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Asymmetric construction of 4H-pyrano[3,2-b]indoles via cinchoninecatalyzed 1,4-addition of 2-ylideneoxindole with malononitrile Jin Zhou, Biao Wang, Xiang-Hong He, Li Liu, Jun Wu, Jing Lu, Cheng Peng, Chao-Long Rao, and Bo Han J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00430 • Publication Date (Web): 28 Mar 2019 Downloaded from http://pubs.acs.org on March 29, 2019

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The Journal of Organic Chemistry

Asymmetric construction of 4H-pyrano[3,2-b]indoles via cinchonine-catalyzed 1,4-addition of 2-ylideneoxindole with malononitrile Jin Zhou,§ Biao Wang,§ Xiang-Hong He, Li Liu, Jun Wu, Jing Lu, Cheng Peng, Chao-Long Rao* and Bo Han* Key laboratory of Characteristic Chinese Resource in Southwest China, School of Pharmacy and School of Public health, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China. E-mail: [email protected], [email protected]

√

√ √ √

ABSTRACT: A highly enantioselectivity [4+2] annulation of 2-ylideneoxindole with malononitrile has been accomplished by cinchonine-catalyzed under mild conditions. The corresponding Enantiomerically enriched 4H-pyrano[3,2-b]indoles were generated in moderate to high yields (up to 94%) with excellent enantioselectivities (up to 98% ee). To explain the stereoselectivity of the organocatalytic Michael-ammonization cascade, we also carried out the control experiments and proposed plausible transition-state models for the catalytic cycle based on the observed stereochemistry of the products. In addition, some of the products showed moderate antibacterial activity against S. aureus and S. epidermidis in vitro, which might be considered as a potential clue for the discovery of new antimicrobial agents.

INTRODUCTION Multicyclic scaffolds useful for synthetic chemistry and medicine are attractive in research and industry.1 A particularly attractive scaffold for drug development is the fusion of pyran with indole.2 The indole scaffold, commonly considered a “privileged structure” in drug discovery,3 is a ubiquitous heterocycle in natural products and compounds used to treat cancer,4 type II diabetes,5 and HIV infection.6 Similarly, pyran-bearing skeletons are presented in various natural products and bioinspired synthetic compounds.7 4H-pyran-containing architectures show antibacterial, antiviral and antifungal activities.8 In 2012, Balasubramanian’s group reported a green, one-pot

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approach to synthesize substituted pyrano[2,3-c]pyrazoles in aqueous ethanol under non-catalytic conditions. These compounds showed good activity against Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), showing minimal inhibitory concentrations (MICs) of 1.56-6.25 μg/mL.9 In 2017, Vinay Sunagar and co-workers demonstrated a green approach to transform 4-formylcou-marins into 4-coumarin-4H-pyrans, which showed excellent activity against Gram-positive S. aureus and Gram-negative E. coli with MICs of 0.4-0.8 μg/mL.10 In the same year, Hao’s group synthesized dihydropyran derivatives via a one-pot reaction in ethanol; the products showed excellent antibacterial MICs of 0.125-0.220 μg/mL.11

Figure 1. Examples of bioactive compounds with pyran-fused indole structures.

A popular medicinal synthetic target is the pyran-fused indole framework, which exists in many natural products and pharmaceuticals and which exhibits myriad biological activities (Figure 1). Pyran-fused indole derivatives I and II show antiproliferative activity,12 derivative III (Cebranopadol) functions as an opioid analgesic of the benzenoid class,13 and derivative IV inhibits the RNA polymerase of hepatitis C virus.14 The naturally occurring pyran-fused indole hyrtimomine A (V) is cytotoxic,15 while the naturally occurring pleiomaltinine (VI) can bypass multidrug resistance.16 This suggests that the asymmetric construction of pyran-fused indole compounds may provide leads for drug discovery and for diverse areas of organic synthesis. Most previous efforts to construct pyrano-fused indoles have focused on the synthesis of chiral hydropyrano[2,3-b]indoles (Scheme 1a) via N-heterocyclic carbene (NHC) catalysis, calcium phosphate catalysis, tertiary amine catalysis or N,N’-dioxide/metal catalysis.17 Few methods exist to

