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Enantioselective Synthesis of Yohimbine Analogs by an Organocatalytic and Pot-economic Strategy Hsin-Kai Kao, Xin-Jie Lin, Bor-Cherng Hong, Van-Wei Yang, and Gene-Hsiang Lee J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01193 • Publication Date (Web): 11 Jul 2019 Downloaded from pubs.acs.org on July 17, 2019

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The Journal of Organic Chemistry

Enantioselective Synthesis of Yohimbine Analogs by an Organocatalytic and Pot-economic Strategy Hsin-Kai Kao,† Xin-Jie Lin,† Bor-Cherng Hong,*,† Van-Wei Yang,† and Gene-Hsiang Lee‡ †

Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, 621, Taiwan, R.O.C., and Instrumentation Center, National Taiwan University, Taipei, 106, Taiwan, R.O.C.

ABSTRACT: An efficient and one-pot method has been developed for the enantioselective synthesis of pentacyclic indole derivatives with the yohimbane skeleton via a sequence of asymmetric Michael–Michael–Mannich–reduction–amidation–BischlerNapieralski–reduction reactions with high diastereoselectivity and enantioselectivities (up to >99% ee). The seven-step reaction sequence, which generates five bonds and five stereocenters, can be conducted with a pot-economic synthetic strategy and one-pot operation in good yields. The structure and absolute stereochemistry of two products were confirmed by X-ray crystallography analysis.

Yohimbane-type alkaloids1 represent a series of naturally occurring alkaloids bearing a common structural motif of a dodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline ring system (Figure 1). A broad spectrum of biological activities has been observed in the family of yohimbane alkaloids. For example, yohimbine, deserpidine, rescinnamine, and reserpine exhibit antihypertensive, adrenergic, and antipsychotic properties,2 as well as activities against the α-2 adrenergic receptor, dopamine receptor, ATP-sensitive potassium channel, and 5hydroxytryptamine receptor.3 Yohimbine has been approved for manifold medicinal uses including as antihypertensive drugs, as antipsychotic drugs for the relief of psychotic behavior, as a mydriatic, and for the treatment of impotence.4 However, some of the yohimbane-type compounds, e.g., reserpine, the clinical use has been limited because of the side-effects. In light of this background and the search for lead compounds with better biological activities, several asymmetric synthetic methods for the construction of the yohimbane systems have been developed.5 For instance, the synthesis of the yohimbane-type alkaloids venenatine and alstovenine with a divergent strategy was established by Sarpong and coworkers.5f The synthesis of yohimbine and corynanthe alkaloid analogues with multicomponent assembly processes was revealed by Martin and his coworkers.5e Hiemstra et al. accomplished the total synthesis of (+)-yohimbine via the binolphosphoric acidcatalyzed enantioselective Pictet−Spengler reaction.5g The synthesis of protoemetine, protoemetinol, and yohimbane with a chiral pentenolide-based unified strategy was achieved by Hong et al.5a The enantioselective total synthesis of (+)-alphayohimbine with a bicyclic guanidine-catalyzed tandem isomeri-

zation intramolecular-Diels-Alder (IMDA) reaction of alkynes was accomplished by Tan and coworkers.5d Despite these advances, an efficient and enantioselective synthesis of the yohimbine analogs, i.e., the yohimbane system, with the application of the domino catalytic reactions in the generation of the multi-stereocenters and the multi-ring formation cascade continues to be a fascinating subject for exploration. The chemical synthesis of the designated molecules with a pot-economic strategy and a one-pot synthetic operation has recently received much attention.6 Especially, with the assistance of organocatalysis,7 domino reactions,8 and multicomponent reactions,9 the one-pot syntheses can efficiently access the particularly attractive functionalized polycycles with excellent diastereoselectivities and enantioselectivities.

Figure 1. Examples of naturally occurring yohimbane-type compounds and the synthetic yohimbane.

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Enlightened by the aforementioned background and our continuing efforts in exploring the organocatalytic domino reactions,10 we considered a scenario in which the asymmetric synthesis of the chiral yohimbane motif could be achieved by a series of cascade reactions, and moreover, the process could be performed in a one-pot operation (Scheme 1). Retrosynthetic analysis of the yohimbane-type compound 1 with the BischlerNapieralski reaction and reductive transformation provides the indole amide 2, which could be obtained from the Mannich reduction of tryptamine 3 and aldehyde 4 followed by amidation of the reaction intermediate. The carboxaldehyde 4 can be obtained from the organocatalytic enantioselective double Michael reaction of nitroalkene 5 and enal 6.11 Previously, we have utilized utilized the carboxaldehyde 4 for the synthesis of inside yohimbane via the Pictet-Spengler–lactamization reaction (Scheme 2). Scheme 1. Retrosynthetic analysis of yohimbane-type compound 1.

Scheme 2. The synthesis of inside yohimbane.

7

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-i

-i

99

8

g R1 = Ph; R2 = MeO; R3 = H h R1 = Ph; R2 = Cl; R3 = H

49

99

82 (65)g 76

-i

-i

9

i R1 = Ph; R2 = Me; R3 = H

-

i

-i

99

88

10

j R1 = Ph; R2 = H; R3 = Br

-i

67

-i

99

70

11

k R1 = 4-BrC6H4; R2 = R3 =H

36

52

82

99

81

62

69

a The reactions were performed with 20 mol % of catalyst in a screw capped vial at ambient temperature (∼25–30 °C). b Reaction time for the 1st step reaction. c dr>19:1. d Yields of 4 isolated, reaction in CH2Cl2 (DCM). e Determined by HPLC with a chiral column (Chiralpak IC). f Yields of 2 isolated; reaction of 4 in 1,2-dichloroethane (DCE). g Reaction of 4 in CH2Cl2. h Yields of 2 isolated from 5 via the one-pot operation in CH2Cl2 for both steps. i 36 h and 85% yield of 4a, as described in entry 1.

The initial double Michael cascade of nitroalkene 5 and enal 6a was achieved with Jørgensen–Hayashi catalyst12 in CH2Cl2 to give a 85% yield of adduct 4a with 99% ee (Table 1).11 Treatment of (4a) with tryptamine (3a) and NaBH(OAc)3 in 1,2dichloroethane at ambient temperature for 6 h provided 2a in 86% yield. The two-pot, one isolation of intermediate 4a, sequence can be achieved in an one-pot operation to afford lactam 2a in 75% yield, where the second step reaction, Mannich– reduction-amidation process, was performed in CH2Cl2 as was the transformation in the first step reaction. (Table 1, entry 1). Subsequently, a series of enal 6, tryptamine 3 and nitroalkene 5 was applied in this reaction sequence. As shown in Table 1, the one-pot operation for the syntheses of indole lactam 2 were quite general and efficient with high yields, ranging from 4975% yield. However, less yield was observed in the example of 2g, where the second-step reaction gave a lower yield in CH2Cl2 than the reaction in dichloroethane, 65% vs 82% yield (Table 1, entry 7). Table 2. Bischler-Napieralski–reduction process.

Table 1. Michael–Michael–Mannich–reduction-amidation processa

entry

1

a R1 = Ph; R2 = R3 = H

36

yield of 4 (%)c,d 85

2

b R1 = 4-Me2NC6H4; R2 = R3 = H c R1 = 2-Naph; R2 = R3 = H d R1 = 4-MeOC6H4; R2 = R3 = H e R1 = 3,4-MeOC6H4; R2 = R3 = H f R1 = 3,4,5-MeOC6H4; R2 = R3 = H

36

81

98

73

60

80

80

99

73

61

40

86

99

84

61

168

79

99

83

69

168

70

98

75

69

3 4 5 6

substrate 6, 3

time (h)b

ee yield one-pot (%)e of 2 yield of (%)f 2 (%)h 99 86 75

entry

2

1 2 3 4 5 6 7 8 9 10 11

a R1 = Ph; R2 = R3 = H b R1 = 4-Me2NC6H4; R2 = R3 = H c R1 = 2-Naph; R2 = R3 = H d R1 = 4-MeOC6H4; R2 = R3 = H e R1 = 3,4-MeOC6H4; R2 = R3 = H f R1 = 3,4,5-MeOC6H4; R2 = R3 = H g R1 = Ph; R2 = MeO; R3 = H h R1 = Ph; R2 = Cl; R3 = H i R1 = Ph; R2 = Me; R3 = H j R1 = Ph; R2 = H; R3 = Br k R1 = 4-BrC6H4; R2 = R3 = H

yield of 1 (%)a,b 74 82 64 86 77 72 79 64 80 75 72

eec (%) 99d 98 99 99 99 99 99 99 99d 99d 99

a dr>19:1. b Yields of 1 isolated. c Unless otherwise noted, determined by HPLC with a chiral column (Chiralpak IC). d Analyzed with Chiralpak IA.


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The transformation of the indole 2a to 1a was achieved via the Bischler-Napieralski reaction–reduction process (Table 2).13 To a solution of 2a in toluene was added POCl3, and the solution was heated to reflux for ca. 3 h, until the completion of the reaction. The solution was concentrated in vacuo to give a residue. To this residue was added MeOH, followed by the addition of NaBH4. The reaction mixture was stirred at room temperature for 1 h, followed by the addition of an aqueous NaHCO3 solution to quench the reaction. After the regular work-up procedure, the crude product was purified by silica-gel flash column chromatography to afford a 74% yield of product 1a with 99% ee (Table 2, entry 1). Other amide 2 analogs (2b-2k) were also transformed to the corresponding yohimbine analogs 1b-1k (Table 2, entries 2–11). The transformation process was quite general with high yield, and the enantiomeric excess of the products 1 was around 98-99% ee, which was essentially the same as that observed in the aforementioned cyclohexanecarboxaldehyde 4 isolation process (Table 1). The structures and, in particular, the absolute configurations of (–)-1d and (–)-1j were confirmed explicitly based on the single crystal X-ray crystallographic analyses (see Supporting Information for details). Table 3. One-pot Michael–Michael–Mannich–reduction– amidation–Bischler-Napieralski–reduction process

entry

1

1 2 3 4 5 6 7 8 9 10 11 12 13

a R1 = Ph; R2 = R3 = H b R1 = 4-Me2NC6H4; R2 = R3 = H c R1 = 2-Naph; R2 = R3 = H d R1 = 4-MeOC6H4; R2 = R3 = H e R1 = 3,4-MeOC6H4; R2 = R3 = H f R1 = 3,4,5-MeOC6H4; R2 = R3 = H g R1 = Ph; R2 = MeO; R3 = H h R1 = Ph; R2 = Cl; R3 = H i R1 = Ph; R2 = Me; R3 = H j R1 = Ph; R2 = H; R3 = Br k R1 = 4-BrC6H4; R2 = R3 = H l R1 = 4-FC6H4; R2 = R3 = H m R1 = 4-NO2C6H4; R2 = R3 = H

a

(one-pot) yield of 1 (%)a 54b 54 53 58 47 44 40 (54)c 44 48 45 39 41b 38b

Yields of 1 isolated. b 99% ee, determined by HPLC with a chiral column. c After completion of the 1st reaction, the solvent was evaporated and DCE was added into the reaction mixture for the 2nd-step reaction.

