1 Introduction
Tetrahydro-γ-carbolines represent an important class of indole‑containing heterocyclic alkaloids found in natural products and constitute the core motifs of numerous biologically active molecules.[1] They always exhibit a broad spectrum of pharmacological properties, including antiviral, antibacterial, antitumor, and anti‑inflammatory activities.[2] As illustrated in Scheme 1a, representative examples such as gevotroline, dimebon, 5‑HT6 antagonists, and Tadalafil analogues all feature polycyclic tetrahydro‑γ‑carboline frameworks.[3] Consequently, these important scaffolds have attracted considerable attention, driving the need for efficient synthetic methods to access them.
To date, general and efficient asymmetric catalytic approaches for constructing chiral tetrahydro-γ-carbolines remain underdeveloped. Asymmetric iso-Pictet-Spengler cyclization promoted by organocatalysis or transition‑metal catalysis stands out as a powerful synthetic tool.[4] In 2011, Jacobsen and coworkers[5] reported a one-pot condensation of isochromanamines with aldehydes to generate indole- containing imines, which subsequently underwent an asym- metric iso-Pictet-Spengler cyclization catalyzed by a chiral thiourea/benzoic acid synergistic dual‑catalyst system, affording chiral tetrahydro-γ-carboline derivatives with excellent enantioselectivity. In 2016, Shi and coworkers[6] developed a chiral phosphoric acid (CPA)-catalyzed three- component reaction involving an asymmetric [3＋3]-cyclo- addition between 2-indolylmethanols and azomethine ylides generated in situ from aldehydes and amino esters, delivering chiral tetrahydro-γ-carbolines in good yields with high enantioselectivity. Concurrently, Deng and co-workers described Cu-[7] or Ag-catalyzed[8] asymmetric [3＋3]-cy- cloadditions of azomethine ylides with electron‑deficient 2-vinylindoles, providing multi‑substituted chiral tetrahydro-γ-carboline derivatives in moderate to high yields with excellent stereocontrol. In 2019, our group[9] established an efficient asymmetric cascade allylation[10]/iso-Pictet- Spengler cyclization between azomethine ylides and indolyl allyl carbonates promoted by cooperative bimetallic Cu/Ir catalytic system, enabling the stereodivergent synthesis of chiral tetrahydro-γ-carbolines. More recently, we accomplished Ir-catalyzed asymmetric cascade allylation/iso- Pictet-Spengler cyclization of arylidenaminomalonates with indolyl allyl carbonates, yielding tetrahydro-γ-carboline derivatives in good yields with excellent stereoselectivity (Scheme 1b).[11] Carreira’s group[12a-12e] demonstrated that readily available allylic alcohols, in the presence of an acid promoter, could undergo Ir-catalyzed asymmetric allylic substitution with suitable nucleophiles. Inspired by these advances, we envisioned that easily accessible indolyl allylic alcohols, when activated by an acid promoter, might participate in an asymmetric cascade allylation/iso-Pictet- Spengler cyclization with azomethine ylides, offering a convenient route to chiral tetrahydro-γ-carboline derivatives. In this design, the acid promoter would play a dual role in activating the allylic alcohol and facilitating the subsequent iso-Pictet-Spengler cyclization. Moreover, replacing allyl carbonates with allylic alcohols generates water as the sole by-product, enhancing atom economy and aligning with green chemistry principles.
2 Results and discussion
To validate the feasibility of this proposed tandem allylation/iso-Pictet-Spengler cyclization, phenyl iminomalonate 1a and branched 2-indolyl allylic alcohol 2a were selected as the model substrates. Employing [Ir(cod)Cl]2 and Carreira’s ligand (S)-L as the catalytic system, together with CCl3COOH as the acid promoter in 1,2-dichloro- ethane, this cascade reaction proceeded smoothly, furnishing the desired product 3aa in 54% yield with high diastereoselectivity (11∶1 dr) and moderate enantioselectivity (Table 1, Entry 1). Other acid promoters, including Brønsted acid CF3COOH and Lewis acids Zn(OTf)2, Yb(OTf)3, and Sc(OTf)3 (Table 1, Entries 2~5), were screened. CF3COOH could promote the reaction to afford the product in 45% yield with 7∶1 dr and 98% ee (Table 1, Entry 2). In addition, Zn(OTf)2 afforded the product in 40% yield with >20∶1 dr and 96% ee. Given the potential sensitivity of the reaction system to moisture, which could compromise both efficiency and enantioselectivity, 3 Å molecular sieves were added to the reaction system. Pleasingly, the reaction yield was improved significantly (62% yield, 96% ee, Entry 6). Increasing the loading of Zn(OTf)2 did not lead to further notable improvement. Subsequent solvent screening identified 1,4-dioxane as the optimal choice, delivering product 3aa in moderate yield and excellent enantioselectivity (67% yield, 99% ee, Table 1, Entry 11).
