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Article

Diastereodivergent Construction of Octahydrophenanthridinone and Octahydrophenanthridine Cores

by
Chunzhao Sun
1,
Hiromichi Nishikawa
1,
Tsubasa Inokuma
1,2,3 and
Ken-ichi Yamada
1,2,*
1
Graduate School of Pharmaceutical Sciences, Tokushima University, Shomachi 770-8505, Tokushima, Japan
2
Research Cluster on “Key Material Development”, Tokushima University, Shomachi 770-8505, Tokushima, Japan
3
Research Cluster on “Hybrid Modality Exploration”, Tokushima University, Shomachi 770-8505, Tokushima, Japan
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(2), 371; https://doi.org/10.3390/molecules30020371
Submission received: 27 December 2024 / Revised: 10 January 2025 / Accepted: 14 January 2025 / Published: 17 January 2025
(This article belongs to the Special Issue Synthesis of Bioactive Compounds: Volume II)
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Abstract

:
Diastereodivergent synthesis of octahydrophenanthridinone and octahydrophenanthridine skeletons, structural motifs often found in biologically active natural products, is described. We previously reported a total synthesis of a pancratistatin analog using novel octahydrophenanthridinone construction. In this study, we examined the generality of our method and its extension to octahydrophenanthridine formation. Conjugate addition of diarylcuprates to nitrosocyclohexenes, which were generated in situ from 2-chlorocyclohexanone oximes, provided 2-arylcyclohexanone oximes. Subsequent reduction of the oxime moiety gave cis- and trans-configured amines. Both amines were separately converted into the corresponding octahydrophenanthridinones and octahydrophenanthridines via hexahydrophenanthridine intermediates.

Graphical Abstract

1. Introduction

Octahydrophenanthridine and octahydrophenanthridinone are structural motifs often found in natural products such as pancratistatin, dihydronarciclasine, lycorine, and chelidonine (Figure 1) [1,2,3]. These natural products possess interesting biological activities such as antitumor activities [4,5] and antiviral activities [6,7]. Recently, derivatives of these natural products also possess potential activities as well as the parent natural products [8,9]. Therefore, the development of the methodologies for constructing these structures contributes not only to natural product synthesis but also to developing novel drug candidates derived from these natural products [10].
The representative strategy for octahydrophenanthridinone synthesis is initiated by amide formation of benzoic acid with cyclohexanamine bearing a leaving group at the β-position. Subsequent cyclization of the amide is accomplished via photo-induced cyclization [11], intramolecular nucleophilic substitution [12], and Heck reaction [13] to yield the desired structural cores. Another approach involves a coupling reaction of the arene and the cyclohexane moieties followed by lactamization. In this strategy, the first ring connection was realized by conjugated addition to cyclohexene [14,15,16,17,18,19], nucleophilic substitution to cyclohexane [20,21], or Suzuki–Miyaura coupling [22]. After introducing an amino group, the resulting coupling products were converted to octahydrophenanthridinones via lactam formation such as a Bischler−Napieralski reaction [23,24,25], formylation followed by oxidation [26], or ester–amide exchange [27]. An octahydrophenanthridine core was constructed by a Pictet–Spengler reaction of the same intermediate [14,28] as well as reduction of octahydrophenanthridinone [15,16,17] and hexahydrophenanthridine [29].
During our synthetic study on a pancratistatin epimer [30], we established a novel strategy for the construction of an octahydrophenanthridinone core, involving coupling between aryl and cyclohexane rings by the reaction of diarylcuprate and α-acetoxy oxime, reduction of the oxime to give cis-amine, formylation using hexamethyleneteramine (HMTA) [31] followed by intramolecular imine formation, and oxidation of the imine to give lactam [32] (Scheme 1).
Based on this achievement, we envisioned that this strategy could be applied to the divergent synthesis of both octahydrophenanthridinone and octahydrophenanthridine (Scheme 2). First, the coupling of aryl bromide A and oxime B, bearing an α-leaving group gives α-aryl oxime C [33]. Subsequently, β-aryl amine D, generated by reduction of C, is converted into cyclic imine E. Oxidation and reduction of E would then afford oxazolidinone F and oxazolidine G, respectively. It is noteworthy that separation of cis- and trans-isomers of D makes both cis- and trans-isomers of F and G available. This would be a desirable feature for use in the drug discovery stage.

2. Results and Discussion

Our investigation commenced with the screening of copper salts for the coupling reaction of 5-bromobenzo[d][1,3]dioxole 1a and 2-chlorocyclohexanone oxime 2 (Table 1). According to Weinreb’s report [34], 1a was treated with butyllithium and cuprous iodide in tetrahydrofuran (THF) to prepare the corresponding organocuprate. The reaction of the cuprate and 2 provided 2-arylated oxime 3a in 75% yield (entry 1). Although the use of cuprous acetate in place of iodide led to decreased yield (entry 2), the use of cuprous cyanide slightly improved the yield (entry 3). Finally, we found that cuprous 2-thiophenecarboxylate (CuTC) was the optimal copper source (entry 4). When diethyl ether was used as solvent instead of THF, the yield of 3a significantly decreased to 9% (entry 5).
Next, we examined the generality of the reaction (Table 2). Trisubstituted aryl bromide 1b was also converted to the corresponding arylated product 3b in good yield (entry 1). Methoxyphenyl bromides 1c–e gave products 3c–e in moderate to good yields (entries 2–4). Furthermore, the reaction was applicable to aryl bromides such as 1f–h, bearing a C1 unit at the ortho-positions (entries 5–7). Unfortunately, aryl bromides having an ester and an amide moiety failed to afford 3i and 3j, respectively, presumably due to the low nucleophilicity of the cuprates (entries 8 and 9).
We then explored reduction of 2-arylated oxime 3a to prepare 2-arylcyclohexanamine 4a (Table 3). Palladium-catalyzed hydrogenation, samarium(II)-mediated reduction, and reduction using DIBAL-H, LiB(s-Bu)3H, NaB(OAc)3H, and NaBH3CN resulted in either no reaction or the formation of unknown products (entries 1–6). Among the conditions tested, the reaction using sodium borohydride with nickel chloride [35,36] produced the desired amine 4a as a 1:1 mixture of cis- and trans-isomers in moderate yields (entry 7). These diastereomers were readily separated by silica gel column chromatography. The assignment of cis- and trans-4a is based on the 1H and 13C NMR spectra of cis-4a, which are in good agreement with those reported [37]. The coupling constants between the adjacent benzylic and amino methine protons (3.0 and 11.0 Hz for cis- and trans-4a, respectively) are also consistent with the assignment. Interestingly, when the reduction was performed with molybdenum trioxide [36], the trans-isomer was preferentially produced with a 3:1 diastereomer ratio (entry 8). These results might suggest that the tortional strain and the steric repulsion between a hydride source and the aryl group are competitive in the reaction with nickel chloride, while the steric repulsion might be less severe with a hydride source derived from sodium borohydride and molybdenum trioxide.
We next applied the reduction with nickel chloride to obtain other amines with stereodivergency (Table 4). The results showed that substitution at meta- and para-positions of aryl groups was tolerated, and the reduction provided both diastereomers of the corresponding amines (entries 1–3), whereas ortho-substituted variants, such as 3e–h, failed to give the desired amines, possibly due to the steric hindrance of the ortho-substituents (entries 4–7).
Next, the lactam formation of 4 to give octahydrophenanthridinone was carried out using HMTA followed by oxidation with sodium chlorite (Table 5). Both cis- and trans-4a were converted into the corresponding lactam 5a in moderate yields (entries 1 and 2). The other substrates were successfully transformed into the corresponding tricyclic compounds except cis- and trans-4d (entries 3–6). The failed cyclization of cis- and trans-4d would be attributed to the electron deficiency at the meta-positions of the oxygen functionalities (entries 7 and 8).
The cyclization of 4d was achieved using the Bischler–Napieralski reaction [38] (Scheme 3). Thus, cis- and trans-4d were separately converted to the corresponding ethyl carbamates, and the following reactions with polyphosphoric acid provided cis- and trans-5d in moderate yields.
An octahydrophenanthridine skeleton was also constructed from 4a via the imine intermediate (Scheme 4). Thus, cis- and trans-4a were separately converted into the corresponding imine intermediates using HMTA, and subsequent reduction with sodium borohydride in ethanol afforded cis-6 and trans-6 in good yields.

