Protecting-Group-Free Total Synthesis of Anticancer (±)-Melotenine A

Abstract

Melotenine A, isolated from Melodinus tenuicaudatus, possesses significant anticancer activity against several human cancer cell lines. The synthesis of (±)-melotenine A was achieved without the use of any protecting groups in 11 steps with an overall yield of 6.7%. The key steps of our strategy were a Diels–Alder reaction to construct the tetracyclic framework and ring-closing metathesis to form the seven-membered ring of (±)-melotenine A.

(–)-Melotenine A (1) was isolated from a medicinal plant, Melodinus tenuicaudatus, by Luo and co-workers in 2010.[1] It possesses an unprecedented 6/5/5/6/7-fused pentacyclic skeleton, as shown in Figure [1]. This natural product is strongly active against several cancer cell lines including breast cancer, hepatocellular carcinoma, myeloid leukemia, pancreatic cancer, and lung cancer.

In 2013, the asymmetric total synthesis of (–)-melotenine A was first reported by Andrade and co-workers in 14 steps with 1% overall yield.[2] The synthesis started by condensing N-tosyl-3-indolecarboxaldehyde as an A/B ring precursor and (R)-N-tert-butanesulfinamide as a chiral auxiliary to form an N-sulfinylimine. The C and D rings of this natural product were formed in one pot by a sequential reaction consisting of an intramolecular Mitsunobu reaction and an intramolecular aza-Baylis–Hillman reaction or vinylogous Mannich/olefin isomerization. Finally, the E ring was constructed by a Piers annulation. In 2019, Fan and co-workers also reported their attempts toward the synthesis of melotenine.[3] Their strategy consisted of tandem aminolysis/double aza-Michael addition of para-dienone to establish the A/B/C/D ring system and ring-closing metathesis to form the E ring.

Besides its potent anticancer properties, we became interested in the synthesis of melotenine A because we envisioned that this compound could be prepared efficiently and conveniently in a few steps from an analogue of a known compound. Scheme [1] shows our retrosynthetic analysis of melotenine A. The E ring of this compound could be formed by ring-closing metathesis of diene 2 followed by dehydration. Compound 2 could be prepared with a Grignard reaction of ketone 3 and vinylmagnesium bromide. The tetracyclic framework of compound 3 could be constructed by an intramolecular Diels–Alder reaction of precursor 4. This type of transformation was previously performed by Kuehne and co-workers in order to synthesize compound 3′ from precursor 4′, which was in turn prepared from tryptamine hydrochloride (5).[4] Therefore, we planned to use the same strategy to build the skeleton of compound 3 by replacing the benzyl group of compound 4′ with an allyl group.

We began the synthesis of melotenine A with the Pictet­–Spengler condensation of tryptamine hydrochloride (5) and methyl bromopyruvate (6) to form compound 7 in an excellent yield (Scheme [2]).[5] In this step, the desired product was collected by filtration and used in the following step without further purification. Compound 7 was then heated in pyridine at refluxing temperature to provide olefinic indoloazepine 8 in 79% yield over 2 steps. Next, compound 8 was treated with NaBH₃CN under acidic conditions to give compound 9 with almost quantitative yield (99%). Without purification by column chromatography, this compound subsequently underwent an intermolecular aza-Michael reaction with 3-butyn-2-one (10) to provide vinylogous amide 11 in an excellent yield (90%).[4a] Under acidic conditions, this compound further underwent an intramolecular Michael­ reaction followed by isomerization to afford bridged indoloazepine 12 in 98% yield. To avoid the conversion of product 12 back into the starting material 11, this compound had to be immediately employed in the subsequent step without column chromatography on silica gel. Next, compound 12 underwent a nucleophilic substitution reaction with allyl bromide (13a) to provide quaternary ammonium bromide 14a in 40% yield. The yield of the desired product 14b was significantly improved to 89% when allyl iodide (13b) was employed instead of 13a. Similar to the reactions performed by Kuehne and co-workers,[4a] compound 14b fragmented when it was heated with triethylamine in methanol to give indolylacrylate 4. This compound subsequently underwent an intramolecular Diels–Alder reaction when it was again treated with triethylamine in refluxing toluene to provide tetracyclic compound 3 in 76% yield over 2 steps.

With ketone 3 in hand, it was treated with vinylmagnesium bromide at 0 °C to provide an approximately 10:1 diastereomeric mixture of 2a (54% yield) and 2b (5% yield) (Scheme [3]). The relative configuration of the major product 2a was unambiguously confirmed by X-ray crystallography.[6] Examination of the most stable conformer of ketone 3 revealed that the si-face of the carbonyl carbon could be easily accessed by the Grignard reagent to provide 2a whereas the re-face could be blocked by the D ring, as shown in Figure [2]. In this reaction, although excess vinylmagnesium bromide (3 equiv) was employed, the carbonyl group (C=O) of the ester moiety did not undergo the Grignard reaction. This was presumably because deprotonation of the pyrrolidine NH also took place to generate enolate intermediate 3′, thus preventing the Grignard reagent from attacking the carbonyl carbon of the ester group.