Encouraged by these developments, the seven-step reactions, Michael–Michael–Mannich–reduction–amidation–BischlerNapieralski–reduction sequence, was performed in a one-pot manner (Table 3). For example, to a solution of nitroalkene 5 and cinnamaldehyde (1.3 equiv) in CH2Cl2 was added a solution of the catalyst (0.2 equiv) and DABCO (0.2 equiv) in CH2Cl2. The resulting solution was stirred at ambient temperature (25-30 °C) for 36 h, until the completion of the reaction. To the reaction mixture was sequentially added CH2Cl2, tryptamine and NaBH(OAc)3. The resulting solution was stirred at room temperature until the completion of the reaction. The resulting solution was concentrated in vacuo to give a residue. To this crude product was added toluene and purified POCl3. The solution was heated to reflux, until the completion of the reaction, followed by concentration in vacuo to give a residue. To the residue was added MeOH, followed by the addition of NaBH4. The reaction mixture was stirred at room temperature for 1 h, followed by the addition of aqueous NaHCO3 to quench the reaction. After the regular work-up and flash column silica-gel chromatography purification, product 1a was obtained in 54% yield. Generally, the isolated yields of yohimbine analogs 1 by these transformations were quite promising, ranging from 3858% yields. Additionally, switching of the solvent in the second-step reaction, by evaporation of CH2Cl2 from the freshly prepared double Michael adduct 4, followed by the addition of dichloroethane, and followed by the same subsequent reaction process, afforded the higher yields of 1g, 54% vs 40% (Table 3, entry 7). The enantiomeric excess of the products 1 remained the same as the aforementioned two-pot reaction process (Table 2). For example, 1a, which was obtained from the one-pot process, was observed to have 99% ee, and the same high enantioselectivities (99% ee) were observed in the products 1l and 1m (Table 3, entries 1, 12 and 13). It is noteworthy that the overall average yields of these one-pot septuple reactions were around 48%, which is an average of nearly 90% yield for each bondformation reaction. In addition, the reaction sequence affording yohimbine analogs 1, forming five chemical bonds, would engender five chiral centers, leading to a maximum of 32 possible stereoisomers, yet only one enantiomer was observed in this process. Scheme 3. Proposed Reaction Mechanism.

To account for the stereoselective formation of product 1 from 4, a plausible mechanism is proposed as depicted in Scheme 3. Direct reductive amination and spontaneous lactamization of 4a provides lactam 7a. Treatment of 7a with POCl3 resulted in the formation of iminium intermediate 8a (the conformer illustrated was generated by SPARTAN’14, Conformer Distribution, Molecular Mechanics, MMFF). Reduction of the



iminium 8a with NaBH4, where the hydride approache from the less sterically hindered side of the iminium, renders product 1a. In addition, the high diastereoselectivity of the final products could also be governed by the stable trans-fused arrangement of polycycle 1a since the stereogenic center on the tetrahydro-βcarboline scaffold is known to be subject to epimerization, thereby affording the most stable isomers in many reactions.14 In summary, we have accomplished a concise and asymmetric synthesis of yohimbine analogs, containing five stereogenic centers, from a readily available ethyl 6-nitrohex-2-enoate 5, α,β-unsaturated aldehyde and tryptamine via a sequence of enantioselective Michael–Michael–Mannich–reduction– amidation-Bischler-Napieralski–reduction reactions with high diastereoselectivities and high enantioselectivities (98–99% ee). The seven-step reaction sequence, which generates five bonds and five stereogenic centers, can be managed in a one-pot operation with only a one-step purification, establishing the poteconomic synthetic strategy. The structures and absolute configurations of the products (–)-1d and (–)-1j have been unambiguously illustrated by the X-ray crystallographic analyses. Given the prevalence of the yohimbine analogues in nature and the history of their physiological activities, this asymmetric and competent process could constitute an adequate protocol in related natural and unnatural product syntheses. █ EXPERIMENTAL SECTION General Information. All solvents were reagent grade. NMR spectra were acquired on Varian Unity INOVA-500, Bruker AscendTM 400 or Bruker DPX-400 spectrometer. The enantiomeric excess (ee) values were determined by HPLC with a DAICEL chiral column, Chiralpak IA, or IC (0.46 x 25 cm, 5 μ particle size) and using the eluent of IPA-hexane, EtOAchexane, or THF-hexane. The HPLC system was equipped with a diode array detector (Hitachi L-2455) and pump (L-2130). The melting points are uncorrected and were determined by an automated melting point system (Stanford Research Systems, MPA100). Optical rotation values were measured by a digital polarimeter (Jasco P-2000). General Procedure for the Synthesis of Products 4 and 2. To a solution of nitroalkene 5 (20 mg, 0.107 mmol, 1.0 equiv)11b and cinnamaldehyde (16.8 mg, 0.127 mmol, 1.2 equiv) in CH2Cl2 (0.25 mL) was added a solution of catalyst I (7 mg, 0.02 mmol, 0.2 equiv), and DABCO (2.3 mg, 0.021 mmol, 0.2 equiv) in CH2Cl2 (0.25 mL). The resulting solution was stirred at ~30 °C for 36 h until the completion of the reaction, as monitored by TLC. The resulting mixture was diluted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo to give the crude residue. The residue was purified by flash column chromatography with 20% EtOAc–hexane (Rf = 0.23 in 20% EtOAc–hexane) to give product 4a (29 mg, 85% yield). To a solution of 4a (30 mg, 0.094 mmol, 1 equiv) and tryptamine (18.1 mg, 0.113 mmol, 1.2 equiv) in 1,2-dichloroethane (1.6 mL) was added NaBH(OAc)3 (139.4 mg, 0.658 mmol, 7 equiv). The resulting solution was stirred at ~30 °C for 6 h until the completion of the reaction, as monitored by TLC. The resulting solution was diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to give the crude residue. The residue was purified by flash column chromatography with 70% EtOAc–hexane (Rf =

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0.20 in 70% EtOAc–hexane) to give product 2a (33.9 mg, 86% yield). Ethyl 2-((1S,2S,3S,4R)-2-formyl-4-nitro-3phenylcyclohexyl)acetate (4a). 29 mg (85% yield); 1H NMR (400 MHz, CDCl3): δ 9.31 (d, J = 4.0 Hz, 1 H), 7.29 – 7.24 (m, 2 H), 7.23 – 7.18 (m, 1 H), 7.17 – 7.13 (m, 2 H), 4.74 – 4.67 (m, 1 H), 4.09 (q, J = 7.0 Hz, 2 H), 3.47 (t, J = 11.5 Hz, 1 H), 2.66 – 2.55 (m, 1 H), 2.43 – 2.08 (m, 3 H), 2.24 – 2.08 (m, 3 H), 1.49 – 1.36 (m, 1 H), 1.22 (t, J = 7.0 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3): δ 201.3 (CH), 171.4 (C), 136.0 (C), 129.2 (2 CH), 128.4 (CH), 127.8 (2 CH), 89.9 (CH), 60.7 (CH2), 58.1 (CH), 47.9 (CH), 37.8 (CH2), 33.4 (CH), 31.0 (CH2), 29.2 (CH2), 14.1 (CH3).11a Chiral HPLC analysis for 4a: Chiralpak IC (elute: 15% EtOAc−hexane), flow rate 1.0 mL/min, detector: 254 nm, t1 = 8.90 min, t2 = 9.97 min, 0.4:99.6 er. (4aS,7R,8S,8aS)-2-(2-(1H-indol-3-yl)ethyl)-7-nitro-8phenyloctahydroisoquinolin-3(4H)-one (2a). white solids, 33.9 mg (86% yield); m.p. 248–249 °C; [α]D28 20.7 (c 5.0, CHCl3); IR (neat): 3252, 2933, 1627, 1548, 1498, 1453, 1374, 752, 700 cm-1; 1H NMR (500 MHz, CDCl3): δ 8.22 (s, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.26 – 7.21 (m, 3 H), 7.18 (dd, J = 7.5 Hz, 1 H), 7.06 (dd, J = 7.5 Hz, 1 H), 6.92 – 6.86 (m, 2 H), 6.85 (brs, 1 H), 4.60 (td, J = 11.5, 3.8 Hz, 1 H), 3.61 – 3.52 (m, 1 H), 3.39 – 3.31 (m, 1 H), 2.96 – 2.81 (m, 2 H), 2.72 (td, J = 11.5, 2.9 Hz, 2 H), 2.55 (dd, J = 17.5, 5.0 Hz, 1 H), 2.44 (dd, J = 12.0, 5.0 Hz, 1 H), 2.36 – 2.29 (m, 1 H), 2.08 – 1.91 (m, 3 H), 1.67 – 1.56 (m, 1 H), 1.55 – 1.45 (m, 1 H), 1.26 – 1.12 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.3 (C), 136.5 (C), 136.1 (C), 129.0 (2 CH), 128.0 (2 CH), 127.5 (C), 121.9 (2 CH), 121.7 (CH), 119.1 (CH), 118.7 (CH), 112.9 (C), 111.2 (CH), 90.4 (CH), 52.6 (CH2), 50.7 (CH), 48.4 (CH2), 41.4 (CH), 38.4 (CH), 35.9 (CH2), 30.9 (CH2), 30.0 (CH2), 22.7 (CH2); MS (m/z, relative intensity): 417 (M+, 1), 275 (1), 212 (1), 145 (1), 143 (100), 130 (14), 115 (3), 91 (4); HRMS (EI) m/z: [M]+ Calcd for [C25H27N3O3]+ 417.2052; Found 417.2057. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for [C25H28N3O3]+ 418.2131; Found 418.2135. Ethyl 2-((1S,2S,3S,4R)-3-(4-(dimethylamino)phenyl)-2formyl-4-nitrocyclohexyl)acetate (4b). Colorless oil; 62.7 mg (81% yield); 1H NMR (400 MHz, CDCl3): δ 9.30 (d, J = 4.0 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 2 H), 6.58 (d, J = 8.8 Hz, 2 H), 4.69– 4.60 (m, 1 H), 4.10 (q, J = 7.2 Hz, 2 H), 3.36 (t, J = 11.5 Hz, 1 H), 2.87 (s, 6 H), 2.58–4.90 (m, 1 H), 2.43–2.26 (m, 3 H), 2.22– 2.04 (m, 3 H), 1.48–1.33 (m, 1 H), 1.22 (t, J = 7.2 Hz, 3 H); 13 C{1H} NMR (100 MHz, CDCl3): δ 201.7 (CH), 171.6 (C), 150.3 (C), 128.5 (2 CH), 122.8 (C), 112.7 (2 CH), 90.4 (CH), 60.7 (CH2), 58.3 (CH), 47.2 (CH), 40.2 (2 CH3), 38.0 (CH2), 33.5 (CH), 31.0 (CH2), 29.4 (CH2), 14.1 (CH3).11a Chiral HPLC analysis for 4b: Chiralpak IC (elute: 15% EtOAc−hexane), flow rate 1.0 mL/min, detector: 254 nm, t1 = 16.8 min, t2 = 23.6 min, 1:99 er. (4aS,7R,8S,8aS)-2-(2-(1H-indol-3-yl)ethyl)-8-(4(dimethylamino)phenyl)-7-nitrooctahydroisoquinolin-3(4H)-one (2b).White solids, 37 mg (73% yield); m.p. 245–246 °C; [α]D28 27.2 (c 0.5, CHCl3); IR (neat): 3253, 2933, 1620, 1548, 1524, 1350, 1221, 749 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.94 (brs, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.17 (dd, J = 7.0, 7.0 Hz, 1 H), 7.06 (dd, J = 7.0, 7.0 Hz, 1 H), 6.89 (d, J = 2.0 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 2 H), 6.59 (d, J = 8.0 Hz, 2 H), 4.59 (td, J = 11.5, 3.5 Hz, 1 H), 3.56 – 3.41 (m, 2 H), 2.93 (s, 6 H), 2.94 – 2.86 (m, 2 H), 2.80 – 2.72 (m, 1 H), 2.70 –