Table 1 Optimization of the reaction conditionsa |
| Entry | Acid (mol%) | Solvent | Yieldb/% | eec/% |
|---|---|---|---|---|
| 1 | Cl3CCO2H (25) | DCE | 54 | 81 |
| 2 | F3CCO2H (25) | DCE | 45 | 98 |
| 3 | Yb(OTf)3 (25) | DCE | 73 | 11 |
| 4 | Sc(OTf)3 (25) | DCE | 64 | 23 |
| 5 | Zn(OTf)2 (25) | DCE | 40 | 96 |
| 6d | Zn(OTf)2 (25) | DCE | 62 | 96 |
| 7d | Zn(OTf)2 (50) | DCE | 67 | 96 |
| 8d | Zn(OTf)2 (100) | DCE | 68 | 96 |
| 9d | Zn(OTf)2 (50) | DCM | 53 | 81 |
| 10d | Zn(OTf)2 (50) | THF | 63 | 98 |
| 11d | Zn(OTf)2 (50) | 1,4-Dioxane | 67 | 99 |
| 12d | Zn(OTf)2 (50) | PhMe | 58 | 93 |
a Reaction conditions: 1a (0.24 mmol, 1.2 equiv.), 2a (0.2 mmol, 1 equiv.), acid (25~100 mol%), [Ir(cod)Cl]2 (2 mol%), (S)-L (8 mol%) in 2.0 mL of solvent at room temperature for 24 h. The dr value was determined by the crude 1H NMR analysis. 11∶1 dr in Entry 1, 7∶1 dr in Entry 2. b Yields of isolated products. c The ee values were determined by chiral HPLC analysis. d 3 Å MS (80.0 mg). DCM=dichloromethane, DCE=1,2-dichloroethane, THF=tetrahydrofuran. |
With the optimized conditions in hand, the substrate scope was evaluated by examining arylidenaminomalonates bearing varied substituents on the aromatic ring. As summarized in Table 2, substrates with either electron‑donating (Me, MeO) or electron-withdrawing (Cl, Br) groups reacted smoothly, affording the corresponding chiral tetrahydro‑γ‑ carboline derivatives 3aa~3ja in good yields with high diastereoselectivity and excellent enantioselectivity (60%~70% yield, >20∶1 dr, 96%~>99% ee; Entries 1~10). Furthermore, the iminomalonate derived from 2-naphth- aldehyde (1k) was also compatible, delivering the desired product 3ka in 60% yield with excellent stereoselectivity (>20∶1 dr, >99% ee, Table 2, Entry 11). The protocol proved effective for heteroaromatic substrate 1l derived from 2-thiophenyl aldehyde, providing the expected product 3la in 63% yield with >20∶1 dr and 98% ee (Table 2, Entry 12). The influence of the ester group on the iminomalonate scaffold was also investigated. Replacing the ethyl ester with isopropyl ester (1m) proceeded smoothly, affording the corresponding product 3ma in 70% yield with >20∶1 dr and >99% ee (Table 2, Entry 13). Notably, the more challenging alkyl-substituted substrate (1n) was also amenable to this catalytic system, affording the desired product 3na in moderate yield and excellent enantioselectivity (58% yield, 98% ee, Table 2, Entry 14).
Table 2 Substrate scope study for iminomalonatesa |
| Entry | R/R' | 3 | Yieldb/% | eec/% |
|---|---|---|---|---|
| 1 | C6H5/Et (1a) | 3aa | 67 | 99 |
| 2 | p-MeC6H4/Et (1b) | 3ba | 60 | 98 |
| 3 | m-MeC6H4/Et (1c) | 3ca | 62 | 96 |
| 4d | o-MeC6H4/Et (1d) | 3da | 65 | －>99 |
| 5 | p-ClC6H4/Et (1e) | 3ea | 70 | >99 |
| 6 | m-ClC6H4/Et (1f) | 3fa | 64 | 96 |
| 7 | o-ClC6H4/Et (1g) | 3ga | 62 | 98 |
| 8 | p-MeOC6H4/Et (1h) | 3ha | 64 | >99 |
| 9 | m-MeOC6H4/Et (1i) | 3ia | 64 | >99 |
| 10 | p-BrC6H4/Et (1j) | 3ja | 65 | >99 |
| 11 | 2-Naphthyl/Et (1k) | 3ka | 60 | >99 |
| 12 | Thiophen-2-yl/Et (1l) | 3la | 63 | 98 |
| 13 | p-ClC6H4/iPr (1m) | 3ma | 70 | >99 |
| 14d | Cy/Et (1n) | 3na | 58 | －98 |
a Reaction conditions: 1 (0.24 mmol, 1.2 equiv.), 2a (0.2 mmol, 1 equiv.), Zn(OTf)2 (50 mol%), [Ir(cod)Cl]2 (2 mol%), (S)-L (8 mol%), 3 Å MS (80.0 mg) in 2.0 mL of 1,4-dioxane at room temperature. The dr value was determined by the crude 1H NMR analysis. b Yields of isolated products. c The ee values were determined by chiral HPLC analysis. d Carreira’s ligand (R)-L was used. |
Encouraged by these above excellent results, the scope with respect to indolyl allylic alcohols 2 was further explored using iminomalonate 1a as the coupling partner. As summarized in Table 3, it was found that the substituents at various positions (C-4, -5, -6, or -7) of the indole ring had little impact on reactivity and stereoselectivity, furnishing the corresponding [3＋3] annulation products 3ab~3af in 50%~80% yields, >20∶1 dr and 93%~>99% ee. In addition, imine substrates derived from glycine and alanine esters were found to be unreactive under the standard reaction conditions, presumably due to their low reactivity.