3. Conclusions

In conclusion, we successfully developed stereodivergent construction of octahydrophenanthridinone and octahydrophenanthridine cores via α-arylation of α-chloro oxime followed by reduction and cyclization. This protocol would enable divergent synthesis of these structural cores using various aryl bromide and cyclohexanone oximes.

4. Materials and Methods

4.1. General Information

All anhydrous reactions were carried out under a positive atmosphere of argon in dried glassware. Dehydrated solvents were purchased for the reactions and used without further desiccation. Analytical thin-layer chromatography was performed on Merck TLC silica gel 60F254 silica gel plates. Visualization was accomplished with molibudenium phosphate, p-anisaldehyde, Hannessian’s cocktail, or ninhydrin. Column chromatography was performed using Silica Gel 60N (particle size 0.040–0.050 mm) purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). NMR spectra were recorded using a Bruker AV400N, Bruker AV500N (Bruker Corporation, Billerica, MA, USA) or JEOL JNM-ECZL500R (JEOL Ltd., Tokyo, Japan) in the stated solvents using tetramethylsilane as an internal standard. Chemical shifts were reported in parts per million (ppm) on the δ scale from an internal standard (NMR descriptions: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). Coupling constants, J, are reported in Hertz. Mass spectra were recorded on a Waters/Micromass SQD2, MICROMASS® LCT PREMIERTM (ESI-TOF). Optical rotations were measured using a JASCO P-2200 polarimeter (JASCO Corp., Tokyo, Japan) (concentration in g·dL−1). IR was measured using a JASCO FT-IR 6200 (JASCO Corp., Tokyo, Japan). Melting point was determined on J-SCIENCE RFS-10. Unless otherwise noted, reagents were used without further purification. The substrates 1b [39], 1f [40], 1g [41], 1h [42], 1i [43], 1j [44], and 1k [45] were prepared according to the literature procedures.