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2.60 (m, 2 H), 2.56 (dd, J = 17.5, 5.0 Hz, 1 H), 2.37 – 2.30 (m, 1 H), 2.09 – 1.93 (m, 3 H), 1.71 – 1.51 (m, 2 H), 1.27 – 1.16 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.4 (C), 150.1 (C), 136.2 (C), 127.5 (C), 123.8 (C), 122.0 (2 CH), 121.7 (CH), 119.3 (CH), 118.9 (2 CH), 113.2 (C), 112.8 (2 CH), 111.1 (CH), 90.9 (CH), 52.6 (CH2), 50.0 (CH), 48.2 (CH2), 41.7 (CH), 40.4 (2 CH3), 38.5 (CH2), 36.1 (CH), 31.0 (CH2), 30.2 (CH2), 22.7 (CH2); MS (m/z, relative intensity): 460 (M+, 4), 318 (11), 317 (56), 271 (15), 270 (16), 160 (16), 144 (31), 143 (100), 134 (49), 130 (48). HRMS (EI) m/z: [M]+ Calcd for [C27H32N4O3]+ 460.2474; Found 460.2457. Ethyl 2-((1S,2S,3S,4R)-2-formyl-3-(naphthalen-2-yl)-4nitrocyclohexyl)acetate (4c). Colorless oil; 31.5 mg (80% yield); 1 H NMR (400 MHz, CDCl3): δ 9.34 (d, J = 4.0 Hz, 1 H), 7.83 – 7.70 (m, 3 H), 7.62 (s, 1 H), 7.49 – 7.40 (m, 2 H), 7.30 (dd, J = 8.6, 1.8 Hz, 1 H), 4.89– 4.77 (m, 1 H), 4.11 (q, J = 7.2 Hz, 2 H), 3.65 (t, J = 11.6 Hz, 1 H), 2.79 – 2.67 (m, 1 H), 2.49 – 2.29 (m, 3 H), 2.25 – 2.07 (m, 3 H), 1.55 – 1.32 (m, 1 H), 1.23 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3): δ 201.2 (CH), 171.4 (C), 133.3 (C), 133.2 (C), 133.0 (C), 129.2 (CH), 127.8 (CH), 127.63 (CH), 127.61 (CH), 126.5 (CH), 126.4 (CH), 124.6 (CH), 89.8 (CH), 60.7 (CH2), 57.9 (CH), 48.0 (CH), 37.8 (CH2), 33.5 (CH), 31.0 (CH2), 29.2 (CH2), 14.1 (CH3).11a Chiral HPLC analysis for 4c: Chiralpak IC (elute: 15% EtOAc−hexane), flow rate 1.0 mL/min, detector: 254 nm, t1 = 12.4 min, t2 = 13.9 min, 0.3:99.7 er. (4aS,7R,8S,8aS)-2-(2-(1H-indol-3-yl)ethyl)-8(naphthalen-2-yl)-7-nitrooctahydroisoquinolin-3(4H)-one (2c). White solids; (37.2 mg, 73% yield); m.p. 233–234 °C; [α]D28 38 (c 0.5, CHCl3); IR (neat): 3243, 2930, 1626, 1548, 749 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.85 – 7.80 (m, 1 H), 7.85 – 7.64 (m, 3 H), 7.54 – 7.47 (m, 2 H), 7.41 (d, J = 7.5 Hz, 2 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.13 (dd, J = 7.5, 7.5 Hz, 1 H), 7.03 (d, J = 7.5 Hz, 1 H), 6.98 (dd, J = 7.5, 7.5 Hz, 1 H), 6.74 (s, 1 H), 4.75 (td, J = 11.5, 3.5 Hz, 1 H), 3.60 – 3.51 (m, 1 H), 3.35 – 3.26 (m, 1 H), 2.94 – 2.73 (m, 4 H), 2.58 (dd, J = 17.5, 5.0 Hz, 1 H), 2.47 – 2.35 (m, 2 H), 2.12 – 1.97 (m, 3 H), 1.75 – 1.56 (m, 2 H), 1.33 – 1.17 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.2 (C), 136.0 (C), 133.3 (C), 133.0 (C), 129.0 (C), 127.8 (2 CH), 127.7 (CH), 127.4 (C), 126.5 (2 CH), 126.3 (CH), 122.0 (CH), 121.5 (CH), 119.2 (2 CH), 118.7 (CH), 113.1 (C), 111.1 (CH), 90.3 (CH), 52.8 (CH2), 50.9 (CH), 48.3 (CH2), 41.5 (CH), 38.5 (CH2), 36.0 (CH), 31.0 (CH2), 30.1 (CH2), 22.8 (CH2); MS (m/z, relative intensity): 467 (M+, 0.1), 325 (1), 262 (1), 144 (14), 143 (100), 130 (13). HRMS (EI) m/z: [M]+ Calcd for [C29H29N3O3]+ 467.2209; Found 467.2206. Ethyl 2-((1S,2S,3S,4R)-2-formyl-3-(4-methoxyphenyl)-4nitrocyclohexyl)acetate (4d). Colorless oil; 128.4 mg, (86% yield); 1H NMR (500 MHz, CDCl3): δ 9.30 (d, J = 4.0 Hz, 1 H), 7.06 (d, J = 8.5 Hz, 2 H), 6.79 (d, J = 8.5 Hz, 2 H), 4.68 – 4.60 (m, 1 H), 4.09 (q, J = 7.0 Hz, 2 H), 3.72 (s, 3 H), 3.41 (t, J = 11.5 Hz, 1 H), 2.61 – 2.50 (m, 1 H), 2.42 – 2.27 (m, 3 H), 2.23 – 2.05 (m, 3 H), 1.48 – 1.35 (m, 1 H), 1.22 (t, J = 7.0 Hz, 3 H); 13 C{1H} NMR (125 MHz, CDCl3): δ 201.4 (CH), 171.5 (C), 159.4 (C), 128.9 (2 CH), 127.7 (C), 114.6 (2 CH), 90.2 (CH), 60.7 (CH2), 58.2 (CH), 55.1 (CH3), 47.2 (CH), 37.9 (CH2), 33.5 (CH), 31.0 (CH2), 29.3 (CH2), 14.1 (CH3).11a Chiral HPLC analysis for 4d: Chiralpak IC (elute: 25% EtOAc−hexane), flow rate 1.0 mL/min, detector: 254 nm, t1 = 5.37 min, t2 = 5.91 min, 0.4:99.6 er.