transform

chiral

hydropyrano[3,2-b]indoles,

which

are


the

isomeric

skeleton

of

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hydropyrano[2,3-b]indoles. In 2014, Ender’s group reported NHC-catalyzed enantioselective [3+3] annulation of indolin-3-ones with bromoenals to furnish 2H-pyrano[3,2-b]indole-2-ones (Scheme 1b).18 Our group reported secondary amine-catalyzed enantioselective [4+2] annulation of (Z)-2-benzylidene-indolin-3-one with aldehyde to form chiral 2H-pyrano[3,2-b]indole derivatives via inverse-electron-demand oxa-Diels-Alder reaction.19 As part of our continuing interest in applying organocatalysis to the construction of hydropyrano[3,2-b]indoles based on a variety of annulation types, we report here the application of cinchonine to catalyse formation of chiral 4H-pyrano[3,2-b]indole derivatives (Scheme 1c).

Scheme 1. Asymmetric synthesis of hydropyran-fused indoles

RESULTS AND DISCUSSION We initially examined cinchona alkaloid-based thiourea, squaramide or chiral bifunctional-urea as potential catalysts.20 This is because the acidic α-H of malononitrile can be deprotonated by a Lewis base, while 2-ylidene-indolin-3-one can be activated by acidic H-bond donors. First, we selected (Z)-2-benzylideneindolin-3-one (1a) and malononitrile (2) in toluene as the model substrates, and quinine (3a) as the catalyst. Incubating them together at -10 oC for 24 h led to smooth [4+2] annulation, affording the desired product 4a in 88% yield with excellent enantioselectivity (Table 1, entry 1). Cinchona alkaloid catalysts 3b-3e promoted formation of the desired products, with catalyst 3c showing the most satisfactory yield of 93% and ee of 95% (entries 2 and 4-5 vs 3). Other chiral bifunctional catalysts (3f-3h) provided similar yield but lower enantio-selectivities (entries 6-8). Choice of solvent affected the reaction (entries 9-12); toluene



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provided 4a in good yield with high enantioselectivity (entries 9-12 vs 3). Reducing the reaction temperature to -20

o

C and extending the reaction time led to slightly lower yield but

enantioselectivity of 98% ee (entry 13).

Table 1. Optimization of asymmetric [4+2] annulation conditions. a

Entry

3

Solvent

yieldb (%)

eec (%)

1

3a

Toluene

88

-93

2

3b

Toluene

90

-92

3

3c

Toluene

96

95

4

3d

Toluene

78

90

5

3e

Toluene

85

94

6

3f

Toluene

83

93

7

3g

Toluene

81

90

8

3h

Toluene

200 oC, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.03 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 12.4, 7.6 Hz, 3H), 7.52 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 11.6, 7.6 Hz, 3H), 7.39 (t, J = 7.6 Hz, 1H), 7.34-7.25 (m, 3H), 7.19-7.05 (m, 4H), 5.26 (s, 1H),

13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.3, 143.8,

136.3, 136.0, 134.6, 134.0, 129.6, 128.6, 127.5, 127.1, 126.5, 126.4, 124.8, 120.3, 119.9, 118.5, 117.1, 115.1, 59.1, 54.9, IR (CH2Cl2, cm-1): 3425, 3327, 2201, 1732, 1664, 1637, 1598, 1450, 1398, 1358, 1174, 754, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H17N3O3SNa, 450.0888; Found 450.0889.