4.2. General Procedure for the Coupling Reaction of Aryl Bromide and α-Chloro Oxime

To a solution of bromoarene 1 (0.80 mmol) in dry THF (3 mL), a 1.60 M hexane solution of BuLi (0.50 mL, 0.80 mmol) was added dropwise at –78 °C, and the mixture was stirred for 30 min to give a solution of the corresponding organolithium. Then, the mixture was added to a suspension of CuTC (97 mg, 0.40 mmol) in dry THF (1 mL) at 0 °C via cannulation, and this mixture was stirred at 0 °C for 20 min to give a suspension of the corresponding diarylcuprate. The mixture was cooled to –78 °C, and to the mixture, a solution of 2 (0.20 mmol) in dry THF (0.5 mL + 0.25 mL wash) was added via cannulation. The mixture was warmed to 0 °C and stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl (5 mL), and the whole was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc 9:1 to 5:1) to give coupling product 3.
2-(Benzo[d][1,3]dioxol-5-yl)cyclohexan-1-one Oxime (3a)
Isolated yield: 85%. Pale yellow solid of mp 119–122 °C. 1H NMR (500 MHz, CDCl3): δ 7.68 (br s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 1.5 Hz, 1H), 6.67 (dd, J = 8.0, 1.5 Hz, 1H), 5.93 (s, 2H), 3.40 (dd, J = 9.5, 5.5 Hz, 1H), 2.97 (dt, J = 14.0, 5.0 Hz, 1H), 2.11 (m, 1H), 2.04–1.95 (m, 2H), 1.88–1.79 (m, 2H), 1.65–1.55 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 162.1 (C), 147.5 (C), 146.0 (C), 134.4 (C), 121.1 (CH), 108.7 (CH), 108.1 (CH), 100.8 (CH2), 47.8 (CH), 33.4 (CH2), 25.7 (CH2), 24.7 (CH2), 23.9 (CH2). LRMS (ESI) (m/z): 232 [M–H]−. HRMS (ESI) (m/z): [M–H]− calcd for C13H14NO3, 232.0974; found, 232.0967. IR (KBr): 3250, 2940, 2866, 1667, 1504, 1488, 1471, 1440, 1237, 1213, 1040, 725.
2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)cyclohexan-1-one Oxime (3b)
Isolated yield: 83%. White solid of mp 151–154 °C. 1H NMR (400 MHz, CDCl3): δ 6.45 (s, 1H), 6.40 (s, 1H), 5.94 (s, 2H), 3.89 (s, 3H), 3.41 (dd, J = 9.0, 5.5 Hz, 1H), 3.00 (m, 1H), 2.15 (m, 1H), 2.04–1.95 (m, 2H), 1.90–1.79 (m, 2H), 1.65–1.60 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 161.9 (C), 148.7 (C), 143.3 (C), 135.1 (C), 133.7 (C), 107.7 (CH), 102.4 (CH), 101.2 (CH2), 56.5 (CH3), 48.2 (CH), 33.5 (CH2), 25.6 (CH2), 24.8 (CH2), 24.0 (CH2). LRMS (ESI) (m/z): 262 [M–H]−. HRMS (ESI) (m/z): [M–H]− calcd for C14H16NO4, 262.1079; found, 262.1089. IR (KBr): 3210, 2941, 2879, 2784, 1634, 1509, 1450, 1430, 1238, 1044.
2-(3-Methoxyphenyl)cyclohexan-1-one Oxime (3c)
Isolated yield: 71%. Pale yellow solid of mp 119–120 °C. 1H NMR (400 MHz, CDCl3): δ 7.23 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 7.0 Hz, 1H), 6.81–6.75 (m, 2H), 3.80 (s, 3H), 3.49 (dd, J = 9.0, 5.0 Hz, 1H), 2.93 (m, 1H), 2.24 (m, 1H), 2.14–1.98 (m, 2H), 1.89–1.78 (m, 2H), 1.66–1.57 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 162.2 (C), 159.5 (C), 142.3 (C), 129.2 (C), 120.6 (C), 114.2 (C), 111.7 (C), 55.1 (CH3), 47.8 (CH), 33.0 (CH2), 25.7 (CH2), 24.5 (CH2), 23.8 (CH2). LRMS (ESI) (m/z): 220 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C13H18NO2, 220.1338; found, 220.1351. IR (KBr): 3201, 2931, 2833, 1662, 1609, 1583, 1488, 1446, 1262, 1051, 966, 926, 771, 745, 700.
2-(4-Methoxyphenyl)cyclohexan-1-one Oxime (3d)
Isolated yield: 73%. Pale yellow solid of mp 165–166 °C. 1H NMR (400 MHz, CDCl3): δ 7.15 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 6.71 (br s, 1H), 3.79 (s, 3H), 3.45 (dd, J = 8.0, 7.0 Hz, 1H), 3.01 (m, 1H), 2.22–2.12 (m, 1H), 2.06–1.98 (m, 2H), 1.88–1.80 (m, 2H), 1.64–1.56 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 162.8 (C), 158.1 (C), 132.7 (C), 129.1 (Cx2), 113.7 (Cx2), 55.2 (CH3), 47.2 (CH), 33.4 (CH2), 25.8 (CH2), 24.7 (CH2), 23.9 (CH2). LRMS (ESI) (m/z): 220 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C13H18NO2, 220.1338; found, 220.1328. IR (KBr): 3193, 2939, 2835, 1667, 1611, 1514, 1461, 1441, 1248, 1037, 970, 924, 841, 809, 778, 754.
