Formal Syntheses of Dictyodendrins B, C, and E by a Multi-Substituted Indole Synthesis

Abstract

The dictyodendrins are a family of marine alkaloids, which possess a highly substituted pyrrolo[2,3-c]carbazole core. This core structure can be regarded as a multi-substituted indole and aniline moiety. To achieve a concise synthesis of dictyodendrins, we planned to capitalize on our previously developed multi-substituted indole synthesis. By using this method along with two C–H functionalizations, formal syntheses of dictyodendrins B, C, and E were achieved.

Dictyodendrins A–J are alkaloids from marine sponges (Figure [1] A). Of these compounds, dictyodendrins A–E were isolated from the Japanese sponge Dictyodendrilla verongiformis, and structurally assigned by Fusetani and Matsunaga in 2003.[1a] These are the first natural marine products to show telomerase inhibitory activity, and therefore could potentially be lead compounds for anticancer drugs.[2] Dictyodendrins F–J were isolated from an Australian sponge of the genus Ianthella by Capon and co-workers in 2012.[1b] These natural products have β-selectase (β-site APP-cleaving enzyme: BACE) inhibitory activity, which is expected to be applied to the research of Alzheimer’s disease.[3] As a structural feature, all analogues except dictyodendrin J possess a highly substituted pyrrolo[2,3-c]carbazole core.

Dictyodendrins have attracted attention as synthetic targets due to their important biological activities and unique structures, and to date, nine research groups have reported total syntheses including our group.[4] Pyrrolo[2,3-c]carbazole, the main skeleton of dictyodendrins, is a ring-fused structure of pyrrole and carbazole, but it can also be regarded as a structure in which an aniline is attached to the C4 and C5 positions of an indole. There have been three reports on the synthesis of dictyodendrins using the construction of the main skeleton by connecting the indole with the aniline moiety (Figure [1] B). Tokuyama and co-workers reported the synthesis of dictyodendrins by benzyne-mediated cyclization and cross-coupling/C–H aminationHH of multi-substituted indoles with aryl azides.[4e] [f] Jia and co-workers constructed the main skeleton by Buchwald–Hartwig amination of the multi-substituted indole obtained from the Larock indole synthesis with an aniline moiety, followed by intramolecular C–H arylation.[4h] Gaunt and co-workers reported an elegant synthesis using C–H functionalization leading to multi-substituted indoles, and then conducted a Suzuki–Miyaura coupling with aryl azides (aniline moiety), followed by intramolecular C–H amination to form the main skeleton.[4j] In all of these synthetic examples, the unique indole synthetic method was key. Hence, we proposed that an efficient synthesis of the dictyodendrin family could be achieved through the synthesis of a multi-substituted indole by a coupling/ring transformation strategy developed in our laboratory (Figure [1] C).[5] In this method, an ynamide intermediate containing thiophene S,S-dioxide was synthesized by a simple four-unit coupling reaction. Then, the ynamide was reacted with the thiophene S,S-dioxide via an inverse-electron-demand [4+2] cycloaddition and oxidation/deprotection to give pentaarylindole (PAI). Subsequent two-fold arylation of PAI led to heptaarylindole (HAI), in which all C–H/N–H bonds of the indole are substituted with aryl groups.[6] A variety of multi-substituted indoles can be synthesized by simply changing the substituents at each site. Based on this multi-substituted indole synthesis, we set out to synthesize the dictyodendrin family (Figure [1] D). As a forward synthetic plan, ynamide [4+2] cycloaddition would afford a multi-substituted indoline, followed by oxidation/C–H amination to a pyrrolo[2,3-c]carbazole. After several functionalizations including a C–H functionalization to the pyrrolocarbazole, the compound would lead to a synthetic intermediate of dictyodendrins B, C, and E that was generated by Fürstner and co-workers.[4a] [b]

First, the synthesis of the key multi-substituted indoline was conducted (Scheme [1] A). The synthesis was commenced with a Suzuki–Miyaura coupling of 1-azido-2-bromobenzene (1) with 3-thiopheneboronic acid (2) in the presence of a palladium catalyst and base to afford 3-arylthiophene 3 in 94% yield. We initially attempted a ring-opening of aryl aziridine as in our previous work,[5] however, the reaction did not proceed at all. Therefore, the ring-opening reaction of aryl epoxide was followed by two steps to sulfonylamide. Alcohol 5 was synthesized by epoxide opening of 2-(4-methoxyphenyl)oxirane (4) with 3-arylthiophene 3 under Lewis acid conditions. Although we extensively investigated this epoxide-opening reaction using various Lewis acids and conditions, TMSOTf gave the best results to give alcohol 5 in a low 23% yield, along with 48% recovered starting material 3 (see the Supporting Information for details).[7] Alcohol 5 was subsequently converted to amide 6 by Mitsunobu reaction with NHBocNs and removal of the Boc group, followed by bromination at the C5-position of the thiophene to afford Ns-amide 6 in 57% yield over 3 steps. In order to examine the [4+2] cycloaddition with ynamides, the synthesis of two thiophene oxides 7 and 8 was carried out. Thiophene S,S-dioxide 7 can be readily prepared by oxidation with mCPBA. S-Oxide 8 was also prepared using mCPBA in the presence of an excess amount of BF₃·OEt₂ to suppress over-oxidation.[6a] Then, ynamide formation from 7 and 8 with alkynylating agents, followed by [4+2] cycloaddition, was investigated (Scheme [1] B). After screening of several alkynylation conditions (see the Supporting Information for details), when hypervalent iodine alkynylating agent 9 and Cs₂CO₃ were used,[8] we successfully obtained the desired indoline 10 in 42% yield from S,S-dioxide 7 and in 29% yield from S-oxide 8. Since the yield of 10 from S,S-dioxide 7 was higher than that of S-oxide 8, we selected 7 as the more appropriate precursor. Since a methoxy-bearing alkynylating agent could not be prepared, we selected a bromo-bearing alkynylating agent 11. The bromide will be converted to methoxy group at the late-stage of the synthesis. To make dictyodendrins, we also reacted 7 with alkynylating agent 11 and succeeded in producing the desired indoline 12 in 42% yield.

