Asymmetric Catalytic Concise Synthesis of Hetero-3,3′-Bisoxindoles for the Construction of Bispyrroloindoline Alkaloids

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Jul 2021Asymmetric Catalytic Concise Synthesis of Hetero-3,3′-Bisoxindoles for the Construction of Bispyrroloindoline Alkaloids Jian Xu, Ziwei Zhong, Mingyi Jiang, Yuqiao Zhou, Xiaohua Liu and Xiaoming Feng Jian Xu Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610065 , Ziwei Zhong Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610065 , Mingyi Jiang Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610065 , Yuqiao Zhou Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610065 , Xiaohua Liu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610065 and Xiaoming Feng *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610065 https://doi.org/10.31635/ccschem.020.202000443 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Asymmetric nucleophilic addition of 3-substituted N-Boc oxindoles to 3-bromooxindoles was designed to directly construct hetero-3,3′-bisoxindoles, with varying vicinal quaternary carbon stereocenters and N-substituents. The reaction progressed efficiently with high yields, good diastereo- and enantioselectivity (up to >99% ee) under mild reaction conditions catalyzed by chiral N,N′-dioxide/metal complexes. This methodology enabled the facile transformation of the generated hetero-3,3'-bisoxindoles into diverse hexahydropyrroloindole alkaloids with potential antiparasitic and anticancer properties. Download figure Download PowerPoint Introduction Dimeric and polymeric hexahydropyrroloindoles (HPIs) are a family of alkaloid natural products with essential and diverse biological activities (Scheme 1).1–3 The existence of similar subunits and contiguous stereogenic quaternary carbon atoms within these molecules is of great interest to organic synthetic chemists. After the preparation and structure validation through total synthesis,4–7 this aspect of asymmetric catalysis to intricate selectively as HPI-type alkaloids has received widespread attention over the last decade. Generally, the focus and difficulty of the catalytic asymmetric approaches are the construction of sterically hindered vicinal all-carbon quaternary stereocenters at C3a and C3a′ positions, where the C3a–C3a′ bond is weak, according to the bond length determined by X-ray structural analysis.8–11 The existed examples usually involved reactions using 3-substituted oxindole derivatives as starting materials.12–16 Although various investigators earlier reported alkylation of 3-hydroxyoxindoles and the related materials,12–15 as well as an addition of indoles to isatylidene-3-acetaldehydes16 to enable the formation of one-quaternary-centered oxindole derivatives, several transformation steps were required to achieve the bisoxindole units. The enantioselective synthesis of HPIs from tryptamine derivatives provided an alternative route for assembling dimeric and polyoligomers of HPIs.17–21 Noteworthily, the direct construction of vicinal all-carbon quaternary stereocentered bisoxindoles for the synthesis of cyclotryptamine alkaloids arose from the use of homo-bisoxindole derivatives A–C (Scheme 1). Asymmetric reactions included double Michael reaction of N-Boc-protected bisoxindoles A initiated by Kanai and Matsunaga's group,22 homo/hetero dialkylation by Tu's group,23 Pd-catalyzed decarboxylative asymmetric allylic alkylation (Pd-DAAA) of dienol dicarbonate B by Trost's group,24 and double decarboxylative allylation of ester-bearing meso-precursor C by Bisai's group.25,26 Scheme 1 | Representative asymmetric catalytic strategies for the construction of hexahydropyrroloindole alkaloid natural products. Download figure Download PowerPoint The 3a,3a′-bispyrrolidino[2,3-b]indoline structure is embedded as the core unit in the selected four dimeric hexahydropyrroloindole alkaloid natural products shown in Scheme 1, with variation as N–H or N-methyl substituents at pyrrolidine or indoline moieties. Despite the wonderful pioneering synthetic strategies and novel catalytic systems, a limitation exists regarding the acquisition of high diastereoselectivity and heterologous at N-substitution of the key 3,3′-bisoxindole synthons. We envisioned that it would be appealing