Next, we planned to perform ring-closing metathesis on compound 2a (Scheme [4]). Since basic amines can deactivate the catalytic reactivity of Grubbs catalysts by strongly coordinating to the metal center,[7] we were concerned about this reaction although some weakly basic phenylamines, and hindered secondary and tertiary amines, have been successfully employed in metathesis reactions.[7a] This problem may be solved by either converting the amines into their corresponding ammonium salts[8] or performing the metathesis in the presence of acids.[9] Therefore, we initially performed this reaction with the second-generation Grubbs catalyst in the presence of p-TsOH in refluxing toluene, but only decomposition occurred. Surprisingly, when the reaction was performed in the absence of p-TsOH, pentacyclic compound 15a was obtained in 50% yield. Unfortunately, all of our attempts to perform an elimination reaction on compound 15a failed to provide melotenine A. For example, when 15a was treated with I₂ and PPh₃ in CH₂Cl₂ at room temperature or 0 °C for 4 days,[2a] a complex mixture of unidentified products was obtained. No reaction took place when p-TsOH[10] was employed in benzene or toluene at room temperature, and decomposition occurred when the reaction was performed at reflux. Other reagents such as I₂ (neat),[11] TMSI,[12] SOCl₂,[13] and Ac₂O/pyridine[14] gave a complex mixture of unidentified products. When milder Burgess[15] or Martin[16] dehydrating reagent was employed, no reaction was observed. Since the hydroxyl group of this compound is in the concave face, our attempts to convert this group into a better leaving group such as a tosylate group were not successful. For example, no reaction occurred when 15a was treated with p-TsCl, pyridine, and DMAP in CH₂Cl₂ [17] at room temperature, and heating this reaction at reflux only led to decomposition. Alternatively, compound 15a was treated with PDC with the expectation that oxidative rearrangement might occur to provide enone 17,[18] but only decomposition occurred. It should be noted that compound 15a was not very stable since it decomposed in only a few days despite storing in a freezer. This could be a reason why many reactions performed at elevated temperatures led to decomposition. Therefore, we decided to also perform an elimination reaction on alcohol 2a in order to provide compound 16, which would be subjected to ring-closing metathesis in the following step. To this end, various reagents (e.g., SOCl₂, Ac₂O or POCl₃ in the presence of pyridine, p-TsCl/pyridine/DMAP, MsCl/Et₃N, PPh₃/I₂, and p-TsOH) were employed, but the desired product was not observed.

With these disappointing results, we then turned to focus on using alcohol 2b as a precursor for ring-closing metathesis. Since this compound was produced in a very low yield, we first needed to adjust the reaction conditions to improve its yield. After several attempts, we found that we could obtain a 1:1 mixture of alcohols 2a (30% yield) and 2b (30% yield) when the Grignard reaction was performed at room temperature (Scheme [5]). A possible explanation is that as the temperature increased, the C19–C20 bond of the ketone moiety could rotate more freely, thus resulting in no diastereoselectivity. With alcohol 2b in hand, it was treated with the second-generation Grubbs catalyst in refluxing toluene, and pentacyclic compound 15b was obtained in an excellent yield (95%). This yield was much higher than that of compound 15a presumably because of the stability of 15b. Although compound 15a is only 0.9 kcal/mol higher in energy than compound 15b [calculated at the M06-2X/6-31G(d,p) level of theory], we found that 15b was much more stable since no decomposition was observed after storing 15b in a freezer for months. Finally, alcohol 15b was treated with I₂ and PPh₃ according to the procedure described by Andrade and co-workers to provide (±)-melotenine A in 50% yield.[2a] It should be noted that extensive investigation of this elimination reaction using various conditions was also performed by Andrade and co-workers, but none of these conditions could provide the desired natural product.[2b]

In summary, the synthesis of anticancer (±)-melotenine A was achieved in 11 steps with 6.7% overall yield starting from commercially available tryptamine hydrochloride. Since no protecting group was employed, the synthesis is relatively short and efficient. Our key steps included a Diels–Alder reaction to construct the C/D ring system and ring-closing metathesis to form the E ring. We found that our strategy led to a pair of diastereomeric alcohols 15a and 15b. While 15b could be transformed to (±)-melotenine A, all of our attempts employing 15a resulted in decomposition or no reaction.

