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DOI: 10.1055/s-0034-1378659
Synthesis of C-10 Tabersonine Analogues by Palladium-Catalyzed Cross-Coupling Reactions
Publication History
Received: 09 April 2014
Accepted after revision: 25 June 2014
Publication Date:
27 August 2014 (online)
Abstract
A series of C-10-substituted tabersonine analogues have been synthesized via palladium-catalyzed cross-coupling reactions. To be specific, tabersonine reacted with NIS in TFA to generate the 10-iodotabersonine, which participated in palladium-catalyzed or palladium/copper co-catalyzed cross-coupling reactions, such as Suzuki–Miyaura cross-coupling reaction, Heck reaction, and Sonogashira cross-coupling reaction, to afford C-10 tabersonine analogues. These protocols provide the possibility of introducing substituents with structural diversity and complexity into the C-10 of tabersonine for the pharmacological activity screening.
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Key words
tabersonine - palladium catalysis - Suzuki–Miyaura cross-coupling reaction - Heck reaction - Sonogashira cross-coupling reactionNatural products and direct derivatives have played an extremely vital role in the discovery and development of new pharmaceuticals.[1] Until now, many strategies have been developed to synthesize various analogues of natural products, such as total synthesis, semisynthesis, and biosynthesis.[2] Palladium-catalyzed cross-coupling reactions, including Suzuki–Miyaura cross-coupling reaction,[3] Heck reaction,[4] and Sonogashira cross-coupling reaction[5] are nowadays widely used in organic synthetic chemistry to construct diverse C–C bonds.[6] They also play an essential role in the derivatization of natural products.[7] For instance, the synthesis of sclerotiorin analogues with Sonogashira cross-coupling reaction,[7a] the synthesis of analogues of the aglycone of natural product fortuneanoside E with Suzuki–Miyaura cross-coupling reaction,[7d] and the synthesis of tyramine-derived natural products and analogues with Heck reaction.[7h]
Tabersonine belongs to the Aspidosperma family,[8] which is one of the largest groups of indole alkaloids. In this family, tabersonine serves as the crucial biosynthetic predecessor of other Aspidosperma alkaloids, most notably vindoline,[9] which is the key part of the Vinca alkaloids, such as vinblastine and vincristine.[10] Different bisindole alkaloids have been synthesized using tabersonine as the chemical progenitor.[11] Furthermore, tabersonine has rich sources, such as Amnosia tabemaemontana Walt, Cantharanthus roseus, and Voacanga africana Stepf. It has been reported that tabersonine displays antitumor activity[12] and hypotensive activity.[13] Given its biological abundance, valuable biological activities, and importance in the biosynthesis and semisynthesis of the Vinca alkaloids, tabersonine is worthy of further structural modification study. Herein, we report the synthesis of C-10 tabersonine analogues through the classical palladium-catalyzed cross-coupling reactions (Scheme [1]).
In order to obtain a suitable chemical precursor for the palladium-catalyzed cross-coupling reactions, the halogenation reaction of tabersonine with N-iodosuccinimide (NIS) in acetonitrile at room temperature was explored. Unfortunately, the required halotabersonine was not generated. Afterwards, trifluoroacetic acid (TFA) was chosen to replace acetonitrile as the solvent in this reaction.[14] This enabled the complete conversion of tabersonine into 10-iodotabersonine (1) (Scheme [2]), which was confirmed by LC-MS and NMR spectra. Then, 10-iodotabersonine (1) was selected as the starting material to study the palladium-catalyzed cross-coupling reactions.
Initially, the Suzuki–Miyaura cross-coupling reaction of 10-iodotabersonine (1) and phenylboronic acid (2a) was carried out with K2CO3, and PdCl2(dppf) in toluene under N2 at 100 °C for eight hours. The product 3a was isolated in 35% yield (Table [1], entry 1). Encouraged by this result, the effects of palladium catalyst, solvent, base, and temperature on this model reaction were further examined. Different palladium catalysts (5 mol%) were first selected to catalyze the reaction of 10-iodotabersonine (1) with phenylboronic acid 2a in the presence of K2CO3 in toluene under N2 at 100 °C for eight hours (entries 1–4). We found that Pd(PPh3)4 exhibited the best catalytic effect, providing the product 3a in 75% yield (entry 4). On the basis of the above result, this model reaction using Pd(PPh3)4 as the catalyst was carried out in various solvents, to obtain the desired product in the yields ranging from 25 to 75% (entries 4–8). It was evident that toluene was better than other solvents. Furthermore, the effect of base was explored on the yields, which showed that K2CO3 was better than Na2CO3 and Cs2CO3 (entries 4, 9, and 10). To explore the effect of temperature on the yields, the model reaction was performed with Pd(PPh3)4 as the catalyst and K2CO3 as the base in toluene at temperatures ranging from 60 to 100 °C (entries 4, 11, and 12). The results revealed that the yields of product 3a were improved as the temperature was increased. Thus, the following optimal reaction conditions were obtained: Pd(PPh3)4 as the catalyst, K2CO3 as the base, toluene as the solvent, and reaction temperature at 100 °C.
a Conditions: 10-iodotabersonine (1; 0.65 mmol), phenylboronic acid (2; 1.3 mmol), base (1.0 mmol), and palladium catalyst (5 mol%) in solvent (5 mL) under N2.
b Isolated yields.
The optimal reaction conditions were then utilized for the corresponding cross-coupling reactions of 10-iodotabersonine (1) with various arylboronic acids. As shown in Table [2], the arylboronic acids carrying electron-donating groups (Me, BnO, MeO) or electron-withdrawing group (F) afforded the corresponding products 3 in moderate yields ranging from 70–82% (Table [2], entries 2–5). However, little of the desired products were observed when arylboronic acids with strong electron-withdrawing groups (NO2, CN) or heteroarylboronic acid were used as the substrates under the same reaction condition for 24 hours. When 5 mol% of TBAF·3H2O (tetrabutylammonium fluoride trihydrate) was subsequently added to the above reaction mixtures as the co-catalyst and the solvent was changed into toluene/water (5:1), the desired products were obtained in moderate yields (entries 6–8). In addition, the steric hindrance effect from the arylboronic acid had no significant impact on the overall yields of the products. For instance, the arylboronic acid with MeO at the ortho, meta, or para position could react efficiently to give the corresponding products without any obvious difference (entries 4 and 9–10).
a Conditions: 10-iodotabersonine (1; 0.65 mmol), arylboronic acid 2 (1.3 mmol), K2CO3 (1.0 mmol), and Pd(PPh3)4 (5 mol%) in toluene (5 mL) under argon at 100 °C.
b Isolated yields.
c Toluene/H2O (5:1) was used as solvent, and TBAF·3H2O (5 mol%) was added as the co-catalyst.
10-Iodotabersonine (1) was also a good substrate for the Heck reaction. In the process of optimizing the reaction condition, it was found that combining Pd(OAc)2 with POT (tri-o-tolylphosphine) as the catalyst and using Et3N as the base in DMF could effectively promote the reaction between 10-iodotabersonine (1) and 4 [ethyl acrylate (4a), acrylamide (4b), or styrene (4c)], affording the corresponding products in 72, 74, and 64% yield, respectively (Table [3]).
 |
||||
|
Entry |
4 |
R1 |
Product |
Yield (%)b |
|
1 |
4a |
CO2Et |
5 |
72 |
|
2 |
4b |
CONH2 |
6 |
74 |
|
3 |
4c |
Ph |
7 |
64 |
a Conditions: 10-iodotabersonine (1; 0.65 mmol), 4 (3.25 mmol), Et3N (3.25 mmol), Pd(OAc)2 (25 mol%), and POT (50 mol%) in DMF (5 mL) under N2 at 100 °C for 12 h.
b Isolated yields.