to develop a versatile methodology from readily available starting compounds for diastereo- and enantioselective synthesis of hetero-3,3′-bisoxindoles, varying both the vicinal quaternary stereocenters and the N-protection groups to facilitate a concise enantioselective synthesis of the family of homo- and hetero-HPI alkaloids. Herein, we developed an entirely new route to construct C3a–C3a′ bond of bisoxindoles directly with all-carbon quaternary centers from two types of readily available oxindole derivatives (Scheme 1). A series of hetero 3,3′-disubstituted bisoxindoles with a single N-Boc protective group were obtained in good yield with high diastereo- and enantioselectivities (up to 92% yield, >19∶1 dr, 99% ee). Upon a simple modification, the concise asymmetric syntheses of both hetero- and home-dimers of HPI alkaloid natural product series were readily accessible. Experimental Methods General procedure for asymmetric coupling reaction of oxindole 1 with 2a The reaction was conducted with Ni(BF4)2·6H2O (3.4 mg, 0.01 mmol, 10 mol%), L3-PiPr2 (6.5 mg, 0.01 mmol, 10 mol%), and 3-bromo-3-methyl oxindole 2a (22.5 mg, 0.10 mmol) in tetrahydrofuran (THF; 1.0 mL). The mixture was stirred at 35 °C for 30 min. N-Boc-protected oxindole 1 (0.15 mmol) and tripropylamine (nPr3 N, 23 µL, 0.12 mmol, 1.2 equiv) were added, and the resulting mixture was stirred at 50 °C under air until the complete conversion of 2a to crude mixture of 3, detected by thin-layer chromatography (TLC) (24–72 h). The reaction mixture was subjected to column chromatography on silica gel and eluted with petroleum ether:ethyl acetate = 3∶1 to afford the corresponding pure product 3. General procedure for asymmetric coupling reaction of oxindole 1b with 2b–2p The reaction was conducted with MgBr2·Et2O (2.6 mg, 0.01 mmol, 10 mol%), L3-PiEt3 (7.2 mg, 0.011 mmol, 11 mol%), and 3-bromo-3-substituted oxindole 2 (0.10 mmol) in THF (0.5 mL). The mixture was stirred at 35 °C for 30 min. After concentrating in vacuo, N-Boc-protected oxindole 1b (45.8 mg, 0.15 mmol), K3PO4 (25.5 mg, 0.12 mmol, 1.2 equiv), and 1,2-dichloromethane (DCM; 1.0 mL) were added. The resulting mixture was stirred at 20 °C under air until the complete conversion of 2 (24–48 h), as detected by thin-layer chromatography (TLC). The reaction mixture was then subjected to column chromatography on silica gel and eluted with petroleum ether:ethyl acetate = 4∶1 to afford the corresponding product 3. Results and Discussion The hetero-coupling of two oxindole units is based on the addition of 3-substituted N-Boc oxindoles 1 to o-azaxylylene, generated from 3-substituted 3-halooxindoles 2, with the assistance of a base.27–35 Racemic products were obtained in moderate yield with poor diastereoselectivity in the presence of either an organic or inorganic base. As described in Scheme 2, N-Boc-protected oxindole 1a and 3-bromo-3-methyloxindole 2a were selected as the model substrates to show the efficiency of this route. Feng's chiral N,N'-dioxide–metal complex catalysts were used to control the stereoselectivity in view of their performance in several asymmetric reactions.36–42 An initial exploration showed that the reaction performed well, adapting chiral nickel complex of N,N'-dioxide L3-PiPr2, demonstrated to be a promising catalyst in the addition reaction of silyl ketene imines to indol-2-one species in a previous report.43 High diastereo- and enantioselectivity were obtained in DCE or THF, but the reactivity slightly increased at a higher reaction temperature in THF. The desired hetero-3-acetate-3′-methyl-substituted bisoxindole 3aa was isolated in 88% yield, 95∶5 dr, and 95% ee (Scheme 2). Following this optimized condition, we first evaluated the scope of N–H 3-bromo-3-methyloxindole 2a with different 3-substituted N-Boc oxindoles 1 in the reaction (Table 1). We found that different ester groups had a slight effect on the reaction, affording excellent results of the related products 3ba−3da (80–92% yield, 19∶1 dr, 92–97% ee). When 3-benzyl-substituted oxindole was used, the stereoselectivity dropped a little, and the major diastereomer obtained was 88% ee of 3ea (80% yield, 10∶1 dr). The reaction of 3-methyl-containing oxindole gave 3,3′-dimethyl bisoxindole 3fa in 76% yield and 9∶1 dr, and