¹H NMR spectra were recorded at 400 MHz, and ¹³C NMR spectra were recorded at 100 MHz, using a Bruker 400 MHz spectrometer. Chemical shifts (δ) are reported in parts per million relative to the solvent residual signal of CDCl₃ (δ 7.26 ppm) or DMSO-d ₆ (δ 2.50 ppm) for ¹H NMR spectra, and relative to the center line of CDCl₃ (δ 77.16 ppm) or DMSO-d ₆ (δ 39.52 ppm) for ¹³C NMR spectra. Multiplicities are given as the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), and combinations thereof. Coupling constants (J) are reported in hertz (Hz). High-resolution mass spectra (HRMS) were recorded on a quadrupole time-of-flight (QTOF) micro-TOPQIII mass spectrometer equipped with an electrospray ionization (ESI) source. HRMS data were given in m/z within a tolerance of 10 ppm of the theoretically calculated value, and measurements are given in Da. IR spectra were recorded on a PerkinElmer attenuated total reflectance (ATR) spectrophotometer. Melting points were determined using a melting point apparatus with hot-stage microscopy from Bibby Stuart Scientific Company. All reactions were monitored by TLC performed on silica gel 60Å F₂₅₄ aluminum sheets. Visualization of the developed chromatograms was performed by UV absorbance at 254 and 368 nm. Flash column chromatography was performed on silica gel F₆₀ (mesh size 40–63 μm) purchased from SiliCycle Inc. All commercially available reagents were used without further purification unless otherwise noted. All reactions were set up under a nitrogen or an argon atmosphere and anhydrous reactions were performed using flame-dried glassware and standard syringe septum techniques. Anhydrous solvents were obtained by distillation over calcium hydride (MeCN, CH₂Cl₂, toluene, pyridine, and Et₃N). MeOH was distilled from magnesium under a nitrogen atmosphere. THF and Et₂O were dried by distillation from sodium benzophenone ketyl under a nitrogen atmosphere.

Methyl 1-(Bromomethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate (7)[5]

A suspension of tryptamine hydrochloride (5) (10.0 g, 50.8 mmol) and methyl bromopyruvate (6) (6.28 mL, 58.9 mmol) in MeOH (120 mL) was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. Then, water (150 mL) was added to the crude residue. To the vigorously stirred crude mixture, ammonium hydroxide solution was added until the mixture became basic and a precipitate formed. The precipitate was then collected by filtration and washed with ether to provide compound 7 (15.6 g, 95% yield) as a brown solid. This compound was subsequently employed in the next step without further purification.

¹H NMR (400 MHz, CDCl₃): δ = 8.33 (s, 1 H), 7.52 (d, J = 7.4 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.22 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.13 (ddd, J = 8.1, 7.0, 1.0 Hz, 1 H), 4.23 (d, J = 10.8 Hz, 1 H) and 4.12 (d, J = 10.0 Hz, 1 H), 3.86 (s, 3 H), 3.79 (d, J = 10.6 Hz, 1 H) and 3.66 (d, J = 10.0 Hz, 1 H), 3.25 (t, J = 5.7 Hz, 2 H), 2.86–2.74 (m, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 172.1, 136.4, 128.4, 126.8, 123.1, 120.0, 119.0, 112.7, 111.4, 63.4, 53.4, 50.6, 40.6 and 39.5, 22.0.

Methyl 1,2,3,6-Tetrahydroazepino[4,5-b]indole-5-carboxylate (8)[4b]

A solution of compound 7 (2.00 g, 6.19 mmol) in pyridine (8 mL) was heated at reflux for 2 h. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure (co-evaporation with toluene). The crude residue was dissolved in CH₂Cl₂ (100 mL) and washed with water (3 × 30 mL). The organic phase was dried over Na₂SO₄, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica gel (EtOAc/hexane, 1:2) to give compound 8 (1.25 g, 83% yield) as a light brown or yellow solid; mp 151–152 °C (recrystallized in EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 10.45 (s, 1 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.43 (dd, J = 7.3, 1.0 Hz, 1 H), 7.35 (dd, J = 6.8, 1.3 Hz, 1 H), 7.18–7.03 (m, 2 H), 5.28 (s, 1 H), 3.81 (s, 3 H), 3.54 (q, J = 4.6 Hz, 2 H), 3.16–3.14 (m, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 169.6, 146.0, 134.4, 131.8, 127.9, 120.6, 118.8, 116.5, 110.7, 109.5, 93.0, 51.4, 45.8, 26.7.

Methyl 1,2,3,4,5,6-Hexahydroazepino[4,5-b]indole-5-carboxylate (9)[4b]

To a solution of compound 8 (5.00 g, 20.6 mmol) in glacial AcOH (37 mL) was added NaBH₃CN (3.36 g, 57.8 mmol) in small portions over a period of 30 min. Then, the reaction mixture was stirred at room temperature for 30 min. After cooling the reaction mixture in an ice bath, a solution of ammonium hydroxide was slowly added until the mixture turned to basic. The mixture was then diluted with CH₂Cl₂ (100 mL), and washed with water (3 × 30 mL). The organic phase was dried over Na₂SO₄, and the solvent was removed under reduced pressure to provide the desired product as a light brown, foamy solid (4.99 g, 99% yield). This compound was subsequently employed in the next step without further purification.