As outlined in Scheme 2, a possible reaction pathway was proposed for this transformation. The racemic allylic alcohol 2a undergoes oxidative addition with the iridium catalyst [Ir*] in the presence of an activator, providing the electrophilic π-allyl-Ir intermediate int-II. Subsequent asymmetric allylic substitution of this intermediate int-II by the nucleophilic intermediate int-I generating in situ from imine ester substrate 1a would afford int-III. This intermediate then goes through Pictet-Spengler cyclization to ultimately furnish the desired product 3aa.
Table 3 Substrate scope study for 2-indolyl allylic alcoholsa |
 |
a Reaction conditions: 1a (0.24 mmol, 1.2 equiv.), 2 (0.2 mmol, 1 equiv.), Zn(OTf)2 (50 mol%), [Ir(cod)Cl]2, (2 mol%), (S)-L (8 mol%), 3 Å MS (80.0 mg) in 2.0 mL of 1,4-dioxane at room temperature. Yields of isolated products. The dr value was determined by the crude 1H NMR analysis. The ee values were determined by chiral HPLC analysis. |
3 Conclusions
In summary, we have developed Ir-catalyzed asymmetric cascade allylation/iso-Pictet-Spengler cyclization between iminomalonates and easily available indolyl allylic alcohols in the presence of Lewis acid Zn(OTf)2. This strategy offers a direct and efficient route to access a variety of chiral tetrahydro-γ-carboline derivatives containing two non-adja- cent stereocenters in moderate to good yields with excellent stereoselectivity (50%~80% yields, >20∶1 dr, 96~>99% ee). The generation of water as the sole by‑product endows this protocol with good atom economy and aligns with the principles of sustainable synthesis.
4 Experimental section
4.1 General experimental information
Unless stated otherwise, all reactions were carried out in flame-dried glassware under a dry nitrogen atmosphere. All solvents were purified and dried according to the standard methods prior to use. All catalytic reactions were performed in Schlenk tubes under an atmosphere of nitrogen. Commercially available reagents were used without further purification. Column chromatography was performed using silica gel (300~400 mesh). Melting points were measured with a SGW X-4 micro melting point apparatus. 1H NMR (400 MHz), 13C NMR (100 MHz) spectra were recorded on a Bruker Avance III HD 400 MHz NMR spectrometer. High-resolution mass spectra (HRMS) were recorded using ESI-TOF technique. Optical rotations were measured in CHCl3 on a Rudolph Autopol VI polarimeter. Enantiomeric excess values were measured by high performance liquid chromatography (HPLC) using Daicel Chiralcel columns with hexane/isopropanol as eluent. The racemic products were obtained by running reactions with racemic catalysts or blending equal amount of two enantiomers.
4.2 General procedure for Ir-catalyzed asymmetric cascade allylation/iso-Pictet-Spengler cyclization with arylidenaminomalonates
Under a nitrogen atmosphere, a flame-dried 10 mL Schlenk tube was charged with [Ir(cod)Cl]2 (2.7 mg, 0.004 mmol, 2 mol%), Carreira’s ligand (S)-L (8.2 mg, 0.016 mmol, 8 mol%). After the tube was evacuated and backfilled with nitrogen, anhydrous 1,4-dioxane (1.0 mL) was added, then stirred at room temperature for 15 min while the solution turned dark red. Then, 2-indolyl allylic alcohols 2 (0.2 mmol, 1.0 equiv.) and 3 Å MS (80.0 mg) were added, the reaction mixture immediately turned light yellow. Iminoesters 1 (0.24 mmol, 1.2 equiv.) and Zn(OTf)2 (36.4 mg, 0.1 mmol, 0.5 equiv.) were added sequentially. The reaction mixture was stirred at room temperature until iminoesters 1 were consumed (monitored by TLC deactivated by triethylamine), which was evaporated under reduced pressure. The crude residue was purified by flash chromatography [V(petroleum ether)/V(EtOAc)=20/1~10/1] to give the desired products 3. The dr value was determined by 1H NMR spectrum of the product, and the enantiomeric excess was recorded by HPLC analysis in comparison with the racemic sample.
