Introduction

The Natural products and synthetic compounds containing tetrahydro-β-carboline (THβC) skeletons are endowed with various biological activities1,2. THβCs as fundamental privileged heterocyclic frameworks are widely distributed in a large family of indole alkaloids, such as eburnamonine, arboricine, arbornamine (Fig. 1a). THβCs are also important backbones in a large variety of bioactive molecules and pharmaceutical compounds, such as yohimbine, tadalafil, and reserpine (Fig. 1a). Consequently, tetrahydro-β-carbolines covering a wide variety of structural types have represented attractive targets for synthesis, and have stimulated the development of efficient approaches and strategies to build up such architectures3. Synthetic methodologies especially in asymmetric manner are of considerable interest and in great demand and have been constant pursuit for chemists. Among the reported methods, one time-honored method for the synthesis of chiral THβCs is asymmetric Pictet–Spengler (PS) reaction of tryptamines or tryptamine derivatives with aldehydes or ketones, which presents the most direct and straightforward strategy. Since the pioneering enantioselective catalytic PS transformation reported by List in 20064, a large number of asymmetric variants of this reaction have been developed (Fig. 1b-a)5,6,7,8,9,10,11. In addition, other synthetic methods developed thus far such as asymmetric hydrogenation of imines12,13,14,15,16 or iminium salts17,18 bearing dihydro-β-carboline (DHβC) moiety (Fig. 1b-b), and catalytic enantioselective addition of nucleophiles to cyclic imines or iminium electrophiles19,20,21 (Fig. 1b-c) have been shown to be elegant alternative methods toward optically pure THβCs. Some advances in enantioselective oxidative C‒H functionalization of N-carbamoyl THβCs (Fig. 1b-d)22,23,24, aza-Diels-Alder reaction of 3-vinylindoles with ketimines followed by migration (Fig. 1b-e)25, intramolecular cyclization of N-allenamides (Fig. 1b-f)26, [3 + 3] annulation of 2-vinylindoles and aziridines (Fig. 1b-g)27, and multi-step synthesis involving carbene insertion/intramolecular aza-Michael reaction/hydrogenation28 (Fig. 1b-h) have provided powerful strategies for asymmetric synthesis of C1-substituted THβCs. Recently, intramolecular cyclization such as cyclization of 2-aminoaryl alkynones29, allylic alkylation of 2-indolyl allyl carbonates30,31,32, and allylic dearomatization/migration of 3-indolyl allyl carbonates33 has displayed the forceful ability in the construction of C4-substituted chiral THβCs.

Fig. 1: Relevance of THβCs and state of the art in catalytic asymmetric syntheses of THβCs.
figure 1

a Representative THβC-type natural products and bioactive compounds. b Previous asymmetric approaches towards THβCs.

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Despite the considerable progress for enantioselective synthesis of THβCs, existing methods commonly face significant challenges that remain to be solved. First is how to synthesize THβC derivatives with continuous multi-chiral centers in one-step, especially the continuous stereocenters adjacent to C1 position. Till now, most methods focus on the step-by-step construction of continuous stereocenters initiated by first building chiral enter at C1 position. There have been only several examples reported to access continuous stereocenters in one step15,34,35,36. Second is how to synthesize 1,1-disubstituted THβCs possessing C1-chiral quaternary carbon center enantioselectively. Enantioselective formation of quaternary stereocenters is a longstanding crucial challenge in THβCs synthesis. To date, most catalytic asymmetric methods towards 1,1-disubstituted THβCs focused on PS-type reactions34,37,38,39,40,41,42,43,44,45,46,47. Asymmetric alkylation of 1-cyano substituted THβCs48 as well as Friedel–Crafts reaction between isoindolo-β-carboline-derived hydroxylactam and indole have been reported to furnish 1,1-disubstituted THβCs49. Third is how to illustrate the utility of the developed methods in the synthesis of natural products and biologically active molecules. Efficient collective assembly of complex natural products with architectural and stereochemical divergence from a general method remains highly desirable. Although THβCs are core structures of natural products and integral parts of bioactive compounds, aside from PS reaction and Noyori asymmetric hydrogenation of imine or iminium, a few methodologies have been widely applied to the total synthesis of THβC-type natural products and bioactive compounds15,24,25,46,50,51,52,53,54. The development of a general method for collective total syntheses of diverse THβC-type indole alkaloid natural products and bioactive compounds remains a formidable challenge.

To address these challenges, we hypothesized that a possible solution might arise from investigation of unified platform starting materials for their ability to construct quaternary stereocenters and undergo further transformation for a large collection of natural product syntheses. We considered that 3,4-dihydro-β-carboline-2-oxide (Fig. 2), a type of nitrone containing DHβC skeleton, represented an attractive platform molecule to synthesize THβC-type structural motif. Taking advantage of nitrone chemistry, 3,4-dihydro-β-carboline-2-oxide has been reported to be reactive in 1,3-dipolar cycloaddition with dipolarphiles55,56,57,58,59,60,61. However, the 3,4-dihydro-β-carboline-2-oxide chemistry was unexplored in enantioselective form. Towards this end, we wished to develop the asymmetric conversion of 3,4-dihydro-β-carboline-2-oxides and explore their application in natural product syntheses. Herein, we disclosed catalytic enantioselective 1,3-dipolar cycloaddition of 3,4-dihydro-β-carboline-2-oxide with vinyl ether, providing a highly efficient protocol toward three types of chiral tetrahydro-β-carboline fused isoxazolidines containing two stereocenters, three continuous stereocenters, and quaternary stereocenters through varying easily accessible vinyl ether substrates. This work presented a strategy for enantioselective synthesis of THβCs. More importantly, the endo/exo selectivity of our 1,3-dipolar cycloaddition differed from traditional nitrone chemistry62,63. The presence of nitrone group in 3,4-dihydro-β-carboline-2-oxide can controllably and easily lead into functionalization for further transformation. The resultant formation of N‒O bond of isoxazolidine conferred structural advantages that could be cleaved by assorted alkyl halides to induce additional functionality and complexity that would be difficult to be achieved from traditional approaches. This protocol enabled access to 40 THβC-type indole alkaloid natural products belonging to five families and enantiodivergent total syntheses of eburnane-alkaloids, therefore rendered collective syntheses of natural products.