(4aS,7R,8S,8aS)-2-(2-(1H-indol-3-yl)ethyl)-8-(4methoxyphenyl)-7-nitrooctahydroisoquinolin-3(4H)-one (2d). White solids; 32.3 mg (84% yield); m.p. 234–235 °C; [α]D28 27.3 (c 1.0, CHCl3); IR (neat): 3269, 2927, 1627, 1549, 1512, 1456, 1374, 1249, 1181, 1032, 833, 751, 569 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.19 (brs, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.17 (dd, J = 8.0, 8.0 Hz, 1 H), 7.06 (dd, J = 8.0, 8.0 Hz, 1 H), 6.87 (d, J = 2.0 Hz, 1 H), 6.83 – 6.71 (m, 4 H), 4.55 (td, J = 11.5, 4.0 Hz, 1 H), 3.76 (s, 3 H), 3.63 – 3.52 (m, 1 H), 3.43 – 3.31 (m, 1 H), 2.97 – 2.81 (m, 2 H), 2.74 – 2.62 (m, 2 H), 2.55 (dd, J = 17.5, 5.0 Hz, 1 H), 2.48 (dd, J = 12.0, 5.0 Hz, 1 H), 2.36 – 2.28 (m, 1 H), 2.08 – 1.91 (m, 3 H), 1.68 – 1.55 (m, 1 H), 1.55 – 1.43 (m, 1 H), 1.26 – 1.10 (m, 1 H); 13 C{1H} NMR (100 MHz, CDCl3): δ 168.3 (C), 159.1 (C), 136.2 (C), 128.4 (C), 127.5 (C), 122.0 (2 CH), 121.7 (CH), 119.2 (2 CH), 118.8 (2 CH), 114.3 (CH), 113.0 (C), 111.2 (CH), 90.7 (CH), 55.2 (CH3), 52.6 (CH2), 50.0 (CH), 48.4 (CH2), 41.5 (CH), 38.4 (CH2), 36.0 (CH), 30.9 (CH2), 30.1 (CH2), 22.7 (CH2); MS (m/z, relative intensity): 447 (M+, 0.2), 317 (0.5), 144 (14), 143 (100), 130 (13). HRMS (EI) m/z: [M]+ Calcd for [C26H29N3O4]+ 447.2158; Found 447.2145. Ethyl 2-((1S,2S,3S,4R)-3-(3,4-dimethoxyphenyl)-2formyl-4-nitrocyclohexyl)acetate (4e). Colorless oil; 31.9 mg, 79% yield); 1H NMR (500 MHz, CDCl3): δ 9.32 (d, J = 4.0 Hz, 1 H), 6.78 – 6.68 (m, 2 H), 6.60 (d, J = 2.0 Hz, 1 H), 4.71 – 4.62 (m, 1 H), 4.09 (q, J = 7.1 Hz, 2 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 3.40 (t, J = 11.6 Hz, 1 H), 2.59 – 2.51 (m, 1 H), 2.42 – 2.27 (m, 3 H), 2.21 – 2.05 (m, 3 H), 1.48 – 1.35 (m, 1 H), 1.22 (t, J = 7.1 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 201.3 (CH), 171.5 (C), 149.3 (C), 149.0 (C), 128.2 (C), 120.1 (CH), 111.6 (CH), 110.9 (CH), 90.1 (CH), 60.7 (CH2), 58.2 (CH), 55.9 (CH3), 55.8 (CH3), 47.7 (CH), 37.9 (CH2), 33.5 (CH), 31.0 (CH2), 29.3 (CH2), 14.1 (CH3).11a Chiral HPLC analysis for 4e: Chiralpak IC (elute: 30% EtOAc−hexane), flow rate 1.0 mL/min, detector: 254 nm, t1 = 10.0 min, t2 = 19.6 min, 0.5:99.5 er. (4aS,7R,8S,8aS)-2-(2-(1H-indol-3-yl)ethyl)-8-(3,4dimethoxyphenyl)-7-nitrooctahydroisoquinolin-3(4H)-one (2e). White solids; 41.8 mg (83% yield); m.p. 220–221 °C; [α]D28 14.5 (c 4.4, CHCl3); IR (neat): 3727, 3627, 3417, 3253, 2934, 1627, 1548, 1498, 1453, 1374, 1343, 751, 701, 670 cm-1; 1H NMR (500 MHz, CDCl3): δ 8.22 (s, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.32 (d, J = 7.5 Hz, 1 H), 7.15 (dd, J = 7.5, 7.5 Hz, 1 H), 7.05 (dd, J = 7.5, 7.5 Hz, 1 H), 6.87 (s, 1 H), 6.70 (brs, 1 H), 6.46 (brs, 2 H), 4.60 (td, J = 11.5, 3.5 Hz, 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.60 – 3.50 (m, 1 H), 3.46 – 3.37 (m, 1 H), 2.89 (t, J = 7.0 Hz, 2 H), 2.78 – 2.64 (m, 2 H), 2.60 – 2.50 (m, 2 H), 2.39 – 2.29 (m, 1 H), 2.09 – 1.94 (m, 3 H), 1.70 – 1.47 (m, 2 H), 1.30 – 1.15 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.3 (C), 149.1 (C), 148.8 (C), 136.2 (C), 128.9 (C), 127.4 (C), 121.9 (CH), 121.7 (CH), 119.2 (2 CH), 118.6 (CH), 112.9 (C), 111.6 (CH), 111.2 (2 CH), 90.7 (CH), 55.8 (2 CH3), 52.5 (CH2), 50.4 (CH), 48.2 (CH2), 41.6 (CH), 38.4 (CH2), 36.0 (CH), 30.9 (CH2), 30.0 (CH2), 22.8 (CH2); MS (m/z, relative intensity): 477 (M+, 0.1), 151 (3), 146 (1), 145 (1), 144 (14), 143 (100), 131 (2), 130 (12). HRMS (EI) m/z: [M]+ Calcd for [C27H31N3O5]+ 477.2264; Found 477.2258. Ethyl 2-((1S,2S,3S,4R)-2-formyl-4-nitro-3-(3,4,5trimethoxyphenyl)cyclohexyl)acetate (4f). Colorless oil; 92.0 mg (70% yield); 1H NMR (400 MHz, CDCl3): δ 9.34 (d, J = 4.0 Hz, 1 H), 6.33 (s, 2 H), 4.72 – 4.63 (m, 1 H), 4.09 (q, J = 7.0



Hz, 2 H), 3.79 (s, 6 H), 3.76 (s, 3 H), 3.40 (t, J = 11.5 Hz, 1 H), 2.60 – 2.52 (m, 1 H), 2.42 – 2.26 (m, 3 H), 2.22 – 2.03 (m, 3 H), 1.47 – 1.36 (m, 1 H), 1.22 (t, J = 7.0 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3): δ 201.1 (CH), 171.5 (C), 153.6 (2 C), 138.0 (C), 131.4 (C), 104.9 (2 CH), 89.9 (CH), 60.75 (CH2), 60.74 (CH3), 58.0 (CH), 56.2 (2 CH3), 48.3 (CH), 37.8 (CH2), 33.5 (CH), 31.1 (CH2), 29.3 (CH2), 14.1 (CH3).11a Chiral HPLC analysis for 4f: Chiralpak IC (elute: 15% EtOAc−hexane), flow rate 1.0 mL/min, detector: 254 nm, t1 = 23.5 min, t2 = 29.8 min, 0.8:99.2 er. (4aS,7R,8S,8aS)-2-(2-(1H-indol-3-yl)ethyl)-7-nitro-8(3,4,5-trimethoxyphenyl)octahydroisoquinolin-3(4H)-one (2f). White solids; 37.2 mg (75% yield); m.p. 234–235 °C; [α]D28 +20.4 (c 5.0, CHCl3); IR (neat): 3271, 2930, 1630, 1594, 1504, 1459, 1426, 1371, 1330, 1243, 1126, 1007, 799, 748, 663 cm-1; 1 H NMR (500 MHz, CDCl3): δ 8.23 (s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.14 (dd, J = 7.5, 7.5 Hz, 1 H), 7.04 (dd, J = 7.5, 7.5 Hz, 1 H), 6.86 (brs, 1 H), 6.17 (brs, 2 H), 4.63 (td, J = 11.5, 36 Hz, 1 H), 3.82 (s, 6 H), 3.79 (s, 3 H), 3.61 – 3.51 (m, 1 H), 3.50 – 3.41 (m, 1 H), 2.90 (t, J = 7.0 Hz, 2 H), 2.80 – 2.64 (m, 2 H), 2.62 – 2.51 (m, 2 H), 2.39 – 2.31 (m, 1 H), 2.08– 1.90 (m, 3 H), 1.68 – 1.56 (m, 1H), 1.55 – 1.44 (m, 1 H), 1.28 – 1.14 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.2 (C), 137.8 (2 C), 136.2 (C), 132.2 (2 C), 127.4 (C), 121.9 (2 CH), 121.7 (2 CH), 119.2 (CH), 118.5 (CH), 112.8 (C), 111.23 (CH), 90.3 (CH), 60.8 (CH3), 56.4 (2 CH3), 52.5 (CH2), 51.0 (CH), 48.2 (CH2), 41.7 (CH), 38.4 (CH2), 35.9 (CH), 31.0 (CH2), 30.0 (CH2), 22.8 (CH2); MS (m/z, relative intensity): 507 (M+, 0.5), 458 (1), 364 (5), 317 (3), 181 (4), 143 (100), 130 (13). HRMS (EI) m/z: [M]+ Calcd for [C28H33N3O6]+ 507.2369; Found 507.2372. (4aS,7R,8S,8aS)-2-(2-(5-methoxy-1H-indol-3-yl)ethyl)-7nitro-8-phenyloctahydroisoquinolin-3(4H)-one (2g). To a solution of 4a (21 mg, 0.066 mmol, 1 equiv) and 5methoxytryptamine (17 mg, 0.089 mmol, 1.4 equiv) in 1,2dichloroethane (1.1 mL) was added NaBH(OAc)3 (34 mg, 0.16 mmol, 2.4 equiv). The resulting solution was stirred at ~30 °C for 6 h until the completion of the reaction, as monitored by TLC. The resulting solution was diluted with EtOAc, washed with saturated aq NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to give the crude residue. The residue was purified by flash column chromatography with 70% EtOAc– hexane (Rf = 0.23 in 90% EtOAc–hexane) to give product 2g (24 mg, 82% yield). Selected data for 2g: white solids, m.p. 247–248 °C; [α]D28 18.0 (c 1.0, CHCl3); IR (neat): 3253, 2934, 1626, 1549, 1490, 1450, 1374, 1215, 758, 702 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1 H), 7.27 – 7.20 (m, 4 H), 6.95 – 6.91 (s, 3 H), 6.86 – 6.82 (s, 2 H), 4.63 (td, J = 11.6, 4.0 Hz, 1 H), 3.80 (s, 3 H), 3.55 – 3.47 (m, 1 H), 3.43 – 3.35 (m, 1 H), 2.90 – 2.79 (m, 2 H), 2.78 – 2.71 (m, 2 H), 2.57 (dd, J = 17.5, 5.0 Hz, 1 H), 2.49 (dd, J = 12.3, 5.0 Hz, 1 H), 2.39 – 2.33 (m, 1 H), 2.08 – 1.96 (m, 3 H), 1.71 – 1.53 (m, 2 H), 1.30 – 1.17 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.3 (C), 154.0 (C), 136.6 (C), 131.3 (C), 129.0 (2 CH), 128.0 (2 CH), 127.9 (C), 122.5 (CH), 112.8 (C), 112.3 (2 CH), 111.9 (CH), 100.5 (CH), 90.5 (CH), 55.9 (CH3), 52.7 (CH2), 50.8 (CH), 48.3 (CH2), 41.5 (CH), 38.4 (CH2), 36.0 (CH), 31.0 (CH2), 30.1 (CH2), 22.8 (CH2); MS (m/z, relative intensity): 447 (M+, 1), 174 (15), 173 (100), 160 (17), 158 (7), 145 (7), 144 (4), 86 (11), 84 (17). HRMS (EI) m/z: [M]+ Calcd for [C26H29N3O4]+ 447.2158; Found 447.2149.