Next, we attempted to access Fürstner’s intermediate from the obtained indoline 12 (Scheme [2]). From 12, pyrrolocarbazole 13 could be synthesized by intramolecular C–H amination,[4e] [f] [j] removal of the nosyl group, then oxidation of the indoline to the corresponding indole. First, the C–H amination of 12 was investigated by heating at 160 °C in o-dichlorobenzene. The expected indoline was not obtained, but surprisingly, the desired pyrrolocarbazole 13 was directly obtained in 16% yield, indicating spontaneous denosylation and oxidation. Pyrrolocarbazole 13 was crystallized from toluene/hexane and its structure was confirmed by X-ray crystallographic analysis.[9] Although the three reactions proceeded efficiently in a single step, several undetermined by-products were formed, resulting in low yields. We hypothesized that the cause of the complexity of the reaction was due to the acid generated during the removal of the nosyl group. Therefore, K₂CO₃ was added to neutralize the acid, and the yield of 13 significantly improved to 64%.

We then attempted a formal syntheses of dictyodendrins B, C, and E by elaborating the resulting pyrrolocarbazoles to known synthetic intermediates. From 13, an isopropoxy group needed to be introduced at the C7 position, an alkyl chain needed to be installed at the N3 position, and the C–Br bond needed to be methoxylated to reach the synthetic intermediate of Fürstner and co-workers. First, for the isopropoxylation of the C7 position, we selected C–H borylation. When pyrrolocarbazole 13 was subjected to iridium-catalyzed C–H borylation conditions,[10] only the compound with borylation at the C2 position, not at the C7 position, was obtained in 62% yield when 1.4 equivalents of B₂pin₂ was used. When the amount of B₂pin₂ was increased to 2.6 equivalents, compound 14 with borylated C2 and C7 positions was obtained in 66% yield as judged by ¹H NMR analysis. It should be noted that 14 and other borylated products were unstable to purification by silica gel column chromatography, and these compounds could not be isolated. Although C7-selective borylation was not achieved, introducing a boryl group at the C7 position was successful. Then, we considered that if C7-selective isopropoxylation or C2-selective protodeborylation of 14 were possible, we would be able to generate the desired product 15. To this end, a chemoselective isopropoxylation at the C7 position was conducted by using Cu(OAc)₂ as an oxidant and DMAP/4Å MS as additives onto 14 in a mixture of CH₂Cl₂ and ⁱ PrOH.[10] As a result, not only the isopropoxylation of the C7 position, but also the protodeborylation of the C2 position proceeded under these conditions, and the desired 15 was successfully obtained in a single step (33% yield, 22% in two steps from 13), along with recovered 13 in 21% yield. We believe that the regioselective protodeborylation is possible because the electron-rich C2 position is easily protonated.[11] Next, for the alkylation of 15 at the N3 position, treatment of 15 with alkyl tosylate and potassium hydroxide gave the desired N6-alkylated product 17, but the yield was only 5%. Contrary to our expectations, the N-alkylation product was preferentially obtained. After extensive investigation, the desired product 17 was obtained with complete N3 selectivity and moderate yield when the leaving group was changed to bromide 16, the base was modified to NaOH, and 18-crown-6 was employed as an additive.[4l] Although the reason for the selective alkylation at the N3 position remains unclear, it might be that the repulsion with the unshared electrons of the oxygen atom of the isopropoxy group at the C7 position prevents the generation of deprotonated anions at the N6 position. Finally, methoxylation of the two bromo atoms of 17 with copper iodide and sodium methoxide[4j] [l] [8] led to the synthetic intermediate 18 of Fürstner and co-workers, thus completing the formal synthesis of dictyodendrins B, C, and E.

In summary, we have accomplished the formal syntheses of dictyodendrins by a multi-substituted indole synthesis. We constructed a highly substituted pyrrolocarbazole skeleton by alkynylation and intramolecular C–H amination of thiophene S,S-dioxide, which is different from the conventional method. From here, a four-step functionalization including C–H borylation led to a known intermediate, and the formal syntheses of dictyodendrins B, C, and E were achieved. Furthermore, pyrrolocarbazole 15 with unsubstituted C2 and N3 positions could be a common intermediate toward the synthesis of other dictyodendrin analogues, which are currently ongoing projects in our laboratory.