2-(2-Methoxyphenyl)cyclohexan-1-one Oxime (3e)
Isolated yield: 84%. White solid of mp 186–187 °C. 1H NMR (400 MHz, CDCl3): δ 7.21 (d, J = 8.0 Hz, 2H), 6.96 (t, J = 8.0 Hz, 1H), 6.88 (t, J = 8.0 Hz, 1H), 3.87 (dd, J = 12.0, 4.0 Hz, 1H), 3.80 (s, 3H), 3.40 (m, 1H), 1.97–1.87 (m, 5H), 1.70–1.50 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 162.0 (C), 156.7 (C), 129.4, (C), 128.5 (CH), 127.6 (CH), 120.4 (CH), 110.5 (CH), 55.5 (CH3), 41.4 (CH), 33.0 (CH2), 25.9 (CH2), 25.8 (CH2), 24.8 (CH2). LRMS (ESI) (m/z): 220 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C13H18NO2, 220.1338; found, 220.1340. IR (KBr): 3267, 3064, 2998, 2938, 2845, 1714, 1671, 1598, 1492, 1461, 1324, 1240, 1132, 1047, 1031, 973, 930, 900, 756.
2-(2-(Triisopropylsilyloxymethyl)phenyl)cyclohexan-1-one Oxime (3f)
Isolated yield: 64%. White solid of mp 122–123 °C. 1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.0 Hz, 1H), 7.25–7.17 (m, 3H), 4.81 (d, J = 12.0 Hz,1H), 4.62 (d, J = 12.0 Hz, 1H), 3.76 (dd, J = 12.0, 4.0 Hz, 1H), 3.40 (d, J = 13.0 Hz, 1H), 2.04 (m, 1H), 1.99–1.89 (m, 3H), 1.75 (t, J = 13.0 Hz, 1H), 1.66–1.48 (m, 3H), 1.26–1.11 (m, 2H), 1.07 (d, J = 3.0 Hz, 9H), 1.05 (d, J = 3.0 Hz, 9H). 13C NMR (101 MHz, CDCl3): δ 161.9 (C), 152.0 (C), 138.7 (C), 127.6 (CH), 127.5 (CH), 127.1 (CH), 126.5 (CH), 63.8 (CH2), 43.9 (CH), 33.7 (CH2), 26.1 (CH2), 25.8 (CH2), 24.8 (CH2), 18.07 (CH3x3), 18.05 (CH3x3), 12.0 (CHx3). LRMS (ESI) (m/z): 388 [M+Na]+. HRMS (ESI) (m/z): [M+Na]+ calcd for C22H37NNaO2Si, 398.2491; found, 398.2491. IR (KBr): 3278, 3179, 3089, 2946, 2866, 2716, 1461, 1360, 1252, 1079, 1038, 1013. 993, 881, 747, 672, 638.
2-(2-(Benzyloxymethyl)phenyl)cyclohexan-1-one Oxime (3g)
Isolated yield: 66%. White solid of mp 149–150 °C. 1H NMR (400 MHz, CDCl3): δ 7.38–7.28 (m, 8H), 7.25–7.21 (m, 1H), 6.90 (br s, 1H), 4.55 (t, J = 12.0 Hz, 2H), 4.47 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 3.72 (dd, J = 12.0, 4.5 Hz, 1H), 3.38 (d, J = 15.0 Hz, 1H), 2.04 (m, 1H), 1.97–1.88 (m, 3H), 1.67 (m, 1H), 1.55–1.45 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 162.4 (C), 140.1 (C), 138.4 (C), 135.6 (C), 129.7 (CH), 128.4 (CH), 128.2 (CH), 128.1 (CH), 127.9 (CH), 127.6 (CH), 126.5 (CH), 72.1 (CH2), 70.6 (CH2), 44.2 (CH), 33.8 (CH2), 26.0 (CH2), 25.7 (CH2), 24.7 (CH2). LRMS (ESI) (m/z): 348 [M+K]+. HRMS (ESI) (m/z): [M+K]+ calcd for C20H23KNO2, 348.1366; found, 348.1378. IR (KBr): 3223, 3062, 3036, 2925, 2867, 1493, 1450, 1410, 1360, 1102, 1071, 1022, 978, 934, 903, 745, 696.
2-(2-(Methoxymethyl)phenyl)cyclohexan-1-one Oxime (3h)
Isolated yield: 67%. White solid of mp 139–140 °C. 1H NMR (400 MHz, CDCl3): δ 7.34–7.29 (m, 3H), 7.23 (m, 1H), 6.73 (br s, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.32 (d, J = 12.0 Hz, 1H), 3.75 (dd, J = 12.0, 4.0 Hz, 1H), 3.46 (dt, J = 14.0, 3.5 Hz, 1H), 3.35 (s, 3H), 2.10–1.92 (m, 4H), 1.83 (m, 1H), 1.69–1.60 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 162.3 (C), 139.8 (C), 135.7 (C), 129.3 (CH), 128.0 (CH), 127.9 (CH), 126.5 (CH), 73.1 (CH2), 58.0 (CH3), 44.3 (CH), 33.8 (CH2), 26.0 (CH2), 25.8 (CH2), 24.8 (CH2). LRMS (ESI) (m/z): 272 [M+K]+. HRMS (ESI) (m/z): [M+K]+ calcd for C14H19NO2K, 272.1053; found, 272.1047. IR (KBr): 3414, 3256, 2927, 2867, 2827, 1667, 1488, 1443, 1360, 1216, 1183, 1080, 975, 931, 903, 788.

