81 (m, 2H), 6.73 – 6.68 (m, 1H), 5.68 (s, 1H), 5.14 (s, 1H), 5.01 (s, 1H), 1.36 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.0, 152.6, 149.4 (J = 243 Hz), 136.0, 132.0, 130.7, 130.6, 130.0, 129.9, 127.9, 125.4, 125.2 (J = 13 Hz), 124.5, 120.7, 119.9 (J = 6 Hz), 119.6, 116.4, 115.8, 107.3, 107.1, 43.6, 34.4, 30.3; 19F NMR (376 MHz, CDCl3) δ (ppm) 135.4; IR (KBr): 3648, 3628, 3545, 3446, 2960, 1576, 1506, 668, 472, 457 cm-1; HRMS (ESI-TOF) m/z: [M - H]Calcd for C29H31FNO2 444.2344, found 444.2326; Enantiomeric ratio = 95:5, determined by HPLC (Daicel Chiralpak OJ-H, hexane/isopropanol = 95:5, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 43.540 min (major), tR = 67.777 min (minor). (R)-2,6-di-tert-butyl-4-((5-fluoro-2-hydroxyphenyl)(1H-indol-3-yl)methyl)phenol (3ab): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 81% yield (36.1 mg); brown solid; m.p. 102.9-104.1 oC; [α]D20 = +40.1 (c 0.72, acetone); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.24 – 7.17 (m, 1H), 7.08 (s, 2H), 7.07 – 7.02 (m, 1H), 6.88 – 6.81 (m, 1H), 6.81 – 6.75 (m, 1H), 6.74 – 6.67 (m, 2H), 5.66 (s, 1H), 5.17 (s, 1H), 4.99 (s, 1H), 1.38 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.3 (J = 236 Hz), 152.8, 150.2, 150.1, 136.9, 136.1, 132.0 (J = 6 Hz), 131.6, 126.7, 125.4, 123.9, 122.6, 119.9, 119.8, 117.8, 117.3 (J = 8 Hz), 116.4 (J = 23 Hz), 114.1 (J = 23 Hz), 111.3, 43.8, 34.4, 30.4; 19F NMR (376 MHz, CDCl3) δ (ppm) 123.5; IR (KBr): 3853, 3838, 3735, 3649, 2960, 1558, 1507, 668, 472, 457 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C29H31FNO2 444.2344, found 444.2328; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak AD-H,


Page 24 of 40

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hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 10.990 min (minor), tR = 13.283 min (major). (R)-2,6-di-tert-butyl-4-((5-chloro-2-hydroxyphenyl)(6-fluoro-1H-indol-3-yl)methyl)phen ol (3kc): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 97% yield (46.4 mg); brown solid; m.p. 91.3-92.0 oC; [α]D20 = +34.5 (c 0.93, acetone); 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.20 – 7.09 (m, 2H), 7.05 (s, 2H), 7.03 – 6.97 (m, 2H), 6.85 – 6.72 (m, 2H), 6.65 (s, 1H), 5.60 (s, 1H), 5.18 (s, 1H), 5.14 (s, 1H), 1.37 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.4, 160.2 (J = 237 Hz), 152.9 (J = 8 Hz), 136.8 (J = 12 Hz), 136.1, 131.6, 131.2, 129.7, 127.8, 125.5, 125.2, 124.3, 124.2, 123.3, 120.6 (J = 10 Hz), 118.0, 117.9, 108.7 (J = 24 Hz), 97.6 (J = 26 Hz), 43.8, 34.4, 30.3; IR (KBr): 3735, 3649, 3420, 2960, 1457, 1157, 804, 668, 472, 457 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C29H30ClFNO2 478.1954, found 478.1936; [M - H]Calcd for C29H30ClFNO2 480.1925, found 480.1929; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak IB, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 8.727 min (minor), tR = 9.263 min (major). (R)-2,6-di-tert-butyl-4-((6-fluoro-1H-indol-3-yl)(2-hydroxy-5-methylphenyl)methyl)phenol (3kd): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 97% yield (44.3 mg); brown solid; m.p. 95.7-96.1 oC; [α]D20 = +43.0 (c 0.89, acetone); 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.18 (dd, J = 8.7, 5.4 Hz, 1H), 7.08 (s, 2H), 7.04 – 6.99 (m, 1H), 6.98 – 6.93 (m, 1H), 6.86 – 6.83 (m, 1H), 6.80 – 6.74 (m, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.68 – 6.60 (m, 1H), 5.60 (s, 1H), 5.14 (s, 1H), 4.97 (s, 1H), 2.21 (s, 3H), 1.37 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.2 (J = 236 Hz), 152.6, 152.0, 136.9 (J = 12 Hz), 135.9, 132.1, 130.6, 129.8, 129.3, 128.5, 125.4, 124.2, 124.1, 123.6, 120.9 (J = 10 Hz), 118.9, 116.4, 108.5 (J = 24 Hz), 97.6, 97.3, 44.2,