(R)-2-amino-4-(2-chlorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon itrile (4b): white solid, 42 mg, 91% yield, ee 92%, [α]D25 = -89.99 (c 0.1, DCM), m.p. >200 oC, 1

H NMR (400 MHz, DMSO-d6) δ (ppm) 8.05 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.58 (d,

J = 7.2 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m, 4H), 7.40 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.12 (s, 2H), 6.98 (d, J = 7.2 Hz, 1H), 5.76 (s, 1H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.7, 140.4, 137.1, 136.2, 134.6, 134.1, 132.3, 129.8, 129.7, 128.7, 127.7, 126.6, 126.2, 124.8, 120.1, 119.4, 117.2, 117.0, 115.0, 57.3, 55.0, IR (CH2Cl2, cm-1): 3422, 3336, 2195, 1658, 1637, 1593, 1450, 1408, 1369, 1169, 749, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SClNa 484.0499; Found 484.0497. (R)-2-amino-4-(3-chlorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon


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itrile (4c): white solid, 42 mg, 91% yield, ee 91%, [α]D25 = -145.98 (c 0.1, DCM), m.p. 196-198 o

C, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.06 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H),

7.62 (d, J = 7.2 Hz, 1H), 7.55-7.44 (m, 4H), 7.43-7.31 (m, 3H), 7.18 (s, 2H), 7.13 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 5.31 (s, 1H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.3, 146.2, 136.5, 136.0, 134.7, 134.1, 133.1, 130.6, 129.6, 127.2, 127.1, 126.6, 126.5, 126.2, 124.9, 120.2, 119.7, 117.5, 117.2, 115.1, 58.5, 54.9, IR (CH2Cl2, cm-1): 3419, 3328, 2201, 1732, 1663, 1638, 1593, 1450, 1400, 1361, 1175, 746, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SClNa 484.0499; Found 484.0498.

(R)-2-amino-4-(4-chlorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon itrile (4d): white solid, 41 mg, 89% yield, ee 98%, [α]D25 = -299.95 (c 0.1, DCM), m.p. >200 oC, 1

H NMR (400 MHz, DMSO-d6) δ (ppm) 8.05 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 12.4, 7.6 Hz, 3H),

7.55-7.43 (m, 4H), 7.40 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.22-7.07 (m, 4H), 5.29 (s, 1H),

13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.3, 142.7, 136.5, 136.0, 134.6, 134.1,

131.7, 129.6, 129.3, 128.6, 126.6, 126.4, 124.9, 120.3, 119.8, 117.9, 117.2, 115.1, 58.6, 54.9, IR (CH2Cl2, cm-1): 3412, 3358, 2186, 1658, 1621, 1594, 1449, 1399, 1372, 1170, 725, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SClNa 484.0499; Found 484.0500.

(R)-2-amino-4-(2-bromophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon itrile (4e): white solid, 47 mg, 93% yield, ee 98%, [α]D25 = -236.96 (c 0.1, DCM), m.p. >200 oC, 1

H NMR (600 MHz, DMSO-d6) δ (ppm) 8.06 (d, J = 12.0 Hz, 1H), 7.63 (t, J = 6.0 Hz, 2H), 7.58

(d, J = 6.0 Hz, 2H), 7.52 (d, J = 6.0 Hz, 1H), 7.50-7.45 (m, 3H), 7.41 (t, J = 9.0 Hz, 1H), 7.25 (s, 1H), 7.21-7.17 (m, 1H), 7.13 (s, 2H), 5.75(s, 1H), 13C{1H} NMR (150 MHz, DMSO-d6) δ (ppm) 159.6, 137.1, 136.3, 134.6, 134.1, 133.1, 129.7, 128.9, 128.2, 126.6, 126.2, 124.8, 122.8, 120.1, 119.3, 117.2, 115.0, 57.4, 54.9, IR (CH2Cl2, cm-1): 3424, 3336, 2194, 1657, 1637, 1593, 1450, 1407, 1369, 1169, 725, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SBrNa 527.9993; Found 527.9994.

(R)-2-amino-4-(3-bromophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon itrile (4f): white solid, 43 mg, 85% yield, ee 90%, [α]D25 = -204.97 (c 0.1, DCM), m.p. >200 oC,



1

H NMR (400 MHz, DMSO-d6) δ (ppm) 8.08 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.63 (t,

J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.52-7.44 (m, 4H), 7.41 (t, J = 7.6 Hz, 1H), 7.33-7.26 (m, 2H), 7.19 (s, 2H), 7.15 (d, J = 8.0 Hz, 1H), 5.32 (s, 1H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.4, 146.4, 136.5, 136.0, 134.6, 134.1, 130.8, 130.0, 129.6, 126.6, 126.4, 124.8, 121.8, 120.2, 119.7, 117.5, 117.2, 115.1, 58.6, 54.9, IR (CH2Cl2, cm-1): 3448, 3355, 2190, 1652, 1628, 1588, 1451, 1403, 1370, 1171, 754, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SBrNa 527.9993; Found 527.9990.