Fig. 2: Catalytic asymmetric synthesis of THβCs from nitrone.
figure 2

a Development of the asymmetric conversion of 3,4-dihydro-β-carboline-2-oxides. b Our design of unified platform starting materials to construct various THβCs with varied architectures for collective total syntheses of natural products.

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Results

To test our hypothesis, the preliminary studies began with the investigation of chiral phosphoric acid64,65,66,67,68,69,70,71,72,73,74 catalyzed 1,3-dipolar cycloaddition of 3,4-dihydro-β-carboline-2-oxide with vinyl ether (Table 1). 3,4-Dihydro-β-carboline-2-oxide 1a and vinyl ether 2a were chosen as initial substrates. The reaction catalyzed by BINOL-derived chiral phosphoric acid 4a was first conducted in DCM at −20 °C. The desired tetrahydro-β-carboline fused isoxazolidine 3a was obtained in 37% yield with 5:1 dr and 50% ee (entry 1). Then, different solvents were screened (entries 1–6), and CHCl3 (entry 2) was found to be the best solvent, affording 3a with moderate diastereoselectivity (7:1 dr) and enantioselectivity (73% ee). Molecular sieves were proved to be beneficial for the improvement of enantioselectivity (entries 7–9), and the ee value was improved to 81% with the addition of 3 Å MS (entry 7). Encouraged by this promising result, various chiral phosphoric acids were screened. To our delight, the yield of 3a was dramatically enhanced without deterioration of diastereoselectivity and enantioselectivity when BINOL-derived CPA 4b was used as catalyst (entry 10). CPAs 4e derived from SPINOL (entry 13) and 4j derived from H8-BINOL (entry 14) couldn’t give higher enantiomeric excess. Thus, extensive evaluation of CPA catalysts confirmed that the optimal catalyst was 4b. Then, it is indicated that lower reaction temperature was better for the diastereoselectivity and enantioselectivity. Overall, systematic evaluation of the reaction variables such as solvent, additive, catalyst, and reaction temperature identified the optimal reaction condition shown in entry 16, which gave 3a in 85% yield with >19:1 dr and 98% ee.

Table 1 Screening the reaction conditions
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With the optimized reaction conditions in hand, we sought to apply this catalytic enantioselective protocol to the synthesis of an array of chiral functionalized tetrahydro-β-carboline fused isoxazolidines. As shown in Fig. 3, we first evaluated the substrates scope of 3,4-dihydro-β-carboline-2-oxide 1 in the reaction with vinyl ether 2a. It is revealed that 3,4-dihydro-β-carboline-2-oxide substrates reacted smoothly in this cycloaddition reaction. The 4-, 5-, 6- or 7-positions of indole core in 1 could be substituted by various electron-rich and electron-deficient groups, affording the desired tetrahydro-β-carboline fused isoxazolidine products in good yields with high diastereoselectivities and enantioselectivities (3a–3m). 3,4-Dihydro-β-carboline-2-oxide substrates bearing increased steric hindrance around 7-substitution patterns of indole ring exhibit excellent enantioselectivities as well. The absolute configuration of 3g was confirmed by X-ray diffraction analysis and those of other products were assigned accordingly. We also demonstrated the scalability of this protocol by a 5 mmol scale experiment of 1a with 2a under standard reaction condition. The gram-scale reaction smoothly provided 3a in 82% yield with >19:1 dr and 98% ee. Cyclic vinyl ether was compatible in this reaction as well, and the transformation proceeded well when using DCE as solvent, furnishing 3n in 78% yield with 90% ee. We next turned our attention to the use of other type of alkene to investigate the substrate scope for establishing three continuous stereocenters. When the alkene was changed to (E)-4-methoxy-3-buten-2-one 2b, 3,4-dihydro-β-carboline 2-oxide bearing electron-rich and electron-deficient groups on the indole core were well tolerated regardless of the steric effect. In these cases, the corresponding tetrahydro-β-carboline fused isoxazolidine products (5a–5t) were afforded in high yields with excellent diastereoselectivities and enantioselectivities. It is noteworthy that the enantiodivergent cycloaddition between 1a and 2b was performed as well, enantiomer ent-5a was obtained in 91% yield with 93% ee when using (R)-4b as catalyst. The absolute configuration of 5d was confirmed by X-ray diffraction analysis and those of other products were assigned accordingly. In an effort to broaden the substrates scope, we sought to use different nitrone substrates that may provide access to other THβC skeletal frameworks, which were difficult to be accessed by previous synthetic protocols. Enantioselective synthesis of 1,1-disubstituted THβCs is one of the most difficult tasks in THβCs synthesis. To this end, we went on to examine whether the developed method could be extended to the construction of chiral 1,1-disubstituted THβCs with sterically congested C1-quaternary stereocenter. When nitrone 6 was employed, the transformation showed excellent performance on this type of substrates bearing a great variety of functional groups, leading to efficient construction of chiral 1,1-disubstituted THβCs (7a–7g) in high efficiency with excellent stereoselectivities. The absolute configuration of 7b was confirmed by X-ray diffraction analysis and those of other products were assigned accordingly. Moreover, we further showed the ability of our developed asymmetric cycloaddition method in the construction of chiral 1,1-disubstituted THβCs with three continuous stereocenters containing one quaternary stereocenter, and the reaction proceeded smoothly, leading to the formation of 7h in 88% yield with 99% ee.