Unless otherwise noted, all reactions were performed with anhyd solvents under an atmosphere of N₂ in dried glassware using standard vacuum-line techniques. All workup and purification procedures were carried out with reagent-grade solvents in air. CH₂Cl₂, THF, and toluene were purified by a Glass Contour Ultimate Solvent System. P( ^t Bu)₃·HBPh₄, NHBocNs, DIAD, imidazole, NBS, dtbpy, B₂pin₂, and 18-crown-6 were obtained from Tokyo Chemical Industry (TCI). TMSOTf, and Cu(OAc)₂ were obtained from FUJIFILM Wako Pure Chemical Corporation. PPh₃, K₂CO₃, BF₃·OEt₂, Cs₂CO₃, 3-thiopheneboronic acid (2), DMAP, and CuI were obtained from KANTO Chemical. mCPBA, [IrOMe(COD)]₂, and 4-methoxyphenethyl bromide (16) were obtained from Sigma-Aldrich Japan. MS 4Å was obtained from Junsei Chemical Co., Ltd. Pd₂(dba)₃·CHCl₃, 1-azido-2-bromobenzene (1) 2-(4-methoxyphenyl)oxirane (4), alkynylating agent 9, and alkynylating agent 11 were synthesized according to procedures and the spectra matched with those of compounds reported in the literature. All work-up and purification procedures were carried out with reagent-grade solvents in air.

Analytical TLC was performed using silica-gel 70 TLC Plate-Wako (0.25 mm). The developed chromatogram was analyzed by UV lamp (254 nm). Flash column chromatography was performed with Biotage Isolera^® equipped with Biotage SNAP Cartridge SNAP Ultra columns and hexane/EtOAc as an eluent. Preparative TLC (PTLC) was performed using Wakogel B5-F silica coated plates (0.75 mm) prepared in our laboratory. High-resolution mass spectra were conducted on Thermo Fisher Scientific Exactive (ESI). NMR spectra were recorded on a JEOL JNM-ECS-400, a JNM-ECZ-400 (¹H 400 MHz, ¹³C 101 MHz) and a Bruker Avance 600 (¹³C 151 MHz). Chemical shifts for ¹H NMR are expressed in parts per million (ppm) relative to TMS (δ = 0.00) or CHDCl₂ (δ = 5.32). ¹³C NMR are expressed in ppm relative to CDCl₃ (δ = 77.0) or DMSO-d ₆ (δ = 39.52) or CD₂Cl₂ (δ = 53.8). Data are reported as follows: chemical shift, multiplicity (br = broad signal, s = singlet, d = doublet, dd = doublet of doublets, t = triplet, hept = heptet, td = triplet of doublets, m = multiplet), coupling constant (Hz), and integration.

Synthesis of Ynamide Precursors

3-(2-Azidophenyl)thiophene (3)

1-Azido-2-bromobenzene (1; 20.0 g, 101 mmol, 1.0 equiv), 3-thiopheneboronic acid (2; 19.4 g, 152 mmol, 1.5 equiv), Pd₂(dba)₃·CHCl₃ (0.73 g, 0.71 mmol, 0.70 mol%), and P( ^t Bu)₃·HBPh₄ (0.74 g, 1.4 mmol, 1.4 mol%) were dissolved in THF (200 mL, 0.5 M). To the reaction mixture was added 6.0 M aq NaOH (51 mL, 3.0 equiv) and stirred for 4 h at 65 °C. The mixture was diluted with EtOAc and H₂O. The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by Isolera (hexane/EtOAc 19:1 to 6:1) to afford biaryl 3 as a colorless oil; yield: 19.5 g (95 mmol, 94%).

¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.49 (m, 1 H), 7.44 (dd, J = 7.5, 1.6 Hz, 1 H), 7.36–7.31 (m, 3 H), 7.23–7.21 (m, 1 H), 7.18–7.14 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 138.02, 136.89, 130.56, 128.54, 128.49, 128.18, 125.03, 124.95, 123.76, 118.89.

HRMS (DART): m/z calcd for C₁₀H₈N₃S [M + H]⁺: 202.0433; found: 202.0432.

2-(3-(2-Azidophenyl)thiophen-2-yl)-2-(4-methoxyphenyl)ethan-1-ol (5)

To a 1.0 L round-bottomed flask were added biaryl 3 (15.2 g, 75.5 mmol, 1.0 equiv), 2-(4-methoxyphenyl)oxirane (4; 11.3 g, 75.5 mmol, 1.0 equiv), and CH₂Cl₂ (240 mL, 0.2 M). After cooling to –78 °C, TMSOTf (13.7 mL, 75.5 mmol, 1.0 equiv) was slowly added. After 1 h, another 1.0 equiv of TMSOTf was added, and the reaction mixture was stirred for 1 h at –78 °C. The mixture was quenched with aq NaHCO₃ and extracted with CH₂Cl₂: The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by Isolera (hexane/EtOAc 9:1 to 6:1) to afford alcohol 5 as a pale yellow liquid; yield: 5.87 g (17.3 mmol, 23%) and biaryl 3 was recovered (7.22 g, 36.0 mmol, 48%).

¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.36 (m, 1 H), 7.26 (d, J = 5.2 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 1 H), 7.14–7.09 (m, 4 H), 6.93 (d, J = 5.2 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 2 H), 4.26 (t, J = 7.4 Hz, 1 H), 4.00 (d, J = 7.4 Hz, 2 H), 3.77 (s, 3 H), 1.72 (br s, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 158.45, 141.45, 138.34, 136.03, 132.80, 131.77, 129.59, 129.04, 128.91, 128.41, 124.56, 122.96, 118.58, 114.01, 67.24, 55.18, 46.85.

HRMS (ESI): m/z calcd for C₁₉H₁₇N₃O₂SNa [M + Na]⁺: 374.0934; found: 374.0930.

N-(2-(3-(2-Azidophenyl)-5-bromothiophen-2-yl)-2-(4-methoxyphenyl)ethyl)-4-nitrobenzenesulfonamide (6)

To a 500 mL round-bottomed flask were added alcohol 5 (9.09 g, 25.9 mmol, 1.0 equiv), PPh₃ (11.5 g, 44.0 mmol, 1.7 equiv), NHBocNs (13.3 g, 44.0 mmol, 1.7 equiv), and THF (130 mL, 0.2 M). To the mixture was added diisopropyl azodicarboxylate (DIAD: 23.1 mL, 1.9 M in toluene, 44.0 mmol, 1.7 equiv) at 0 °C. The resulting solution was warmed to RT and stirred overnight. The reaction mixture was quenched with aq NaHCO₃ and extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by Isolera (hexane/EtOAc 4:1 to 2:1) to afford the intermediate Boc-amine (15.9 g). The product was used in the next step without further purification.

To a 300 mL round-bottomed flask were added K₂CO₃ (17.3 g, 125 mmol, 5.0 equiv), imidazole (8.51 g, 125 mmol, 5.0 equiv), MeCN (125 mL, 0.2 M), and Boc-amine (15.9 g). The mixture was stirred overnight at 60 °C. The mixture was quenched with aq NH₄Cl and extracted with EtOAc. The combined extracts were washed with aq NaHCO₃, dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by Isolera (hexane/EtOAc 4:1 to 2:1) to afford the intermediate Ns-amine (13.2 g). The product was used in the next step without further purification.

To a 300 mL round-bottomed flask were added NBS (4.39 g, 24.7 mmol, 1.0 equiv), Ns-amine (13.2 g), and THF (123 mL, 0.2 M). The reaction mixture was stirred for 9 h at RT. The mixture was quenched with aq NaHCO₃ and extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by Isolera (hexane/EtOAc 4:1 to 2:1) to afford bromothiophene 6 as a brown solid; yield: 9.0 g (14.7 mmol, 57% yield over 3 steps).

¹H NMR (400 MHz, CDCl₃): δ = 7.94 (dd, J = 7.2, 2.0 Hz, 1 H), 7.81 (dd, J = 7.8, 1.2 Hz, 1 H), 7.74–7.65 (m, 2 H), 7.46 (td, J = 8.0, 1.2 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 7.18 (td, J = 8.0, 1.2 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 2 H), 6.82 (s, 1 H), 6.75 (d, J = 8.8 Hz, 2 H), 5.46 (t, J = 6.0 Hz, 1 H), 4.16 (t, J = 8.0 Hz, 1 H), 3.75 (s, 3 H), 3.56 (dd, J = 8.0, 6.0 Hz, 2 H).

¹³C NMR (101 MHz, CDCl₃): δ = 158.89, 147.71, 142.76, 138.50, 136.56, 133.58, 133.50, 132.73, 132.13, 131.50, 131.23, 130.79, 129.71, 128.33, 126.61, 125.42, 124.76, 118.58, 114.30, 110.36, 55.23, 48.91, 44.30.

HRMS (ESI): m/z calcd for C₂₅H₂₁BrN₅O₅S₂ [M + H – N₂]⁺: 586.0101; found: 586.0098.

N-(2-(3-(2-Azidophenyl)-5-bromo-1,1-dioxidothiophen-2-yl)-2-(4-methoxyphenyl)ethyl)-4-nitrobenzenesulfonamide (7)

To a 50 mL round-bottomed flask were added bromothiophene 6 (1.60 g, 2.74 mmol, 1.0 equiv), mCPBA (77%; 1.53 g, 6.84 mmol, 2.5 equiv), and 1,2-dichloroethane (54 mL, 0.05 M). The reaction mixture was stirred for 6 h at 65 °C. The mixture was quenched with aq NaHCO₃ and aq Na₂S₂O₃. The mixture was extracted with CH₂Cl₂, the combined extracts were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by Isolera (hexane/EtOAc 4:1 to 2:1) to afford S,S-dioxide 7 as a yellow solid; yield: 1.25 g (2.0 mmol, 74%).

¹H NMR (400 MHz, CDCl₃): δ = 8.04–8.01 (m, 1 H), 7.86–7.84 (m, 1 H), 7.74–7.66 (m, 2 H), 7.51 (td, J = 7.6, 1.5 Hz, 1 H), 7.26–7.24 (m, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.14–7.07 (m, 3 H), 6.81 (s, 1 H), 6.79 (d, J = 8.7 Hz, 2 H), 6.05 (t, J = 7.2, 6.2 Hz, 1 H), 4.21 (dd, J = 9.8, 6.2 Hz, 1 H), 3.94–3.86 (m, 1 H), 3.77 (s, 3 H), 3.67–3.60 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃): δ = 159.18, 147.89, 138.68, 138.52, 138.14, 133.85, 133.55, 132.79, 131.60, 131.57, 130.57, 129.89, 129.07, 128.47, 125.48, 125.06, 123.21, 118.89, 118.29, 114.23, 55.24, 45.36, 45.12.