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For the same reaction in CH2Cl2: To a solution of 4a (33 mg, 0.10 mmol, 1.0 equiv) and 5-methoxytryptamine (24 mg, 0.13 mmol, 1.2 equiv) in CH2Cl2 (1.7 mL) was added NaBH(OAc)3 (47 mg, 0.22 mmol, 2.1 equiv). The resulting solution was stirred at ~30 °C for 6 h until the completion of the reaction, as monitored by TLC. The resulting solution was diluted with EtOAc, washed with saturated aq NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to give the crude residue. The residue was purified by flash column chromatography with 90% EtOAc–hexane to give product 2g (30 mg, 65 % yield). (4aS,7R,8S,8aS)-2-(2-(5-chloro-1H-indol-3-yl)ethyl)-7nitro-8-phenyloctahydroisoquinolin-3(4H)-one (2h): White solids; 43.2 mg (76% yield); m.p. 212–213 °C; [α]D28 18.2 (c 1.5, CHCl3); IR (neat): 3255, 2926, 2857, 1625, 1548, 1500, 1455, 1374, 1100, 891, 799, 758, 701 cm-1; 1H NMR (500 MHz, CDCl3): δ 8.05 (s, 1 H), 7.39 (s, 1 H), 7.29 – 7.19 (m, 4 H), 7.18 – 7.12 (m, 1 H), 6.91 – 6.80 (m, 3 H), 4.61 (td, J = 11.5, 4.0 Hz, 1 H), 3.63 (dt, J = 13.0, 6.5 Hz, 1 H), 3.25 – 3.17 (m, 1 H), 2.95 – 2.86 (m, 1 H), 2.83 – 2.65 (m, 3 H), 2.57 (dd, J = 17.5, 5.0 Hz, 1 H), 2.36 (dd, J = 13.0, 5.0 Hz, 2 H), 2.13 – 1.95 (m, 3 H), 1.70 – 1.58 (m, 1 H), 1.56 – 1.45 (m, 1 H), 1.32 – 1.17 (m, 1 H); 13 C{1H} NMR (125 MHz, CDCl3): δ 168.4 (C), 136.5 (C), 134.5 (C), 129.0 (2 CH), 128.8 (C), 128.0 (2 CH), 125.0 (C), 123.2 (CH), 122.3 (2 CH), 118.5 (CH), 113.2 (C), 112.3 (CH), 90.5 (CH), 52.8 (CH2), 50.8 (CH), 48.6 (CH2), 41.5 (CH), 38.4 (CH2), 36.0 (CH), 31.0 (CH2), 30.1 (CH2), 22.6 (CH2); MS (m/z, relative intensity): 451 (M+, 0.8), 405 (1), 287 (2), 275 (4), 228 (2), 212 (2), 180 (5), 179 (33), 178 (17), 177 (100), 164 (15), 91 (12). HRMS (EI) m/z: [M]+ Calcd for [C25H26ClN3O3]+ 451.1663; Found 451.1633. (4aS,7R,8S,8aS)-2-(2-(5-methyl-1H-indol-3-yl)ethyl)-7nitro-8-phenyloctahydroisoquinolin-3(4H)-one (2i). White solids; 47.6 mg (88% yield); m.p. 241–242 °C; [α]D28 23.4 (c 1.0, CHCl3); IR (neat): 3260, 2922, 1625, 1548, 1498, 1372, 799, 758, 701 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1 H), 7.30 – 7.18 (m, 5 H), 7.02 (d, J = 8.5 Hz, 1 H), 6.88 (d, J = 3.5 Hz, 2 H), 6.82 (s, 1 H), 4.61 (td, J = 11.5, 3.5 Hz, 1 H), 3.61 – 3.51 (m, 1 H), 3.39 – 3.28 (m, 1 H), 2.97 – 2.78 (m, 2 H), 2.77 – 2.67 (m, 2 H), 2.59 (dd, J = 17.5, 5.0 Hz, 1 H), 2.48 – 2.30 (m, 2 H), 2.43 (s, 3 H), 2.12 – 1.93 (m, 3 H), 1.72 – 1.59 (m, 1 H), 1.57 – 1.47 (m, 1 H), 1.29 – 1.15 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.3 (C), 136.5 (C), 134.5 (C), 129.0 (2 CH), 128.3 (C), 128.0 (2 CH), 127.8 (C), 123.6 (2 CH), 121.9 (CH), 118.4 (CH), 112.7 (C), 110.9 (CH), 90.5 (CH), 52.7 (CH2), 50.8 (CH), 48.6 (CH2), 41.4 (CH), 38.4 (CH2), 35.9 (CH), 31.0 (CH2), 30.2 (CH2), 22.7 (CH2), 21.5 (CH3); MS (m/z, relative intensity): 431 (M+, 1), 158 (18), 157 (100), 144 (22), 115 (5), 91 (7). HRMS (EI) m/z: [M]+ Calcd for [C26H29N3O3]+ 431.2209; Found 431.2203. (4aS,7R,8S,8aS)-2-(2-(6-bromo-1H-indol-3-yl)ethyl)-7nitro-8-phenyloctahydroisoquinolin-3(4H)-one (2j). White solids; 54.2 mg (70% yield); m.p. 221–222 °C; [α]D28 20.4 (c 1.0, CHCl3); IR (neat): 3248, 2932, 1625, 1548, 1500, 1452, 1372, 1336, 804, 758, 701, 572 cm-1; 1H NMR (500 MHz, CDCl3): δ 8.04 (s, 1 H), 7.47 (d, J = 1.5 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 7.27 – 7.23 (m, 3 H), 7.14 (dd, J = 8.5, 1.5 Hz, 1 H), 6.92 (d, J = 3.0 Hz, 2 H), 6.84 (d, J = 1.5 Hz, 1 H), 4.64 (td, J = 11.5, 4.0 Hz, 1 H), 3.60 – 3.50 (m, 1 H), 3.38 – 3.28 (m, 1 H), 2.91 – 2.68 (m, 4 H), 2.56 (dd, J = 17.5, 5.0 Hz, 1 H), 2.43 (dd, J = 12.0, 5.0 Hz, 1 H), 2.40 – 2.33 (m, 1 H), 2.08 – 1.95 (m, 3 H),


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1.72 – 1.49 (m, 2 H), 1.30 – 1.17 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.3 (C), 136.9 (C), 136.5 (C), 129.1 (2 CH), 128.1 (2 CH), 126.4 (C), 122.6 (2 CH), 122.3 (CH), 120.0 (CH), 115.6 (C), 114.2 (CH), 113.4 (C), 90.4 (CH), 52.7 (CH2), 50.8 (CH), 48.2 (CH2), 41.7 (CH), 38.4 (CH2), 36.0 (CH), 30.9 (CH2), 30.1 (CH2), 22.7 (CH2); MS (m/z, relative intensity): 497 (M+2, 1), 496 (M+H, 0.4), 495 (M+, 1), 287 (2), 275 (4), 224 (15), 223 (99), 222 (16), 221 (100), 210 (12), 208 (12), 143 (9), 142 (8), 129(14), 128 (6), 115 (12), 91 (16). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for [C25H27BrN3O3]+ 496.1236; Found 496.1233. Ethyl 2-((1S,2S,3S,4R)-3-(4-bromophenyl)-2-formyl-4nitrocyclohexyl)acetate (4k). Pale yellow oil; 69.8 mg (82% yield); 1H NMR (500 MHz, CDCl3): δ 9.33 (d, J = 4.0 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 2 H), 4.65 (td, J = 11.5, 4.0 Hz, 1 H), 4.11 (q, J = 7.0 Hz, 2 H), 3.46 (t, J = 11.5 Hz, 1 H), 2.59 (td, J = 11.5, 4.0 Hz, 1 H), 2.45 – 2.28 (m, 3 H), 2.24 – 2.05 (m, 3 H), 1.50 – 1.40 (m, 1 H), 1.23 (t, J = 7.0 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 200.9 (CH), 171.2 (C), 135.1 (C), 132.3 (2 CH), 129.5 (2 CH), 122.3 (C), 89.6 (CH), 60.7 (CH2), 57.8 (CH), 47.2 (CH), 37.7 (CH2), 33.5 (CH), 30.8 (CH2), 29.1 (CH2), 14.0 (CH3); excat mass (ESI) calculated for C17H20BrNNaO5 (M++Na): 420.0423; found: 420.0421. Chiral HPLC analysis for 4k: Chiralpak IC (elute: 10% EtOAc−hexane), flow rate 1.0 mL/min, detector: 254 nm, t1 = 16.1 min, t2 = 17.5 min, 0.2:99.8 er. (4aS,7R,8S,8aS)-2-(2-(1H-indol-3-yl)ethyl)-8-(4bromophenyl)-7-nitrooctahydroisoquinolin-3(4H)-one (2k). White solids; 40.6 mg (81% yield); m.p. 228–229 °C; [α]D28 – 47.9 (c 1.1, CHCl3); IR (neat): 3266, 2927, 2858, 1627, 1549, 1495, 1452, 1372, 1341, 1289, 1218, 1073, 1008, 814, 752 cm-1; 1 H NMR (500 MHz, CDCl3): δ 8.29 (s, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.38 – 7.29 (m, 3 H), 7.20 (dd, J = 8.0, 7.5 Hz, 1 H), 7.07 (dd, J = 7.5, 7.5 Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 6.67 (d, J = 8.5 Hz, 2 H), 4.49 (td, J = 11.5, 4.0 Hz, 1 H), 3.70 – 3.62 (m, 1 H), 3.31 – 3.23 (m, 1 H), 3.00 – 2.92 (m, 1 H), 2.89 – 2.81 (m, 1 H), 2.63 (t, J = 11.5 Hz, 2 H), 2.55 (dd, J = 17.5, 5.0 Hz, 1 H), 2.35 – 2.27 (m, 2 H), 2.03 (dd, J = 17.5, 12.0 Hz, 1 H), 1.99 – 1.88 (m, 2 H), 1.63 – 1.51 (m, 1 H), 1.44 – 1.33 (m, 1 H), 1.20 – 1.08 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.2 (C), 136.2 (C), 135.5 (C), 132.1 (2 CH), 127.5 (C), 122.0 (2 CH), 121.83 (C), 121.80 (2 CH), 119.2 (CH), 118.7 (CH), 113.0 (C), 111.3 (CH), 90.1 (CH), 52.6 (CH2), 50.1 (CH), 48.6 (CH2), 41.2 (CH), 38.3 (CH2), 35.8 (CH), 30.8 (CH2), 29.9 (CH2), 22.8 (CH2); MS (m/z, relative intensity): 497 (M++2, 0.1), 495 (M+, 0.1), 451 (0.1), 449 (0.1), 294 (0.2), 292 (0.2), 144 (15), 143 (100), 130 (17), 115 (5), 77 (2). HRMS (ESI-TOF) m/z: [M]+ Calcd for [C25H26BrN3O3]+ 495.1158; Found 495.1152. General procedure for the one-pot preparation of (4aS,7R,8S,8aS)-2-(2-(1H-indol-3-yl)ethyl)-7-nitro-8phenyloctahydroisoquinolin-3(4H)-one (2a). To a solution of nitroalkene 5 (36 mg, 0.192 mmol, 1.0 equiv) and cinnamaldehyde (33 mg, 0.25 mmol, 1.3 equiv) in CH2Cl2 (0.5 mL) was added a solution of catalyst I (14 mg, 0.04 mmol, 0.2 equiv), DABCO (4 mg, 0.043 mmol, 0.2 equiv) in CH2Cl2 (0.5 mL). The resulting solution was stirred at ~30 °C for 36-48 h until the completion of the reaction, as monitored by TLC. To this recation mixture was sequentially added tryptamine (44 mg, 0.275 mmol, 1.4 equiv) in CH2Cl2 (1.6 mL) and NaBH(OAc)3 (86 mg, 0.406 mmol, 2.1 equiv). The resulting solution was stirred at ~30 °C for 6 h until the completion of the reaction, as monitored