Fig. 3: Substrate scope of nitrones and vinyl ethers.
figure 3

Reaction condition A: 1 (0.20 mmol), 2a or 2b (0.40 mmol), catalyst (0.02 mmol), and 3 Å MS (300 mg) in CHCl3 (2.0 mL) at −60 °C. Reaction condition B: 6 (0.20 mmol), 2a (0.40 mmol), catalyst (0.02 mmol), and 3 Å MS (300 mg) in DCE (2.0 mL) at −60 °C. Isolated yield. d.r. >19:1. The ee values were determined by chiral HPLC analysis. a 6-nOct-4a was used. b DCM was used. c DCE was used. d (R)-4b was used as catalyst. e Toluene as solvent at −20 °C.

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In previous reported CPA-catalyzed nitrone chemistry, when nitrone underwent 1,3-dipolar cycloaddition with vinyl ether, Z-type nitrone delivered endo products62, while E-type nitrone delivered exo products63. Due to the H-bonding interaction between CPA and nitrone oxygen atom, the traditional endo/exo selectivity could be rationalized by the steric repulsion between the substrates. Interestingly, the endo/exo selectivity of our 1,3-dipolar cycloaddition differed from previous works. In our work, opposite results were observed. Z-nitrones gave exo products and E-nitrones gave endo products. To further understand the reaction mechanism, the density functional theory (DFT) calculations were performed to explore the origin of the endo- or exo-selectivity. The FMO analysis provides a clear mechanistic model for these dipolar cycloaddition reactions involving various combinations of dipoles and dipolarophiles. The most stable transition state structures for endo- and exo-cycloaddition reactions are illustrated in Fig. 4a and Supplementary Fig. 6, aligning well with experimental selectivity. In cycloaddition reactions between 1,3-dipole 1a and vinyl ethers 2a, it is rationalized that H-bonding between nitrone oxygen atom and CPA resulted in a repulsive effect between the ethoxy group and the catalyst in exo type TS1b, leading to 4.3 kcal/mol higher free energy of TS1b-exo than that of TS1a-endo. The much smaller steric hindrance of endo approach TS1a allowed vinyl ether to react with nitrone via favored endo selective way. However, the DFT calculations revealed that the reaction of nitrone 1a with vinyl ether 2b exhibited different H-bonding interaction. In the TS2, CPA acted as bifunctional catalyst activating both nitrone and vinyl ether via H-bonding interaction between indole N‒H group and vinyl ether alkoxy group. The steric repulsion between methoxy group and CPA made exo selective TS2b disfavored than endo selective TS2a. Ester group substituted Z-type nitrone 6 exhibited different endo/exo selectivity. When Z-type nitrone 6b reacted with vinyl ether 2a, the exo approach via TS3b was more favored than endo approach via TS3a. The steric repulsion between the ethoxy group of vinyl ether and the catalyst in endo selective TS3a leaded to the result that favored exo cycloaddition product via TS3b was obtained. When ester-substituted Z-type nitrone 6b reacted with vinyl ether 2b, the steric repulsion between the methoxy group of vinyl ether and the catalyst in exo selective TS4b was considered to be a major steric hindrance factor. Thus, an endo type product via TS4a was observed.

Fig. 4: Investigation of the mechanism.
figure 4

a The key transition states of 1,3-dipolar cycloaddition reactions. Gibbs free energy (in kcal/mol) obtained at the level of SMD(solvent)-B3LYP-D3/def2TZVP//B3LYP-D3/6-31G*. In accordance with experimental conditions, chloroform was utilized as the solvent for reactions involving 1a and 2a/2b with catalyst 4b. Dichloroethane was employed as the solvent for reactions of 6b and 2a with catalyst 4a. Additionally, toluene was the chosen solvent for reactions of 6b and 2b with catalyst 4a. b FMO diagram for the 1,3-dipolar cycloaddition reactions. HF/6-31G*//B3LYP-D3/6-31G*-computed orbital energies in eV are shown.

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DFT calculations demonstrated that the hydrogen bonding interaction between chiral phosphoric acid catalysts and substrates facilitated the 1,3-dipolar cycloaddition reactions. In contrast, the uncatalyzed 1,3-dipolar cycloaddition reactions exhibited higher energy barriers compared to their chiral phosphoric acid-catalyzed counterparts (Supplementary Figs. 7 and 8). Notably, the dipolar cycloaddition transition states predominantly followed a concerted pathway75, where C‒C and C‒O bonds formed simultaneously within a single transition state. Interestingly, for the cycloaddition reaction involving 1a and 2b with catalyst 4b, a favorable stepwise pathway was identified, with C‒O bond formation occurring first via TS2a-endo-I, followed by the C‒C bond formation via TS2a-endo-II, which was the rate-determining step (Supplementary Fig. 14). We postulated that the favorable H-bonding interaction between 4b and 2b stabilized the zwitterionic intermediate, allowing for the localization of the stepwise transition states. On the contrary, the exo-cycloaddition via the concerted transition state TS2b-exo required a higher barrier than TS2a-endo-II by 6.0 kcal/mol. In reactions between ester-substituted Z-type nitrone 6b and vinyl ether, 2b, a favorable n → π* interaction76 (from the lone pair of ethoxyl group O of 2b to the π* orbital of the carbonyl group of 6b) existed in the transition state TS3b-exo, which might be the origin of the exo-selectivity.