Besides the Suzuki–Miyaura reaction and Heck reaction, other palladium-catalyzed cross-coupling reactions have also been explored using 10-iodotabersonine (1) as the substrate, such as the Sonogashira,[15] the cyanation,[16] and the carbonylation reaction.[17] The Sonogashira reaction of 1 with trimethylsilylacetylene or phenylacetylene was catalyzed by Pd(PPh3)4 and CuI in a mixed solvent system (DMF–Et3N, 1:1) to give the desired products 8 and 9 in moderate yields. In the cyanation reaction, 10-iodotabersonine (1) reacted with K4[Fe(CN)6]·3H2O in the presence of Pd(PPh3)4 as the catalyst and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) as the base, affording the C-10 cyanotabersonine (10) in 72% yield. In addition, 10-iodotabersonine (1) could also react with phenyl formate to give the one carbon-elongated carboxylic acid phenyl ester derivative 11 in 58% yield (Scheme [3]).
In conclusion, the preparation of a series of synthetic C-10 tabersonine analogues via two-step reactions starting from 10-iodotabersonine (1) has been reported. Tabersonine reacts with NIS in TFA to generate the 10-iodotabersonine (1), which participated in the palladium-catalyzed or palladium/copper co-catalyzed cross-coupling reactions, such as Suzuki–Miyaura cross-coupling reaction, Heck reaction, and Sonogashira cross-coupling reaction, to afford C-10 tabersonine analogues. These protocols provide the possibility of introducing substituents with structural diversity and complexity into the C-10 of tabersonine for the pharmacological activity screening.
Tabersonine, reagents (including NIS, palladium catalysts, CuI, POT, arylboronic acids) and all solvents were analytically pure grade and were used without further purification. Column chromatography (CC) was performed on silica gel (200–300 mesh). TLC was performed on GF254 silica gel plates (Yantai Huiyou Inc., China). IR spectra were recorded as KBr pellets on a Thermo Nicolet 6700 spectrometer. 1H and 13C spectra were recorded on AMX 400 or Bruker Avance III/500 instruments in the solvent indicated. HRMS-ESI were recorded on a Micromass Q-Tof Global mass spectrometer and MS-ESI were recorded on a Bruker Esquire 3000 Plus spectrometer.
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10-Iodotabersonine (1)
NIS (5.89 g, 26.19 mmol) was added slowly to a solution of tabersonine (8.00 g, 23.81 mmol) in TFA (40 mL). The mixture was stirred at r.t. for 3 h, evaporated under vacuum to remove TFA, and then sat. aq NaHCO3 was added, adjusting the pH to 8. The aqueous layer was extracted with CH2Cl2 (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), and concentrated to give the crude product, which was purified by column chromatography on silica gel (hexane–acetone–Et3N, 250:2:1); yield: 10.79 g (98%); white spumous solid; mp 122.4–123.0 °C.
IR (KBr): 3363, 2960, 1676, 1603, 1468, 1437, 1269, 1163, 1115, 806 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.98 (s, 1 H), 7.49 (d, J = 1.6 Hz, 1 H), 7.43 (dd, J = 8.1, 1.6 Hz, 1 H), 6.60 (d, J = 8.1 Hz, 1 H), 5.78 (ddd, J = 10.0, 4.6, 1.3 Hz, 1 H), 5.70 (dt, J = 10.0, 1.3 Hz, 1 H), 3.76 (s, 3 H), 3.45 (ddd, J = 15.9, 4.7, 1.2 Hz, 1 H), 3.20 (dt, J = 15.9, 1.2 Hz, 1 H), 3.04 (t, J = 7.2 Hz, 1 H), 2.72–2.65 (m, 1 H), 2.62 (d, J = 1.3 Hz, 1 H), 2.54 (dd, J = 15.1, 1.7 Hz, 1 H), 2.40 (d, J = 15.1 Hz, 1 H), 2.09–2.01 (m, 1 H), 1.81 (ddd, J = 11.7, 4.7, 1.0 Hz, 1 H), 1.02–0.93 (m, 1 H), 0.91–0.82 (m, 1 H), 0.64 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.08, 165.67, 143.17, 140.89, 136.61, 132.93, 130.53, 125.03, 111.53, 93.06, 82.63, 70.24, 55.28, 51.32, 51.15, 50.58, 44.67, 41.25, 28.69, 27.23, 7.70.
ESI-MS: m/z = 463 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H24IN2O2: 463.0877; found: 463.0886.
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C-10-Substituted Tabersonine Derivatives 3; General Procedure
A 25 mL round-bottomed flask was charged with 10-iodotabersonine (1; 300 mg, 0.65 mmol), arylboronic acid 2 (1.3 mmol), K2CO3 (138 mg, 1.0 mmol), and a magnetic stir bar. Toluene (5 mL) was added, followed by Pd(PPh3)4 (37.6 mg, 5 mol%). The flask was sealed with parafilm and the stirred solution was deaerated by four vaccum–argon cycles. The mixture was heated to 100 °C. After completion of the reaction (TLC, eluent: hexane–acetone–Et3N, 200:5:1), the mixture was diluted with EtOAc (20 mL), filtered through Celite, and concentrated. The crude products were purified by column chromatography (hexane–acetone–EtN3 gradient) to give 3a–k (Table [2]).
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10-Phenyltabersonine (3a)
Yield: 201 mg (75%); white spumous solid; mp 91.9–92.3 °C.
IR (KBr): 3367, 2960, 1674, 1612, 1475, 1437, 1274, 1165, 1113, 764 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.06 (s, 1 H), 7.55 (d, J = 7.8 Hz, 2 H), 7.46–7.37 (m, 4 H), 7.31 (t, J = 7.8 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 5.80 (ddd, J = 9.9, 4.6, 1.2 Hz, 1 H), 5.73 (dt, J = 9.9, 1.2 Hz, 1 H), 3.78 (s, 3 H), 3.48 (ddd, J = 15.9, 4.6, 1.0 Hz, 1 H), 3.22 (dt, J = 15.9, 1.0 Hz, 1 H), 3.07 (t, J = 7.2 Hz, 1 H), 2.79–2.75 (m, 1 H), 2.74 (d, J = 1.2 Hz, 1 H), 2.57 (dd, J = 15.1, 1.6 Hz, 1 H), 2.46 (d, J = 15.1 Hz, 1 H), 2.14–2.07 (m, 1 H), 1.87 (dd, J = 11.7, 4.0 Hz, 1 H), 1.08–1.00 (m, 1 H), 0.93–0.86 (m, 1 H), 0.66 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.00, 166.64, 142.66, 141.36, 138.80, 134.07, 132.99, 128.72, 128.72, 126.80, 126.80, 126.69, 126.63, 124.86, 120.40, 109.41, 92.46, 70.12, 55.16, 51.04, 51.00, 50.52, 44.60, 41.31, 28.47, 26.98, 7.49.
ESI-MS: m/z = 413 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C27H29N2O2: 413.2224; found: 413.2234.