by TLC. The resulting solution was diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to give the crude residue. The residue was purified by flash column chromatography with 90% EtOAc–hexane (Rf = 0.36 in 90% EtOAc–hexane) to give product 2a (60 mg, 75% yield). General Procedure for the Synthesis of (3R,4S,4aS,13bS,14aS)-3-Nitro-4-phenyl1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]-isoquinoline (1a). To a solution of 2a (28 mg, 0.067 mmol, 1.0 equiv) in toluene (1 mL) was added POCl3 (0.15 mL, 1.61 mmol, 24 equiv), and the solution was heated to reflux for 3 h, until the completion of the reaction, as monitored by TLC. The solution was concentrated in vacuo to give a residue. To the residue was added MeOH (1.2 mL), followed by the addition of NaBH4 (20 mg, 0.53 mmol, 7.8 equiv). The reaction mixture was stirred at room temperature for 1 h, followed by the addition of water to quench the reaction. The mixture was extracted with EtOAc, and the organic solution was washed with brine, dried over MgSO4 and concentrated in vacuo to give crude residue. The crude product was purified by flash column chromatography with 30% EtOAc-hexane (Rf = 0.25 for 1a in 30% EtOAc-hexane) to afford product 1a (20 mg, 74% yield) as a white solid. Selected data for 1a: white solids, m.p. 198–199 °C; [α]D28 –53.7 (c 3.25, CHCl3); IR (neat): 3412, 3029, 2916, 1547, 1450, 1374, 1212, 749, 700, 673 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.72 (s, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 7.35 – 7.22 (m, 4 H), 7.21 – 7.12 (brs, 2 H), 7.12 (dd, J = 7.5, 7.5 Hz, 1 H), 7.06 (dd, J = 7.5, 7.5 Hz, 1 H), 4.74 (ddd, J = 11.5, 11.5, 4.0 Hz, 1 H), 3.29 (d, J = 11.5 Hz, 1 H), 2.94 (t, J = 11.5 Hz, 1 H), 2.91 – 2.80 (m, 2 H), 2.66 – 2.58 (m, 1 H), 2.55 – 2.46 (m, 2 H), 2.45 – 2.38 (m, 1 H), 2.18 – 1.93 (m, 4 H), 1.87 – 1.77 (m, 1 H), 1.58 – 1.48 (m, 1 H), 1.47 – 1.34 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3): δ 137.6 (C), 136.0 (C), 134.2 (C), 128.9 (CH), 127.8 (2 CH), 127.4 (C), 121.5 (CH), 119.5 (2 CH), 118.2 (2 CH), 110.7 (CH), 108.3 (C), 91.4 (CH), 59.6 (CH), 58.8 (CH2), 52.9 (CH2), 51.0 (CH), 44.4 (CH), 40.6 (CH), 36.3 (CH2), 31.6 (CH2), 30.4 (CH2), 21.6 (CH2); MS (m/z, relative intensity): 402 (M++1, 23), 401 (M+, 100), 400 (M+-1, 81), 355 (23), 353 (27), 221 (33), 169 (56), 156 (37), 144 (37), 143 (36), 129 (30), 117 (41), 115 (31), 91 (38). HRMS (EI) m/z: [M]+ Calcd for [C25H27N3O2]+ 401.2103; Found 401.2082. Chiral HPLC analysis for 1a: Chiralpak IA (elute: 25% i-PrOH−hexane), flow rate 1.0 mL/min, detector: 217 nm, t1 = 9.9 min, t2 = 18.9 min, 0.04:99.96 er. N,N-dimethyl-4-((3R,4S,4aS,13bS,14aS)-3-nitro1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinolin-4yl)aniline (1b). Pale yellow solid; 31.6 mg (82% yield); m.p. 266–267 °C; [α]D28 –39.8 (c 0.45, CHCl3); IR (neat): 2925, 2855, 1725, 1615, 1548, 1524, 1455, 1372, 1222, 1040, 946, 816, 753 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.74 (s, 1 H), 7.42 (d, J = 7.5 Hz, 1 H), 7.28 (d, J = 7.5 Hz, 1 H), 7.12 (dd, J = 7.5, 7.5 Hz, 1 H), 7.06 (dd, J = 7.5, 7.5 Hz, 1 H), 7.04 – 6.91 (brs, 2 H), 6.64 (d, J = 7.0 Hz, 2 H), 4.67 (td, J = 11.5, 4.0 Hz, 1 H), 3.28 (d, J = 11.5 Hz, 1 H), 2.91 (s, 6 H), 2.90 – 2.79 (m, 3 H), 2.67– 2.55 (m, 2 H), 2.54 – 2.45 (m, 1 H), 2.42 – 2.34 (m, 1 H), 2.17 – 1.90 (m, 4 H), 1.84 – 1.70 (m, 2 H), 1.56 – 1.31 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3): δ 149.9 (C), 136.0 (C), 134.3 (C), 127.4 (C), 124.9 (C), 121.4 (CH), 119.5 (2 CH), 118.2 (2 CH), 112.8 (2 CH), 110.7 (CH), 108.3 (C), 91.9 (CH),



59.6 (CH), 58.9 (CH2), 52.9 (CH2), 50.2 (CH), 44.5 (CH), 40.7 (CH), 40.5 (2 CH3), 36.4 (CH2), 31.6 (CH2), 30.5 (CH2), 21.6 (CH2); MS (m/z, relative intensity): 445 (M++1, 14), 444 (M+, 48), 443 (35), 414 (15), 398 (19), 368 (13), 160 (15), 134 (27), 97 (33), 83 (45), 69 (67), 57 (85), 55 (90), 43 (100). HRMS (EI) m/z: [M]+ Calcd for [C27H32N4O2]+ 444.2525; Found 444.2509. Chiral HPLC analysis for 1b: Chiralpak IC (elute: 20% EtOAc−hexane), flow rate 1.0 mL/min, detector: 275 nm, t1 = 7.4 min, t2 = 8.5 min, 0.36:99.64 er. (3R,4S,4aS,13bS,14aS)-4-(naphthalen-2-yl)-3-nitro1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1c). Pale yellow solid; 18.5 mg (64% yield); m.p. 233–234 °C; [α]D28 –123.3 (c 0.52, CHCl3); IR (neat): 3579, 3167, 3052, 2933, 2826, 1545, 1452, 1372, 1211, 1102, 813, 739 cm-1; 1H NMR (500 MHz, CDCl3, 50 °C): δ 7.84 – 7.75 (m, 3 H), 7.62 (brs, 2 H), 7.49 – 7.42 (m, 2 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.11 (dd, J = 8.0, 7.0 Hz, 1 H), 7.05 (dd, J = 8.0, 7.0 Hz, 1 H), 4.87 (td, J = 11.5, 4.0 Hz, 1 H), 3.32 (d, J = 11.5 Hz, 1 H), 3.15 (t, J = 11.5 Hz, 1 H), 2.89 – 2.79 (m, 1 H), 2.78 – 2.72 (m, 1 H), 2.63 – 2.55 (m, 1 H), 2.53 – 2.43 (m, 3 H), 2.24 – 1.90 (m, 5 H), 1.65 – 1.56 (m, 1 H), 1.53 – 1.40 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3, 50 °C): 136.3 (C), 134.3 (C), 133.6 (C), 133.2 (C), 128.9 (CH), 127.9 (2CH), 127.7 (2CH), 127.6 (C), 126.3 (CH), 126.1 (CH), 121.6 (CH), 119.6 (CH), 118.2 (CH), 110.8 (CH), 110.1 (C), 108.6 (C), 91.5 (CH), 59.7 (CH), 59.1 (CH2), 52.9 (CH2), 51.3 (CH), 44.7 (CH), 40.9 (CH), 36.6 (CH2), 31.8 (CH2), 30.7 (CH2), 21.7 (CH2); MS (m/z, relative intensity): 452 (M++1, 29), 451 (M+, 100), 450 (68), 405 (34), 403 (31), 221 (48), 202 (23), 184 (29), 170 (32), 169 (85), 167 (67), 156 (63), 144 (58), 143 (48), 141 (80), 128 (32), 115 (24). HRMS (EI) m/z: [M]+ Calcd for [C29H29N3O2]+ 451.2260; Found 451.2241. Chiral HPLC analysis for 1c: Chiralpak IC (elute: 15% EtOAc−hexane), flow rate 1.0 mL/min, detector: 275 nm, t1 = 8.6 min, t2 = 9.6 min, ~0:>100 er. (3R,4S,4aS,13bS,14aS)-4-(4-methoxyphenyl)-3-nitro1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1d). Pale yellow solid; 33.2 mg (86% yield); m.p. 213–214 °C; [α]D28 –109.6 (c 1.0, CHCl3); IR (neat): 3379, 2925, 2852, 1548, 1515, 1449, 1375, 1261, 1144, 1025, 804, 746, 670 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.72 (s, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.15 – 7.03 (m, 4 H), 6.83 (d, J = 7.5 Hz, 2 H), 4.68 (td, J = 11.5, 4.0 Hz, 1 H), 3.77 (s, 3 H), 3.28 (d, J = 11.0 Hz, 1 H), 2.93 – 2.81 (m, 3 H), 2.67 – 2.59 (m, 1 H), 2.55 – 2.47 (m, 2 H), 2.43 – 2.36 (m, 1 H), 2.16 – 1.91 (m, 4 H), 1.83 – 1.71 (m, 1 H), 1.56 – 1.32 (m, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 159.0 (C), 136.0 (C), 134.2 (C), 129.5 (C), 127.4 (C), 121.5 (2 CH), 119.5 (2 CH), 118.2 (CH), 114.3 (2 CH), 110.7 (CH), 108.3 (C), 91.7 (CH), 59.6 (CH), 58.8 (CH2), 55.2 (CH3), 52.9 (CH2), 50.3 (CH), 44.5 (CH), 40.6 (CH), 36.3 (CH2), 31.5 (CH2), 30.4 (CH2), 21.6 (CH2); MS (m/z, relative intensity): 432 (M++1, 30), 431 (M+, 100), 430 (79), 429 (13), 385 (32), 383 (30), 234 (11), 221 (14), 169 (14), 147(14), 143 (16). HRMS (EI) m/z: [M]+ Calcd for [C26H29N3O3]+ 431.2209; Found 431.2192. Chiral HPLC analysis for 1d: Chiralpak IC (elute: 25% i-PrOH−hexane), flow rate 1.0 mL/min, detector: 275 nm, t1 = 7.98 min, t2 = 8.85 min, 0.07:99.93 er.