equally high enantioselectivity was detected for each diastereomer (90% and 91% ee) after the reaction temperature was reduced to 20 °C. Generally, the electron-donating or electron-withdrawing group on the oxindole backbone had no noticeable effect on the reaction. The corresponding products 3ga− 3na were obtained in good yields with excellent dr and ee values (59–91% yields, >19∶1 dr, and 87–95% ee). The reaction of 3-acetate N-Boc oxindoles with chloro-substituent at different positions yielded the desired products 3ga– 3ia with satisfactory stereoselectivity and moderate yield at a lower temperature. Besides, the two diastereoisomers of hetero-bisoxindoles 3 in this reaction was separated by column chromatography, and the absolute configuration of the major diastereomer 3aa was confirmed as (3 R,3′R) by X-ray crystal diffraction analysis (see the supporting crystallographic data for 3aa). These data are available free of charge at the Cambridge Crystallographic Data Center (CCDC 2009509). Scheme 2 | The model reaction for the synthesis of bisoxindole 3aa. Download figure Download PowerPoint Table 1. | Substrate Scope of N-Boc-Protected Oxindolesa aUnless otherwise noted, the reactions were performed with 2a (0.10 mmol), 1a–1n (1.5 equiv), tripropylamine (nPr3N, 1.2 equiv), and L3-PiPr2/Ni(BF4)2·6H2O (10 mol%, 1∶1) in THF (1.0 mL) at 50 °C under an atmosphere air for 24 h. The ee values were determined by high-performance liquid chromatography (HPLC) analysis with a chiral stationary phase, and dr values were determined by 1H NMR analysis of the crude products. bAt 40 °C for 72 h. cIn DCE at 20 °C for 16 h. dAt 35 °C for 72 h. Exposure of 3-bromo-3-benzoyloxindole 2b to the catalytic system consisting of L3-PiPr2, Ni(BF4)2·6H2O, and nPr3 N led to a poor outcome ( 3bb, 57% yield, 90∶10 dr, and 30% ee; see Supporting information Table S5). Next, we investigated the critical enantioselective coupling of the electrophilic 3-benzoyloxindole 2b with nucleophilic methyl 3-acetate-substituted oxindole 1b (Scheme 3). The enantioselectivity improved to 83% ee if MgBr2·Et2O was used as the metal precursor. Finally, we established that a chiral N,N'-dioxide L3-PiEt3 with 2,4,6-triethylaniline substituents delivered the hetero-bisoxindole 3bb in 66% yield with K3PO4 (1.2 equiv) as the base in DCM at 20 °C under an air atmosphere. Although the diastereoselectivity was poor (79∶21 dr), excellent enantioselectivity was observed for each diastereoisomer (94/95% ee). Scheme 3 | The model reaction for the synthesis of bisoxindole 3bb. Download figure Download PowerPoint Further, the chiral magnesium catalyst of L3-PiEt3/MgBr2·Et2O, was applied to a wide range of 3-substituted-3-bromooxindoles 2 with 1b (Table 2). The corresponding C3a–C3a′ coupled hetero-bisoxindoles 3bc– 3bp could be isolated in excellent enantioselectivity (up to 99% ee) for each diastereomer in most cases. The diastereoselectivities decreased (2.3∶1–9∶1 dr) with enhancing the steric hindrance on the 3-substituent of electrophilic oxindoles 2 ( 3bc, 3be vs. 3bd, 3bh). Notably, 3-allyl and 3-acetate-substituted-3-bromooxindoles were also amenable to the reaction, affording the products 3be and 3bf with excellent enantioselectivities (93–96% ee), which played critical roles in the construction of homo- and hetero HPI alkaloids. Moreover, the reaction was amenable to other aryl or heteroaromatic groups, including thienyl, furyl, and 1-naphthyl group ( 3bg, 3bi, 3bj). Also, we employed 3-benzyl-3-bromooxindoles, containing electron-donating or electron-withdrawing groups at different positions on the benzyl moiety, and the reaction afforded the corresponding products ( 3bl– 3 bp) with decent ee values (95–99%), reasonable yields (52–61%), and good dr values (3∶1–19∶1). Table 2 | Substrate Scope of N–H 3-Bromooxindolesa aUnless otherwise noted, the reactions were performed with 2b–2p (0.10 mmol), 1b (1.5 equiv), K3PO4 (1.2 equiv), and L3-PiEt3/MgBr2·Et2O (10 mol%, 1.1∶1) in DCM (1.0 mL) at 20 °C under an air atmosphere for 30 h. The ee values were determined by chiral HPLC analysis with a chiral stationary phase, and dr values were determined by 1H NMR analysis of crude products. bThe reactions were performed with L3-PiPr2/Sc(OTf)3 (10 mol%, 1.1∶1), K3PO4 (1.2 equiv) in DCE