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10-(4-Methylphenyl)tabersonine (3b)
Yield: 213 mg (77%); white spumous solid; mp 102.5–103.1 °C.
IR (KBr): 3369, 2960, 1674, 1612, 1479, 1435, 1273, 1165, 1113, 808 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.04 (s, 1 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 1.7 Hz, 1 H), 7.36 (dd, J = 8.0, 1.7 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 2 H), 6.86 (d, J = 8.0 Hz, 1 H), 5.80 (ddd, J = 9.9, 4.6, 1.3 Hz, 1 H), 5.73 (dt, J = 9.9, 1.3 Hz, 1 H), 3.78 (s, 3 H), 3.47 (ddd, J = 15.5, 4.3, 1.0 Hz, 1 H), 3.22 (dt, J = 15.5, 1.0 Hz, 1 H), 3.06 (t, J = 7.0 Hz, 1 H), 2.78–2.74 (m, 1 H), 2.73 (s, 1 H), 2.57 (dd, J = 15.1, 1.8 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.39 (s, 3 H), 2.14–2.06 (m, 1 H), 1.87 (dd, J = 11.7, 3.9 Hz, 1 H), 1.08–0.99 (m, 1 H), 0.93–0.84 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.01, 166.72, 142.41, 138.75, 138.50, 136.35, 134.06, 133.02, 129.43, 129.43, 126.65, 126.65, 126.45, 124.86, 120.27, 109.38, 92.34, 70.13, 55.17, 51.03, 50.98, 50.54, 44.60, 41.33, 28.44, 26.97, 21.05, 7.49.
ESI-MS: m/z = 427 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C28H31N2O2: 427.2380; found: 427.2369.
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10-(4-Benzyloxyphenyl)tabersonine (3c)
Yield: 269 mg (80%); white spumous solid; mp 102.3–102.8 °C.
IR (KBr): 3367, 2962, 1674, 1610, 1477, 1435, 1236, 1158, 1113, 814 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H), 7.50–7.44 (m, 4 H), 7.43–7.37 (m, 3 H), 7.36–7.31 (m, 2 H), 7.04 (d, J = 8.8 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 1 H), 5.80 (ddd, J = 10.0, 4.6, 1.2 Hz, 1 H), 5.72 (dt, J = 10.0, 1.2 Hz, 1 H), 5.11 (s, 2 H), 3.78 (s, 3 H), 3.47 (ddd, J = 15.9, 4.5, 1.0 Hz, 1 H), 3.22 (dt, J = 15.9, 1.0 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 1 H), 2.79–2.74 (m, 1 H), 2.73 (d, J = 1.2 Hz, 1 H), 2.57 (dd, J = 15.1, 1.7 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.14–2.06 (m, 1 H), 1.86 (dd, J = 11.4, 4.3 Hz, 1 H), 1.08–0.98 (m, 1 H), 0.93–0.85 (m, 1 H), 0.65 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.01, 166.72, 157.87, 142.18, 138.78, 136.99, 134.25, 133.73, 133.02, 128.60, 128.60, 127.97, 127.80, 127.80, 127.46, 127.46, 126.22, 124.84, 120.06, 115.12, 115.12, 109.40, 92.29, 70.12, 70.10, 55.18, 51.03, 51.00, 50.51, 44.58, 41.30, 28.46, 26.99, 7.49.
ESI-MS: m/z = 519 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C34H35N2O3: 519.2642; found: 519.2652.
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10-(4-Methoxyphenyl)tabersonine (3d)
Yield: 236 mg (82%); white spumous solid; mp 118.4–119.2 °C.
IR (KBr): 3367, 2961, 1674, 1612, 1479, 1436, 1238, 1160, 1113, 818 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.04 (s, 1 H), 7.48 (d, J = 8.1 Hz, 2 H), 7.39 (d, J = 1.2 Hz, 1 H), 7.33 (dd, J = 8.1, 1.2 Hz, 1 H), 6.97 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.1 Hz, 1 H), 5.80 (dd, J = 9.9, 3.8 Hz, 1 H), 5.72 (d, J = 9.9 Hz, 1 H), 3.85 (s, 3 H), 3.78 (s, 3 H), 3.47 (dd, J = 15.9, 4.7 Hz, 1 H), 3.22 (d, J = 15.9 Hz, 1 H), 3.06 (t, J = 8.0 Hz, 1 H), 2.79–2.74 (m, 1 H), 2.73 (s, 1 H), 2.57 (dd, J = 15.1, 1.4 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.14–2.06 (m, 1 H), 1.87 (dd, J = 11.6, 4.1 Hz, 1 H), 1.06–0.99 (m, 1 H), 0.91–0.84 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.01, 166.73, 158.66, 142.15, 138.77, 134.01, 133.77, 133.01, 127.79, 127.79, 126.20, 124.83, 120.06, 114.15, 114.15, 109.39, 92.26, 70.13, 55.35, 55.18, 51.01, 50.99, 50.51, 44.58, 41.30, 28.45, 26.98, 7.48.
ESI-MS: m/z = 443 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C28H31N2O3: 443.2329; found: 443.2320.
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10-(4-Fluorophenyl)tabersonine (3e)
Yield: 196 mg (70%); white spumous solid; mp 107.3–107.4 °C.
IR (KBr): 3369, 2960, 1676, 1612, 1479, 1435, 1275, 1163, 1113, 816 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.05 (s, 1 H), 7.53–7.46 (m, 2 H), 7.38 (d, J = 1.6 Hz, 1 H), 7.32 (dd, J = 8.0, 1.6 Hz, 1 H), 7.11 (t, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.0 Hz, 1 H), 5.80 (ddd, J = 10.0, 4.6, 1.3 Hz, 1 H), 5.72 (dt, J = 10.0, 1.3 Hz, 1 H), 3.78 (s, 3 H), 3.48 (ddd, J = 15.7, 4.7, 1.2 Hz, 1 H), 3.23 (d, J = 15.7 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 1 H), 2.79–2.74 (m, 1 H), 2.73 (s, 1 H), 2.57 (dd, J = 15.1, 1.7 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.15–2.06 (m, 1 H), 1.86 (dd, J = 11.7, 3.8 Hz, 1 H), 1.07–0.98 (m, 1 H), 0.93–0.84 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.99, 166.51, 163.04 and 161.08 (1 J C,F = 245.0 Hz), 142.65, 138.90, 137.50 and 137.48 (4 J C,F = 3.2 Hz), 133.12, 132.96, 128.31 and 128.25 (3 J C,F = 7.8 Hz), 126.59, 124.82, 120.25, 115.61 and 115.44 (2 J C,F = 21.2 Hz), 109.43, 92.54, 70.13, 55.17, 51.05, 50.46, 44.58, 41.24, 29.69, 28.52, 27.04, 7.49.
ESI-MS: m/z = 431 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C27H28FN2O2: 431.2129; found: 431.2118.
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10-(3-Nitrophenyl)tabersonine (3f)
Yield: 220 mg (74%); yellow spumous solid; mp 112.1–112.8 °C.