(R)-2-amino-4-(4-bromophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon itrile (4g): white solid, 45 mg, 89% yield, ee 97%, [α]D25 = -120.98 (c 0.1, DCM), m.p. >200 oC, 1

H NMR (400 MHz, DMSO-d6) δ (ppm) 8.05 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 8.4 Hz, 3H),

7.51-7.45 (m, 6H), 7.39 (t, J = 7.6 Hz, 1H), 7.16 (s, 2H), 7.08 (d, J = 8.4 Hz, 2H), 5.27 (s, 1H), 13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.2, 143.1, 136.4, 136.0, 134.6, 134.1, 131.5,

129.7, 129.6, 126.6, 126.4, 124.9, 120.2, 120.2, 119.8, 117.8, 117.2, 115.1, 58.6, 55.1, IR (CH2Cl2, cm-1): 3409, 3326, 2193, 1659, 1635, 1595, 1447, 1398, 1370, 1171, 724, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SBrNa 527.9993; Found 527.9991.

(R)-2-amino-4-(4-fluorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbon itrile (4h): white solid, 38 mg, 85% yield, ee 96%, [α]D25 = -272.96 (c 0.1, DCM), m.p. >200 oC, 1

H NMR (600 MHz, DMSO-d6) δ (ppm) 8.03 (d, J = 12.0 Hz, 1H), 7.64 (d, J = 12.0 Hz, 2H), 7.61

(t, J = 12.0 Hz, 1H), 7.51 (d, J = 6.0 Hz, 1H), 7.45 (t, J = 12.0 Hz, 3H), 7.38 (t, J = 6.0 Hz, 1H), 7.17-7.10 (m, 6H), 5.28 (s, 1H),

13

C{1H} NMR (150 MHz, DMSO-d6) δ (ppm) 161.7 (d, JCF =

241.8 Hz), 159.3, 140.0, 136.4, 136.0, 134.7, 134.2, 129.6, 129.5 (d, JCF = 8.1 Hz) ,126.6, 126.5, 124.9, 120.4, 119.9, 118.3, 117.2, 115.4(d, JCF = 21.5 Hz), 115.1, 59.0, 54.9, IR (CH2Cl2, cm-1): 3431, 3319, 2194, 1659, 1601, 1506, 1446, 1396, 1357, 1169, 1151, 722, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SFNa 468.0794; Found 468.0798.

(R)-2-amino-4-(2,4-dichlorophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-car bonitrile (4i): white solid, 40 mg, 81% yield, ee 80%, [α]D25 = -227.96 (c 0.1, DCM), m.p. >200 o

C, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.01 (d, J = 8.4 Hz, 1H), 7.62-7.54 (m, 3H), 7.53 (d,


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J = 2.0 Hz, 1H), 7.50-7.39 (m, 4H), 7.35 (t, J = 7.6 Hz, 1H), 7.20 (dd, J = 8.4, 2.0 Hz, 1H), 7.12 (s, 2H), 6.94 (d, J = 7.2 Hz, 1H), 5.69 (s, 1H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.7, 139.4, 137.2, 136.3, 134.6, 134.2, 133.2, 132.4, 131.6, 129.7, 129.1, 127.8, 126.7, 126.1, 124.8, 120.0, 119.3, 117.2, 116.4, 115.0, 56.8, 54.9, IR (CH2Cl2, cm-1): 3427, 3361, 2183, 1653, 1611, 1583, 1448, 1381, 1170, 724, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H15N3O3SCl2Na 518.0109; Found 518.0110.