Diethyl (1R,4R)-5-methyl-1-phenyl-4-vinyl-1,2,4,5-te- trahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3aa): Yield 67%, 57.9 mg, yellow thick oil. The product was analyzed by HPLC to determine the enantiomeric excess:>99% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=6.2 and 8.1 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.46~7.40 (m, 2H), 7.36~7.28 (m, 3H), 7.24 (s, 1H), 7.11~7.06 (m, 1H), 6.83~6.76 (m, 1H), 6.75~6.73 (m, 1H), 6.09~6.03 (m, 1H), 5.35~5.25 (m, 2H), 5.15 (s, 1H), 4.50 (d, J=8.3 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.18 (t, J=7.1 Hz, 2H), 3.70 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.3, 168.1, 142.9, 137.6, 135.9, 134.4, 128.9, 128.4, 127.8, 124.9, 121.0, 119.2, 118.9, 109.7, 108.8, 71.5, 62.2, 62.0, 55.6, 42.3, 29.1, 14.20, 14.17. HRMS (ESI) calcd for C26H29O4N2 [M＋H]＋ 433.2122, found 433.2099.
Diethyl (1R,4R)-5-methyl-1-(p-tolyl)-4-vinyl-1,2,4,5-te- trahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3ba): Yield 60%, 53.6 mg, yellow solid, m.p. 41~43 ℃. The product was analyzed by HPLC to determine the enantio- meric excess: 98% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=7.0 and 11.6 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.35~7.28 (m, 2H), 7.25~7.23 (m, 1H), 7.12~7.08 (m, 3H), 6.88~6.73 (m, 2H), 6.11~6.02 (m, 1H), 5.34~5.25 (m, 2H), 5.11 (d, J=1.4 Hz, 1H), 4.49 (dd, J=8.3, 1.3 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.21~4.11 (m, 2H), 3.69 (s, 3H), 2.34 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.3, 168.2, 139.9, 137.6, 137.3, 136.0, 134.4, 129.1, 128.7, 124.9, 121.0, 119.3, 119.2, 118.8, 109.8, 108.8, 71.5, 62.2, 62.0, 55.2, 42.3, 29.1, 21.3, 14.20, 14.17. HRMS (ESI) calcd for C27H31O4N2 [M＋H]＋ 447.2278, found 447.2258.
Diethyl (1R,4R)-5-methyl-1-(m-tolyl)-4-vinyl-1,2,4,5-te- trahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3ca): Yield 62%, 55.4 mg, yellow oil. The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=4.8 and 5.4 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.24 (d, J=3.8 Hz, 2H), 7.22~7.17 (m, 2H), 7.12~7.05 (m, 2H), 6.84~6.76 (m, 2H), 6.10~6.04 (m, 1H), 5.34~5.25 (m, 2H), 5.10 (d, J=1.5 Hz, 1H), 4.49 (dd, J=8.4, 1.3 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.21~4.12 (m, 2H), 3.70 (s, 3H), 2.31 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.3, 168.2, 142.7, 137.9, 137.5, 136.0, 134.4, 129.5, 128.6, 128.2, 125.9, 121.0, 119.3, 119.2, 118.9, 109.7, 108.7, 71.5, 62.2, 62.0, 55.6, 42.3, 29.1, 21.5, 14.20, 14.17. HRMS (ESI) calcd for C27H31O4N2 [M＋H]＋ 447.2278, found 447.2256.
Diethyl (1S,4S)-5-methyl-1-(o-tolyl)-4-vinyl-1,2,4,5-te- trahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3da): Carreira’s ligand (R)-L was used. Yield 65%, 58.1 mg, white solid, m.p. 72~74 ℃. The product was analyzed by HPLC to determine the enantiomeric excess: >99% ee (Chiralpak AD-H, i-propanol/hexane (V/V=3/97), flow rate 1.0 mL/min, λ=254 nm); tr=7.8 and 8.2 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.26 (d, J=8.3 Hz, 1H), 7.17 (d, J=7.7 Hz, 3H), 7.13~7.02 (m, 2H), 6.84~6.79 (m, 1H), 6.64 (d, J=8.0 Hz, 1H), 6.12~5.95 (m, 1H), 5.41 (s, 1H), 5.35~5.25 (m, 2H), 4.49 (d, J=8.5 Hz, 1H), 4.31~4.12 (m, 4H), 3.70 (s, 3H), 2.87 (s, 1H), 2.66~2.32 (m, 3H), 1.31~1.21 (m, 6H); 13C NMR (100 MHz, Chloroform-d) δ: 169.3, 168.1, 140.1, 137.5, 135.7, 134.6, 130.2, 129.3, 127.5, 124.7, 121.0, 119.2, 119.1, 118.8, 109.6, 108.7, 71.5, 62.1, 62.0, 50.3, 42.2, 29.1, 19.2, 14.22, 14.17. HRMS (ESI) calcd for C26H29O4N2 [M＋H]＋ 447.2278, found 447.2259.