IR (KBr): 3367, 2960, 1676, 1608, 1529, 1471, 1348, 1271, 1113, 737 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.12 (s, 1 H), 8.40 (t, J = 2.0 Hz, 1 H), 8.15 (ddd, J = 8.2, 2.0, 0.9 Hz, 1 H), 7.90–7.84 (dt, J = 8.2, 2.0 Hz, 1 H), 7.58 (t, J = 8.0 Hz, 1 H), 7.46 (d, J = 1.8 Hz, 1 H), 7.42 (dd, J = 8.1, 1.8 Hz, 1 H), 6.92 (d, J = 8.1 Hz, 1 H), 5.81 (ddd, J = 10.0, 4.7, 1.4 Hz, 1 H), 5.73 (dt, J = 10.0, 1.4 Hz, 1 H), 3.79 (s, 3 H), 3.49 (ddd, J = 16.0, 4.7, 1.2 Hz, 1 H), 3.27 (dt, J = 16.0, 1.2 Hz, 1 H), 3.09 (t, J = 7.2 Hz, 1 H), 2.82–2.74 (m, 1 H), 2.77 (d, J = 1.3 Hz, 1 H), 2.58 (dd, J = 15.1, 1.8 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.16–2.08 (m, 1 H), 1.88 (ddd, J = 11.6, 4.7, 1.1 Hz, 1 H), 1.07–0.99 (m, 1 H), 0.96–0.86 (m, 1 H), 0.66 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.95, 166.03, 148.71, 143.74, 143.05, 139.30, 132.77, 132.71, 131.36, 129.61, 127.08, 124.85, 121.46, 121.29, 120.26, 109.68, 93.11, 70.13, 55.12, 51.14, 51.07, 50.38, 44.62, 41.11, 28.54, 27.08, 7.52.
ESI-MS: m/z = 458 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C27H28N3O4: 458.2074; found: 458.2066.
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10-(4-Cyanophenyl)tabersonine (3g)
Yield: 199 mg (70%); white spumous solid; mp 115.5–116.7 °C.
IR (KBr): 3363, 2956, 2224, 1678, 1601, 1477, 1275, 1163, 1113, 816 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.12 (s, 1 H), 7.72–7.62 (m, 4 H), 7.44 (s, 1 H), 7.40 (dd, J = 8.1, 1.8 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 5.80 (ddd, J = 10.0, 4.6, 1.3 Hz, 1 H), 5.72 (d, J = 10.0 Hz, 1 H), 3.78 (s, 3 H), 3.48 (ddd, J = 15.8, 4.7, 1.2 Hz, 1 H), 3.24 (d, J = 15.8 Hz, 1 H), 3.08 (d, J = 7.2 Hz, 1 H), 2.79–2.71 (m, 1 H), 2.73 (s, 1 H), 2.58 (dd, J = 15.2, 1.7 Hz, 1 H), 2.44 (d, J = 15.2 Hz, 1 H), 2.15–2.07 (m, 1 H), 1.86 (dd, J = 11.8, 3.8 Hz, 1 H), 1.07–0.97 (m, 1 H), 0.93–0.83 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.89, 165.90, 145.70, 143.87, 139.20, 132.77, 132.54, 132.54, 131.71, 127.14, 127.14, 127.14, 124.78, 120.28, 119.14, 109.88, 109.64, 93.16, 70.11, 55.03, 51.13, 51.04, 50.36, 44.56, 41.08, 28.54, 27.07, 7.49.
ESI-MS: m/z = 438 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C28H28N3O2: 438.2176; found: 438.2185.
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10-(2-Furyl)tabersonine (3h)
Yield: 178 mg (68%); white spumous solid; mp 101.1–101.8 °C.
IR (KBr): 3365, 2960, 1676, 1612, 1471, 1437, 1267, 1165, 1113, 727 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.07 (s, 1 H), 7.53 (d, J = 1.3 Hz, 1 H), 7.47 (dd, J = 8.1, 1.7 Hz, 1 H), 7.43 (d, J = 1.7 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 6.53 (d, J = 3.3 Hz, 1 H), 6.45 (dd, J = 3.3, 1.8 Hz, 1 H), 5.80 (ddd, J = 9.9, 4.6, 1.3 Hz, 1 H), 5.72 (dt, J = 9.9, 1.3 Hz, 1 H), 3.77 (s, 3 H), 3.47 (ddd, J = 15.9, 4.7, 1.2 Hz, 1 H), 3.24 (dt, J = 15.9, 1.2 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 1 H), 2.80–2.74 (m, 1 H), 2.73 (d, J = 1.2 Hz, 1 H), 2.56 (dd, J = 15.1, 1.7 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.12–2.04 (m, 1 H), 1.84 (dd, J = 11.7, 3.9 Hz, 1 H), 1.05–0.95 (m, 1 H), 0.94–0.85 (m, 1 H), 0.64 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.91, 166.30, 154.32, 142.52, 141.20, 138.56, 132.90, 124.83, 124.02, 123.75, 117.26, 111.56, 109.34, 103.22, 92.59, 69.97, 54.99, 51.02, 50.94, 50.49, 44.55, 41.27, 28.38, 26.85, 7.46.
ESI-MS: m/z = 403 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C25H27N2O3: 403.2016; found: 403.2006.
#
10-(3-Methoxyphenyl)tabersonine (3i)
Yield: 230 mg (80%); white spumous solid; mp 119.3–119.7 °C.
IR (KBr): 3367, 2960, 1674, 1606, 1475, 1437, 1273, 1163, 1113, 779 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.06 (s, 1 H), 7.44 (d, J = 1.8 Hz, 1 H), 7.38 (dd, J = 8.0, 1.8 Hz, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.09 (t, J = 2.2 Hz, 1 H), 6.89–6.84 (m, 2 H), 5.80 (ddd, J = 9.8, 4.6, 1.3 Hz, 1 H), 5.72 (dt, J = 9.8, 1.3 Hz, 1 H), 3.87 (s, 3 H), 3.78 (s, 3 H), 3.47 (ddd, J = 15.8, 4.6, 1.2 Hz, 1 H), 3.23 (dt, J = 15.8, 1.2 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 1 H), 2.79–2.74 (m, 1 H), 2.73 (s, 1 H), 2.57 (dd, J = 15.1, 1.7 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.14–2.06 (m, 1 H), 1.86 (dd, J = 11.6, 3.8 Hz, 1 H), 1.06–0.99 (m, 1 H), 0.92–0.84 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3 H)
13C NMR (125 MHz, CDCl3): δ = 168.99, 166.60, 159.88, 142.90, 142.79, 138.77, 133.84, 132.97, 129.70, 126.72, 124.88, 120.43, 119.37, 112.90, 111.57, 109.36, 92.51, 70.09, 55.32, 55.14, 51.04, 50.97, 50.51, 44.59, 41.30, 28.46, 26.97, 7.49.
ESI-MS: m/z = 443 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C28H31N2O3: 443.2329; found: 443.2322.
#
10-(2-Methoxyphenyl)tabersonine (3j)
Yield: 207 mg (76%); white spumous solid; mp 90.5–91.0 °C.