¹H NMR (400 MHz, CDCl₃): δ = 8.28 (s, 1 H), 7.49 (dd, J = 7.7, 1.2 Hz, 1 H), 7.30 (dd, J = 7.8, 1.0 Hz, 1 H), 7.16 (ddd, J = 8.1, 7.0, 1.3 Hz, 1 H), 7.10 (ddd, J = 8.1, 7.0, 1.2 Hz, 1 H), 3.87 (dd, J = 4.7, 2.8 Hz, 1 H), 3.73 (s, 3 H), 3.61 (d, J = 4.7 Hz, 1 H) and 3.58 (d, J = 4.7 Hz, 1 H), 3.32 (dd, J = 5.4, 2.4 Hz, 1 H) and 3.29 (dd, J = 4.2, 3.2 Hz, 1 H), 3.26 (d, J = 2.9 Hz, 1 H) and 3.23 (d, J = 2.9 Hz, 1 H), 3.01–2.98 (m, 1 H), 2.96–2.94 (m, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 172.5, 135.1, 131.9, 128.8, 121.9, 119.5, 118.3, 114.7, 110.8, 52.5, 50.8, 49.8, 48.3, 27.9.

Methyl 3-((E)-3-Oxobut-1-en-1-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (11)[4a]

To a solution of compound 9 (4.00 g, 16.4 mmol) in MeCN (60 mL) was added 3-butyn-2-one (10) (1.84 mL, 23.4 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (EtOAc/hexane, 4:1) to provide compound 11 (4.62 g, 90% yield) as a light brown or yellow foamy solid.

¹H NMR (400 MHz, CDCl₃): δ = 8.53 (s, 1 H), 7.65 (d, J = 12.7 Hz, 1 H), 7.50 (d, J = 7.9 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.19 (ddd, J = 8.2, 7.0, 1.3 Hz, 1 H), 7.12 (ddd, J = 7.5, 7.0, 1.1 Hz, 1 H), 5.21 (d, J = 13.7 Hz, 1 H), 4.31–4.07 (m, 2 H), 3.96 (dd, J = 14.1, 3.5 Hz, 1 H), 3.77 (s, 3 H), 3.63–3.47 (m, 2 H), 3.20–3.13 (m, 2 H), 2.13 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 196.0, 170.7, 151.8, 135.1, 129.2, 128.1, 122.5, 119.8, 118.1, 112.9, 111.0, 97.0, 54.6, 53.0, 50.1, 46.9, 25.4, 21.5.

Methyl 11-(2-Oxopropyl)-1,2,4,6-tetrahydro-3,10b-methanoazepino[4,5-b]indole-5-carboxylate (12)[4a]

To a solution of compound 11 (5.00 g, 16.0 mmol) in anhydrous THF (175 mL) was added dropwise a saturated HCl solution in Et₂O (7.2 mL). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The resulting residue was dissolved in CH₂Cl₂ (20 mL) and washed with 1 M NaOH (2 × 20 mL). The organic phase was dried over Na₂SO₄, and the solvent was removed under reduced pressure to give compound 12 (4.90 g, 98% yield) as a brown solid. To avoid the conversion of compound 12 back into the starting material 11, it was immediately employed in the next step without further purification.

¹H NMR (400 MHz, CDCl₃): δ = 8.96 (s, 1 H), 7.18 (td, J = 7.7, 1.2 Hz, 1 H), 7.13 (d, J = 7.8 Hz, 1 H), 6.89 (td, J = 7.5, 1.0 Hz, 1 H), 6.85 (dt, J = 7.9, 0.8 Hz, 1 H), 3.98 (d, J = 16.1 Hz, 1 H), 3.72 (s, 3 H), 3.53 (dd, J = 10.4, 4.9 Hz, 1 H), 3.45 (d, J = 16.2 Hz, 1 H), 3.39 (ddd, J = 10.0, 9.5, 5.0 Hz, 1 H), 2.89–2.72 (m, 3 H), 2.38 (ddd, J = 13.4, 8.9, 4.7 Hz, 1 H), 2.29–2.25 (m, 1 H), 2.23 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 206.5, 168.9, 165.2, 145.0, 129.0, 128.6, 123.8, 121.1, 109.6, 86.2, 64.8, 57.8, 53.9, 52.2, 50.9, 43.3, 43.1, 30.2.