34.4, 30.4, 20.8; IR (KBr): 3628, 3587, 3566, 3446, 2958, 1653, 1506, 668, 649, 457 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H33FNO2 458.2501, found 458.2482; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 7.583 min (minor), tR = 8.677 min (major). (R)-2,6-di-tert-butyl-4-((6-fluoro-1H-indol-3-yl)(2-hydroxy-5-methoxyphenyl)methyl)ph enol (3ke): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 60% yield (28.5 mg); brown solid; m.p. 96.2-97.3 oC; [α]D20 = +27.5 (c 0.57, acetone); 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.19 (dd, J = 8.7, 5.4 Hz, 1H), 7.07 (s, 2H), 7.04 – 6.98 (m, 1H), 6.82 – 6.74 (m, 2H), 6.72 – 6.68 (m, 1H), 6.67 – 6.64 (m, 1H), 6.57 (d, J = 3.0 Hz, 1H), 5.62 (s, 1H), 5.14 (s, 1H), 4.78 (s, 1H), 3.66 (s, 3H), 1.35 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1 (J = 237 Hz), 153.6, 152.6, 148.1, 136.8 (J = 13 Hz), 136.0, 131.9, 131.3, 125.4, 124.2, 124.1, 123.5, 120.8 (J = 10 Hz), 118.5, 117.1, 115.9, 112.5, 108.5 (J = 10 Hz), 97.6, 97.3, 55.6, 44.0, 34.4, 30.4; IR (KBr): 3648, 3628, 3587, 3420, 2957, 1558, 1506, 668, 649, 457 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H33FNO3 474.2450, found 474.2438; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 21.523 min (minor), tR = 26.657 min (major). (R)-4-((4-bromo-2-hydroxyphenyl)(6-fluoro-1H-indol-3-yl)methyl)-2,6-di-tert-butylphen ol (3kf): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 54% yield (28.1 mg); yellow solid; m.p. 99.8-101.7 oC; [α]D20 = +37.5 (c 0.56, acetone); 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.22 – 7.11 (m, 1H), 7.10 – 6.94 (m, 5H), 6.90 – 6.72 (m, 2H), 6.64 (s, 1H), 5.59 (s, 1H), 5.25 (s, 1H), 5.17 (s, 1H), 1.37 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.2 (J = 237 Hz), 155.0, 152.8, 136.9 (J = 12 Hz), 136.2, 131.4, 131.3, 129.2, 125.3, 124.3, 124.2,


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123.8, 123.3, 120.8, 120.7 (J = 10 Hz), 119.7, 118.1, 108.6 (J = 24 Hz), 97.6 (J = 26 Hz), 43.4, 34.4, 30.3; IR (KBr): 3586, 3566, 3545, 3446, 2959, 1652, 1456, 668, 649, 472 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C29H30BrFNO2 522.1449, found 522.1430; [M - H]- Calcd for C29H30BrFNO2 524.1429, found 524.1437; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80:20, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 5.427 min (major), tR = 6.247 min (minor). (R)-2,6-di-tert-butyl-4-((2-hydroxyphenyl)(1-methyl-1H-indol-3-yl)methyl)phenol (3pa): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 79% yield (35.0 mg); brown solid; m.p. 91.4-91.6 oC; 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.27 (m, 2H), 7.25 – 7.19 (m, 1H), 7.19 – 7.12 (m, 1H), 7.16 (s, 2H), 7.05 – 6.98 (m, 2H), 6.90 – 6.82 (m, 2H), 6.57 (s, 1H), 5.67 (s, 1H), 5.18 (s, 1H), 5.14 (s, 1H), 3.73 (s, 3H), 1.37 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.3, 152.5, 137.7, 135.8, 132.3, 130.2, 130.0, 128.3, 127.8, 127.3, 125.4, 122.0, 120.6, 120.0, 119.1, 116.6, 116.5, 109.2, 44.0, 34.4, 32.8, 30.3; IR (KBr):3657, 3650, 3620, 3588, 1701, 1559, 1473, 1457, 1436, 1229, 805, 739 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C30H34NO2 440.2595, found 440.2577; Enantiomeric ratio = 52:48, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80:20, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 3.733 min (minor), tR = 4.193 min (major). 2-((1H-indol-3-yl)(phenyl)methyl)-4-methoxyphenol