IR (KBr): 3367, 2958, 1674, 1612, 1477, 1437, 1238, 1163, 1113, 754 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H), 7.41 (d, J = 1.5 Hz, 1 H), 7.35 (dd, J = 8.2, 1.5 Hz, 1 H), 7.33–7.27 (m, 2 H), 7.02 (td, J = 7.4, 1.0 Hz, 1 H), 6.98 (d, J = 8.2 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 5.79 (ddd, J = 9.9, 4.7, 1.3 Hz, 1 H), 5.72 (td, J = 9.9, 1.3 Hz, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.46 (ddd, J = 15.9, 4.7, 1.2 Hz, 1 H), 3.18 (dt, J = 15.9, 1.2 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 1 H), 2.76–2.69 (m, 1 H), 2.72 (d, J = 1.3 Hz, 1 H), 2.56 (dd, J = 15.1, 1.7 Hz, 1 H), 2.46 (d, J = 15.1 Hz, 1 H), 2.13–2.06 (m, 1 H), 1.89 (dd, J = 11.7, 3.9 Hz, 1 H), 1.08–1.00 (m, 1 H), 0.94–0.86 (m, 1 H), 0.66 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.02, 166.91, 156.35, 142.17, 137.76, 133.15, 130.87, 130.72, 130.68, 128.87, 128.10, 124.92, 122.88, 120.88, 111.29, 108.75, 92.21, 69.93, 55.57, 55.15, 51.00, 50.91, 50.56, 44.57, 41.40, 28.57, 26.98, 7.49.
ESI-MS: m/z = 443 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C28H31N2O3: 443.2329; found: 443.2320.
#
10-(3,5-Dimethoxyphenyl)tabersonine (3k)
Yield: 259 mg (78%); white spumous solid; mp 107.2–107.9 °C.
IR (KBr): 3367, 2958, 1676, 1603, 1469, 1435, 1257, 1157, 1113, 816 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.06 (s, 1 H), 7.42 (d, J = 1.8 Hz, 1 H), 7.37 (dd, J = 8.0, 1.8 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 6.69 (d, J = 2.2 Hz, 2 H), 6.43 (t, J = 2.2 Hz, 1 H), 5.80 (ddd, J = 10.0, 4.6, 1.3 Hz, 1 H), 5.71 (dt, J = 10.0, 1.3 Hz, 1 H), 3.85 (s, 6 H), 3.78 (s, 3 H), 3.47 (ddd, J = 16.0, 4.6, 1.2 Hz, 1 H), 3.21 (dt, J = 16.0, 1.2 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 1 H), 2.78–2.71 (m, 1 H), 2.72 (s, 1 H), 2.57 (dd, J = 15.1, 1.7 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.13–2.06 (m, 1 H), 1.86 (dd, J = 11.4, 4.3 Hz, 1 H), 1.08–0.98 (m, 1 H), 0.92–0.85 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.99, 166.57, 161.01, 161.01, 143.62, 142.91, 138.73, 133.90, 132.95, 126.71, 124.89, 120.44, 109.29, 105.31, 105.31, 98.22, 92.55, 70.08, 55.42, 55.42, 55.13, 51.04, 50.95, 50.50, 44.59, 41.30, 28.44, 26.96, 7.49.
ESI-MS: m/z = 473 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H33N2O4: 473.2435; found: 473.2443.
#
C-10 Substituted Tabersonine Derivatives 5–7; General Procedure
A mixture of 10-iodotabersonine (1; 300 mg, 0.65 mmol), 4 [ethyl acrylate (4a), acrylamide (4b), or styrene (4c), 3.25 mmol], Et3N (328 mg, 3.25 mmol), Pd(OAc)2 (36.4 mg, 25 mol%), and POT (98.8 mg, 50 mol%) in DMF (5 mL) was heated under N2 in round-bottomed flask at 100 °C for 12 h. The cooled mixture was diluted with distilled H2O (40 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel (hexane–acetone–Et3N, 200:2:1) to give 5–7.
#
Ethyl (E)-3-(Tabersonin-10-yl)acrylate (5)
Yield: 203 mg (72%); white spumous solid; mp 80.1–80.7 °C.
IR (KBr): 3361, 2960, 1680, 1604, 1483, 1435, 1254, 1161, 1111, 816 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.13 (s, 1 H), 7.65 (d, J = 15.9 Hz, 1 H), 7.42 (s, 1 H), 7.32 (dd, J = 8.0, 1.6 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.32 (d, J = 15.9 Hz, 1 H), 5.80 (ddd, J = 10.0, 4.7, 1.3 Hz, 1 H), 5.70 (dt, J = 10.0, 1.3 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.75 (s, 3 H), 3.47 (ddd, J = 16.0, 4.7, 1.2 Hz, 1 H), 3.22 (dt, J = 16.0, 1.2 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 1 H), 2.75–2.69 (m, 1 H), 2.68 (d, J = 1.2 Hz, 1 H), 2.56 (dd, J = 15.2, 1.7 Hz, 1 H), 2.43 (d, J = 15.2 Hz, 1 H), 2.11–2.03 (m, 1 H), 1.81 (dd, J = 11.4, 4.1 Hz, 1 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.04–0.93 (m, 1 H), 0.90–0.83 (m, 1 H), 0.64 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.83, 167.38, 165.53, 145.25, 144.85, 138.92, 132.74, 129.57, 127.26, 124.90, 120.53, 114.86, 109.30, 93.69, 70.01, 60.29, 54.74, 51.14, 50.97, 50.40, 44.55, 41.14, 28.63, 27.02, 14.36, 7.48.
ESI-MS: m/z = 435 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C26H31N2O4: 435.2278; found: 435.2268.
#
(E)-3-(Tabersonin-10-yl)acrylamide (6)
Yield: 195 mg (74%); white spumous solid; mp 162.4–163.1 °C.
IR (KBr): 3348, 2960, 1670, 1597, 1483, 1437, 1261, 1163, 1111, 814 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.13 (s, 1 H), 7.59 (d, J = 15.6 Hz, 1 H), 7.40 (d, J = 1.2 Hz, 1 H), 7.31 (dd, J = 8.1, 1.2 Hz, 1 H), 6.79 (d, J = 8.1 Hz, 1 H), 6.35 (d, J = 15.6 Hz, 1 H), 5.79 (ddd, J = 10.0, 4.7, 1.4 Hz, 1 H), 5.70 (d, J = 10.0 Hz, 1 H), 3.77 (s, 3 H), 3.47 (ddd, J = 16.0, 4.7, 1.2 Hz, 1 H), 3.22 (dt, J = 16.0, 1.2 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 1 H), 2.74–2.68 (m, 1 H), 2.67 (d, J = 1.3 Hz, 1 H), 2.55 (dd, J = 15.2, 1.7 Hz, 1 H), 2.42 (d, J = 15.2 Hz, 1 H), 2.10–2.02 (m, 1 H), 1.80 (dd, J = 11.2, 4.3 Hz, 1 H), 1.03–0.92 (m, 1 H), 0.90–0.80 (m, 1 H), 0.63 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.81, 168.32, 165.57, 144.97, 142.63, 138.83, 132.74, 129.23, 127.23, 124.81, 120.52, 116.26, 109.33, 93.48, 70.04, 54.73, 51.14, 50.98, 50.38, 44.51, 41.08, 28.55, 26.99, 7.46.
ESI-MS: m/z = 406 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C24H28N3O3: 406.2125; found: 406.2113.
#
(E)-10-Styryltabersonine (7)
Yield: 182 mg (64%); white spumous solid; mp 94.2–95.0 °C.