Diethyl (1R,4R)-1-(4-chlorophenyl)-5-methyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxyl-ate (3ea): Yield 70%, 65.4 mg, yellow oil. The product was analyzed by HPLC to determine the enantiomeric excess:>99% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=8.3 and 12.5 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.42~7.33 (m, 2H), 7.32~7.25 (m, 3H), 7.13~7.08 (m, 1H), 6.86~6.82 (m, 1H), 6.76~6.73 (m, 1H), 6.15~5.97 (m, 1H), 5.34~5.25 (m, 2H), 5.14 (d, J=1.3 Hz, 1H), 4.50 (dd, J=8.3, 1.3 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.17 (dd, J=7.1, 4.2 Hz, 2H), 3.69 (s, 3H), 2.96 (s, 1H), 1.30 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.1, 168.0, 141.5, 137.6, 135.8, 134.5, 133.4, 130.2, 128.6, 124.7, 121.2, 119.3, 119.0, 109.2, 108.9, 71.4, 62.3, 62.1, 54.9, 42.2, 29.1, 14.19, 14.16. HRMS (ESI) calcd for C26H28O4N2Cl [M＋H]＋ 467.1732, found 467.1705.
Diethyl (1R,4R)-1-(3-chlorophenyl)-5-methyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxyl-ate (3fa): Yield 64%, 59.7 mg, yellow solid, m.p. 44~46 ℃. The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=5.6 and 6.8 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.41 (d, J=2.1 Hz, 1H), 7.33~7.30 (m, 1H), 7.28~7.23 (m, 3H), 7.13~7.08 (m, 1H), 6.87~6.83 (m, 1H), 6.79~6.76 (m, 1H), 6.15~5.99 (m, 1H), 5.35~5.27 (m, 2H), 5.13 (d, J=1.4 Hz, 1H), 4.50 (dd, J=8.3, 1.3 Hz, 1H), 4.27 (qd, J=7.1, 1.4 Hz, 2H), 4.20 (d, J=3.5 Hz, 2H), 3.70 (s, 3H), 3.00 (s, 1H), 1.31 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.1, 168.0, 145.1, 137.6, 135.8, 134.5, 134.2, 129.7, 129.0, 128.1, 127.1, 124.7, 121.2, 119.4, 119.1, 119.0, 109.0, 108.9, 71.4, 62.3, 62.1, 55.3, 42.3, 29.1, 14.19, 14.16. HRMS (ESI) calcd for C26H27O4N2Cl [M＋H]＋ 467.1732, found 467.1712.
Diethyl (1S,4R)-1-(2-chlorophenyl)-5-methyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxyl-ate (3ga): Yield 62%, 57.9 mg, yellow oil. The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=6.6 and 7.2 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.43 (dd, J=8.0, 1.3 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.25~7.17 (m, 2H), 7.15~7.07 (m, 2H), 6.88~6.84 (m, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.05 (ddd, J=17.1, 10.0, 8.4 Hz, 1H), 5.74 (s, 1H), 5.33~5.25 (m, 2H), 4.51 (d, J=8.4 Hz, 1H), 4.32~4.11 (m, 4H), 3.71 (s, 3H), 3.20 (s, 1H), 1.31 (d, J=7.1 Hz, 3H), 1.23 (d,J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.2, 168.1, 139.6, 137.6, 135.8, 135.1, 133.9, 131.1, 129.1, 128.9, 127.4, 121.2, 119.3, 119.3, 119.0, 108.9, 108.6, 71.5, 62.3, 62.1, 42.2, 29.1, 14.20, 14.16. HRMS (ESI) calcd for C26H28O4N2Cl [M＋H]＋ 467.1732, found 467.1712.
Diethyl (1R,4R)-1-(4-methoxyphenyl)-5-methyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarbo-xylate (3ha): Yield 64%, 59.2 mg, yellow oil. The product was analyzed by HPLC to determine the enantiomeric excess: >99% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=10.6 and 13.5 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.38~7.30 (m, 2H), 7.24 (s, 1H), 7.11~7.07 (m, 1H), 6.88~6.74 (m, 4H), 6.06 (ddd, J=17.1, 10.1, 8.3 Hz, 1H), 5.35~5.23 (m, 2H), 5.17~5.04 (m, 1H), 4.56~4.43 (m, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.24~4.10 (m, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 2.93 (s, 1H), 1.30 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.3, 159.2, 137.6, 136.0, 135.1, 134.4, 129.9, 124.9, 121.0, 119.3, 119.2, 118.9, 113.8, 110.0, 108.8, 71.5, 62.2, 62.0, 55.3, 54.9, 42.2, 29.1, 14.20, 14.16. HRMS (ESI) calcd for C27H31O5N2 [M＋H]＋ 463.2227, found 463.2209.