4.3. General Procedure for the Reduction of α-Aryl Oxime

To a mixture of oxime 3 (0.80 mmol) and NiCl2·6H2O (400 mg, 1.68 mmol) in EtOH (10 mL), NaBH4 (250 mg, 6.61 mmol) was added portion-wise at 0 °C, and the mixture was stirred at room temperature. After 30 min, EtOAc (20 mL) and H2O (20 mL) were added to the mixture, and the whole was filtered through a Celite pad, which was successively washed with EtOAc (20 mL × 3). The combined washings were washed with H2O and brine, dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc 3:1, EtOAc, EtOAc/EtOH 1:2, and then EtOH) to give cis- and trans-4.
cis-2-(Benzo[d][1,3]dioxol-5-yl)cyclohexan-1-amine (cis-4a)
Isolated yield: 34%. Colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.77 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 1.5 Hz, 1H), 6.66 (dd, J = 8.0, 1.5 Hz, 1H), 5.93 (s, 2H), 3.20 (q, J = 3.0 Hz, 1H), 2.73 (dt, J = 12.5, 3.0 Hz, 1H), 1.93–1.81 (m, 3H), 1.71 (m, 1H), 1.65–1.49 (m, 3H), 1.36 (m, 1H), 1.16 (br s, 2H). 13C NMR (125 MHz, CDCl3): δ 147.6 (C), 145.7 (C), 138.8 (C), 120.2 (CH), 108.12 (CH), 108.05 (CH), 100.7 (CH2), 51.6 (CH), 47.1 (CH), 33.4 (CH2), 26.4 (CH2), 24.1 (CH2), 19.4 (CH2). LRMS (ESI) (m/z): 220 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C13H18NO2, 220.1338; found, 220.1346. IR (NaCl): 3003, 2932, 2859, 1559, 1487, 1442, 1243, 1227, 775, 722.
trans-2-(Benzo[d][1,3]dioxol-5-yl)cyclohexan-1-amine (trans-4a)
Isolated yield: 37%. Colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.76 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 1.5 Hz, 1H), 6.68 (dd, J = 7.5, 1.5 Hz, 1H), 5.93 (s, 2H), 2.75 (td, J = 11.0, 3.5 Hz, 1H), 2.15 (td, J = 11.0, 3.5 Hz, 1H), 1.97 (m, 1H), 1.85–1.75 (m, 3H), 1.48–1.16 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 147.8 (C), 146.0 (C), 138.6 (C), 120.9 (CH), 108.3 (CH), 107.7 (CH), 100.8 (CH2), 55.1 (CH), 53.6 (CH), 35.6 (CH2), 34.3 (CH2), 26.4 (CH2), 25.6 (CH2). LRMS (ESI) (m/z): 220 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C13H18NO2, 220.1338; found, 220.1346. IR (NaCl): 3021, 2933, 1557, 1505, 1441, 1219, 775, 741.
cis-2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)cyclohexan-1-amine (cis-4b)
Isolated yield: 44%. Pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.43 (s, 1H), 6.38 (s, 1H), 5.94 (s, 2H), 3.90 (s, 3H), 3.22 (q, J = 2.0 Hz, 1H), 2.72 (dt, J = 10.0, 2.0 Hz, 1H), 1.96–1.80 (m, 3H), 1.71 (m, 1H), 1.64–1.48 (m, 3H), 1.36 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 148.8 (C), 143.4 (C), 139.6 (C), 133.4 (C), 106.8 (CH), 101.6 (CH2), 101.2 (CH), 56.6 (CH3), 51.6 (CH), 47.4 (CH), 33.3 (CH2), 26.4 (CH2), 24.1 (CH2), 19.4 (CH2). LRMS (ESI) (m/z): 250 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C14H20NO3, 250.1443; found, 250.1455. IR (NaCl): 3038, 3000, 2934, 2858, 1559, 1507, 1451, 1317, 1135, 1092, 825, 650.
trans-2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)cyclohexan-1-amine (trans-4b)
Isolated yield: 44%. Pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 6.42 (d, J = 1.0 Hz, 1H), 6.41 (d, J = 1.0 Hz, 1HH), 5.94 (s, 2H), 4.27 (br s, 2H), 3.90 (s, 3H), 2.85 (td, J = 10.5, 4.0 Hz, 1H), 2.32 (t, J = 10.5 Hz, 1H), 2.05 (m, 1H), 1.85–1.81 (m, 2H), 1.76 (m, 1H), 1.49–1.26 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 149.2 (C), 143.6 (C), 137.7 (C), 133.9 (C), 107.4 (CH), 101.3 (CH2), 101.1 (CH), 56.5 (CH3), 55.0 (CH), 51.8 (CH), 33.9 (CH2), 33.5 (CH2), 25.9 (CH2), 25.2 (CH2). LRMS (ESI) (m/z): 250 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C14H20NO3, 250.1443; found, 250.1445. IR (NaCl): 3049, 2994, 1556, 1511, 1449, 1222, 770.
cis-2-(3-Methoxyphenyl)cyclohexan-1-amine (cis-4c)
Isolated yield: 33%. Colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.24 (t, J = 8.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.76 (s, 1H), 6.75 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H), 3.25 (q, J = 2.5, 1H), 2.78 (dt, J = 12.5, 5.0 Hz, 1H), 1.95 (m, 1H), 1.91–1.82 (m, 2H), 1.73 (tt, J = 13.0, 4.0 Hz, 1H), 1.64–1.49 (m, 3H), 1.36 (m, 1H), 1.14 (br s, 2H). 13C NMR (125 MHz, CDCl3): δ 159.6 (C), 146.5 (C), 129.2 (CH), 120.0 (CH), 113.5 (CH), 111.1 (CH), 55.1 (CH3), 51.4 (CH), 47.5 (CH), 33.5 (CH2), 26.3 (CH2), 23.7 (CH2), 19.5 (CH2). LRMS (ESI) (m/z): 206 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C13H20NO, 206.1545; found, 206.1554. IR (NaCl): 3155, 3035, 3000, 1558, 1465, 1381, 1227, 1197, 908, 739.
trans-2-(3-Methoxyphenyl)cyclohexan-1-amine (trans-4c)
Isolated yield: 31%. Colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.23 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.78 (s, 1H), 6.76 (d, J = 7.5 Hz, 1H), 3.81 (s, 3H), 2.83 (td, J = 10.5, 3.0 Hz, 1H), 2.21 (td, J = 10.5, 3.5 Hz, 1H), 1.99 (m, 1H), 1.86–1.73 (m, 3H), 1.55–1.19 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 159.8 (C), 146.0 (C), 129.6 (CH), 120.1 (CH), 113.6 (CH), 111.7 (CH), 55.1 (CH3), 54.9 (CH), 53.6 (CH), 35.1 (CH2), 34.0 (CH2), 26.3 (CH2), 25.5 (CH2). LRMS (ESI) (m/z): 206 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C13H20NO, 206.1545; found, 206.1535. IR (NaCl): 3162, 2994, 2930, 2852, 1583, 1493, 1355, 1289, 1112, 821, 686, 652.
cis-2-(4-Methoxyphenyl)cyclohexan-1-amine (cis-4d)
Isolated yield: 33%. Colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.13 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H), 3.21 (m, 1H), 2.76 (m, 1H), 1.98–1.80 (m, 3H), 1.71 (m, 1H), 1.65–1.43 (m, 3H), 1.42–1.31 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 158.4 (C), 134.9 (C), 128.5 (CH), 114.1 (CH), 55.3 (CH3), 51.9 (CH), 45.4 (CH), 29.6 (CH2), 26.0 (CH2), 24.1 (CH2), 19.4 (CH2). LRMS (ESI) (m/z): 206 [M+H]+. HRMS (ESI) (m/z): [M+Na]+ calcd for C13H19NNaO, 228.1364; found, 228.1372. IR (KBr): 3346, 3253, 2935, 1739, 1670, 1657, 1512, 1251, 1033, 817.
trans-2-(4-Methoxyphenyl)cyclohexan-1-amine (trans-4d)
Isolated yield: 27%. White solid of mp 90–94 °C. 1H NMR (400 MHz, CDCl3): δ 7.14 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H), 2.79 (td, J = 10.5, 4.0 Hz, 1H), 2.20 (m, 1H), 2.00 (m, 1H), 1.84–1.74 (m, 2H), 1.51–1.21 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 158.2 (C), 136.1 (C), 128.6 (CH), 114.0 (CH), 55.2 (CH3), 55.1 (CH), 52.2 (CH), 34.8 (CH2), 34.1 (CH2), 26.3 (CH2), 25.5 (CH2). LRMS (ESI) (m/z): 228 [M+Na]+. HRMS (ESI) (m/z): [M+Na]+ calcd for C13H19NNaO, 228.1363; found, 228.1364. IR (KBr): 3262, 2936, 2859, 1453, 1252, 1031.