HRMS (ESI): m/z calcd for C₂₅H₂₁BrN₅O₇S₂ [M + H]⁺: 646.0060; found: 646.0062.

N-(2-(3-(2-Azidophenyl)-5-bromo-1-oxidothiophen-2-yl)-2-(4-methoxyphenyl)ethyl)-4-nitrobenzenesulfonamide (8)

Following the procedure reported in the literature,[5] to a 200 mL round-bottomed flask were added bromothiophene 6 (1.4 g, 2.28 mmol, 1.0 equiv) and CH₂Cl₂ (11 mL, 0.2 M). After cooling to –20 °C, BF₃·OEt₂ (2.86 mL, 22.8 mmol, 10 equiv) was added to the reaction mixture. After stirring for 10 min, mCPBA (77%; 511 mg, 2.28 mmol, 1.0 equiv) in CH₂Cl₂ (5.0 mL) was added dropwise (four times every hour), and the resultant mixture was further stirred at –20 °C for 1 h. The reaction was quenched with aq NaHCO₃ and aq Na₂S₂O₃. The mixture was extracted with CH₂Cl₂, dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by Isolera (hexane/EtOAc 4:1 to 2:1) to afford an inseparable mixture of S-oxides 8a and 8b as a yellow solid; yield: 480 mg (0.76 mmol, 33%); 8a/8b = 85:15 or 15:85, and 6 was recovered (435 mg, 0.71 mmol, 31% yield).

For the ¹H and ¹³C NMR spectra of the mixture of 8a and 8b, see the Supporting Information.

HRMS (ESI): m/z calcd for C₂₅H₂₁BrN₅O₆S₂ [M + H]⁺: 630.0111; found: 630.0109.

Ynamide Formation and the [4+2] Cycloaddition of S,S-Dioxide and S-Oxide

4-(2-Azidophenyl)-6-bromo-3-(4-methoxyphenyl)-1-((4-nitrophenyl)sulfonyl)-7-phenylindoline (10)

To a test tube were added S,S-dioxide 7 (12.9 mg, 0.020 mmol, 1.0 equiv), Cs₂CO₃ (9.8 mg, 0.030 mmol, 1.5 equiv), and 9 (10.4 mg, 0.030 mmol, 1.5 equiv). To the mixture was added 1,4-dioxane (0.4 mL, 0.05 M) at RT. The reaction mixture was stirred overnight at 80 °C. The mixture was passed through a short silica gel pad with EtOAc as eluent and concentrated in vacuo. This residue was purified by PTLC (hexane/EtOAc 6:1) to afford indoline 10 as a pale yellow solid; yield: 5.8 mg (0.085 mmol, 42%).

¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.49 (m, 2 H), 7.37 (s, 1 H), 7.34–7.26 (m, 3 H), 7.21–7.16 (m, 2 H), 7.05 (t, J = 7.6 Hz, 2 H), 6.98–6.89 (m, 4 H), 6.77 (d, J = 8.7 Hz, 2 H), 6.58 (d, J = 8.7 Hz, 2 H), 4.68 (dd, J = 12.1, 7.6 Hz, 1 H), 4.46 (t, J = 7.6 Hz, 1 H), 4.09 (dd, J = 12.1, 7.6 Hz, 1 H), 3.70 (s, 3 H).

¹³C NMR (101 MHz, DMSO-d ₆, 100 °C): δ = 157.74, 145.99, 141.69, 138.38, 136.63, 136.45, 135.94, 133.49, 133.04, 131.90, 131.85, 130.94, 130.12, 129.89, 129.03, 128.79, 128.71, 128.36, 127.35, 126.93, 124.03, 123.74, 122.37, 117.89, 113.09, 61.10, 54.69, 46.04 (one peak was missing due to overlapping).

¹³C NMR (101 MHz, CDCl₃): δ = 158.33, 146.24, 142.54, 138.63, 137.39, 137.30, 136.50, 134.28, 133.45, 132.79, 132.42, 131.92, 131.34, 130.96, 130.73, 130.37, 129.52, 129.43, 129.26, 129.00, 128.12, 127.58, 124.29, 123.75, 123.65, 117.85, 113.41, 62.97, 55.19, 47.69 (one excess peak was observed, probably due to rotamer).

HRMS (ESI): m/z calcd for C₃₃H₂₅BrN₅O₅S [M + H]⁺: 682.0754; found: 682.0751.

4-(2-Azidophenyl)-6-bromo-7-(4-bromophenyl)-3-(4-methoxyphenyl)-1-((4-nitrophenyl)sulfonyl)indoline (12)

To a 100 mL round-bottomed flask were added S,S-dioxide 7 (430 mg, 682 μmol), Cs₂CO₃ (622 mg, 1.91 mmol, 2.8 equiv), and 11 (408 mg, 0.96 mmol, 1.4 equiv). To the mixture was added 1,4-dioxane (17 mL, 0.05 M). The reaction mixture was stirred overnight at 50 °C. The mixture was passed through a short silica gel pad with EtOAc as eluent and concentrated in vacuo. This residue was purified by Isolera (hexane/EtOAc 9:1 to 6:1) to afford indoline 12 as a pale yellow solid; yield: 220 mg (0.29 mmol, 42%).