(3ai):

Preparative

thin

layer

chromatography (petroleum ether/Acetone = 5/1); 98% yield (16.3 mg); white solid; m.p. 164.8-165.1 oC; [α]D20 = +11.7 (c 0.33, acetone); 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.34 – 7.26 (m, 5H), 7.26 – 7.23 (m, 1H), 7.22 – 7.15 (m, 1H), 7.06 – 6.98 (m, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.75 – 6.67 (m, 2H), 6.54 (d, J = 3.0 Hz, 1H), 5.80 (s, 1H), 4.67 (s,



1H), 3.65 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.7, 147.9, 142.1, 136.9, 131.1, 129.0, 128.6, 126.9, 126.8, 124.0, 122.6, 119.8, 117.5, 117.1, 116.3, 112.3, 111.2, 55.6, 43.6; IR (KBr): 3629,

3567, 3432, 2922, 1647, 1636, 1265, 1041, 745, 663 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C22H19NO2 328.1343, found 328.1338; Enantiomeric ratio = 87:13, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 8.143 min (major), tR = 29.433 min (minor). Procedure for the larger scale synthesis of product 3aa To the mixture of indole 1a (1.2 mmol), p-QM derivative 2a (1.0 mmol), chiral phosphoric acid 4e (0.1 mmol) and MgSO4 (1 g) was added acetone (20 mL), which was stirred at -30 oC for 12 h. After the completion of the reaction which was indicated by TLC, the reaction mixture was directly purified by flash column chromatography to afford pure product 3aa in 99% yield (423 mg). Procedure for the synthesis of product 5 Under argon atmosphere, compound 3fa (0.05 mmol), 4-chlorophenylboronic acid (0.075 mmol), CsCO3 (0.1 mmol), Pd(OAc)2 (0.0025 mmol) and butyldi-1-adamantylphosphine (0.003 mmol) were added to a dried tube. After adding DME (0.6 mL) to the reaction system, the reaction mixture was stirred at 80 oC for 12 h. After the completion of the reaction which was indicated by TLC, the reaction mixture was directly purified by preparative thin layer chromatography to give pure product 5. (R)-2,6-di-tert-butyl-4-((5-(4-chlorophenyl)-1H-indol-3-yl)(2-hydroxyphenyl)methyl)phe nol (5): Preparative thin layer chromatography (petroleum ether/EtOAc = 5/1); 79% yield (21.3 mg); brown solid; m.p. 102.2-103.7 oC; [α]D20 = +30.1 (c 0.43, acetone); 1H NMR (400 MHz,


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CDCl3) δ 8.07 (s, 1H), 7.45 – 7.36 (m, 5H), 7.33 (d, J = 8.5 Hz, 2H), 7.20 – 7.13 (m, 1H), 7.11 (s, 2H), 7.04 (d, J = 7.3 Hz, 1H), 6.90 – 6.81 (m, 2H), 6.75 (s, 1H), 5.73 (s, 1H), 5.15 (s, 1H), 5.09 (s, 1H), 1.36 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.1, 152.6, 140.9, 136.5, 136.0, 132.3, 132.2, 131.9, 130.1, 130.0, 128.7, 128.5, 128.0, 127.5, 125.5, 124.7, 122.0, 120.8, 119.1, 118.4, 116.5, 111.5, 43.7, 34.4, 30.4; IR (KBr): 3702, 3670, 3629, 3013, 2787, 1559, 1458, 1093, 1023, 807 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C35H35ClNO2 536.2362, found 536.2349; Enantiomeric ratio = 94:6, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 17.097 min (minor), tR = 21.770 min (major).

Acknowledgements

We are grateful for financial support from National Natural Science Foundation of China (21772069, 21702077 and 21831007), Natural Science Foundation of Jiangsu Province (BK20160003 and BK20170227), Young Medical Talents Project of Jiangsu Province (QNRC2016571), Six Kinds of Talents Project of Jiangsu Province (SWYY-025) and Undergraduate Project of Jiangsu Province (201810320049Z).

Supporting Information: 1H

and 13C NMR spectra of substrates 2b, 2f and products 3 and 5, HPLC spectra of products 3

and 5, X-ray single-crystal data for product 3ba (PDF) Single-crystal data of product 3ba (CIF)



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Catalytic Asymmetric Conjugate Addition of Indoles to para-Quinone

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