at 20 °C for 18 h. The scalable reaction allowed for the ready production of a gram of 3-acetate-3′-vinyl bisoxindole 3be with 8∶1 dr and 94/98% ee for two diastereomers (Scheme 4). Following Tu's group elegant synthesis of (−)-chimonanthidine from N,N′-Boc-protected hetero-bisoxindole analogues23 along with methods by Trost's and Bisai's groups,24,25 the synthesis of enantiomeric HPI alkaloids, including (+)-chimonanthidine and further methylated (+)-folicanthine were feasible. More importantly, the heterodimeric oxindoles characterized by one N-protective group implied that the catalytic products had more possibilities in the synthesis of HPIs with N–H-based indoline moieties. For instance, the construction of homo- and hetero-HPI alkaloids was available from optically enriched 3bf. The determination of the absolute configuration via crystal diffraction analysis of the isolated major diastereomer of 3bf and its derivatives such as 6 needed particular notice because of the easy crystallization of racemic compound from solvents. The N–H-based derivative 7 from major enantiomeric 3bf was determined to be (3R,3′R) by careful X-ray crystal diffraction analysis contained in the supporting crystallographic data of 7. These data could also be obtained free of charge at the CCDC deposition (CCDC 2012382). Thus, the methylation of the product (3R,3′R)- 3bf (>19∶1 dr, 93% ee, after column chromatography) following deprotection of the N-Boc group afforded one N-methyl substituted 4 in 95% yield, then another free N–H was protected by the benzyl group to afford heterobisoxindole 5 in 90% yield. The key building block diol-intermediate 6 was obtained effciently (79% yield) by reducing 5 with LiBH4, with maintained enantioselectivity, which could be readily converted to (+)-calycanthidine in three steps, according to previous reports by Overman's group.44–46 The synthesis of two N–H free chimonanthine could follow a similar procedure if two N-Bn groups were introduced into diol, which could be removed in the final step. In addition, N–H-based (+)-calycanthidine has been used for the enantioselective synthesis of polypyrrolidinoindoline (+)-idiospermuline after several steps.45,46 As a result, the hexahydropyrroloindole alkaloids shown in Scheme 1 with selective protection of N–H by the methyl group could be available through these new asymmetric catalytic reactions. Scheme 4 | Gram scale-up and formal synthesis of (+)-chimonanthidine, (+)-calycanthidine, and the related. Download figure Download PowerPoint The stereocontrol of this coupling reaction was considered based on the previous studies on the catalyst structures47,48 and the outcome of this reaction process. A diastereo- and enantioselective nucleophilic attack model (Figure 1) for generating major isomers was suggested. In the presence of the base, electrophilic partner o-azaxylylene was generated from 3-bromooxindole 2 and might be activated by the cation from the salt. On the other side, the 3-substituted oxindole 1 coordinated to the metal center of the chiral catalyst with the two oxygens enhancing the acidity of the proton at the C3 position, thereby facilitating the enolization step. As shown in Figure 1, the addition occurs from the Si-face of oxindole species of 1, possibly due to the steric hindrance of the amide unit on the right. The diastereocontrol steps from the steric hindrance rooted in the Re-Si facial approach of the two reactants, as well as the block of the left subunit of the ligand, leading to a favorable Si–Si-face attack (TS-A), yielding the major (3R,3′R)-configured products. When the 3-substituent R on 3-bromooxindole 2 changed from methyl to other groups, the steric congestion of the R group with ester in oxindole 1 increased (TS-A and TS-C), and with the left amide subunit of the ligand (TS-B), thereby indicating that the gap for the two diastereomers decreased, leading to reduced dr values. Figure 1 | The rationalization for diastereo- and enantioselectivity for the synthesis of bisoxindoles. Download figure Download PowerPoint Conclusion We have developed an efficient catalytic asymmetric coupling reaction between N-Boc-protected 3-substituted oxindoles and 3-bromo 3-substituted oxindoles. 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