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(3R,4S,4aS,13bS,14aS)-4-(3,4-dimethoxyphenyl)-3-nitro1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1e). Pale yellow solid; 22.3 mg (77% yield); m.p. 188–189 °C; [α]D28 –53.0 (c 1.0, CHCl3); IR (neat): 3379, 2925, 2852, 1548, 1515, 1449, 1375, 1261, 1144, 1025, 804, 746, 670 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.72 (s, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.15 – 7.09 (m, 1 H), 7.09 – 7.04 (m, 1 H), 6.85 – 6.55 (brm, 3 H), 4.71 (td, J = 11.5, 4.0 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.29 (d, J = 10.0 Hz, 1 H), 2.94 – 2.83 (m, 3 H), 2.69 – 2.61 (m, 1 H), 2.58 – 2.49 (m, 2 H), 2.45 – 2.37 (m, 1 H), 2.18 – 2.07 (m, 2 H), 2.03 (t, J = 11.0 Hz, 1 H), 2.00 – 1.93 (m, 1 H), 1.85 – 1.74 (m, 1 H), 1.57 – 1.47 (m, 1 H), 1.46 – 1.33 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3): δ 148.5 (2 C), 136.0 (C), 134.2 (C), 129.9 (C), 127.4 (C), 121.5 (CH), 119.5 (2 CH), 118.2 (2 CH), 110.7 (2 CH), 108.3 (C), 91.6 (CH), 59.6 (CH), 58.8 (CH2), 55.9 (CH3), 55.8 (CH3), 52.9 (CH2), 50.8 (CH), 44.5 (CH), 40.6 (CH), 36.3 (CH2), 31.5 (CH2), 30.4 (CH2), 21.6 (CH2); MS (m/z, relative intensity): 462 (M++1, 28), 461 (M+, 100), 460 (M+-1, 73), 415 (33), 413 (26), 221 (34), 169 (49), 156 (38), 144 (44). HRMS (EI) m/z: [M]+ Calcd for [C27H31N3O4]+ 461.2315; Found 461.2293. Chiral HPLC analysis for 1e: Chiralpak IC (elute: 50% EtOAc−hexane), flow rate 1.0 mL/min, detector: 254 nm, t1 = 4.6 min, t2 = 5.6 min, 0.4:99.6 er. (3R,4S,4aS,13bS,14aS)-3-nitro-4-(3,4,5trimethoxyphenyl)-1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1f). Pale yellow solid; 17.4 mg (72% yield); m.p. 195–196 °C; [α]D28 –59.4 (c 0.8, CHCl3); IR (neat): 3579, 3167, 3054, 2937, 2826, 1544, 1450, 1372, 1210, 1102, 812, 741 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.70 (s, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.12 (dd, J = 7.5, 7.5 Hz, 1 H), 7.06 (dd, J = 7.5, 7.5 Hz, 1 H), 6.35 (brs, 2 H), 4.74 (td, J = 11.6, 4.0 Hz, 1 H), 3.83 (s, 6 H), 3.81 (s, 3 H), 3.31 (d, J = 11.0 Hz, 1 H), 2.95 – 2.83 (m, 3 H), 2.70 – 2.62 (m, 1 H), 2.60 – 2.49 (m, 2 H), 2.47 – 2.39 (m, 1 H), 2.20 – 1.94 (m, 4 H), 1.86 – 1.75 (m, 1 H), 1.66 – 1.48 (m, 2 H), 1.47 – 1.35 (m, 1 H); 13C{1H} NMR (125 MHz, CDCl3): δ 137.4 (C), 136.1 (2 C), 134.1 (C), 133.2 (2 C), 127.3 (C), 121.5 (CH), 119.5 (2 CH), 118.2 (2 CH), 110.7 (CH), 108.3 (C), 91.3 (CH), 60.8 (CH3), 59.6 (CH), 58.8 (CH2), 56.1 (2 CH3), 53.0 (CH2), 51.4 (CH), 44.5 (CH), 40.6 (CH), 36.3 (CH2), 31.7 (CH2), 30.4 (CH2), 21.6 (CH2); MS (m/z, relative intensity): 492 (M++1, 28), 491 (M+, 100), 490 (68), 445 (37), 443 (25), 222 (27), 221 (45), 184 (37), 181 (38), 169 (61), 156 (58), 144 (73), 143 (52), 98 (56), 80 (63), 60 (65). HRMS (EI) m/z: [M]+ Calcd for [C28H33N3O5]+ 491.2420; Found 491.2415. Chiral HPLC analysis for 1f: Chiralpak IC (elute: 13% iPrOH−hexane), flow rate 1.0 mL/min, detector: 260 nm, t1 = 40.5 min, t2 = 47.6 min, ~100:~0 er. (3R,4S,4aS,13bS,14aS)-10-methoxy-3-nitro-4-phenyl1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1g). White solids; 19 mg (79% yield); m.p. 218–219 °C; [α]D28 –82.1 (c 1.2, CHCl3); IR (neat): 3416, 2912, 1548, 1483, 1455, 1372, 1297, 1212, 1149, 787, 756, 701 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.56 (s, 1 H), 7.30 (dd, J = 7.5, 7.5 Hz, 2 H), 7.27 – 7.22 (m, 1 H), 7.20 – 7.12 (m, 1 H), 7.16 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 2.3 Hz, 1 H), 6.77 (dd, J = 8.5, 2.3 Hz, 1 H), 4.74 (td, J = 11.5, 3.7 Hz, 1 H), 3.81 (s, 3 H), 3.28 (d, J = 11.5 Hz, 1 H), 2.95 (t, J = 11.5 Hz, 1 H), 2.89 – 2.78 (m, 2 H), 2.66 – 2.38


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(m, 4 H), 2.18 – 1.93 (m, 4 H), 1.88 – 1.77 (m, 1 H), 1.58 – 1.48 (m, 1 H), 1.47 – 1.35 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3): δ 154.1 (C), 137.6 (C), 135.2 (C), 131.1 (C), 128.9 (C and CH), 127.83 (2 CH), 127.80 (2 CH), 111.4 (CH), 111.2 (CH), 108.2 (C), 100.5 (CH), 91.4 (CH), 59.7 (CH), 58.9 (CH2), 55.9 (CH3), 52.9 (CH2), 51.0 (CH), 44.4 (CH), 40.6 (CH), 36.3 (CH2), 31.6 (CH2), 30.4 (CH2), 21.7 (CH2); MS (m/z, relative intensity): 432 (M++1, 18), 431 (M+, 75), 430 (56), 385 (16), 383 (21), 251 (18), 199 (26), 186 (18), 174 (22), 143 (100), 117 (30), 115 (22), 91 (33). HRMS (EI) m/z: [M]+ Calcd for [C26H29N3O3]+ 431.2209; Found 431.2203. Chiral HPLC analysis for 1g: Chiralpak IC (elute: 25% i-PrOH−hexane), flow rate 1.0 mL/min, detector: 275 nm, t1 = 13.2 min, t2 = 16.2 min, ~0:~100 er. (3R,4S,4aS,13bS,14aS)-10-chloro-3-nitro-4-phenyl1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1h). White solids; 24.6 mg (64% yield); m.p. 221–222 °C; [α]D28 – 95.8 (c 0.5, CHCl3); IR (neat): 3410, 2925, 1548, 1446, 1374, 1303, 1212, 1110, 802, 756, 701, 591 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.72 (s, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 7.30 (dd, J = 7.5, 7.5 Hz, 2 H), 7.28 – 7.22 (m, 1 H), 7.17 (d, J = 7.5 Hz, 2 H), 7.21 – 7.10 (m, 1 H), 7.06 (dd, J = 8.5, 2.0 Hz, 1 H), 4.74 (td, J = 11.5, 4.0 Hz, 1 H), 3.28 (d, J = 11.5 Hz, 1 H), 2.95 (t, J = 11.5 Hz, 1 H), 2.87 – 2.77 (m, 2 H), 2.60 – 2.39 (m, 4 H), 2.18 – 1.95 (m, 4 H), 1.87 – 1.77 (m, 1 H), 1.55 – 1.49 (m, 1 H), 1.48 – 1.36 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3): δ 137.5 (C), 135.8 (C), 134.4 (C), 128.9 (2 CH), 128.5 (C), 127.9 (2 CH), 125.2 (C), 121.7 (2 CH), 117.8 (CH), 111.7 (CH), 108.3 (C), 91.4 (CH), 59.5 (CH), 58.8 (CH2), 52.7 (CH2), 51.0 (CH), 44.5 (CH), 40.5 (CH), 36.3 (CH2), 31.6 (CH2), 30.5 (CH2), 21.5 (CH2); MS (m/z, relative intensity): 437 (M++2, 35), 436 (M++1, 53), 435 (M+, 100), 434 (86), 405 (23), 404 (24), 389 (47), 387 (26), 203 (30), 190 (22), 117 (26), 115 (22), 91 (41). HRMS (EI) m/z: [M]+ Calcd for [C25H26N3O2Cl]+ 435.1714; Found 435.1689. Chiral HPLC analysis for 1h: Chiralpak IC (elute: 25% i-PrOH−hexane), flow rate 1.0 mL/min, detector: 275 nm, t1 = 6.0 min, t2 = 6.7 min, ~0:~100 er. (3R,4S,4aS,13bS,14aS)-10-methyl-3-nitro-4-phenyl1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1i). white solids; 30.8 mg (80% yield); m.p. 228–229 °C; [α]D28 – 58.6 (c 0.5, CHCl3); IR (neat): 3410, 2916, 1547, 1450, 1372, 1303, 1106, 797, 758, 700, 668 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.57 (s, 1 H), 7.34 – 7.21 (m, 3 H), 7.21 – 7.12 (m, 4 H), 6.94 (d, J = 8.0 Hz, 1 H), 4.74 (td, J = 11.0, 4.0 Hz, 1 H), 3.28 (d, J = 11.0 Hz, 1 H), 2.95 (t, J = 11.0 Hz, 1 H), 2.88 – 2.77 (m, 2 H), 2.62 – 2.54 (m, 1 H), 2.53 – 2.38 (m, 3 H), 2.40 (s, 3 H), 2.18 – 1.96 (m, 4 H), 1.89 – 1.78 (m, 1 H), 1.54 – 1.36 (m, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 137.6 (C), 134.4 (2 C), 128.9 (C), 128.7 (2 CH), 127.8 (2 CH), 127.62 (C), 123.0 (2 CH), 118.0 (CH), 110.3 (CH), 107.9 (C), 91.5 (CH), 59.7 (CH), 58.9 (CH2), 53.0 (CH2), 51.1 (CH), 44.5 (CH), 40.6 (CH), 36.4 (CH2), 31.6 (CH2), 30.5 (CH2), 21.6 (CH2), 21.5 (CH3); MS (m/z, relative intensity): 415 (M+, 98), 414 (82), 369 (38), 367 (31), 355 (30), 295 (51), 281 (38), 221 (100), 183 (35), 147 (50), 91 (43), 73 (55), 57 (55), 55 (53), 43 (58), 41 (50). HRMS (EI) m/z: [M]+ Calcd for [C26H29N3O2]+ 415.2260; Found 415.2254. Chiral HPLC analysis for 1i: Chiralpak IA (elute: 30% i-PrOH−hexane), flow rate 1.0 mL/min, detector: 275 nm, t1 = 7.5 min, t2 = 13.0 min, 0.6:99.4 er.