(R)-2-amino-4-(4-nitrophenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonit rile (4j): white solid, 24 mg, 51% yield, ee 64%, [α]D25 = -254.96 (c 0.1, DCM), m.p. >200 oC, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.18 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.52-7.45 (m, 3H), 7.41 (t, J = 8.0 Hz, 3H), 7.25 (s, 2H), 5.48 (s, 1H),

13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.4,

150.9, 146.5, 136.7, 136.0, 134.7, 134.2, 129.7, 128.7, 126.8, 126.5, 125.0, 123.9, 120.2, 119.5, 117.3, 116.9, 115.1, 99.5, 57.8, IR (CH2Cl2, cm-1): 3419, 3322, 2204, 1661, 1635, 1592, 1520, 1448, 1404, 1345, 1170, 747, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N4O5SNa 495.0739; Found 495.0741.

(R)-2-amino-4-(2-methoxyphenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carb onitrile (4k): white solid, 39 mg, 85% yield, ee 82%, [α]D25 = -38.99 (c 0.1, DCM), m.p. >200 oC, 1


J =7.6 Hz, 3H), 7.44 (t, J = 7.6 Hz, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.27-7.21 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.95 (s, 2H), 6.85-6.78 (m, 2H), 5.60 (s, 1H), 3.72 (s, 3H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 160.0, 156.8, 136.7, 136.3, 134.5, 133.9, 131.4, 129.6, 128.7, 128.4, 126.2, 126.1, 124.6, 120.6, 120.3, 12.0.0, 118.1, 116.9, 114.9, 112.0, 58.0, 55.9, 55.0, IR (CH2Cl2, cm-1): 3430, 3325, 2198, 1661, 1638, 1597, 1491, 1451, 1400, 1358, 1173, 757, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H19N3O4SNa 480.0994; Found 480.0996.

(R)-2-amino-4-(4-methoxyphenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carb onitrile (4l): white solid, 41 mg, 90% yield, ee 92%, [α]D25 = -302.95 (c 0.1, DCM), m.p. >200 oC, 1




J = 7.8 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 15.6, 7.8 Hz, 3H), 7.38 (t, J = 7.8 Hz, 1H), 7.05 (s, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.19 (s, 1H), 3.74 (s, 3H), 13C{1H} NMR (150 MHz, DMSO-d6) δ (ppm) 159.1, 158.3, 136.1, 136.1, 135.9, 134.5, 134.0, 129.5, 128.5, 126.4, 126.3, 124.7, 120.3, 112.0, 119.0, 117.0, 115.0, 113.9, 59.4, 55.1, IR (CH2Cl2, cm-1): 3424, 3301, 2196, 1656, 1632, 1591, 1507, 1444, 1404, 1359, 1168, 743, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H19N3O4SNa 480.0994; Found 480.0996.

(R)-2-amino-5-(phenylsulfonyl)-4-(o-tolyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile (4m): white solid, 35 mg, 79% yield, ee 83%, [α]D25 = -30.95 (c 0.1, DCM), m.p. >200 oC, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.03 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.51-7.36 (m, 6H), 7.24 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.05 (s, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.61 (s, 1H), 2.58 (s, 3H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.3, 142.2, 136.6, 136.2, 135.1, 134.6, 133.8, 130.6, 129.6, 127.7, 126.8, 126.7, 126.5, 126.3, 124.7, 120.1, 120.1, 118.7, 117.0, 114.9, 58.6, 54.9, 18.8, IR (CH2Cl2, cm-1): 3427, 3307, 2190, 1656, 1626, 1594, 1490, 1449, 1398, 1362, 1168, 723, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H19N3O3SNa 464.1045; Found 464.1046.

(R)-2-amino-5-(phenylsulfonyl)-4-(p-tolyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile (4n): white solid, 38 mg, 86% yield, ee 87%, [α]D25 = -305.95 (c 0.1, DCM), m.p. >200 oC, 1H NMR (600 MHz, DMSO-d6) δ (ppm) 8.03 (d, J = 18.0 Hz, 1H), 7.70-7.30 (m, 9H), 7.16-7.05 (m, 4H), 6.99 (s, 2H), 5.20 (s, 1H), 2.29 (s, 3H), 13C{1H} NMR (150 MHz, DMSO-d6) δ (ppm) 159.2, 140.8, 136.3, 136.1, 134.5, 134.0, 129.5, 129.1, 127.3, 126.4, 126.3, 124.7, 120.3, 119.9, 118.7, 117.0, 115.0, 59.2, 20.63, IR (CH2Cl2, cm-1): 3410, 3324, 2193, 1659, 1634, 1596, 1447, 1508, 1447, 1400, 1371, 1174, 763, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H19N3O3SNa 464.1045; Found 464.1044.