The additional mechanistic models exhibiting higher energies compared to those depicted in Fig. 4 were presented in Supplementary Figs. 9–13. According to frontier molecular orbital (FMO) analysis (Fig. 4b), in cycloaddition reactions between 1,3-dipole 1a and vinyl ethers 2a, the primary FMO interaction occurred between the HOMO of dipolarophile 2a and the LUMO of 1,3-dipole 1a. Hence, the phosphoric acid preferred to interact with dipole 1a to lower its LUMO. This interaction pattern was also observed in reactions between 6b and 2a. In cycloaddition reactions between 6b and 2b, the energy gap between the HOMO of 6b and the LUMO of 2b (10.28 eV) closely matched that between the HOMO of 2b and the LUMO of 6b (10.75 eV). The DFT-computed results suggested that the phosphoric acid similarly preferred to interact with dipole 6b to lower its LUMO. However, for cycloaddition reactions between 1a and 2b, the primary FMO interaction occurred between the HOMO of 1,3-dipole 1a and the LUMO of dipolarophile 2b, differing from that of the previous cases. Here, the phosphoric acid catalyst 4b tended to activate 2b by forming hydrogen bonding interactions with the acetyl group of 2b.

As mentioned before, the presence of nitrone group in 3,4-dihydro-β-carboline-2-oxide and the resultant N‒O bond in the adducts could provide handles for further functionalization. To showcase the synthetic utility and versatility of our developed method, we commenced our study with postfunctionalization of tetrahydro-β-carboline fused isoxazolidine products (Fig. 5). The N‒O bond of isoxazolidine conferred structural advantages that could be cleaved by different alkyl halides to induce functionality and complexity, thus unlocking access to THβC scaffolds bearing different substituents. With this aim in mind, a range of alkyl halides with various functionalities were subjected to 3a. By forming quaternary ammonium salt intermediate followed with DABCO-promoted ring opening, the THβCs 8a–8d could be afforded in good yields with maintained enantiopurity (Fig. 5, equation 1)77. 3a was further derivatized through N‒O bond cleavage via SmI2/MeOH reduction and Boc protection, delivering primary alcohol 9 in 59% yield for two steps with 91% ee (Fig. 5, equation 2)78. So far, the enantioenriched THβC product 3a has been readily transformed into a diversity of chiral THβC-type compounds with additional functionality and complexity. Therefore, to further showcase the synthetic versatility of our developed method, we anticipated the developed catalytic asymmetric 1,3-dipolar cycloaddition to provide a general platform for the collective syntheses of THβC-type indole alkaloids. The three types of chiral cycloaddition products 3, 5, and 7 with two stereocenters, three continuous stereocenters, and quaternary stereocenters can be further transformed, resulting in important building blocks and advanced intermediates for the synthesis of natural products and their analogs. While notable, all the synthetic transformations shown in Fig. 5 were used in the following total syntheses application. These synthetic applications will be discussed one by one.

Fig. 5
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Post-transformation.

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As shown in Fig. 6, N‒O bond cleavage of 3a by using BnBr and Boc protection of indole N‒H gave ester 10 in 95% yield by one-pot process. Subsequent DIBAL-H reduction followed by reaction with Wittig reagent and hydrolysis with HCO2H/DCM afforded aldehyde 11 in 50% yield over two steps, which underwent a sequential deprotection/reduction to obtain compound 12 in 76% yield. Removal of Boc group gave natural product (−)-harmicine 1379 in 91% yield, which exhibited antileishmanial and antinociceptive activities80 (Fig. 6a). When allyl bromide was used in the N‒O bond cleavage and Boc protection process, the corresponding product 14 was obtained in 75% yield. Reduction of ester group and subsequent Wittig olefination afforded compound 15 in 75% yield over two steps. Then Grubbs II catalyst catalyzed RCM reaction proceeded smoothly to produce tetracyclic compound 16 in 80% yield. Hydrogenation using H2 over Pd/C followed by deprotection of Boc provided (−)-desbromoarborescidine A 1781 in 88% yield over two steps, which exhibited antiproliferative activity82 (Fig. 6b).