Diethyl (1R,4R)-1-(3-methoxyphenyl)-5-methyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b] indole-3,3-dicar-boxylate (3ia): Yield 64%, 59.2 mg, yellow oil. The product was analyzed by HPLC to determine the enantiomeric excess: >99% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=6.5 and 10.0 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.25~7.17 (m, 2H), 7.11~7.07 (m, 1H), 7.05~7.01 (m, 1H), 6.98 (dd, J=2.6, 1.6 Hz, 1H), 6.88~6.79 (m, 3H), 6.07 (ddd, J=17.0, 10.1, 8.3 Hz, 1H), 5.34~5.26 (m, 2H), 5.13 (d, J=1.4 Hz, 1H), 4.50 (dd, J=8.3, 1.2 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.17 (qd, J=7.1, 5.8 Hz, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 1.31 (d, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.2, 159.6, 144.6, 137.6, 136.0, 134.4, 129.4, 124.9, 121.3, 121.0, 119.3, 119.2, 118.9, 114.6, 113.1, 109.6, 108.7, 71.5, 62.2, 62.0, 55.6, 55.2, 42.3, 29.1, 14.20, 14.17. HRMS (ESI) calcd for C27H31O5N2 [M＋H]＋ 463.2227, found 463.2219.
Diethyl (1R,4R)-1-(4-bromophenyl)-5-methyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxyl-ate (3ja): Yield 65%, 66.5 mg, yellow solid, m.p. 165~167 ℃. The product was analyzed by HPLC to determine the enantiomeric excess:>99% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=9.4 and 14.4 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.49~7.40 (m, 2H), 7.33~7.28 (m, 2H), 7.24 (s, 1H), 7.11~7.10 (m, 1H), 6.85~6.82 (m, 1H), 6.75 (d, J=7.9 Hz, 1H), 6.13~5.98 (m, 1H), 5.35~5.25 (m, 2H), 5.13 (d, J=1.3 Hz, 1H), 4.50 (dd, J=8.3, 1.3 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.17 (qd, J=7.1, 3.7 Hz, 2H), 3.69 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.1, 168.0, 142.1, 135.8, 137.6, 134.5, 131.6, 130.6, 124.6, 121.6, 121.2, 119.3, 119.1, 119.0, 109.1, 108.9, 71.4, 62.3, 62.1, 55.0, 42.2, 29.1, 14.21, 14.18. HRMS (ESI) calcd for C26H28O4- N2Br [M＋H]＋ 511.1227, found 511.1199.
Diethyl (1R,4R)-5-methyl-1-(naphthalen-2-yl)-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxyl-ate (3ka): Yield 60%, 57.8 mg, yellow solid, m.p. 148~150 ℃. The product was analyzed by HPLC to determine the enantiomeric excess: >99% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=8.9 and 16.6 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.96 (d, J=1.7 Hz, 1H), 7.88~7.82 (m, 1H), 7.82~7.77 (m, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.53~7.42 (m, 3H), 7.29~7.20 (m, 1H), 7.08~7.03 (m, 1H), 6.73 (d, J=4.1 Hz, 2H), 6.14 (ddd, J=17.1, 10.0, 8.4 Hz, 1H), 5.42~5.21 (m, 3H), 4.54 (d, J=8.4 Hz, 1H), 4.30~4.13 (m, 4H), 3.71 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.3, 168.2, 140.6, 137.6, 136.0, 134.6, 133.4, 133.4, 128.4, 128.0, 127.8, 127.6, 126.9, 125.9, 125.8, 124.9, 121.1, 119.3, 119.2, 119.0, 109.5, 108.8, 71.6, 62.3, 62.1, 55.8, 42.4, 29.2, 14.3, 14.2. HRMS (ESI) calcd for C30H31O4N2 [M＋H]＋ 483.2278, found 483.2256.
Diethyl (1S,4R)-5-methyl-1-(thiophen-2-yl)-4-vinyl-1,2, 4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3la): Yield 63%, 55.2 mg, yellow oil. The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=7.2 and 10.4 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.25~7.19 (m, 3H), 7.14~7.09 (m, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.96 (dd, J=5.1, 3.4 Hz, 1H), 6.90 (ddd, J=8.0, 6.9, 1.0 Hz, 1H), 6.15~5.98 (m, 1H), 5.57 (s, 1H), 5.37~5.24 (m, 2H), 4.52~4.44 (m, 1H), 4.27 (qd, J=7.1, 1.5 Hz, 2H), 4.21~4.09 (m, 2H), 3.68 (s, 3H), 3.12 (d, J=23.4 Hz, 1H), 1.31 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloro- form-d) δ: 169.1, 167.8, 148.1, 137.5, 135.4, 134.1, 125.8, 125.7, 125.5, 124.9, 121.2, 119.5, 119.1, 119.0, 109.6, 108.9, 71.5, 62.3, 62.1, 50.5, 42.3, 29.0, 14.2, 14.1. HRMS (ESI) calcd for C24H27O4N2S [M＋H]＋ 439.1646, found 439.1657.