IR (KBr): 3367, 2958, 1674, 1608, 1481, 1435, 1265, 1163, 1113, 810 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.07 (s, 1 H), 7.50 (d, J = 7.8 Hz, 2 H), 7.41 (s, 1 H), 7.35 (t, J = 7.8 Hz, 2 H), 7.31 (d, J = 7.0 Hz, 1 H), 7.23 (t, J = 7.4 Hz, 1 H), 7.09 (d, J = 16.2 Hz, 1 H), 6.98 (d, J = 16.2 Hz, 1 H), 6.80 (d, J = 8.1 Hz, 1 H), 5.81 (dd, J = 10.0, 4.3 Hz, 1 H), 5.73 (d, J = 10.0 Hz, 1 H), 3.78 (s, 3 H), 3.50 (dd, J = 16.0, 4.8 Hz, 1 H), 3.27 (d, J = 16.0 Hz, 1 H), 3.08 (t, J = 7.0 Hz, 1 H), 2.81–2.75 (m, 1 H), 2.73 (s, 1 H), 2.57 (dd, J = 15.1, 1.6 Hz, 1 H), 2.45 (d, J = 15.1 Hz, 1 H), 2.13–2.05 (m, 1 H), 1.85 (dd, J = 11.7, 4.5 Hz, 1 H), 1.06–0.96 (m, 1 H), 0.92–0.85 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.94, 166.33, 142.89, 137.64, 132.97, 130.31, 128.77, 128.62, 128.62, 128.62, 127.14, 126.83, 126.19, 126.19, 126.08, 124.80, 119.32, 109.36, 92.60, 70.11, 54.98, 51.07, 51.07, 50.51, 44.54, 41.25, 28.45, 26.97, 7.49.
ESI-MS: m/z = 439 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H31N2O2: 439.2380; found: 439.2368.
#
C-10-Substituted Tabersonine Derivatives 8 and 9; General Procedure
A mixture of 10-iodotabersonine (1; 300 mg, 0.65 mmol), trimethylsilylacetylene or phenylacetylene (2.60 mmol), Pd(PPh3)4 (75.2 mg, 10 mol%), and CuI (12.4 mg, 10 mol%) in solvent (DMF–Et3N, 1:1, 5 mL) was stirred under N2 at r.t. for 18 h. The mixture was diluted with EtOAc (10 mL), filtered through Celite, diluted with distilled H2O (40 mL), and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel (hexane–acetone–Et3N, 250:2:1) to give compound 8 or 9.
#
Trimethyl(tabersonin-10-ylethynyl)silane (8)
Yield: 216 mg (77%); white spumous solid; mp 91.8–92.7 °C.
IR (KBr): 3367, 2958, 1680, 1608, 1477, 1435, 1259, 1165, 1113, 858 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.06 (s, 1 H), 7.32 (s, 1 H), 7.29 (d, J = 8.1 Hz, 1 H), 6.72 (d, J = 8.1 Hz, 1 H), 5.78 (dd, J = 10.0, 4.5 Hz, 1 H), 5.69 (d, J = 10.0 Hz, 1 H), 3.76 (s, 3 H), 3.45 (dd, J = 16.0, 4.5 Hz, 1 H), 3.20 (d, J = 16.0 Hz, 1 H), 3.03 (t, J = 7.2 Hz, 1 H), 2.76–2.68 (m, 1 H), 2.66 (s, 1 H), 2.54 (d, J = 15.2 Hz, 1 H), 2.42 (d, J = 15.2 Hz, 1 H), 2.07–2.00 (m, 1 H), 1.77 (dd, J = 11.5, 4.5 Hz, 1 H), 1.00–0.91 (m, 1 H), 0.88–0.80 (m, 1 H), 0.64 (d, J = 7.3 Hz, 3 H), 0.24 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 168.83, 165.79, 143.45, 138.02, 132.81, 132.40, 125.06, 124.88, 114.67, 109.04, 105.84, 93.23, 92.23, 69.87, 54.78, 51.10, 50.88, 50.49, 44.49, 41.24, 28.41, 26.84, 7.48, 0.30, 0.30, 0.30.
ESI-MS: m/z = 433 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C26H33N2O2Si: 433.2306; found: 433.2315.
#
10-Phenylethynyltabersonine (9)
Yield: 213 mg (77%); white spumous solid; mp 91.6–92.4 °C.
IR (KBr): 3363, 2960, 1676, 1610, 1475, 1437, 1267, 1165, 1111, 756 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.09 (s, 1 H), 7.52 (dd, J = 7.8, 1.7 Hz, 2 H), 7.40 (s, 1 H), 7.36 (dd, J = 8.0, 1.6 Hz, 1 H), 7.34–7.30 (m, 3 H), 6.79 (d, J = 8.0 Hz, 1 H), 5.80 (ddd, J = 9.9, 4.6, 1.3 Hz, 1 H), 5.71 (dt, J = 9.9, 1.3 Hz, 1 H), 3.77 (s, 3 H), 3.47 (ddd, J = 16.0, 4.7, 1.3 Hz, 1 H), 3.20 (dt, J = 16.0, 1.3 Hz, 1 H), 3.09–3.03 (m, 1 H), 2.78–2.72 (m, 1 H), 2.70 (d, J = 1.2 Hz, 1 H), 2.56 (dd, J = 15.2, 1.7 Hz, 1 H), 2.44 (d, J = 15.2 Hz, 1 H), 2.11–2.02 (m, 1 H), 1.83 (dd, J = 11.7, 3.9 Hz, 1 H), 1.03–0.95 (m, 1 H), 0.92–0.83 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.84, 165.76, 143.29, 132.88, 131.89, 131.39, 131.39, 131.39, 128.31, 128.31, 128.31, 127.91, 124.74, 123.50, 114.93, 109.25, 93.23, 90.00, 88.00, 69.98, 54.83, 50.96, 50.48, 44.47, 41.24, 28.46, 26.93, 26.88, 7.50.
ESI-MS: m/z = 437 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H29N2O2: 437.2224; found: 437.2235.
#
C-10-Substituted Tabersonine Derivative, 10-Cyanotabersonine (10)
To a mixture of 10-iodotabersonine (1; 300 mg, 0.65 mmol), K4[Fe(CN)6]·3H2O (110 mg, 0.26 mmol), Pd(PPh3)4 (37.6 mg, 5 mol%) under N2 was added t-BuOH–H2O (1:1, 5 mL) and DBU (24.8 mg, 25 mol%). The mixture was stirred at r.t. for 10 min, then heated to 80 °C for 7 h. The cooled mixture was diluted with MeOH (15 mL), filtered through Celite, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (hexane–acetone–Et3N, 300:6:1 → 300:10:1) to give 10; yield: 169 mg (72%); white solid; mp 90.5–91.1 °C.
IR (KBr): 3359, 2960, 1682, 1608, 1479, 1437, 1259, 1165, 1113, 827 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.23 (s, 1 H), 7.47 (s, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 5.80 (ddd, J = 10.0, 4.6, 1.2 Hz, 1 H), 5.69 (dt, J = 10.0, 1.2 Hz, 1 H), 3.77 (s, 3 H), 3.46 (ddd, J = 16.0, 4.3, 1.0 Hz, 1 H), 3.20 (dt, J = 16.0, 1.0 Hz, 1 H), 3.07 (t, J = 7.2 Hz, 1 H), 2.73–2.67 (m, 1 H), 2.65 (d, J = 1.0 Hz, 1 H), 2.56 (dd, J = 15.3, 1.6 Hz, 1H), 2.42 (d, J = 15.3 Hz, 1 H), 2.09–2.01 (m, 1 H), 1.79 (ddd, J = 11.6, 4.5, 1.0 Hz, 1 H), 0.99–0.91 (m, 1 H), 0.90–0.83 (m, 1 H), 0.64 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.61, 164.13, 138.77, 133.23, 132.42, 125.00, 125.00, 119.84, 109.45, 109.45, 103.02, 95.10, 69.90, 54.54, 51.31, 50.92, 50.29, 44.51, 40.94, 28.65, 27.02, 7.46.