Fig. 6: Total synthesis from product 3.
figure 6

a (a) BnBr, MeCN, 25 °C, then DABCO, reflux, then (Boc)2O, DMAP, Et3N, 25 °C; (b) DIBAL-H, Toluene, −78 °C; (c) ClPh3PCH2OCH3, tBuOK, THF, 0–25 °C, then HCO2H, DCM, 25 °C; (d) Pd(OH)2/C, H2, MeOH, 25 °C; (e) TFA, DCM, 25 °C. b (a) Allyl bromide, MeCN, 25 °C, then DABCO, reflux, then (Boc)2O, DMAP, Et3N, 25 °C; (b) DIBAL-H, Toluene, −78 °C; (c) Ph3PMe•Br, tBuOK, THF, 25 °C; (d) Grubbs II, Toluene, 80 °C; (e) Pd/C, H2, EtOH, 25 °C; (f) TFA, DCM, 25 °C. c (a) (Z)-1-Bromo-2-iodo-2-butene, MeCN, 25 °C, then DABCO, reflux, then (Boc)2O, DMAP, Et3N, 25 °C; (b) DIBAL-H, Toluene, −78 °C; (c) MsCl, Et3N, DCM, 0–25 °C, then TMSCN, TBAF, MeCN, 25 °C; (d) MeMgBr, Et2O, 0–25 °C; (e) Pd(PPh3)4, tBuOK, THF, reflux, then silica gel, Toluene, reflux; (f) DIBAL-H, Toluene, −78 °C; (g) (MeO)2P(O)CH2CO2Me, NaH, THF, 25 °C; (h) TFA, DCM, 0–25 °C; (i) Ni(COD)2, Et3N, Et3SiH, MeCN, 25 °C; (j) Crabtree’s catalyst, H2, DCM, 25 °C; (k) LiAlH4, THF, 0–25 °C; (l) LDA, THF, −78 °C, then HCO2Me, −78–25 °C; (m) TMSCHN2, DIPEA, MeCN, MeOH, 25 °C; (n) PtO2, H2, MeOH, 25 °C. d (a) 2,3-Dibromopropene, MeCN, 25 °C, then DABCO, reflux, then (Boc)2O, DMAP, Et3N, 25 °C; (b) DIBAL-H, Toluene, −78 °C; (c) (MeO)2P(O)CH2CO2Me, NaH, THF, 25 °C; (d) TFA, DCM, 25 °C; (e) AIBN, nBu3SnH, Toluene, reflux; (f) (Boc)2O, DMAP, Et3N, DCM, 25 °C; (g) DIBAL-H, Toluene, −78 °C; (h) Allylmagnesium bromide, THF, 0 °C; (i) Hoveyda–Grubbs II, DCM, reflux; (j) Pd/C, H2, MeOH, 25 °C; (k) TFA, DCM, 25 °C; (l) DCC, DMSO, Cl2CHCO2H, 35 °C; (m) DCC, Cl2CHCO2H, DMSO, 35 °C, then TFA, DCM, 25 °C. e (a) MeI, MeCN, 25 °C, then DABCO, reflux, then (Boc)2O, DMAP, Et3N, reflux; (b) DIBAL-H, Toluene, −78 °C; (c) (MeO)2POCH2CO2Me, NaH, THF, 25 °C; (d) PtO2, H2, MeOH, 25 °C; (e) DIBAL-H, Toluene, −78 °C, then TFA, DCM, 0–25 °C; (f) DIBAL-H, Toluene, −78 °C, then TFA, H2O, THF, 0–25 °C.

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Next, we attempted the total synthesis of corynanthe as well as deplancheine family indole-alkaloids. When (Z)-1-bromo-2-iodo-2-butene as ring opening reagent was subjected to 3a, vinyl iodide 18 could be obtained in 82% yield. DIBAL-H reduction of ester afforded alcohol 19 in 76% yield. Mesylation of the primary alcohol and cyanation of mesylate led to the formation of cyano derivative 2083. Then methyl Grignard reagent was used for nucleophilic addition to access ketone 21 in 72% yield. Natural product (−)-arboricine 2284 was afforded in 64% yield by Pd-catalyzed intramolecular cyclization and silica gel promoted deprotection process, which has been reported to reverse multidrug resistance in vincristine-resistant KB (VJ300) cells84. Controlled reduction of 18 to aldehyde followed by Wittig reaction provided ester 23 in 55% yield over two steps. Removal of Boc group by TFA and Ni-promoted intramolecular reductive cyclization gave intermediate 24 and diastereoisomer 25. Reduction of 24 by Crabtree’s catalyst gave single product 26. Reduction of ester in 26 generated (−)-hirsutinol 27 in 81% yield. Condensation of 26 with methyl formate followed by methylation finished the synthesis of (−)-hirsutine 29. Alternatively, LiAlH4 reduction of 25 furnished (−)-geissoschizol 3085 in 84% yield. Moreover, 25 was reduced by PtO2/H2 to produce 31, 32 and 33. These compounds were reduced by LiAlH4 separately to obtain (−)-corynantheidol 3486,87, (−)-dihydrocorynantheol 3588, and (−)-isogeissoschizol 3689. Therefore, seven corynanthe family indole alkaloids were synthesized from the same starting material 3a and ring opening reagent alkyl bromide (Fig. 6c).

Yohimbine as pharmacological probe for the study of α2-adrenoceptor is a prescription drug for the treatment of impotence. Yohimbine is also used for other diseases. The realization of our synthetic method to yohimbine-type alkaloids is our next subject. As illustrated in Fig. 6d, when 2,3-dibromoprop-1-ene was used in N‒O bond cleavage step, similar intermediate 38 could be isolated. Under AIBN and nBu3SnH conditions, radical cyclization of 38 produced desired cyclization product 39 in 65% yield. Boc protection of 39 followed by DIBAL-H reduction of ester group to aldehyde gave 40. Then, nucleophilic addition with allylic Grignard reagent and the following Hoveyda–Grubbs II catalyzed RCM reaction afforded 41 and diastereoisomer 42. Double bond of 41 was reduced to obtain 43 and diastereoisomer 47. Removal of Boc group in 43 produced (-)-17-epi-yohimbol 44 in 82% yield. Double bond reduction of 42 followed by deprotection of Boc generated (−)-yohimbol 4590. (−)-Yohimbol 45 underwent efficient Pfitzner-Moffatt oxidation of hydroxy group, affording (−)-yohimbone 46 in 60% yield. Oxidation of hydroxy group and deprotection of Boc in 47 completed the total synthesis of (−)-alloyohimbone 48. Therefore, four yohimbine-type indole alkaloids were synthesized from the same starting material 3a and ring opening reagent alkyl bromide (Fig. 6d). When 6-Br substituted product 3g was used as starting material, MeI was used in the N‒O bond cleavage process to obtain ester 49. Sequential reduction of ester, Wittig reaction, and reduction of double bond generated common intermediate 50. Reduction of ester in 50 under different conditions could produce antiproliferative (+)-arborescidine B 5182 and (+)-arborescidine C 5291 separately (Fig. 6e).