¹H NMR (400 MHz, CDCl₃): δ = 7.69 (t, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 1 H), 7.36 (s, 1 H), 7.31 (d, J = 7.2 Hz, 1 H), 7.20 (t, J = 8.2 Hz, 1 H), 7.16–7.07 (m, 4 H), 6.97–6.89 (m, 3 H), 6.77 (d, J = 8.7 Hz, 2 H), 6.60 (d, J = 8.7 Hz, 2 H), 4.65 (dd, J = 12.0, 7.0 Hz, 1 H), 4.46 (t, J = 7.0 Hz, 1 H), 4.12 (dd, J = 12.0, 7.0 Hz, 1 H), 3.71 (s, 3 H).

¹³C NMR (101 MHz, DMSO-d ₆, 100 °C): δ = 157.76, 145.78, 141.61, 138.27, 136.44, 136.30, 135.67, 133.28, 131.99, 131.90, 131.84, 131.78, 131.53, 130.93, 130.11, 130.03, 129.03, 128.65, 128.60, 128.30, 123.98, 123.75, 122.03, 121.23, 117.85, 113.07, 61.20, 54.63, 45.97.

HRMS (ESI): m/z calcd for C₂₅H₂₄Br₂N₅O₅S [M + H]⁺: 759.9859; found: 759.9856.

Formal Syntheses of Dictyodendrins B, C, and E

5-Bromo-4-(4-bromophenyl)-1-(4-methoxyphenyl)-3,6-dihydropyrrolo[2,3-c]carbazole (13)

To a 100 mL round-bottomed flask equipped with a reflux condenser were added o-dichlorobenzene (13.6 mL), indoline 12 (520 mg, 0.68 mmol, 1.0 equiv), and K₂CO₃ (94 mg, 0.68 mmol, 1.0 equiv). This mixture was heated at 160 °C and stirred for 2 h under air. The reaction mixture was passed through a short silica gel pad with EtOAc as eluent and concentrated in vacuo. This residue was purified by Isolera (hexane/EtOAc 9:1 to 4:1) to afford pyrrolocarbazole 13 as a pale yellow solid; yield: 239 mg (0.44 mmol, 64%).

¹H NMR (400 MHz, CDCl₃): δ = 8.47 (br s, 1 H), 8.11 (br s, 1 H), 7.71 (d, J = 8.7 Hz, 2 H), 7.50–7.44 (m, 5 H), 7.30 (td, J = 8.0, 1.0 Hz, 1 H), 7.19 (d, J = 2.7 Hz, 1 H), 7.04 (d, J = 8.7 Hz, 2 H), 6.90 (td, J = 8.0, 1.0 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 3.93 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 159.07, 138.54, 135.93, 133.70, 132.19, 132.02, 131.95, 130.50, 129.35, 124.87, 124.64, 123.57, 123.50, 123.06, 122.59, 120.14, 119.15, 118.97, 114.56, 113.50, 110.40, 100.68, 55.48.

HRMS (ESI): m/z calcd for C₂₇H₁₉Br₂N₂O [M + H]⁺: 544.9859; found: 544.9861.

5-Bromo-4-(4-bromophenyl)-7-isopropoxy-1-(4-methoxyphenyl)-3,6-dihydropyrrolo[2,3-c]carbazole (15)

A 20 mL glass vessel tube equipped with a J. Young^® O-ring trap was dried with a heat-gun in vacuo. Then, it was filled with N₂ and cooled to RT. To the glass vessel tube were added pyrrolocarbazole 13 (90 mg, 0.17 mmol, 1.0 equiv), B₂pin₂ (84 mg, 0.33 mmol, 2.0 equiv), and 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbpy; 13 mg, 0.050 mmol, 30 mol%). Then it was moved to N₂ atmosphere in the glove box. To the glass vessel tube were added [IrOMe(COD)]₂ (16 mg, 0.025 mmol, 15 mol%) and THF (1.6 mL, 0.1 M) in the glovebox. The glass vessel tube was sealed with the O-ring trap and then taken out from the glovebox. The mixture was stirred overnight at 70 °C. The mixture was concentrated in vacuo and purified by Isolera (hexane/EtOAc 9:1 to 6:1) to afford 14 (87 mg). Product 14 was used in the next step without further purification. Following the procedure reported in the literature,[6] to a 25 mL round-bottomed flask was added powdered molecular sieves 4Å (150 mg) and dried with a heat-gun in vacuo. Then it was filled with N₂ and cooled to RT. To the flask were added Cu(OAc)₂ (20 mg, 0.11 mmol, 1.0 equiv), DMAP (27 mg, 0.22 mmol, 2.0 equiv), and ⁱ PrOH (2.5 mL). A solution of 14 (87 mg) in CH₂Cl₂ (2.5 mL) was then added to the reaction mixture and the flask was stirred overnight at 40 °C. The reaction mixture was passed through a short silica gel pad with EtOAc as eluent and then concentrated in vacuo. The residue was purified by Isolera (hexane/EtOAc 9:1 to 6:1) to afford pyrrolocarbazole 15 as a white solid; yield: 22 mg (0.036 mmol, 22% over 2 steps).