Diisopropyl (1R,4R)-1-(4-chlorophenyl)-5-methyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-di- carboxylate (3ma): Yield 70%, 70.0 mg, yellow solid, m.p. 188~190 ℃. The product was analyzed by HPLC to determine the enantiomeric excess: >99% ee (Chiralpak IE, i-propanol/hexane=2/98, V/V, flow rate 1.0 mL/min, λ=254 nm); tr=8.8 and 11.2 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.38~7.33 (m, 2H), 7.30~7.23 (m, 3H), 7.10~7.09 (m, 1H), 6.84~6.81 (m, 1H), 6.74 (d, J=7.9 Hz, 1H), 6.05 (ddd, J=17.1, 10.1, 8.4 Hz, 1H), 5.38~5.24 (m, 2H), 5.17~5.06 (m, 2H), 5.04~4.93 (m, 1H), 4.56~4.34 (m, 1H), 3.70 (s, 3H), 1.32~1.24 (m, 9H), 1.09 (d, J=6.2 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 168.6, 167.6, 141.6, 137.6, 135.7, 134.8, 133.4, 130.3, 128.6, 121.1, 119.2, 119.0, 109.1, 108.9, 71.2, 70.0, 69.5, 55.0, 42.1, 29.1, 21.9, 21.7, 21.6, 21.5. HRMS (ESI) calcd for C28H32O4N2Cl [M＋H]＋ 495.2023, found 495.2021.
Diethyl (1S,4S)-1-cyclohexyl-5-methyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b] indole-3,3-dicarbo-xylate (3na): Carreira’s ligand (R)-L was used. Yield 58%, 50.8 mg, yellow oil. The product was analyzed by HPLC to determine the enantiomeric excess: 98% ee (Chiralpak AD-H, i-propanol/hexane (V/V=3/97), flow rate 1.0 mL/min, λ=254 nm); tr=4.7 and 6.4 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.46 (d, J=7.9 Hz, 1H), 7.21 (s, 1H), 7.13~7.06 (m, 1H), 7.02~6.94 (m, 1H), 5.85 (ddd, J=17.1, 10.1, 8.6 Hz, 1H), 5.20~5.08 (m, 2H), 4.30 (d, J=8.6 Hz, 1H), 4.21~4.17 m, 2H), 4.13 (d, J=2.6 Hz, 1H), 3.98 (qd, J=7.1, 2.6 Hz, 2H), 3.58 (s, 3H), 2.22~2.08 (m, 1H), 1.83~1.70 (m, 2H), 1.60~1.44 (m, 5H), 1.24 (d, J=7.1 Hz, 3H), 1.15~1.07 (m, 2H), 1.02 (t, J=7.1 Hz, 3H), 0.80 (td, J=10.9, 9.7, 4.5 Hz, 1H); 13C NMR (100 MHz, Chloroform-d) δ: 169.6, 168.7, 137.7, 136.0, 134.9, 124.9, 120.8, 119.2, 118.7, 118.6, 109.0, 108.9, 71.0, 62.1, 61.7, 54.8, 42.6, 42.0, 30.4, 28.9, 27.3, 26.64, 26.58, 25.4, 14.2, 14.1. HRMS (ESI) calcd for C26H35O4N2 [M＋H]＋ 439.2591, found 439.2584.
Diethyl (1R,4R)-5,9-dimethyl-1-phenyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3ab): Yield 80%, 71.4 mg, yellow thick oil. The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (Chiralpak IE, i-propanol/hexane (V/V=2/98), flow rate 1.0 mL/min, λ=254 nm); tr=9.2 and 11.0 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.25 (d, J=2.8 Hz, 5H), 7.13 (d, J=8.2 Hz, 1H), 7.04~7.01 (m, 1H), 6.64 (d, J=7.1 Hz, 1H), 6.01 (ddd, J=17.7, 10.1, 8.1 Hz, 1H), 5.51 (d, J=1.4 Hz, 1H), 5.36~5.22 (m, 2H), 4.52 (d, J=8.1 Hz, 1H), 4.24 (q, J=7.0 Hz, 2H), 4.17 (dd, J=10.7, 7.1 Hz, 2H), 3.70 (s, 3H), 1.82 (s, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.0, 167.9, 145.4, 138.1, 135.7, 135.2, 130.7, 128.6, 128.4, 127.5, 124.6, 121.5, 120.8, 119.4, 109.4, 106.5, 71.3, 62.3, 62.0, 56.1, 43.0, 29.1, 21.1, 14.19, 14.17. HRMS (ESI) calcd for C27H31O4N2 [M＋H]＋ 447.2278, found 447.2257.