ESI-MS: m/z = 362 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H24N3O2: 362.1863; found: 362.1856.
#
C-10-Substituted Tabersonine Derivative, Phenyl 10-Tabersoninecarboxylate (11)
A mixture of 10-iodotabersonine (1; 300 mg, 0.65 mmol), phenyl formate (157 mg, 1.3 mmol), Pd(OAc)2 (36.4 mg, 25 mol%), P(t-Bu)3·HBF4 (28.3 mg, 15 mol%), and Et3N (263 mg, 2.6 mmol) in anhydrous MeCN (5 mL) was heated under N2 at 80 °C for 15 h. The cooled mixture was diluted with MeCN (15 mL), filtered through Celite, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (hexane–acetone–Et3N, 300:3:1 → 300:5:1) to give 11; yield: 172 mg (58%); white solid; mp 92.6–93.7 °C.
IR (KBr): 3363, 2960, 1680, 1608, 1493, 1437, 1263, 1194, 1111, 746 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.26 (s, 1 H), 8.09 (dd, J = 8.2, 1.5 Hz, 1 H), 8.01 (s, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 7.26 (t, J = 7.4 Hz, 1 H), 7.20 (d, J = 8.3 Hz, 2 H), 6.89 (d, J = 8.2 Hz, 1 H), 5.80 (ddd, J = 10.0, 4.4, 1.2 Hz, 1 H), 5.71 (dt, J = 10.0, 1.2 Hz, 1 H), 3.79 (s, 3 H), 3.47 (ddd, J = 15.9, 4.8, 1.2 Hz, 1 H), 3.23 (dt, J = 15.9, 1.2 Hz, 1 H), 3.07 (t, J = 7.2 Hz, 1 H), 2.82–2.77 (m, 1 H), 2.76 (s, 1 H), 2.58 (dd, J = 15.2, 1.4 Hz, 1 H), 2.47 (d, J = 15.2 Hz, 1 H), 2.12–2.04 (m, 1 H), 1.83 (dd, J = 11.7, 4.4 Hz, 1 H), 1.05–0.94 (m, 1 H), 0.92–0.85 (m, 1 H), 0.66 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 168.75, 165.31, 165.20, 151.08, 147.91, 138.17, 132.61, 131.63, 129.41, 129.41, 125.69, 125.07, 123.33, 121.83, 121.83, 121.48, 108.73, 94.65, 69.84, 54.56, 51.25, 50.86, 50.49, 44.69, 41.32, 28.38, 26.82, 7.49.
HRMS (ESI): m/z [M + H]+ calcd for C28H29N2O4: 457.2122; found: 457.2111.
#
#
Acknowledgment
This work was supported by the National Natural Science Foundation of China (Grants 30925040, 81102329, 81273397), the Chinese National Science & Technology Major Project ‘Key New Drug Creation and Manufacturing Program’ (Grants 2013ZX09508104, 2012ZX09301001-001, 2011ZX09307-002-03), and the Science Foundation of Shanghai (Grant 12XD1405700).
Supporting Information
- for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/products/ejournals/journal/
10.1055/s-00000084.
- Supporting Information
-
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- 2a Voss ME, Ralph JM, Xie D, Manning DD, Chen X, Frank AJ, Leyhane AJ, Liu L, Stevens JM, Budde C, Surman MD, Friedrich T, Peace D, Scott IL, Wolf M, Johnson R. Bioorg. Med. Chem. Lett. 2009; 19: 1245
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- 2f Birch AJ. Pure Appl. Chem. 1963; 7: 527
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- 3b Suzuki A. J. Organomet. Chem. 1999; 576: 147
- 3c Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
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- 4b Dounay AB, Overman LE In The Mizoroki–Heck Reaction . Oestreich M. Wiley; Chichester: 2009. Chap. 16
- 5a Doucet H, Hierso J.-C. Angew. Chem. Int. Ed. 2007; 46: 834
- 5b Chinchilla R, Najera C. Chem. Rev. 2007; 107: 874
- 5c Chinchilla R, Najera C. Chem. Soc. Rev. 2011; 40: 5084
- 6a Handbook of Organopalladium Chemistry for Organic Synthesis . Vol. 1. Negishi E.-I. Wiley; Hoboken: 2002: 1369-1448
- 6b Mitchell TN In Metal-Catalyzed Cross-Coupling Reactions . Diederich F, Stang PJ. Wiley-VCH; Weinheim: 1998. Chap. 4
- 6c Tsuji J. Palladium Reagents and Catalysts: New Perspectives for the 21st Century. Wiley; Hoboken: 2005
- 6d Johansson Seechurn CC. C, Kitching MO, Colacot TJ, Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 5062
- 7a Lin L, Mulholland N, Wu Q.-Y, Beattie D, Huang S.-W, Irwin D, Clough J, Gu Y.-C, Yang G.-F. J. Agric. Food Chem. 2012; 60: 4480
- 7b Runguphan W, O’Connor SE. Org. Lett. 2013; 15: 2850
- 7c Roy AD, Gruschow S, Cairns N, Goss RJ. M. J. Am. Chem. Soc. 2010; 132: 12243
- 7d Bao K, Dai Y, Zhu Z.-B, Tu F.-J, Zhang W.-G, Yao X.-S. Bioorg. Med. Chem. 2010; 18: 6708
- 7e Mc Elroy WT, De Shong P. Tetrahedron 2006; 62: 6945
- 7f Dobler MR, Bruce I, Cederbaum F, Cooke NG, Diorazio LJ, Hall RG, Irving E. Tetrahedron Lett. 2001; 42: 8281
- 7g Beaumard F, Dauban P, Dodd RH. Org. Lett. 2009; 11: 1801
- 7h Achanta S, Liautard V, Paugh R, Organ MG. Chem. Eur. J. 2010; 16: 12797
- 8a Toyota M, Ihara M. Nat. Prod. Rep. 1998; 15: 327
- 8b Saxton JE In The Alkaloids . Vol. 50. Cordell GA. Chap. 9 Academic Press; New York: 1998
- 8c Saxton JE In The Alkaloids . Vol. 51. Cordell GA. Academic Press; New York: 1998. Chap. 1
- 8d Saxton JE. Indoles, Part 4: The Monoterpenoid Indole Alkaloids. Wiley; Chichester: 1983
- 8e Herbert RB In The Monoterpenoid Indole Alkaloids, Supplement to Vol. 25, Part 4 of The Chemistry of Heterocyclic Compounds. Saxton JE. Wiley; Chichester: 1994. Chap. 1
- 8f Saxton JE In The Monoterpenoid Indole Alkaloids, Supplement to Vol. 25, Part 4 of The Chemistry of Heterocyclic Compounds. Saxton JE. Wiley; Chichester: 1994. Chap. 8
- 9a Danieli B, Lesma G, Palmisano G, Riva R. J. Chem. Soc., Perkin Trans. 1 1987; 155
- 9b Danieli B, Lesma G, Palmisano G, Riva R. J. Chem. Soc., Chem. Commun. 1984; 909
- 10a Mangeney P, Zo Andriamialisoa R, Langlois N, Langlois Y, Potier P. J. Am. Chem. Soc. 1979; 101: 2243
- 10b Langlois N, Gueritte G, Langlois Y, Potier P. J. Am. Chem. Soc. 1976; 98: 7017
- 10c Potier P, Langlois N, Langlois Y, Gueritte F. J. Chem. Soc., Chem. Commun. 1975; 670
- 10d Kutney JP, Ratcliffe AH, Treasurywala AM, Wunderly S. Heterocycles 1975; 3: 639
- 11a Rahman A.-U, Basha A. Biosynthesis of Indole Alkaloids . Clarendon Press; Oxford: 1983
- 11b Scott AI. Acc. Chem. Res. 1970; 3: 151
- 12 Luo X, Cai X, Liu Y, Li Y, Xia C, Shi H. Chinese Patent CN102558178, 2012 ; Chem. Abstr. 2012, 157, 229874.