3-Allyl-5-(methoxycarbonyl)-11-(2-oxopropyl)-2,3,4,6-tetrahydro-1H-3,10b-methanoazepino[4,5-b]indol-3-ium Iodide (14b)

To a solution of compound 12 (4.90 g, 15.7 mmol) in THF (78 mL) was added allyl iodide (3.30 mL, 36.1 mmol). The reaction mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure. To the crude residue was added EtOAc (60 mL), and the resulting suspension was stirred for 30 min. The desired product was collected by filtration and washed several times with EtOAc to give compound 14b (6.67 g, 89% yield) as an orange solid. This compound was subsequently employed in the next step without further purification; mp 162–163 °C (recrystallized in EtOAc).

IR (neat): 3424, 1649, 1609 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.30 (s, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.25 (td, J = 7.7, 1.1 Hz, 1 H), 7.13 (d, J = 7.8 Hz, 1 H), 6.91 (td, J = 7.5, 1.1 Hz, 1 H), 6.02 (dq, J = 16.9, 7.5 Hz, 1 H), 5.71 (d, J = 16.7 Hz, 1 H), 5.62 (d, J = 10.1 Hz, 1 H), 4.56–4.43 (m, 2 H), 4.26–4.17 (m, 2 H), 4.08 (dd, J = 12.9, 7.7 Hz, 1 H), 3.96 (dt, J = 13.0, 6.2 Hz, 2 H), 3.77–3.69 (m, 1 H), 3.71 (s, 3 H), 3.60 (d, J = 6.5 Hz, 1 H), 2.65 (td, J = 12.1, 6.6 Hz, 1 H), 2.44–2.37 (m, 1 H), 2.29 (s, 3 H).

¹³C{¹H} NMR (100 MHz, DMSO-d ₆): δ = 203.4, 165.0, 160.5, 145.4, 129.6, 126.8, 126.5, 125.1, 124.8, 121.3, 110.9, 82.0, 69.8, 63.3, 63.2, 59.6, 54.6, 51.0, 38.0, 37.7, 30.1.

HRMS (ESI): m/z [M]⁺ calcd for C₂₁H₂₅N₂O₃: 353.1860; found: 353.1872.

Methyl 4-Acetyl-3-allyl-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate (3)

To a solution of compound 14b (2.00 g, 4.16 mmol) in MeOH (50 mL) was added Et₃N (3.10 mL, 22.0 mmol). The reaction mixture was heated at reflux for 6 h, and then allowed to cool to room temperature. The solvent was removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (EtOAc/ hexane, 1:1 and Et₃N/EtOAc/hexane, 1:4:5) to give compound 4, along with some impurities, as a light yellow solid [1.49 g; HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₄N₂O₃Na: 375.1679; found: 375.1692]. This compound was then dissolved in toluene (45 mL), and Et₃N (7.50mL, 53.4 mmol) was added. The reaction mixture was heated at reflux for 16 h. After allowing the reaction mixture to cool to room temperature, the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica gel (EtOAc/hexane, 1:2) to provide product 3 (1.12 g, 76% yield over 2 steps) as a white foamy solid; mp 118–120 °C (recrystallized in hexane).

IR (film): 3391, 1701, 1671 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.80 (s, 1 H), 7.23 (d, J = 7.4 Hz, 1 H), 7.15 (td, J = 7.7, 1.2 Hz, 1 H), 6.92 (td, J = 7.5, 1.0 Hz, 1 H), 6.81 (d, J = 7.8 Hz, 1 H), 5.99 (ddt, J = 16.8, 10.1, 6.5 Hz, 1 H), 5.28 (dd, J = 17.2, 1.7 Hz, 1 H), 5.16 (dd, J = 10.3, 1.7 Hz, 1 H), 3.76 (s, 3 H), 3.61 (s, 1 H), 3.46 (dd, J = 13.6, 6.0 Hz, 1 H), 3.32 (dd, J = 13.5, 7.1 Hz, 1 H), 3.19 (dt, J = 15.7, 2.3 Hz, 1 H), 3.07 (dd, J = 9.2, 6.3 Hz, 1 H), 2.81 (t, J = 3.6 Hz, 1 H), 2.74 (ddd, J = 12.4, 9.2, 4.9 Hz, 1 H), 2.67 (dd, J = 15.6, 4.1 Hz, 1 H), 2.04 (s, 3 H), 1.99 (dd, J = 12.3, 6.4 Hz, 1 H), 1.73 (dd, J = 11.9, 4.8 Hz, 1 H).

¹³C{¹H} NMR (100 MHz, DMSO-d ₆): δ = 209.4, 166.6, 164.7, 143.4, 137.6, 136.0, 127.4, 121.6, 120.2, 117.3, 110.0, 88.4, 65.8, 56.6, 55.6, 52.2, 50.6, 50.1, 41.9, 27.8, 21.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₄N₂O₃Na: 375.1679; found: 375.1685.