We have established a general straightforward sequence based on our asymmetric 1, 3-dipolar cycloaddition for successful achievement of collective total syntheses of 15 THβC-type indole alkaloid natural products, relying on N‒O bond cleavage of 3 by various alkyl halides. Then, we turned our attention to explore the synthetic application of another type of product 5a with three continuous stereocenters in eburnane-type indole alkaloids synthesis. Eburnane-type indole alkaloids, isolated from the plants of genus Kopsia, possessed potent bioactivities and have attracted enormous attention from synthetic chemists and medicinal chemists. The greatest challenge existed in the synthesis of eburnane-type alkaloids is how to effectively control the cis C20/C21 relative stereochemistry. Till now, synthetic work that has been successfully achieved with excellent diastereoselectivity was rare92,93. In this work, we sought to provide a solution to control the cis C20/C21 relative stereochemistry in the synthesis of eburnane-type alkaloids based on our developed method. As shown in Fig. 7a, our synthesis towards eburnane-type alkaloids started with Boc protection of 5a to get 53 in almost quantitative yield. Ketone in 53 was transformed to alkene by enol-triflation and Pd(PPh3)4-catalyzed reduction, affording 54 in 67% yield over two steps. Similar N‒O cleavage with allyl bromide proceeded well and delivered ester 55 in 89% yield when allyl bromide was used. RCM reaction followed by deprotection of Boc generated cyclization product 56, which was then converted to 57 in 70% yield by stereoselective alkylation94. We surmised that the perfect control of cis C20/C21 relative stereochemistry might be rationalized in terms of electronic interactions between trans- and cis-dianionic intermediate A and A’. Since cis-dianionic intermediate A’ was favored because of the charge repulsion between indole anion and ester enolate in trans-dianionic intermediate A (See Supplementary Fig. 1), electrophilic attack of ethyl iodide from the convex face of A’ afforded 57 as single stereoisomer. Next, the ester group in 57 was reduced to hydroxy group in 58 with DIBAL-H. When LiAlH4 reduction condition was subjected to 57, natural product (−)-14,15-dehydro-17-nor-eburnamonine 59 was obtained. Then, the needed CN unit was installed by mesylation of hydroxy group in 58 and cyanation of the resulting OMs group, furnishing the key intermediate 60. DIBAL-H reduction of 60 afforded the total synthesis of natural products (−)-Δ14-isoeburnamine 61 in 46% yield and (+)-Δ14-eburnamine 6295,96 in 53% yield. PtO2 catalyzed hydrogenation of double bond in 62 generated natural product (+)-eburnamine 6397 in 84% yield. 62 could also be converted to natural product (+)-Δ14-eburnamonine 6496 by Ley oxidation, therefore accomplishing the total synthesis of (+)-Δ14-eburnamonine 64. Hydrogenation of 64 and 61 delivered (−)-eburnamonine 6597 and (−)-isoeburnamine 66 respectively. Under acidic condition (TFA/DCM), (−)-isoeburnamine 66 could be transformed to (−)-eburnamenine 6798 in 86% yield. Similarly, 61 and 62 could also be transformed to natural product (−)-Δ14-eburnamenine 68 under acidic condition. C14/C15 unsaturated bond existed in many eburnane-type natural products, but the total syntheses of this type of natural products were less explored. Our strategy provided a powerful method to construct these natural products. As depicted in Fig. 7b, the key intermediate 60 could be further transformed to other eburnane-type alkaloids. The key intermediate 60 was reduced by DIBAL-H followed by different work-up conditions. HCl in MeOH condition afforded the total synthesis of natural product (+)-Δ14-O-methyl-eburnamine 69 and the total synthesis of natural product (−)-Δ14-O-methyl-isoeburnamine 7096. HCl in EtOH condition gave rise to ethoxy-substituted products 73 and 74. Natural products (+)-O-methyl-eburnamine 7197, (−)-O-methyl-isoeburnamine 7297, (+)-O-ethyl-eburnamine 7597 and (−)-O-ethyl-isoeburnamine 7697 could be obtained respectively by reduction of the double bond in 69, 70, 73 and 74. Oxidation of 58 followed by treatment of the resultant aldehyde immediate with TMSCN delivered 77, which was then converted to 78 by cyano-group hydrolysis and intramolecular amidation. Ultimately, the total synthesis of natural product (+)-eburnamaline 7998 was achieved by a two-step reduction of amide and alkene in 78 with LiAlH4 and PtO2/H2. So far, total synthesis of 16 eburnane-type natural products have been accomplished through our developed asymmetric cycloaddition method.