4.4. General Procedure for the Formation of Phenanthridinones via Formylation and Oxidation

To a solution of 4 (0.15 mmol) in a 3:1 mixture of AcOH and TFA (2.4 mL) at room temperature, hexamethylenetetramine (112 mg, 0.75 mmol) was added. The mixture was heated at 90 °C with continuous stirring for 5 h and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), and NaHCO3 (4.8 g) was carefully added. The mixture was then loaded onto a Celite pad, which was successively washed with EtOAc (20 mL × 3). The combined washings were washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was passed through silica gel column chromatography (hexane/EtOAc 1:2) to give the corresponding imine intermediate. To a solution of the imine in THF (1.1 mL), 2-methyl-2-butene (0.64 mL, 5.5 mmol), water (1.1 mL), NaH2PO4·2H2O (246 mg, 2.20 mmol), and NaClO2 (330 mg, 2.20 mmol) were added at 0 °C. The mixture was allowed to warm up to room temperature. After 35 min, saturated aqueous Na2SO3 (5 mL) was added, and the whole was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/hexane 1:1) to afford 5.
cis-1,3,4,4a,5,11b-Hexahydro-[1,3]dioxolo [4,5-j]phenanthridin-6(2H)-one (cis-5a)
Isolated yield: 29%. White solid. Decomp. at >250 °C. 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 1H), 6.64 (s, 1H), 5.99 (dd, J = 4.0, 1.5 Hz, 2H), 5.37 (br, 1H), 3.88 (dd, J = 7.0, 4.0 Hz, 1H), 2.69 (m, 1H), 1.80–1.70 (m, 2H), 1.65–1.50 (m, 4H), 1.40–1.30 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 166.2 (C), 150.9 (C), 146.7 (C), 121.6 (C), 108.0 (CH), 106.7 (CH), 101.5 (CH2), 50.0 (CH3), 40.3 (CH), 30.2 (CH2), 29.2 (CH2), 24.5 (CH2), 19.8 (CH2). LRMS (ESI) (m/z): 268 [M+Na]+. HRMS (ESI) (m/z): [M+Na]+ calcd for C14H15NNaO3, 268.0950; found, 268.0958. IR (KBr): 3173, 3054, 2936, 2857, 1668, 1493, 1458, 1412, 1388, 1359, 1322, 1262, 1241, 1037, 934, 807, 741.
trans-1,3,4,4a,5,11b-Hexahydro-[1,3]dioxolo[4,5-j]phenanthridin-6(2H)-one (trans-5a)
Isolated yield: 45%. White solid of mp 191–192 °C. 1H NMR (400 MHz, CDCl3): δ 7.54 (s, 1H), 6.76 (s, 1H), 6.01 (s, 2H), 5.57 (s, 2H), 3.22 (td, J = 11.0, 4.0 Hz, 1H), 2.62 (td, J = 11.0, 4.0 Hz, 1H), 2.34 (d, J = 12.0 Hz, 1H), 1.98–1.83 (m, 3H), 1.55–1.25 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 165.6 (C), 151.2 (C), 146.5 (C), 138.2 (C), 123.3 (C), 108.2 (CH), 103.9 (CH), 101.5 (CH2), 55.8 (CH3), 42.0 (CH), 32.2 (CH2), 27.1 (CH2), 25.4 (CH2), 24.1 (CH2). LRMS (ESI) (m/z): 268 [M+Na]+. HRMS (ESI) (m/z): [M+Na]+ calcd for C14H15NNaO3, 268.0950; found, 268.0950. IR (KBr): 3278, 3052, 2935, 2860, 1668, 1503, 1460, 1389, 1361, 1255, 1033, 930, 771.
cis-7-Methoxy-1,3,4,4a,5,11b-hexahydro-[1,3]dioxolo[4,5-j]phenanthridin-6(2H)-one (cis-5b)
Isolated yield: 31%. White solid of mp 189–190 °C. 1H NMR (400 MHz, CDCl3): δ 6.39 (s, 1H), 5.97 (d, J = 12.0 Hz, 2H), 5.34 (br s, 1H), 4.06 (s, 3H), 3.79 (dd, J = 6.5, 3.0 Hz, 1H), 2.60 (m, 1H), 1.82–1.65 (m, 6H), 1.39–1.24 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 164.6 (C), 151.6 (C), 144.9 (C), 141.8 (C), 137.1 (C), 114.5 (C), 101.9 (CH), 101.4 (CH2), 60.8 (CH3), 49.1 (CH), 41.9 (CH), 29.7 (CH2), 28.6 (CH2), 24.6 (CH2), 19.6 (CH2). LRMS (ESI) (m/z): 298 [M+Na]+. HRMS (ESI) (m/z): [M+H]+ calcd for C15H18NO4, 276.1236; found, 276.1222. IR (KBr): 3549, 3480, 3411, 3050, 2941, 2898, 2878, 2842, 1670, 1474, 1388, 1357, 1322, 1217, 1061, 1040, 941, 807, 775.
trans-7-Methoxy-1,3,4,4a,5,11b-hexahydro-[1,3]dioxolo[4,5-j]phenanthridin-6(2H)-one (trans-5b)
Isolated yield: 27%. White solid of mp 204–205 °C. 1H NMR (400 MHz, CDCl3): δ 6.51 (s, 1H), 5.98 (d, J = 12.0 Hz, 2H), 5.62 (br s, 1H), 4.06 (s, 3H), 3.10 (td, J = 12.0, 4.0 Hz, 1H), 2.50 (td, J = 12.0, 4.0 Hz, 1H), 2.28 (d, J = 12.0 Hz, 1H), 1.97–1.87 (m, 3H), 1.50–1.20 (m, 5H). 13C NMR (125 MHz, CDCl3): δ 164.0 (C), 151.6 (C), 144.6 (C), 139.9 (C), 136.7 (C), 116.0 (C), 101.4 (CH2), 99.0 (CH), 60.8 (CH3), 54.6 (CH), 42.9 (CH), 31.7 (CH2), 27.4 (CH2), 25.3 (CH2), 24.0 (CH2). LRMS (ESI) (m/z): 298 [M+Na]+. HRMS (ESI) (m/z): [M+H]+ calcd for C15H18NO4, 276.1236; found, 276.1235. IR (KBr): 3182, 3060, 2926, 2855, 1729, 1663, 1509, 1475, 1363, 1325, 1278, 1217, 1136, 1088, 1035, 927, 797, 769, 727, 630.
cis-9-Methoxy-1,3,4,4a,5,10b-hexahydrophenanthridin-6(2H)-one (cis-5c)
Isolated yield: 47%. White solid of mp 172–178 °C. 1H NMR (500 MHz, CDCl3): δ 8.02 (d, J = 9.0 Hz, 1H), 6.85 (dd, J = 9.0, 2.5 Hz, 1H), 6.69 (d, J = 9.0 Hz, 1H), 5.83 (br s, 1H), 3.91 (q, J = 3.0 Hz, 1H), 3.85 (s, 3H), 2.76 (m, 1H), 1.82 (m, 1H), 1.76–1.55 (m, 5H), 1.44–1.24 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 166.6 (C), 162.7 (C), 146.1 (C), 130.3 (CH), 120.4 (C), 112.1 (CH), 111.8 (CH), 55.3 (CH3), 50.0 (CH), 40.4 (CH), 30.1 (CH2), 29.0 (CH2), 24.5 (CH2), 19.8 (CH2), 19.9 (CH2). LRMS (ESI) (m/z): 254 [M+Na]+. HRMS (ESI) (m/z): [M+H]+ calcd for C14H18NO2, 232.1338; found, 232.1324. IR (KBr): 3179, 2948, 1732, 1658, 1604, 1497, 1254, 816.
trans-9-Methoxy-1,3,4,4a,5,10b-hexahydrophenanthridin-6(2H)-one (trans-5c)
Isolated yield: 50%. White solid of mp 206–209 °C. 1H NMR (500 MHz, CDCl3): δ 8.04 (d, J = 9.0 Hz, 1H), 6.85 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.12 (br s, 1H), 3.86 (s, 3H), 3.27 (td, J = 11.0, 4.0 Hz, 1H), 2.67 (td, J = 11.0, 4.0 Hz, 1H), 2.39 (d, J = 12.0, 1H), 2.11–1.85 (m, 4H), 1.59–1.24 (m, 3H). 13C NMR (125 MHz, CDCl3): δ 166.0 (C), 162.9 (C), 144.2 (C), 130.2 (CH), 122.0 (C), 111.1 (CH), 109.6 (CH), 55.6 (CH), 55.3 (CH3), 42.1 (CH), 32.2 (CH2), 26.7 (CH2), 25.4 (CH2), 24.1 (CH2). LRMS (ESI) (m/z): 254 [M+Na]+. HRMS (ESI) (m/z): [M+Na]+ calcd for C14H17NNaO2, 254.1157; found, 254.1154. IR (KBr): 3179, 3060, 2925, 1734, 1664, 1610, 1394, 1032, 803.