Methyl 3-Allyl-4-(2-hydroxybut-3-en-2-yl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate (2a and 2b)

To a solution of compound 3 (1.12 g, 3.18 mmol) in THF (35 mL) in an ice bath was added 1 M vinylmagnesium bromide in THF (10.0 mL, 10.0 mmol). The reaction mixture was stirred at 0 °C for 3 h. Then, a saturated solution of ammonium chloride (30 mL) was added followed by water (30 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The organic phase was dried over Na₂SO₄, and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica gel (EtOAc/hexane, 1:2) to give compounds 2a (655 mg, 54% yield) and 2b (61 mg, 5% yield) as white solids. When the reaction was performed at room temperature by adding 1 M vinylmagnesium bromide in THF (9.00 mL, 9.00 mmol) to a solution of compound 3 (1.00 g, 2.84 mmol) in THF (32 mL), and the reaction mixture was stirred at room temperature for 3 h, 324 mg (30% yield) of 2a and 324 mg (30% yield) of 2b were obtained. 2a Mp 125–127 °C (recrystallized in hexane).

IR (film): 3392, 1670 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.96 (s, 1 H), 7.20 (d, J = 7.4 Hz, 1 H), 7.14 (td, J = 7.7, 1.2 Hz, 1 H), 6.88 (td, J = 7.5, 1.0 Hz, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 6.03 (dddd, J = 17.5, 10.1, 7.6, 5.4 Hz, 1 H), 5.58 (dd, J = 17.2, 10.7 Hz, 1 H), 5.30 (dd, J = 17.1, 1.6 Hz, 1 H), 5.20 (d, J = 10.0 Hz, 1 H), 4.92 (dd, J = 17.3, 1.3 Hz, 1 H), 4.83 (dd, J = 10.7, 1.3 Hz, 1 H), 3.77 (s, 3 H), 3.60 (ddt, J = 13.9, 5.4, 1.6 Hz, 1 H), 3.26–3.21 (m, 2 H), 3.02 (dd, J = 9.2, 6.2 Hz, 1 H), 2.93 (dt, J = 15.9, 2.3 Hz, 1 H), 2.72 (ddd, J = 12.3, 9.1, 4.7 Hz, 1 H), 2.44 (dd, J = 15.9, 4.4 Hz, 1 H), 2.06 (td, J = 12.0, 6.3 Hz, 1 H), 1.85 (dd, J = 4.5, 2.6 Hz, 1 H), 1.70 (dd, J = 11.8, 4.6 Hz, 1 H), 1.39 (br s, 1 H), 0.99 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 168.5, 166.0, 145.2, 143.1, 137.9, 135.7, 127.9, 122.4, 120.7, 117.6, 111.1, 109.2, 91.2, 74.6, 67.2, 56.3, 56.0, 51.1, 50.1, 49.7, 41.4, 27.3, 20.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₉N₂O₃: 381.2173; found: 381.2177. 2b Mp 64–65 °C (recrystallized in hexane)

IR (ATR): 3368, 1677 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.98 (s, 1 H), 7.17 (d, J = 7.4 Hz, 1 H), 7.13 (td, J = 7.7, 1.2 Hz, 1 H), 6.86 (td, J = 7.5, 1.0 Hz, 1 H), 6.79 (d, J = 7.6 Hz, 1 H), 6.05 (dddd, J = 17.5, 10.1, 7.6, 5.4 Hz, 1 H), 5.40 (dd, J = 17.3, 10.8 Hz, 1 H), 5.32 (dd, J = 17.1, 1.6 Hz, 1 H), 5.20 (d, J = 10.1 Hz, 1 H), 4.67 (dd, J = 17.3, 1.2 Hz, 1 H), 4.46 (dd, J = 10.8, 1.2 Hz, 1 H), 3.76 (s, 3 H), 3.67 (dd, J = 13.8, 5.3 Hz, 1 H), 3.36 (d, J = 1.8 Hz, 1 H), 3.28 (dd, J = 14.0, 7.7 Hz, 1 H), 3.03 (dd, J = 9.2, 6.2 Hz, 1 H), 2.87 (dt, J = 15.8, 2.2 Hz, 1 H), 2.72 (ddd, J = 12.4, 9.1, 4.8 Hz, 1 H), 2.47 (dd, J = 15.9, 4.4 Hz, 1 H), 2.04 (td, J = 12.2, 6.3 Hz, 1 H), 1.95 (dd, J = 4.5, 2.6 Hz, 1 H), 1.69 (dd, J = 11.8, 4.7 Hz, 1 H), 1.25 (br s, 1 H), 1.20 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 168.6, 166.4, 144.3, 143.1, 138.3, 135.9, 127.8, 122.3, 120.7, 117.6, 111.3, 109.1, 91.1, 74.5, 66.8, 56.6, 55.9, 51.1, 51.1, 50.2, 41.5, 28.1, 20.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₉N₂O₃: 381.2173; found: 381.2162.