(3R,4S,4aS,13bS,14aS)-11-bromo-3-nitro-4-phenyl1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1j). Pale yellow solids; 29.2 mg (75% yield); m.p. 212–213 °C; [α]D28 –42.7 (c 1.0, CHCl3); IR (neat): 3408, 3198, 2916, 1547, 1463, 1374, 1297, 1253, 1212, 1156, 1109, 1051, 803, 756, 701 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.70 (s, 1 H), 7.41 (d, J = 1.0 Hz, 1 H), 7.35 – 7.22 (m, 4 H), 7.20 – 7.11 (m, 3 H), 4.74 (td, J = 11.5, 4.0 Hz, 1 H), 3.26 (d, J = 11.0 Hz, 1 H), 2.94 (t, J = 11.5 Hz, 1 H), 2.88 – 2.77 (m, 2 H), 2.63 – 2.54 (m, 1 H), 2.53 – 2.38 (m, 3 H), 2.19 – 1.94 (m, 4 H), 1.87 – 1.77 (m, 1 H), 1.60 – 1.48 (m, 1 H), 1.47 – 1.34 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3) δ 137.5 (C), 136.8 (C), 134.9 (C), 128.9 (CH), 127.9 (2 CH), 126.3 (C), 122.8 (2 CH), 119.4 (2 CH), 114.8 (C), 113.7 (CH), 108.6 (C), 91.4 (CH), 59.4 (CH), 58.8 (CH2), 52.7 (CH2), 51.0 (CH), 44.5 (CH), 40.5 (CH), 36.2 (CH2), 31.5 (CH2), 30.4 (CH2), 21.5 (CH2); MS (m/z, relative intensity): 481 (M++2, 99), 480 (M++1, 94), 479 (M+, 100), 478 (70), 449 (33), 433 (54), 301 (22), 249 (28), 154 (28), 117 (32), 91 (50). HRMS (EI) m/z: [M]+ Calcd for [C25H26BrN3O2]+ 479.1208; Found 479.1190. Chiral HPLC analysis for 1j: Chiralpak IA (elute: 25% i-PrOH−hexane), flow rate 1.0 mL/min, detector: 275 nm, t1 = 7.88 min, t2 = 16.34 min, 0.03:99.97 er. (3R,4S,4aS,13bS,14aS)-4-(4-bromophenyl)-3-nitro1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1k). White solids; 17.4 mg (72% yield); m.p. 233–234 °C; [α]D28 – 74.1 (c 0.6, CHCl3); IR (neat): 3415, 2930, 2895, 2803, 1541, 1490, 1372, 1296, 1013, 814, 746, 506 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.69 (s, 1 H), 7.46 – 7.40 (m, 3 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.16 –7.07 (m, 1 H), 7.09 – 7.03 (m, 3 H), 4.68 (td, J = 11.5, 4.0 Hz, 1 H), 3.30 (d, J = 9.5 Hz, 1 H), 2.93 (t, J = 11.5 Hz, 1 H), 2.89 – 2.82 (m, 2 H), 2.68 – 2.60 (m, 1 H), 2.56 – 2.39 (m, 3 H), 2.17 – 1.96 (m, 4 H), 1.84 – 1.75 (m, 1 H), 1.55 – 1.49 (m, 1 H), 1.47 – 1.36 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3): δ 136.7 (C), 136.0 (C), 134.0 (C), 132.1 (CH), 127.3 (C), 121.8 (C), 121.6 (2 CH), 119.6 (2 CH), 118.2 (2 CH), 110.7 (CH), 108.4 (C), 91.2 (CH), 59.6 (CH), 58.7 (CH2), 52.9 (CH2), 50.5 (CH), 44.4 (CH), 40.5 (CH), 36.3 (CH2), 31.5 (CH2), 30.4 (CH2), 21.6 (CH2); MS (m/z, relative intensity): 481 (M++2, 53), 480 (M++1, 55), 479 (M+, 54), 478 (44), 433 (32), 221 (46), 169 (100), 156 (57), 144 (54), 116 (61), 115 (43). HRMS (EI) m/z: [M]+ Calcd for [C25H26N3O2Br]+ 479.1208; Found 479.1203. Chiral HPLC analysis for 1k: Chiralpak IC (elute: 30% iPrOH−hexane), flow rate 1.0 mL/min, detector: 275 nm, t1 = 5.6 min, t2 = 5.9 min, 0.4:99.6 er. General Procedure for the One-pot Synthesis of 1a. To a solution of nitroalkene 5 (36 mg, 0.2 mmol, 1.0 equiv) and cinnamaldehyde (34 mg, 0.26 mmol, 1.3 equiv) in CH2Cl2 (0.5 mL) was added a solution of catalyst I (13.0 mg, 0.04 mmol, 0.2 equiv), DABCO (4.5 mg, 0.04 mmol, 0.2 equiv) in CH2Cl2 (1.0 mL). The resulting solution was stirred at ~30 °C for 36-96 until the completion of the reaction, as monitored by TLC. To the reaction mixture was sequentially added CH2Cl2 (1.6 mL), tryptamine (43 mg, 0.27 mmol, 1.4 equiv) and NaBH(OAc)3 (90 mg, 0.42 mmol, 2.2 equiv). The resulting solution was stirred at ~30 °C for 6 h until the completion of the reaction, as monitored by TLC. The resulting solution was concentrated in vacuo to give a residue. To this crude product was added toluene (2.5 mL) and purified POCl3 (0.23 mL, 2.5 mmol, 13 equiv). The solution was heated to reflux for 3 h, until the completion of the



reaction, as monitored by TLC. The solution was concentrated in vacuo to give a residue. To the residue was added MeOH (2.7 mL), followed by the addition of NaBH4 (111 mg, 2.9 mmol, 15 equiv) in three portions within 15 minutes. The reaction mixture was stirred at room temperature for 1 h, followed by addition of an aqueous NaHCO3 solution to quench the reaction. The reaction mixture was extracted with EtOAc three times, and the combined organic solution was washed with brine, dried over MgSO4 and concentrated in vacuo to give crude residue. The crude product was purified by flash column chromatography with 30% EtOAc-hexane (Rf = 0.25 for 1a in 30% EtOAchexane) to afford product 1a (42 mg, 54% yield) as white solids. (3R,4S,4aS,13bS,14aS)-4-(4-fluorophenyl)-3-nitro1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1l). White solids; 34.4 mg (prepared from 5 and 6l with one-pot operation, 41% yield); m.p. 271–272 °C; [α]D28 –84.0 (c 0.5, CHCl3); IR (neat): 3398, 2896, 1541, 1508, 1453, 1371, 1221, 836, 744 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.70 (s, 1 H), 7.42 (d, J = 7.7 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.7.20 – 7.10 (m, 3 H), 7.08 – 7.04 (m, 1 H), 7.02 – 6.95 (m, 2 H), 4.68 (td, J = 11.5, 4.1 Hz, 1 H), 3.31 (d, J = 10.8 Hz, 1 H), 2.95 (t, J = 11.5 Hz, 1 H), 2.93 – 2.81 (m, 2 H), 2.68 – 2.59 (m, 1 H), 2.57 – 2.38 (m, 3 H), 2.17 – 2.09 (m, 2 H), 2.08 – 1.96 (m, 2 H), 1.85 – 1.75 (m, 1 H), 1.58 – 1.49 (m, 1 H), 1.48 – 1.36 (m, 2 H); 13 C{1H} NMR (125 MHz, CDCl3): δ 162.2 (d, J = 246.6 Hz, C), 136.1 (C), 134.0 (C), 133.3 (d, J = 3.0 Hz, C), 127.3 (C), 121.6 (2 CH), 119.6 (2 CH), 118.2 (CH), 115.9 (d, J = 19.6 Hz, 2 CH), 110.7 (CH), 108.4 (C), 91.5 (CH), 59.6 (CH), 58.8 (CH2), 52.9 (CH2), 50.3 (CH), 44.5 (CH), 40.6 (CH), 36.3 (CH2), 31.5 (CH2), 30.4 (CH2), 21.6 (CH2). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for [C25H27FN3O2]+ 420.2087; Found 420.2087. Chiral HPLC analysis for 1l: Chiralpak IC (elute: 10% iPrOH−hexane), flow rate 1.0 mL/min, detector: 280 nm, t1 = 14.9 min, t2 = 16.7 min, ~0:~100 er. (3R,4S,4aS,13bS,14aS)-3-nitro-4-(4-nitrophenyl)1,2,3,4,4a,5,7,8,13,13b,14,14adodecahydroindolo[2',3':3,4]pyrido[1,2-b]isoquinoline (1m). White solids; 34.3 mg (prepared from 5 and 6m with one-pot operation, 38% yield); m.p. 204–205 °C; [α]D28 –58.8 (c 0.5, CHCl3); IR (neat): 2925, 2854, 1549, 1520, 1457, 1375, 1347, 923, 904, 758, 735 cm-1; 1H NMR (500 MHz, CDCl3): δ 8.18 (d, J = 8.8 Hz, 2 H), 7.66 (s, 1 H), 7.42 (d, J = 7.7 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.12 (dd, J = 7.5, 7.5 Hz, 1 H), 7.06 (dd, J = 7.5, 7.5 Hz, 1 H), 4.74 (td, J = 11.5, 4.2 Hz, 1 H), 3.32 (d, J = 11.5 Hz, 1 H), 3.11 (t, J = 11.5 Hz, 1 H), 2.94 – 2.75 (m, 2 H), 2.63 (dd, J = 15.0, 5.0 Hz, 1 H), 2.57 – 2.44 (m, 2 H), 2.40 (dd, J = 11.3, 3.6 Hz, 1 H), 2.19 – 1.97 (m, 4 H), 1.90 – 1.80 (m, 1 H), 1.62 – 1.51 (m, 1 H), 1.49 – 1.39 (m, 2 H); 13C{1H} NMR (125 MHz, CDCl3): δ 147.9 (C), 145.4 (C), 136.3 (C), 134.0 (C), 127.5 (C), 124.2 (2 CH), 121.7 (CH), 119.7 (2 CH), 118.3 (2 CH), 110.8 (CH), 108.6 (C), 90.9 (CH), 59.6 (CH), 58.9 (CH2), 53.0 (CH2), 51.0 (CH), 44.6 (CH), 40.7 (CH), 36.5 (CH2), 31.5 (CH2), 30.5 (CH2), 21.7 (CH2). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for [C25H27N4O4]+ 447.2032; Found 447.2031. Chiral HPLC analysis for 1n: Chiralpak IC (elute: 20% i-PrOH−hexane), flow rate 1.0 mL/min, detector: 280 nm, t1 = 19 min, t2 = 25 min, ~100:~0 er. █ ASSOCIATED CONTENT

Page 10 of 12

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxx. ORTEP drawings, crystal parameters, NMR spectra, HPLC analysis data (PDF) X-ray crystallographic data of compound (–)-1d (CCDC 1906773), (–)-1j (CCDC 1918295) (CIF)

■ AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] ORCID Bor-Cherng Hong: 0000-0002-4623-3366 Notes The authors declare no competing financial interest.

■ ACKNOWLEDGMENT We acknowledge the financial support for this study from the Ministry of Science and Technology (MOST, Taiwan) and thank the instrument center of MOST for analyses of compounds.

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