Fig. 7: Total synthesis from product 5a and 7b.
figure 7

a Total syntheses of eburnane-type indole alkaloids. Reagents and conditions: (a) (Boc)2O, DMAP, Et3N, DCM, 25 °C; (b) Comins’ Reagent, LiHMDS, THF, −78 °C; (c) LiCl, Pd(PPh3)4, nBu3SnH, THF, 25 °C; (d) Allyl bromide, MeCN, 25 °C, then DABCO, reflux; (e) Grubbs II, DCM, reflux, then TFA, DCM, 0–25 °C; (f) LDA, HMPA, −78 °C, then EtI, THF, −40 °C; (g) DIBAL-H, Toluene, 0 °C; (h) LiAlH4, THF, 0–25 °C; (i) MsCl, Et3N, DCM, 0–25 °C; (j) TMSCN, TBAF, MeCN, 25 °C; (k) DIBAL-H, Toluene, −78 °C; (l) PtO2, H2, EtOH, 25 °C; (m) TPAP, NMO, DCM, 0–25 °C; (n) TFA, DCM, 0–25 °C. b Total syntheses of eburnane-type indole alkaloids. Reagents and conditions: (a) DIBAL-H, Toluene, −78 °C then HCl in MeOH, 0–25 °C; (b) PtO2, H2, MeOH, 25 °C; (c) DIBAL-H, Toluene, −78 °C then HCl in EtOH, 0–25 °C; (d) PtO2, H2, EtOH, 25 °C; (e) SO3•Py, DMSO, Et3N, 0 °C-25 °C; (f) TMSCN, AlCl3, CHCl3, 0–25 °C; (g) conc. HCl, MeOH, 80 °C; (h) LiAlH4, THF. 0–25 °C. c Total syntheses of (−)-arbornamine. Reagents and conditions: (a) LiAlH4, THF, 0–25 °C; (b) TBDPSCl, Imidazole, DMF, 25 °C; (c) SmI2, MeOH, THF, 25 °C; (d) (Z)-1-Bromo-2-iodo-2-butene, K2CO3, MeCN, 25 °C; (e) MsCl, Et3N, DCM, 0–25 °C; (f) TMSCN, TBAF, MeCN, 25 °C; (g) DIBAL-H, Toluene, −78 °C; (h) PDC, DCM, 25 °C; (i) LiHMDS, THF, PhSeBr, −78 °C, then aq. NH4Cl, H2O2, 0 °C; (j) Ni(COD)2, Et3N, Et3SiH, MeCN, 25 °C; (k) TBAF, THF, 0–25 °C, then LiAlH4, 0 °C.

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Given the prominence of chiral 1,1-disubstituted THβCs with C1-quaternary stereocenter, we then attempted to prove the power of this method in total synthesis of 1,1-disubstituted THβC containing indole alkaloid from chiral tetrahydro-β-carboline fused isoxazolidine product 7b with quaternary stereocenter. As depicted in Fig. 7c, compound 80 was obtained via reduction of ester group in 7b followed by TBDPS protection, which was converted to primary alcohol by SmI2/MeOH promoted N‒O bond cleavage, then selective alkylation of secondary amine generated 81. Mesylation of the primary hydroxyl group and replacement of the resulting mesylate by cyano group followed by DIBAL-H reduction and PDC oxidation generated amide 82 in 51% yield over four steps. Next, conversion of 82 into the α,β-unsaturated amide 83 was performed by a two-step synthetic sequence including the introduction of phenyl-selenyl group and subsequent oxidative cleavage to generate the double bond. A Ni(COD)2-promoted reductive cyclization gave the corresponding product 84. By removing TBDPS group of 84 and reduction of amide, the total synthesis of (−)-arbornamine 8599 was completed.

Having validated our catalytic asymmetric 1,3-dipolar cycloaddition method in total synthesis of various natural products, enantiodivergent synthesis was next pursued. In the case of eburnane-type indole alkaloids, which were characterized by naturally occurrence of enantiomeric pairs, both enantiomers were isolated97. To achieve the enantiodivergent total synthesis of eburnane alkaloids, we sought to apply our developed methods to the synthesis of the full complement of stereoisomeric eburnane indole natural products from the same precursors by adjustment of the stereochemistry of CPA catalyst. To this end, we used ent-5a as a starting material to synthesize corresponding enantiomeric natural products (−)-eburnamine ent-63, (+)-eburnamonine ent-65, (+)-isoeburnamine ent-66, (+)-eburnamenine ent-67, (−)-O-methyl-eburnamine ent-71, (+)-O-methyl-isoeburnamine ent-72, (−)-O-ethyl-eburnamine ent-75 and (+)-O-ethyl-isoeburnamine ent-76 according to the same synthetic routes with similar efficiency and enantioselectivity (Fig. 8). The realization of eburnane alkaloids synthesis with antipodal enantiomeric congeners illustrated that our developed method can readily be applied to the design of enantiodivergent transformations.

Fig. 8: Enantiodivergent total syntheses of eburnane-type alkaloids.
figure 8

Reaction conditions: (a) (Boc)2O, DMAP, Et3N, 25 °C; (b) Comins’ Reagent, LiHMDS, THF, −78 °C; (c) LiCl, Pd(PPh3)4, nBu3SnH, THF, 25 °C; (d) Allyl bromide, MeCN, 25 °C, then DABCO, reflux; (e) Grubbs II, DCM, reflux, then TFA, DCM, 0–25 °C; (f) LDA, HMPA, −78 °C, then EtI, THF, −40 °C; (g) DIBAL-H, Toluene, 0 °C; (h) MsCl, Et3N, DCM, 0–25 °C; (i) TMSCN, TBAF, MeCN, 25 °C; (j) DIBAL-H, Toluene, −78 °C; (k) PtO2, H2, EtOH, 25 °C; (l) TFA, DCM, 0–25 °C; (m) TPAP, NMO, DCM, 0–25 °C; (n) DIBAL-H, Toluene, −78 °C then HCl in MeOH, 0–25 °C; (o) PtO2, H2, MeOH, 25 °C; (p) DIBAL-H, Toluene, −78 °C then HCl in EtOH, 0–25 °C.