Methyl 4-Hydroxy-4-methyl-1,4,4a,4a¹,5,7,12,13-octahydroazepino[3′,2′,1′:7,1]indolo[4,3a-b]indole-6-carboxylate (15a)

A solution of alcohol 2a (200 mg, 0.52 mmol) in toluene (16 mL) was heated at 110 °C. Then, a solution of 2^nd generation Grubbs catalyst (30.0 mg, 0.036 mmol) in toluene (8 mL) was added. The reaction mixture was heated at 110 °C for 24 h, and then allowed to cool to room temperature. The solvent was removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (EtOAc/hexane, 1:4 and 1:2) to provide compound 15a (92 mg, 50% yield) as a yellow solid; mp 119–121 °C (recrystallized in hexane).

IR (film): 3416, 1679 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.09 (s, 1 H), 7.60 (d, J = 7.5 Hz, 1 H), 7.12 (td, J = 7.6, 1.3 Hz, 1 H), 6.86 (td, J = 7.5, 1.0 Hz, 1 H), 6.77 (d, J = 7.7 Hz, 1 H), 5.70 (ddd, J = 11.8, 7.2, 4.6 Hz, 1 H), 5.63 (dd, J = 11.7, 1.6 Hz, 1 H), 3.70 (s, 3 H), 3.59 (dd, J = 13.3, 7.2 Hz, 1 H), 3.52 (d, J = 7.4 Hz, 1 H), 3.36 (dd, J = 9.6, 8.0 Hz, 1 H), 3.23 (ddd, J = 13.5, 4.6, 1.7 Hz, 1 H), 2.87 (dd, J = 16.8, 3.8 Hz, 1 H), 2.76 (ddd, J = 10.8, 9.6, 2.9 Hz, 1 H), 2.58 (dd, J = 16.8, 10.0 Hz, 1 H), 2.39–2.31 (m, 2 H), 1.79 (ddd, J = 12.3, 8.3, 2.3 Hz, 1 H), 1.65 (br s, 1 H), 1.39 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 168.9, 161.6, 143.6, 141.3, 137.0, 127.9, 124.3, 124.0, 121.0, 108.7, 91.5, 76.4, 64.7, 55.4, 51.12, 51.07, 48.0, 36.2, 36.1, 27.7, 21.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₅N₂O₃: 353.1887; found: 353.1877.

Methyl 4-Hydroxy-4-methyl-1,4,4a,4a¹,5,7,12,13-octahydroazepino[3′,2′,1′:7,1]indolo[4,3a-b]indole-6-carboxylate (15b)[2a]

Following the above procedure by replacing alcohol 2a with alcohol 2b (200 mg, 0.52 mmol), compound 15b (176 mg, 95% yield) was obtained as a yellow solid; mp 119–121 °C (recrystallized in hexane).

IR (ATR): 3460, 1677 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.14 (s, 1 H), 7.58 (d, J = 7.6 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 6.86 (t, J = 7.5 Hz, 1 H), 6.78 (d, J = 7.7 Hz, 1 H), 5.71–5.64 (m, 2 H), 3.76 (s, 3 H), 3.76–3.71 (m, 1 H), 3.39 (dd, J = 14.8, 2.6 Hz, 1 H), 3.32 (q, J = 8.5 Hz, 1 H), 3.16 (d, J = 7.4 Hz, 1 H), 2.89–2.78 (m, 2 H), 2.61–2.55 (m, 1 H), 2.51–2.46 (m, 1 H), 2.43–2.37 (m, 1 H), 1.82 (ddd, J = 12.5, 8.6, 3.2 Hz, 1 H), 1.82 (br s, 1 H), 1.10 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 168.9, 162.0, 143.6, 141.2, 137.3, 127.9, 125.1, 124.1, 121.0, 109.0, 91.8, 76.5, 65.7, 55.7, 51.1, 50.2, 48.3, 37.5, 36.2, 22.1, 21.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₅N₂O₃: 353.1860; found: 353.1870.

(±)-Melotenine A (1)[2a]

To a solution of PPh₃ (75 mg, 0.29 mmol) in CH₂Cl₂ (8 mL) was added iodine (66 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 20 min. A solution of 15b (46 mg, 0.13 mmol) in CH₂Cl­₂ (8 mL) was then added, and the reaction mixture was further stirred at room temperature for 4 days. The reaction mixture was quenched with sat. aq NaHCO₃ (10 mL), and the aqueous phase was removed. The organic layer was further washed with sat. aq NaHCO₃ (2 × 10 mL), 5% aq Na₂SO₃ (3 × 10 mL), and sat. NaCl (2 × 10 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc/hexane, 1:5) to provide (±)-melotenine A (22 mg, 50% yield).