(R)-2-amino-4-(4-isopropylphenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-car bonitrile (4o): white solid, 41 mg, 87% yield, ee 85%, [α]D25 = -245.96 (c 0.1, DCM), m.p. >200 o

C, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.03 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H),

7.56-7.51 (m, 3H), 7.48-7.36 (m, 4H), 7.19 (d, J = 8.4 Hz, 2H), 7.08 (s, 2H), 7.04 (d, J = 8.0 Hz,


Page 20 of 30

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2H), 5.22 (s, 1H), 2.92-2.81 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H),

13

C{1H} NMR (100 MHz,

DMSO-d6) δ (ppm) 159.4, 147.2, 141.2, 136.1, 134.6, 133.9, 129.5, 127.3, 126.5, 126.5, 126.3, 124.7, 120.3, 120.0, 118.8, 117.1, 115.0, 99.5, 59.3, 33.05, 23.86, IR (CH2Cl2, cm-1): 3457, 3353, 2190, 1654, 1621, 1586, 1450, 1404, 1365, 1167, 749, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H23N3O3SNa 492.1358; Found 492.1361.

(R)-2-amino-4-(3,4-dimethoxyphenyl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-c arbonitrile (4p): white solid, 39 mg, 80% yield, ee 94%, [α]D25 = -158.97 (c 0.1, DCM), m.p. >200 oC, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.06 (d, J = 8.4 Hz, 1H), 7.63-7.54 (m, 3H), 7.51 (d, J = 7.6 Hz, 1H), 7.48-7.36 (m, 4H), 7.04 (s, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.59 (dd, J = 8.4, 2.0 Hz, 1H), 5.19 (s, 1H), 3.74 (s, 3H), 3.61 (s, 3H),

13

C{1H}

NMR (100 MHz, DMSO-d6) δ (ppm) 159.2, 148.5, 148.0, 136.2, 136.0, 134.5, 134.1, 129.4, 126.3, 124.7, 120.2, 112.0, 119.6, 118.8, 117.1, 115.0, 112.0, 111.5, 59.3, 55.5, 55.4, IR (CH2Cl2, cm-1): 3419, 3354, 2190, 1646, 1611, 1591, 1513, 1448, 1400, 1366, 1169, 718, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H21N3O5SNa 510.1100; Found 510.1102.

(R)-2-amino-4-(furan-2-yl)-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile (4q): white solid, 34 mg, 81% yield, ee 89%, [α]D25 = -127.98 (c 0.1, DCM), m.p. >200 oC, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.03 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.54-7.43 (m, 5H), 7.38 (t, J = 7.6 Hz, 1H), 7.21 (s, 2H), 6.42 (dd, J = 2.8, 2.0 Hz, 1H), 6.27 (d, J = 3.2 Hz, 1H), 5.46 (s, 1H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 160.3, 154.3, 142.4, 136.5, 136.0, 134.7, 134.0, 129.7, 126.5, 126.5, 124.8, 120.3, 119.8, 1171, 116.1, 115.1, 110.7, 106.6, 56.0, 33.1, IR (CH2Cl2, cm-1): 3458, 3356, 2187, 1649, 1610, 1591, 1455, 1403, 1368, 1169, 744, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H15N3O4SNa 440.0681; Found 440.0682.