- 13 Racz-Kotilla E. Herba Hungarica 1975; 14: 57
- 14 Lewin G, Rolland Y, Poisson J. Heterocycles 1980; 14: 1915
- 15 Johnson PD, Sohn J.-H, Rawal VH. J. Org. Chem. 2006; 71: 7899
- 16 Zhang D, Sun H, Zhang L, Zhou Y, Li C, Jiang H, Chen K, Liu H. Chem. Commun. 2012; 48: 2909
- 17 Ueda T, Konishi H, Manabe K. Org. Lett. 2012; 14: 3100
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- 2a Voss ME, Ralph JM, Xie D, Manning DD, Chen X, Frank AJ, Leyhane AJ, Liu L, Stevens JM, Budde C, Surman MD, Friedrich T, Peace D, Scott IL, Wolf M, Johnson R. Bioorg. Med. Chem. Lett. 2009; 19: 1245
- 2b Bernhardt P, McCoy E, O’Connor SE. Chem. Biol. 2007; 14: 888
- 2c McCoy E, O’Connor SE. J. Am. Chem. Soc. 2006; 128: 14276
- 2d Weist S, Süssmuth RD. Appl. Microbiol. Biotechnol. 2005; 68: 141
- 2e Khosla C, Keasling JD. Nat. Rev. Drug Discov. 2003; 2: 1019
- 2f Birch AJ. Pure Appl. Chem. 1963; 7: 527
- 3a Kotha S, Lahiri K, Kashinath D. Tetrahedron 2002; 58: 9633
- 3b Suzuki A. J. Organomet. Chem. 1999; 576: 147
- 3c Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
- 4a Beletskaya IP, Cheprakov AV. Chem. Rev. 2000; 100: 3009
- 4b Dounay AB, Overman LE In The Mizoroki–Heck Reaction . Oestreich M. Wiley; Chichester: 2009. Chap. 16
- 5a Doucet H, Hierso J.-C. Angew. Chem. Int. Ed. 2007; 46: 834
- 5b Chinchilla R, Najera C. Chem. Rev. 2007; 107: 874
- 5c Chinchilla R, Najera C. Chem. Soc. Rev. 2011; 40: 5084
- 6a Handbook of Organopalladium Chemistry for Organic Synthesis . Vol. 1. Negishi E.-I. Wiley; Hoboken: 2002: 1369-1448
- 6b Mitchell TN In Metal-Catalyzed Cross-Coupling Reactions . Diederich F, Stang PJ. Wiley-VCH; Weinheim: 1998. Chap. 4
- 6c Tsuji J. Palladium Reagents and Catalysts: New Perspectives for the 21st Century. Wiley; Hoboken: 2005
- 6d Johansson Seechurn CC. C, Kitching MO, Colacot TJ, Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 5062
- 7a Lin L, Mulholland N, Wu Q.-Y, Beattie D, Huang S.-W, Irwin D, Clough J, Gu Y.-C, Yang G.-F. J. Agric. Food Chem. 2012; 60: 4480
- 7b Runguphan W, O’Connor SE. Org. Lett. 2013; 15: 2850
- 7c Roy AD, Gruschow S, Cairns N, Goss RJ. M. J. Am. Chem. Soc. 2010; 132: 12243
- 7d Bao K, Dai Y, Zhu Z.-B, Tu F.-J, Zhang W.-G, Yao X.-S. Bioorg. Med. Chem. 2010; 18: 6708
- 7e Mc Elroy WT, De Shong P. Tetrahedron 2006; 62: 6945
- 7f Dobler MR, Bruce I, Cederbaum F, Cooke NG, Diorazio LJ, Hall RG, Irving E. Tetrahedron Lett. 2001; 42: 8281
- 7g Beaumard F, Dauban P, Dodd RH. Org. Lett. 2009; 11: 1801
- 7h Achanta S, Liautard V, Paugh R, Organ MG. Chem. Eur. J. 2010; 16: 12797
- 8a Toyota M, Ihara M. Nat. Prod. Rep. 1998; 15: 327
- 8b Saxton JE In The Alkaloids . Vol. 50. Cordell GA. Chap. 9 Academic Press; New York: 1998
- 8c Saxton JE In The Alkaloids . Vol. 51. Cordell GA. Academic Press; New York: 1998. Chap. 1
- 8d Saxton JE. Indoles, Part 4: The Monoterpenoid Indole Alkaloids. Wiley; Chichester: 1983
- 8e Herbert RB In The Monoterpenoid Indole Alkaloids, Supplement to Vol. 25, Part 4 of The Chemistry of Heterocyclic Compounds. Saxton JE. Wiley; Chichester: 1994. Chap. 1
- 8f Saxton JE In The Monoterpenoid Indole Alkaloids, Supplement to Vol. 25, Part 4 of The Chemistry of Heterocyclic Compounds. Saxton JE. Wiley; Chichester: 1994. Chap. 8
- 9a Danieli B, Lesma G, Palmisano G, Riva R. J. Chem. Soc., Perkin Trans. 1 1987; 155
- 9b Danieli B, Lesma G, Palmisano G, Riva R. J. Chem. Soc., Chem. Commun. 1984; 909
- 10a Mangeney P, Zo Andriamialisoa R, Langlois N, Langlois Y, Potier P. J. Am. Chem. Soc. 1979; 101: 2243
- 10b Langlois N, Gueritte G, Langlois Y, Potier P. J. Am. Chem. Soc. 1976; 98: 7017
- 10c Potier P, Langlois N, Langlois Y, Gueritte F. J. Chem. Soc., Chem. Commun. 1975; 670
- 10d Kutney JP, Ratcliffe AH, Treasurywala AM, Wunderly S. Heterocycles 1975; 3: 639
- 11a Rahman A.-U, Basha A. Biosynthesis of Indole Alkaloids . Clarendon Press; Oxford: 1983
- 11b Scott AI. Acc. Chem. Res. 1970; 3: 151
- 12 Luo X, Cai X, Liu Y, Li Y, Xia C, Shi H. Chinese Patent CN102558178, 2012 ; Chem. Abstr. 2012, 157, 229874.
- 13 Racz-Kotilla E. Herba Hungarica 1975; 14: 57
- 14 Lewin G, Rolland Y, Poisson J. Heterocycles 1980; 14: 1915
- 15 Johnson PD, Sohn J.-H, Rawal VH. J. Org. Chem. 2006; 71: 7899
- 16 Zhang D, Sun H, Zhang L, Zhou Y, Li C, Jiang H, Chen K, Liu H. Chem. Commun. 2012; 48: 2909
- 17 Ueda T, Konishi H, Manabe K. Org. Lett. 2012; 14: 3100