4.5. General Procedure for the Formation of Phenanthridinones via a Bischler–Napieralski Reaction

To a solution of 4d (0.055 mmol) in benzene (1.0 mL), anhydrous potassium carbonate (12 mg, 0.082 mmol) and ethyl chloroformate (0.015 mL, 0.14 mmol) were added, and the mixture was heated under reflux for 1 h. Filtration through filter paper and removal of volatile materials in vacuo gave a thick oil, which solidified with the addition of hexane. Recrystallization from hexane/EtOAc (4:1) gave the corresponding carbamate intermediate. A mixture of the carbamate and PPA (200 mg) was heated at 110 °C for 1.5 h. After cooling to room temperature, water (5 mL) was added, and the mixture was filtered through filter paper. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (EtOAc/hexane 1:1) to afford 5d.
cis-8-Methoxy-1,3,4,4a,5,10b-hexahydrophenanthridin-6(2H)-one (cis-5d)
Isolated yield: 44%. White solid of mp 177–178 °C. 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 2.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 8.0, 2.5 Hz, 1H), 5.60 (br, 1H), 3.90 (m, 1H), 3.85 (s, 3H), 2.77 (m, 1H), 1.80–1.32 (m, 8H). 13C NMR (125 MHz, CDCl3): δ 166.6 (C), 158.6 (C), 136.3 (C), 128.5 (C), 127.9 (CH), 120.1 (CH), 111.1 (CH), 55.5 (CH3), 50.2 (CH), 39.3 (CH), 30.3 (CH2), 29.7 (CH2), 29.2 (CH2), 19.9 (CH2). LRMS (ESI) (m/z): 254 [M+Na]+. HRMS (ESI) (m/z): [M+Na]+ calcd for C14H17NNaO2, 254.1157; found, 254.1161. IR (KBr): 3051, 2930, 2895, 1737, 1666, 1493, 1453, 1390, 1321, 1270, 1250, 1037, 804, 771.
trans-8-Methoxy-1,3,4,4a,5,10b-hexahydrophenanthridin-6(2H)-one (trans-5d)
Isolated yield: 61%. White solid of mp 194–195 °C. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 3.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.98 (dd, J = 8.0, 3.0 Hz, 1H), 5.85 (br s, 1H), 3.78 (s, 3H), 3.19 (td, J = 12.0, 4.0 Hz, 1H), 2.59 (td, J = 12.0, 4.0 Hz, 1H), 2.35 (dd, J = 12.0, 3.0 Hz, 1H), 1.92–1.78 (m, 3H), 1.51–1.21 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 165.9 (C), 158.5 (C), 134.5 (C), 130.1 (C), 124.6 (CH), 119.5 (CH), 111.4 (CH), 55.8 (CH3), 55.5 (CH), 41.5 (CH), 32.1 (CH2), 26.9 (CH2), 25.4 (CH2), 24.2 (CH2). LRMS (ESI) (m/z): 254 [M+Na]+. HRMS (ESI) (m/z): [M+H]+ calcd for C14H18NO2, 232.1338; found, 232.1334. IR (KBr): 3191, 3066, 2968, 2872, 2833, 1668. 1494, 1429, 1357, 1313, 1261, 1030, 877, 801, 774, 724, 673.

4.6. General Procedure for the Formation of Phenanthridines via Formylation and Reduction

To a solution of 4a (0.22 mmol) in a 3:1 mixture of AcOH and TFA (3.6 mL) at room temperature, hexamethylenetetramine (151 mg, 1.07 mmol) was added. The mixture was heated at 90 °C with continuous stirring for 5 h and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), and NaHCO3 (5.4 g) was carefully added. The mixture was then loaded onto a Celite pad, which was successively washed with EtOAc (20 mL × 2). The combined washings were washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was passed through silica gel column chromatography (hexane/EtOAc 1:2) to give the imine intermediate. To a solution of the imine in EtOH (3.6 mL), NaBH4 (22.6 mg, 0.598 mmol) was added at 0 °C, and the mixture was stirred at the same temperature. After 10 min, the mixture was diluted with EtOAc and H2O, and the whole was extracted with EtOAc (20 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (CHCl3/MeOH 20:1 to 5:1) to afford 6.
cis-1,2,3,4,4a,5,6,11b-Octahydro-[1,3]dioxolo[4,5-j]phenanthridine (cis-6)
Isolated yield: 66%. Yellow oil. 1H NMR (500 MHz, CDCl3): δ 6.55 (s, 1H), 6.47 (s, 1H), 5.88 (d, J = 1.5 Hz, 1H), 5.87 (d, J = 1.5 Hz, 1H), 4.04 (d, J = 16.0 Hz, 1H), 3.96 (d, J = 16.0 Hz, 1H), 3.07 (dd, J = 7.0, 3.5 Hz, 1H), 2.48 (dt, J = 12.0, 3.0 Hz, 1H), 1.84 (m, 1H), 1.75–1.67 (m, 3H), 1.61–1.50 (m, 2H), 1.48–1.35 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 145.7 (C), 145.6 (C), 134.1 (C), 127.9 (C), 108.5 (CH), 105.7 (CH), 100.5 (CH2), 52.1 (CH), 49.1 (CH2), 39.2 (CH), 31.9 (CH2), 31.4 (CH2), 25.9 (CH2), 20.5 (CH2). LRMS (ESI) (m/z): 232 [M+H]+. HRMS (ESI) (m/z): [M+H]+ calcd for C14H18NO2, 232.1338; found, 232.1324. IR (NaCl): 3031, 2930, 1503, 1482, 1292, 1256.
trans-1,2,3,4,4a,5,6,11b-Octahydro-[1,3]dioxolo[4,5-j]phenanthridine (trans-6)
Isolated yield: 59%. White solid of mp. 86–89 °C. 1H NMR (500 MHz, CDCl3): δ 6.78 (s, 1H), 6.47 (s, 1H), 5.89 (d, J = 1.0 Hz, 1H), 5.88 (d, J = 1.0 Hz, 1H), 4.12 (d, J = 17.0 Hz, 1H), 3.94 (d, J = 17.0 Hz, 1H), 2.41 (td, J = 11.0, 3.5 Hz, 1H), 2.34–2.27 (m, 2H), 1.93–1.81 (m, 3H), 1.46–1.28 (m, 3H), 1.17 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 146.1 (C), 145.5 (C), 131.8 (C), 128.7 (C), 106.0 (CH), 105.6 (CH), 100.6 (CH2), 59.2 (CH), 49.1 (CH2), 43.9 (CH), 33.9 (CH2), 29.8 (CH2), 26.3 (CH2), 25.4 (CH2). LRMS (ESI) (m/z): 232 [M+H]+. HRMS (ESI) (m/z): [M+Na]+ calcd for C14H17NNaO2, 254.1157; found, 254.1149. IR (NaCl): 3315, 2924, 2854, 1631, 1579, 1485, 1258, 1229, 1039, 797.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30020371/s1: The copies of 1H- and 13C-NMR spectra of 3a–h; and cis- and trans 4a–d, 5a–d, and 6 are available online.