IR (ATR): 2920, 2850, 1681 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.06 (s, 1 H), 7.33 (d, J = 7.4 Hz, 1 H), 7.15 (td, J = 7.7, 1.3 Hz, 1 H), 6.89 (td, J = 7.5, 1.0 Hz, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 6.00–5.99 (m, 2 H), 3.81 (d, J = 7.9 Hz, 1 H), 3.79 (s, 3 H), 3.75 (s, 1 H), 3.63 (dd, J = 15.5, 2.9 Hz, 1 H), 3.30 (d, J = 13.6 Hz, 1 H), 3.10–2.99 (m, 3 H), 2.45 (dt, J = 12.5, 8.5 Hz, 1 H), 1.94–1.88 (m, 1 H), 1.87 (s, 3 H).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₃N₂O₂: 335.1754; found: 335.1761.

Conflict of Interest

The authors declare no conflict of interest.

• References

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Corresponding Author

Publication History

Received: 06 August 2021

Accepted after revision: 03 September 2021

Accepted Manuscript online:
03 September 2021

Article published online:
12 October 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Feng T, Li Y, Liu Y.-P, Cai X.-H, Wang Y.-Y, Luo X.-D. Org. Lett. 2010; 12: 968
  CrossrefPubMedSearch in Google Scholar
• 2a Zhao S, Sirasani G, Vaddypally S, Zdilla MJ, Andrade RB. Angew. Chem. Int. Ed. 2013; 52: 8309
  CrossrefPubMedSearch in Google Scholar
• 2b Zhao S, Sirasani G, Vaddypally S, Zdilla MJ, Andrade RB. Tetrahedron 2016; 72: 6107
  CrossrefSearch in Google Scholar
• 3 Du J.-Y, An X.-T, Zhao X.-H, Ma X.-Y, Cao Y.-X, Fan C.-A. Tetrahedron 2019; 75: 1760
  CrossrefSearch in Google Scholar
• 4a Kuehne ME, Earley WG. Tetrahedron 1983; 39: 3707
  CrossrefSearch in Google Scholar
• 4b Kuehne ME, Bohnert JC, Bornmann WG, Kirkemo CL, Kuehne SE, Seaton PJ, Zebovitz TC. J. Org. Chem. 1985; 50: 919
  CrossrefSearch in Google Scholar
• 5 Chen P, Cao L, Li C. J. Org. Chem. 2009; 74: 7533
  CrossrefPubMedSearch in Google Scholar
• 6 CCDC 2094865 (2a) 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. See the Supporting Information for details.
• 7a Compain P. Adv. Synth. Catal. 2007; 349: 1829
  CrossrefSearch in Google Scholar
• 7b Wilson GO, Porter KA, Weissman H, White SR, Sottos NR, Moore JS. Adv. Synth. Catal. 2009; 351: 1817
  CrossrefSearch in Google Scholar
• 8 Fu GC, Nguyen ST, Grubbs RH. J. Am. Chem. Soc. 1993; 115: 9856
  CrossrefSearch in Google Scholar
• 9 Ranaivondrambola T, Hatton W, Felpin F.-X, Evain M, Mathé-Allainmat M, Lebreton J. Synlett 2010; 1631
• 10 Liu Y.-T, Li L.-P, Xie J.-H, Zhou Q.-L. Angew. Chem. Int. Ed. 2017; 56: 12708
  CrossrefPubMedSearch in Google Scholar
• 11 Stavber G, Zupan M, Stavber S. Tetrahedron Lett. 2006; 47: 8463
  CrossrefSearch in Google Scholar
• 12 Aversa MC, Barattucci A, Bonaccorsi P, Giannetto P. Tetrahedron 2002; 58: 10145
  CrossrefSearch in Google Scholar
• 13 Jurissek C, Berger F, Eisenreich F, Kathan M, Hecht S. Angew. Chem. Int. Ed. 2019; 58: 1945
  CrossrefPubMedSearch in Google Scholar
• 14 Guevel A.-C, Hart DJ. J. Org. Chem. 1996; 61: 465
  CrossrefPubMedSearch in Google Scholar
• 15 Blencowe PS, Barrett AG. M. Eur. J. Org. Chem. 2014; 4844
  Crossref
• 16 Sparling BA, Moslin RM, Jamison TF. Org. Lett. 2008; 10: 1291
  CrossrefPubMedSearch in Google Scholar
• 17 Rollin P, Pougny J.-R. Tetrahedron 1986; 42: 3479
  CrossrefSearch in Google Scholar
• 18 Saini G, Mondal A, Kapur M. Org. Lett. 2019; 21: 9071
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material