(R)-2-amino-5-(phenylsulfonyl)-4-(thiophen-2-yl)-4,5-dihydropyrano[3,2-b]indole-3-carbonit rile (4r): white solid, 36 mg, 83% yield, ee 95%, [α]D25 = -147.98 (c 0.1, DCM), m.p. >200 oC, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.06 (d, J = 8.4 Hz, 1H), 7.66-7.61 (m, 3H), 7.51 (d, J = 8.0 Hz, 1H), 7.49-7.45 (m, 3H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 2.0 Hz,



Page 22 of 30

1H), 7.16 (s, 2H), 7.13 (d, J = 7.6 Hz, 1H), 5.29 (s, 1H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.3, 146.4, 136.5, 136.0, 134.7, 134.1, 130.9, 130.0, 129.6, 126.6, 126.4, 124.9, 121.7, 120.2, 119.7, 117.5, 117.2, 115.1, 58.5, 38.7, IR (CH2Cl2, cm-1): 3426, 3323, 2193, 1658, 1635, 1593, 1449, 1410, 1372, 1170, 747, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H15N3O3S2Na 456.0453; Found 456.0451.

(R)-2-amino-8-chloro-4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carboni trile (4s): white solid, 35 mg, 76% yield, ee 86%, [α]D25 = +59.99 (c 0.1, DCM), m.p. >200 oC, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.05 (d, J = 9.2 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.58 (dd, J = 8.8, 1.2 Hz, 2H), 7.52-7.41 (m, 4H), 7.35-7.25 (m, 3H), 7.13-7.09 (m, 4H), 5.24 (s, 1H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.1, 143.5, 135.9, 135.3, 134.8, 132.4, 129.7, 129.3, 128.6, 127.5, 127.2, 126.5, 126.3, 121.5, 120.3, 119.7, 116.7, 116.5, 59.1, 54.9, IR (CH2Cl2, cm-1): 3431, 3326, 2203, 1731, 1661, 1635, 1598, 1448, 1407, 1366, 1173, 714, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SClNa 484.0499; Found 484.0498.

(R)-2-amino-7-bromo-4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-carboni trile (4t): white solid, 39 mg , 77% yield, ee 80%, [α]D25 = +130.98 (c 0.1, DCM), m.p. >200 oC, 1

H NMR (400 MHz, DMSO-d6) δ (ppm) 8.13 (s, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.59 (d, J = 7.2 Hz

3H), 7.48 (t, J = 8.4 Hz, 3H), 7.34-7.23 (m, 3H), 7.11 (d, J = 8.0 Hz, 4H), 5.21 (s, 1H), 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.1, 143.5, 135.9, 135.9, 134.9, 134.6, 129.8, 128.6, 127.9, 127.4, 127.2, 126.4, 119.8, 119.4, 119.3, 119.0, 118.9, 117.4, 59.1, 58.0, IR (CH2Cl2, cm-1): 3428, 3328, 2204, 1731, 1662, 1599, 1449, 1401, 1361, 1170, 720, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H16N3O3SBrNa 527.9993; Found 527.9992.

(R)-2-amino-8-(benzyloxy)-4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrano[3,2-b]indole-3-ca rbonitrile (4u): white solid, 42 mg , 79% yield, ee 93%, [α]D25 = +56.99 (c 0.1, DCM), m.p. >200 o

C, 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.94 (d, J = 9.2 Hz, 1H), 7.65-7.55 (m, 3H),

7.49-7.43 (m, 4H), 7.40 (t, J = 7.6 Hz, 2H), 7.36-7.29 (m, 3H), 7.26 (t, J = 7.2 Hz, 1H), 7.17-7.10 (m, 3H), 7.08 (s, 2H), 7.01 (d, J = 2.4 Hz, 1H), 5.23 (s, 1H), 5.15 (s, 2H),

13

C{1H} NMR (100

MHz, DMSO-d6) δ (ppm) 159.3, 155.9, 143.8, 136.8, 136.5, 135.9, 134.5, 129.6, 128.6, 128.5,


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127.9, 127.6, 127.4, 127.1, 126.4, 121.4, 119.9, 119.3, 116.4, 115.9, 100.4, 69.7, 59.1, 54.9, IR (CH2Cl2, cm-1): 3424, 3330, 2198, 1660, 1637, 1595, 1487, 1450, 1411, 1360, 1155, 698, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C31H23N3O4SNa 556.1307; Found 556.1309.