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (br s, 1 H), 8.11 (br s, 1 H), 7.72 (d, J = 8.2 Hz, 2 H), 7.51–7.46 (m, 4 H), 7.19 (d, J = 2.7 Hz, 1 H), 7.04 (d, J = 8.7 Hz, 2 H), 6.81–6.79 (m, 2 H), 6.33 (t, J = 4.3 Hz, 1 H), 4.76 (hept, J = 6.0 Hz, 1 H), 3.93 (s, 3 H), 1.46 (d, J = 6.0 Hz, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 159.14, 143.62, 136.14, 133.52, 132.27, 132.13, 132.10, 130.50, 130.25, 129.48, 124.74, 123.42, 123.06, 122.65, 120.23, 119.31, 119.12, 117.14, 115.09, 113.57, 107.05, 101.10, 70.73, 55.57, 22.42.

HRMS (ESI): m/z calcd for C₃₀H₂₅Br₂N₂O₂ [M + H]⁺: 603.0277; found: 603.0278.

5-Bromo-4-(4-bromophenyl)-7-isopropoxy-3-(4-methoxyphenethyl)-1-(4-methoxyphenyl)-3,6-dihydropyrrolo[2,3-c]carbazole (17)

To a test tube were added pyrrolocarbazole 15 (2.5 mg, 4.1 μmol, 1.0 equiv), 18-crown-6 (6.6 mg, 25 μmol, 6.0 equiv), and THF (0.08 mL, 0.05 M). To this mixture were added 16 (2.9 mg, 12 μmol, 3.0 equiv) and 8.0 M aq NaOH (1.6 μL, 12 μmol, 3.0 equiv). The mixture was stirred at RT for 36 h. The mixture was passed through a short silica gel pad with EtOAc as eluent and then concentrated in vacuo. This residue was purified by PTLC (hexane/EtOAc 9:1) to afford pyrrolocarbazole 17 as a white solid; yield: 1.4 mg (1.86 μmol, 45%).

¹H NMR (400 MHz, CDCl₃): δ = 8.55 (br s, 1 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 2 H), 7.01 (d, J = 8.0 Hz, 2 H), 6.92 (s, 1 H), 6.79–6.74 (m, 4 H), 6.62 (d, J = 8.7 Hz, 2 H), 6.20 (d, J = 5.5 Hz, 1 H), 4.79–4.72 (m, 1 H), 3.93 (s, 3 H), 3.78–3.72 (m, 5 H), 2.65 (t, J = 8.0 Hz, 2 H) 1.45 (d, J = 6.0 Hz, 6 H).

¹³C NMR (151 MHz, CDCl₃): δ = 158.94, 158.26, 143.48, 138.24, 133.00, 132.64, 132.03, 131.60, 130.30, 129.92, 129.69, 129.56, 129.53, 129.15, 124.68, 123.45, 122.55, 122.22, 119.08, 117.27, 117.10, 115.07, 113.84, 113.42, 107.01, 103.27, 70.66, 55.49, 55.26, 50.06, 37.06, 22.33.

HRMS (ESI): m/z calcd for C₃₉H₃₅Br₂N₂O₃ [M + H]⁺: 737.1009; found: 737.1005.

7-Isopropoxy-5-methoxy-1,4-bis-(4-methoxyphenyl)-3-[2-(4-methoxy-phenyl)ethyl]-3,6-dihydropyrrolo[2,3-c]carbazole (18)

Following the procedure reported in the literature,[4j] [l] [8] NaOMe (163 mg, 3.0 mmol, 4.0 M in MeOH) was prepared in a test tube by the portionwise addition of Na (70 mg, 3.0 mmol) to MeOH (0.75 mL). To another test tube were added pyrrolocarbazole 17 (2.7 mg, 3.6 μmol, 1.0 equiv) and DMF (0.36 mL). Then, the prepared NaOMe solution (0.2 mL, 0.22 mmol, 60 equiv) and CuI (4.1 mg, 21 μmol, 6.0 equiv) were added to the mixture and stirred overnight at 100 °C. The reaction was quenched by aq NH₄Cl. After extraction with EtOAc, the combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by PTLC (hexane/EtOAc 2:1) to afford pyrrolocarbazole 18 as a white solid; yield: 1.3 mg (1.98 μmol, 55%).

¹H NMR (400 MHz, CD₂Cl₂): δ = 8.55 (br s, 1 H), 7.53 (d, J = 8.7 Hz, 2 H), 7.40 (d, J = 8.7 Hz, 2 H), 7.09 (d, J = 8.7 Hz, 2 H), 7.00 (d, J = 8.7 Hz, 2 H), 6.90 (s, 1 H), 6.78 (d, J = 7.2 Hz, 1 H), 6.74–6.69 (m, 3 H), 6.65 (d, J = 8.4 Hz, 2 H), 6.20 (d, J = 8.2 Hz, 1 H), 4.79–4.72 (m, 1 H), 3.93 (s, 3 H), 3.91 (s, 3 H), 3.83 (t, J = 7.8 Hz, 2 H), 3.73 (s, 3 H), 3.66 (s, 3 H), 2.62 (t, J = 7.8 Hz, 2 H), 1.44 (d, J = 6.0 Hz, 6 H).