Author Contributions

All authors contributed to the writing and approved the final version of the manuscript. Conceptualization, K.Y.; methodology, C.S. and K.Y.; validation, C.S., H.N. and T.I.; formal analysis, C.S., T.I. and K.Y.; investigation, C.S., H.N. and T.I.; data curation, C.S.; writing—original draft preparation, C.S.; writing—review and editing, T.I. and K.Y.; visualization, T.I. and K.Y.; supervision, K.Y.; project administration, K.Y.; funding acquisition, T.I. and K.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Fugaku Foundation, the SGH Foundation, the Japan Science Society (Sasakawa Scientific Research Grant), JST (JPMJFS2130), JSPS (KAKENHI JP24H01320), the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Tokushima University (Research Clusters Programs nos. 2201004 and 2402001). C.S. acknowledges the scholarship from JST (JPMJSP2113).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data that support the findings of this study are available in the manuscript and Supplementary Materials of this article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

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Molecules 30 00371 g001
Figure 1. Examples of biologically active natural products with octahydrophenanthridinone and octahydrophenanthridine cores.
Figure 1. Examples of biologically active natural products with octahydrophenanthridinone and octahydrophenanthridine cores.
Molecules 30 00371 g001
Molecules 30 00371 sch001
Scheme 1. Our strategy for construction of an octahydrophenanthridinone core for synthesis of the pancratistatin analog.
Scheme 1. Our strategy for construction of an octahydrophenanthridinone core for synthesis of the pancratistatin analog.
Molecules 30 00371 sch001
Molecules 30 00371 sch002
Scheme 2. Concept of this work: Divergent synthesis of cis- and trans-tricyclic cores.
Scheme 2. Concept of this work: Divergent synthesis of cis- and trans-tricyclic cores.
Molecules 30 00371 sch002
Molecules 30 00371 sch003
Scheme 3. Construction of phenanthridinone from 4d using a Bischler–Napieralski reaction.
Scheme 3. Construction of phenanthridinone from 4d using a Bischler–Napieralski reaction.
Molecules 30 00371 sch003
Molecules 30 00371 sch004
Scheme 4. Reductive construction of phenanthridine from 4a.
Scheme 4. Reductive construction of phenanthridine from 4a.
Molecules 30 00371 sch004
Table 1. Optimization of the coupling reaction [a].
Table 1. Optimization of the coupling reaction [a].
Molecules 30 00371 i001
EntryCu SaltYield (%) [b]
1CuI75
2CuOAc59
3CuCN80
4CuTC85
5 [c]CuTC9
[a] The reactions were performed using 1a (0.80 mmol). [b] Isolated yield. [c] Et2O was used instead of THF.
Table 2. Substrate scope of the coupling reaction [a].
Table 2. Substrate scope of the coupling reaction [a].
Molecules 30 00371 i002
Entry13Yield (%) [b]
1Molecules 30 00371 i003Molecules 30 00371 i00483
2Molecules 30 00371 i005Molecules 30 00371 i00671
3Molecules 30 00371 i007Molecules 30 00371 i00873
4Molecules 30 00371 i009Molecules 30 00371 i01084
5Molecules 30 00371 i011Molecules 30 00371 i01264
6Molecules 30 00371 i013Molecules 30 00371 i01466
7Molecules 30 00371 i015Molecules 30 00371 i01667
8Molecules 30 00371 i017Molecules 30 00371 i0180
9Molecules 30 00371 i019Molecules 30 00371 i0200
[a] The reactions were performed using 1 (0.80 mmol). [b] Isolated yield.
Table 3. Screening of the conditions for reduction of 4a [a].
Table 3. Screening of the conditions for reduction of 4a [a].
Molecules 30 00371 i021
EntryConditionsYield of 4a (%) [b]Comment
cistrans
1H2 (1 atm), Pd(OH)2/C, EtOAc/MeOH00no reaction
2SmI2, THF00complex mixture
3DIBAL-H, THF00no reaction
4LiB(s-Bu)3H, THF00no reaction
5NaB(OAc)3H, THF00no reaction
6NaBH3CN, TFA00complex mixture
7NiCl2·6H2O, NaBH4, EtOH3437
8MoO3, NaBH4, MeOH1751
[a] The reactions were performed using 3a (0.20 mmol). [b] Isolated yield.
Table 4. Substrate scope of reduction of 3 [a].
Table 4. Substrate scope of reduction of 3 [a].
Molecules 30 00371 i022
Entry34Yield (%) [b]
cis-4trans-4
1Molecules 30 00371 i023Molecules 30 00371 i0244444
2Molecules 30 00371 i025Molecules 30 00371 i0263331
3Molecules 30 00371 i027Molecules 30 00371 i0283327
4Molecules 30 00371 i029Molecules 30 00371 i03000
5Molecules 30 00371 i031Molecules 30 00371 i03200
6Molecules 30 00371 i033Molecules 30 00371 i03400
7Molecules 30 00371 i035Molecules 30 00371 i03600
[a] The reactions were performed using 3 (0.2 mmol). [b] Isolated yield.
Table 5. Substrate scope of phenanthridinone formation [a].
Table 5. Substrate scope of phenanthridinone formation [a].
Molecules 30 00371 i037
Entry45Yield (%) [b]
1Molecules 30 00371 i038Molecules 30 00371 i03929
2Molecules 30 00371 i040Molecules 30 00371 i04145
3Molecules 30 00371 i042Molecules 30 00371 i04331
4Molecules 30 00371 i044Molecules 30 00371 i04527
5Molecules 30 00371 i046Molecules 30 00371 i04747
6Molecules 30 00371 i048Molecules 30 00371 i04950
7Molecules 30 00371 i050Molecules 30 00371 i0510
8Molecules 30 00371 i052Molecules 30 00371 i0530
[a] The reactions were performed using 4 (0.1 mmol). [b] Isolated yield over 2 steps.
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Sun, C.; Nishikawa, H.; Inokuma, T.; Yamada, K.-i. Diastereodivergent Construction of Octahydrophenanthridinone and Octahydrophenanthridine Cores. Molecules 2025, 30, 371. https://doi.org/10.3390/molecules30020371

AMA Style

Sun C, Nishikawa H, Inokuma T, Yamada K-i. Diastereodivergent Construction of Octahydrophenanthridinone and Octahydrophenanthridine Cores. Molecules. 2025; 30(2):371. https://doi.org/10.3390/molecules30020371

Chicago/Turabian Style

Sun, Chunzhao, Hiromichi Nishikawa, Tsubasa Inokuma, and Ken-ichi Yamada. 2025. "Diastereodivergent Construction of Octahydrophenanthridinone and Octahydrophenanthridine Cores" Molecules 30, no. 2: 371. https://doi.org/10.3390/molecules30020371

APA Style

Sun, C., Nishikawa, H., Inokuma, T., & Yamada, K.-i. (2025). Diastereodivergent Construction of Octahydrophenanthridinone and Octahydrophenanthridine Cores. Molecules, 30(2), 371. https://doi.org/10.3390/molecules30020371

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