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Discussion

In summary, we have developed the catalytic asymmetric 1,3-dipolar cycloaddition of 3,4-dihydro-β-carboline-2-oxide with vinyl ether, providing a highly efficient protocol toward three types of chiral tetrahydro-β-carboline fused isoxazolidine generating two stereocenters, three continuous stereocenters, and quaternary stereocenters in high yields with excellent diastereoselectivities and enantioselectivities through varying easily accessible vinyl ether substrates. The endo/exo selectivity of our 1,3-dipolar cycloaddition differed from traditional nitrone chemistry. The applicability of our developed method has been realized to collective syntheses of 40 THβC-type indole alkaloid natural products belonging to five families. The method also enabled enantiodivergent total synthesis, thus facilitating the synthesis efficiency. In future, the generality and modularity of this asymmetric cycloaddition method are expected to be shown in total synthesis of other indole alkaloids due to the valuable tetrahydro-β-carboline skeleton.

Methods

General methods

Unless otherwise mentioned, all reagents were purchased from commercial suppliers without further purification. Solvent purification was conducted according to Purification of Laboratory Chemicals (Peerrin, D. D.; Armarego, W. L. and Perrins, D. R., Pergamon Press: Oxford, 1980). Reactions were monitored using Merck Kieselgel 60F254 aluminum plates. TLC was visualized by UV fluorescence (254 nm) then one of the following: KMnO4, phosphomolybdic acid, ninhydrin, p-anisaldehyde, vanillin. If not specially mentioned, flash column chromatography was performed using Yantai xinnuo Chemicals (China) (particle size 0.040–0.063 mm). NMR spectra were recorded on JEOL 400 instruments or Bruker Avance NEO 400 and calibrated by using residual undeuterated chloroform-d (δ 1H = 7.26 ppm, δ 13C = 77.0 ppm) and DMSO-d6 (δ 1H = 2.55 ppm, δ 13C = 39.5 ppm) as internal references. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, b = broad, td = triple doublet, dt = double triplet, dq = double quartet, m = multiplet. Infrared (IR) spectra were recorded on an iCAN 9-T FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded on a Thermo Fisher Q Exactive Orbitrap mass spectrometer using ESI (electrosprayionization) as ionization method.

General procedure for the synthesis of 3

To a stirred solution of 3,4-dihydro-β-carboline 2-oxide 1 (0.20 mmol, 1.0 equiv), (S)-phosphoric acid 4b (0.02 mmol, 0.1 equiv) and 3 Å molecular sieves (300 mg) in CHCl3 (2.0 mL) was added ethyl vinyl ether 2a (0.40 mmol, 2.0 equiv) at −60 °C. The reaction was stirred at −60 °C until TLC indicated that the 3,4-dihydro-β-carboline 2-oxide disappeared. The reaction mixture was directly charged to column chromatography on silica gel (petroleum ether: EtOAc, 4:1-2:1) to give the product.

General procedure for the synthesis of 5

To a stirred solution of 3,4-dihydro-β-carboline 2-oxide 1 (0.20 mmol, 1.0 equiv), (S)-phosphoric acid 4b (0.02 mmol, 0.1 equiv) and 3 Å molecular sieves (300 mg) in CHCl3 (2.0 mL) was added (E)-4-methoxy-3-buten-2-one 2b (0.40 mmol, 2.0 equiv) at −60 °C. The reaction was stirred at −60 °C until TLC indicated that the 3,4-dihydro-β-carboline 2-oxide disappeared. The reaction mixture was directly charged to column chromatography on silica gel (DCM: EtOAc, 20:1) to give the product 5.

General procedure for the synthesis of 7

To a stirred solution of 1-oxycarbonyl-3,4-dihydro-β-carboline 2-oxide 6 (0.20 mmol, 1.0 equiv), (S)-phosphoric acid 4a (0.02 mmol, 0.1 equiv) and 3 Å molecular sieves (300 mg) in DCE (2.0 mL) was added ethyl vinyl ether 2a (0.40 mmol, 2.0 equiv) at −60 °C. The reaction was stirred at −60 °C until TLC indicated that the 1-oxycarbonyl-3,4-dihydro-β-carboline 2-oxide disappeared. The reaction mixture was directly charged to column chromatography on silica gel (petroleum ether: EtOAc, 4:1) to give the product 7.

Computational methods

All calculations were carried out with the Gaussian 16 package100. Geometry optimization and energy calculations were performed with B3LYP-D3101. The 6-31G(d) basis set102,103,104 was used for all atoms. Frequency analysis was conducted at the same level of theory to verify that the stationary points are minima or saddle points. Single point energies were calculated at the B3LYP-D3/def2TZVP level using SMD solvation model105. The frontier molecular orbitals (FMOs) and their energies were computed at the HF/6-31G(d) level using the B3LYP-D3/6-31G(d) geometries. The CYLview106 software was employed for visualizations.