Diethyl (1R,4R)-5,8-dimethyl-1-phenyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3ac): Yield 67%, 59.8 mg, yellow solid, m.p. 40~42 ℃. The product was analyzed by HPLC to determine the enan- tiomeric excess: >99% ee (Chiralpak AD-H, i-propanol/ hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=6.2 and 7.3 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.46~7.40 (m, 2H), 7.36~7.28 (m, 3H), 7.13 (d, J=8.3 Hz, 1H), 6.91 (dd, J=8.4, 1.7 Hz, 1H), 6.57~6.51 (m, 1H), 6.07 (ddd, J=16.9, 10.3, 8.3 Hz, 1H), 5.34~5.24 (m, 2H), 5.16~5.07 (m, 1H), 4.48 (dd, J=8.2, 1.3 Hz, 1H), 4.26 (qd, J=7.2, 0.9 Hz, 2H), 4.16 (p, J=7.2 Hz, 2H), 3.66 (s, 3H), 2.21 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.2, 168.2, 136.01, 135.97, 134.5, 128.9, 128.4, 128.0, 127.7, 125.1, 122.6, 119.1, 118.9, 109.1, 108.5, 71.5, 62.2, 62.0, 55.6, 42.3, 29.1, 21.4, 14.14, 14.16. HRMS (ESI) calcd for C27- H31O4N2 [M＋H]＋ 447.2278, found 447.2259.
Diethyl (1R,4R)-5,7-dimethyl-1-phenyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3ad): Yield 68%, 60.7 mg, yellow thick oil. The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (Chiralpak AD-H, i-propanol/hexane (V/ V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=5.6 and 7.8min. 1H NMR (400 MHz, Chloroform-d) δ: 7.46~7.39 (m, 2H), 7.34~7.27 (m, 3H), 7.05 (s, 1H), 6.70~6.59 (m, 2H), 6.07 (ddd, J=17.0, 10.1, 8.2 Hz, 1H), 5.34~5.24 (m, 2H), 5.13 (d, J=1.4 Hz, 1H), 4.52~4.46 (m, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.23~4.12 (m, 2H), 3.66 (s, 3H), 2.40 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.3, 168.2, 143.0, 138.0, 136.0, 133.8, 130.9, 128.9, 128.4, 127.7, 122.7, 120.5, 119.1, 118.9, 109.6, 108.9, 71.5, 62.2, 62.0, 55.6, 42.2, 29.0, 21.8, 14.20, 14.16. HRMS (ESI) calcd for C27- H31O4N2 [M＋H]＋ 447.2278, found 447.2257.
Diethyl (1R,4R)-5,6-dimethyl-1-phenyl-4-vinyl-1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxylate (3ae): Yield 50%, 44.6 mg, yellow solid, m.p. 95~97 ℃. The product was analyzed by HPLC to determine the enantio- meric excess: 96% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=6.4 and 8.9 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.44~7.37 (m, 2H), 7.34~7.26 (m, 3H), 6.81~6.75 (m, 1H), 6.68~6.64 (m, 1H), 6.60~6.55 (m, 1H), 6.15~6.00 (m, 1H), 5.36~5.22 (m, 2H), 5.12 (d, J=1.3 Hz, 1H), 4.54~4.44 (m, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.18 (dd, J=9.7, 7.1 Hz, 2H), 3.96 (s, 3H), 2.74 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform- d) δ: 169.3, 142.9, 136.0, 134.9, 128.9, 128.4, 127.8, 125.7, 124.3, 120.7, 119.3, 119.0, 117.4, 109.7, 71.6, 62.2, 62.0, 55.5, 42.3, 32.2, 20.4, 14.21, 14.16. HRMS (ESI) calcd for C27H31O4N2 [M＋H]＋ 447.2278, found 447.2258.
Diethyl (1R,4R)-8-chloro-5-methyl-1-phenyl-4-vinyl- 1,2,4,5-tetrahydro-3H-pyrido[4,3-b]indole-3,3-dicarboxyl-ate (3af): Yield 78%, 69.7 mg, yellow oil. The product was analyzed by HPLC to determine the enantiomeric excess: >99% ee (Chiralpak AD-H, i-propanol/hexane (V/V=10/90), flow rate 1.0 mL/min, λ=282 nm); tr=7.8 and 10.5 min. 1H NMR (400 MHz, Chloroform-d) δ: 7.41~7.38 (m, 2H), 7.35~7.31 (m, 3H), 7.14 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 2.1 Hz, 1H), 6.70 (d, J=2.1 Hz, 1H), 6.07 (ddd, J=17.8, 9.7, 8.4 Hz, 1H), 5.39~5.25 (m, 2H), 5.08 (d, J=1.3 Hz, 1H), 4.52~4.41 (m, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.18 (qd, J=7.1, 2.9 Hz, 2H), 3.67 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ: 169.2, 168.0, 142.3, 136.0, 135.9, 135.6, 128.7, 128.6, 128.1, 125.8, 124.6, 121.3, 119.5, 118.5, 109.8, 109.5, 71.4, 62.3, 62.1, 55.4, 42.4, 29.3, 14.22, 14.16. HRMS (ESI) calcd for C26H2O48N2Cl [M＋H]＋ 467.1732, found 467.1712.
Supporting Information 1H NMR and 13C NMR spectra of all products 3aa~3af, and condition optimization data. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.
(Lu, Y.)