(R)-2-amino-5-(methylsulfonyl)-4-phenyl-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile (4v): white solid, 32 mg , 88% yield, ee 80%, m.p. >200 oC, [α]D25 = +42.99 (c 0.1, DCM), 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.88 (dd, J = 6.4, 2.0 Hz, 1H), 7.66-7.61 (m, 1H), 7.48-7.41 (m, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.26 (dt, J = 7.2, 1.2 Hz,1H), 7.15-7.04 (m, 4H), 5.07 (s, 1H), 2.81 (s, 3H),

13

C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 159.4, 143.5, 134.6, 133.7, 128.6, 127.6,

127.2, 126.0, 124.2, 120.0, 119.6, 118.6, 116.9, 114.2, 59.1, 39.8, 38.8, IR (CH2Cl2, cm-1): 3421, 3328, 2194, 1729, 1660, 1638, 1595, 1489, 1451, 1407, 1364, 1166, 749, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H15N3O3SNa 388.0732; Found 388.0733.

(R)-5-acetyl-2-amino-4-phenyl-4,5-dihydropyrano[3,2-b]indole-3-carbonitrile

(4w):

white

solid, 21 mg , 64% yield, ee 96%, [α]D25 = +121.98 (c 0.1, DCM), m.p. >200 oC, 1H NMR (600 MHz, DMSO-d6) δ (ppm) 8.07 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.45-7.42 (m, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 7.2 Hz, 4H), 5.29 (s, 1H), 3.34 (s, 3H),

13

C{1H} NMR (150 MHz, DMSO-d6) δ (ppm) 169.4, 159.4, 143.6,

135.3, 133.4, 128.8, 127.0, 125.9, 123.7, 120.2, 119.4, 117.8, 116.5, 116.0, 59.0, 55.0, 26.5, IR (CH2Cl2, cm-1): 3374, 3209, 2201, 1695, 1662, 1600, 1455, 1401, 1373, 699, HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H15N3O2Na 352.1062; Found 352.1065.

Ethyl 2-amino-3-cyano-5-(phenylsulfonyl)-4,5-dihydropyrano [3,2-b]indole- 4-carboxylate (4x): white solid, 30 mg, 71% yield, ee 0%, m.p. 178-180 oC,1H NMR (400 MHz, CDCl3) δ (ppm) 8.00 (d, J = 8.4, 1H), 7.82 (d, J = 7.6, 2H), 7.55 (t, J = 7.6, 1H), 7.45 (q, J = 8.0, 3H), 7.36 (t, J = 7.6, 1H), 7.27 (t, J = 7.6, 1H), 4.94 (s, 2H), 4.91 (s, 1H), 4.37-4.25 (m, 2H), 1.36 (t, J = 7.2, 3H), 13

C{1H} NMR (100 MHz, CDCl3) δ (ppm) 170.1, 160.7, 138.0, 136.4, 134.2, 134.2, 129.4, 126.8,

126.4, 124.2, 120.0, 118.6, 117.48, 114.5, 113.8, 62.2, 55.9, 39.6, 14.2, IR (CH2Cl2, cm-1): 3476, 3342, 2195, 1733, 1663, 1625, 1583, 1452, 1412, 1364, 1181, 746, HRMS (ESI-TOF) m/z: [M + Na]+ Cacld for C21H17N3O5SNa 446.0787; Found 446.0784.



ASSOCIATED CONTENT Supporting information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org. Antibacterial activity of compound 4; Assignment of the absolute configuration of compound 4a by TD-DFT calculation; NMR spectra of substrate 1; NMR spectra, HPLC chromatograms and IR spectra for products 4.

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. *E-mail: [email protected]. ORCID Bo Han: 0000-0003-3200-4682 Author Contributions §

J. Z. and B. W. contributed equally to this work.

Notes The authors declare no competing financial interest

ACKNOWLEGEMENTS We are grateful for financial support from the National Natural Science Foundation of China (81573588, 81773889, 81630101), the Science & Technology Department of Sichuan Province (2017JZYD0001, 2017JY0323, 2018JY0255).

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