¹³C NMR (151 MHz, CD₂Cl₂): δ = 159.78, 159.25, 158.57, 143.91, 140.75, 132.65, 132.20, 130.84, 130.83, 130.47, 129.98, 129.26, 129.24, 129.13, 127.98, 125.09, 119.59, 118.90, 118.31, 117.21, 117.13, 115.38, 113.95, 113.85, 113.61, 107.01, 71.02, 61.63, 55.74, 55.49, 50.43, 37.22, 22.43 (one peak was missing due to overlapping).

HRMS (ESI): m/z calcd for C₄₁H₄₁N₂O₅ [M + H]⁺: 641.3010; found: 641.3004.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Dr. Kenta Kato (Waseda University) for assistance with X-ray crystallography. The Materials Characterization Central Laboratory in Waseda University is acknowledged for the support of HRMS measurements.

• References

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Corresponding Author

Publication History

Received: 12 February 2022

Accepted after revision: 03 March 2022

Accepted Manuscript online:
03 March 2022

Article published online:
10 October 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

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  CrossrefPubMedSearch in Google Scholar
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• 2 Seimiya H. Drug Deliv. Syst. 2006; 21: 24
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• 3 Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, De Winter HL, Reynolds CH, Tounge BA, Luo C, Scott MK, Huang Y, Braeken M, Pieters SM. A, Berthelot DJ. C, Masure S, Bruinzeel WD, Jordan AD, Parker MH, Boyd RE, Qu J, Alexander RS, Brenneman DE, Reitz AB. J. Med. Chem. 2007; 50: 4261
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  CrossrefPubMedSearch in Google Scholar
• 4c Hirao S, Sugiyama Y, Iwao M, Ishibashi F. Biosci. Biotechnol. Biochem. 2009; 73: 1764
  CrossrefPubMedSearch in Google Scholar
• 4d Hirao S, Yoshinaga Y, Iwao M, Ishibashi F. Tetrahedron Lett. 2010; 51: 533
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• 4e Okano K, Fujiwara H, Noji T, Fukuyama T, Tokuyama H. Angew. Chem. Int. Ed. 2010; 49: 5925
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  Crossref
• 4i Yamaguchi AD, Chepiga KM, Yamaguchi J, Itami K, Davies HM. L. J. Am. Chem. Soc. 2015; 137: 644
  CrossrefPubMedSearch in Google Scholar
• 4j Pitts AK, O’Hara F, Snell RH, Gaunt MJ. Angew. Chem. Int. Ed. 2015; 54: 5451
  CrossrefPubMedSearch in Google Scholar
• 4k Zhang W, Ready JM. J. Am. Chem. Soc. 2016; 138: 10684
  CrossrefPubMedSearch in Google Scholar
• 4l Matsuoka J, Matsuda Y, Kawada Y, Oishi S, Ohno H. Angew. Chem. Int. Ed. 2017; 56: 7444
  CrossrefPubMedSearch in Google Scholar
• 4m Matsuoka J, Inuki S, Matsuda Y, Miyamoto Y, Otani M, Oka M, Oishi S, Ohno H. Chem. Eur. J. 2020; 26: 11150
  CrossrefPubMedSearch in Google Scholar
• 4n Banne S, Reddy DP, Li W, Wang C, Guo J, He Y. Org. Lett. 2017; 19: 4996
  CrossrefPubMedSearch in Google Scholar
• 5 Suzuki S, Asako T, Itami K, Yamaguchi J. Org. Biomol. Chem. 2018; 16: 3771
  CrossrefPubMedSearch in Google Scholar
• 6a Suzuki S, Segawa Y, Itami K, Yamaguchi J. Nat. Chem. 2015; 7: 227
  CrossrefPubMedSearch in Google Scholar
• 6b Suzuki S, Itami K, Yamaguchi J. Angew. Chem. Int. Ed. 2017; 56: 15010
  CrossrefPubMedSearch in Google Scholar
• 6c Asako T, Suzuki S, Itami K, Muto K, Yamaguchi J. Chem. Lett. 2018; 47: 968
  CrossrefSearch in Google Scholar
• 6d Tanaka S, Asako T, Ota E, Yamaguchi J. Chem. Lett. 2020; 49: 918
  CrossrefSearch in Google Scholar
• 6e Asako T, Suzuki S, Tanaka S, Ota E, Yamaguchi J. J. Org. Chem. 2020; 85: 15437
  CrossrefPubMedSearch in Google Scholar
• 7 Taylor SK, Clark DL, Heinz KJ, Schramm SB, Westermann CD, Barnell KK. J. Org. Chem. 1983; 48: 592
  CrossrefSearch in Google Scholar
• 8 Vaillant FL, Courant T, Waser J. Angew. Chem. Int. Ed. 2015; 54: 11200
  CrossrefPubMedSearch in Google Scholar
• 9 CCDC 2070911 (13) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 10 Liyu J, Sperry J. Tetrahedron Lett. 2017; 58: 1699
  CrossrefSearch in Google Scholar
• 11 Loach RP, Fenton OS, Amaike K, Siegel DS, Ozkal E, Movassaghi M. J. Org. Chem. 2014; 79: 11254
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material