Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade

Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade Xiangbing Qi, Xin Wang, Mengjiao Zhang, Xiaolei liu, Mingliang Lou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3336630/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Piperidine and pyridine are the most significant structural components of bioactive molecules. Aza-Achmatowicz rearrangement is a broadly appliable approach to access piperidine or pyridine derivatives owing to the easily adjustable electronic properties of the amino group. When combined with other chemical transformations, such as nucleophilic cyclization or cycloaddition, it provides entries to a variety of polycyclic skeletons present in naturally-derived alkaloids. Herein, we developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of 7( R )-geissoschizol oxindole/7( S )-geissoschizol oxindole. The reaction cascade has a broad substrate scope, with a variety of substitutions on the indoles and furans. Other innovative features include the chemo-selective dearomatization of the pyridinium moiety to form the C(sp 3 )-enriched, three-dimensional spiro[indolizidine-1,3´-oxindole] skeleton and a late-stage, regio- and stereoselective carbene insertion into a C(sp 3 )-H bond that enabled the successful installation of the adjacent carbon functionality for rhynchophylline and isorhynchophylline. In addition, 7( R )-geissoschizol oxindole/7( S )-geissoschizol oxindole were revised to their C-3 epimers and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by the DFT calculations. Physical sciences/Chemistry/Chemical synthesis/Natural product synthesis Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Piperidine and pyridine are frequently observed pharmacophores in drug molecules. 1 – 3 Statistically, over 20% of FDA-approved drugs containing a nitrogen heterocycle were derived from piperidine or pyridine (Fig. 1 a, piperidine ranks No. 1 and pyridine ranks No. 2 respectively). 1 Moreover, they serve as fundamental motifs broadly embedded in bioactive natural products. 4 – 6 Accordingly, the efficient synthetic methods for the construction of compounds with these two motifs are of great value. One convenient method for this is aza-Achmatowicz rearrangement, in which both piperidine and pyridine derivatives can be accessed from the furfuryl amines (Fig. 1 b). 7 – 9 It is a widely studied and practical reaction based on oxidative ring enlargement, in which the resulting products depend on the substituents connected to the nitrogen. 7 – 9 The piperidine derivatives are the products of this transformation when an electron-withdrawing group (EWG) is connected to the nitrogen. In contrast, the intermediate with electron-donating group (EDG) on the nitrogen is not stable and prone to undergo dehydration to form pyridinium derivatives. Both pathways tolerate various functional groups that can be further modified to piperidine and pyridinium derivatives. This enables them to function as an intermediate incorporated into a reaction cascade with other transformations such as cycloaddition and cyclization for the synthesis of polycyclic skeletons of complex alkaloids (Fig. 1 c). 10 – 13 Gin et al. combined the aza-Achmatowicz rearrangement with an intramolecular dipolar cycloaddition, efficiently accessing the aza-tricyclo[5.2.1.0 3,8 ]decane skeleton of hetisine alkaloids through a pyridinium intermediate. 10 In our previous studies, we developed an aza-Achmatowicz rearrangement/indole nucleophilic cyclization cascade to generate an indole-fused azabicyclo-[3.3.1]nonane skeleton through a piperidine intermediate and completed the asymmetric total synthesis of (–)-trinervine and other four indole alkaloids. 11 , 12 Zhang et al. developed an aza-Achmatowicz rearrangement/Mannich-type cyclization cascade to access the highly functional 9-azabicyclo-[3.3.1]nonane skeleton, thereby achieving the asymmetric total synthesis of vinorine. 13 Oxindole is another privileged motif commonly found in biologically active molecules and natural products. 14 , 15 Theoretically, the oxidative rearrangement of electron-rich furfuryl amine and indole can lead to the simultaneous generation of pyridine and oxindole motifs under identical reaction conditions. Accordingly, the designed compound 1 , which has a nitrogen tether connecting the furan and indole motifs, could potentially be utilized as a substrate for a reaction cascade (Fig. 1 d). The furan motif will be transformed into a pyridinium while the indole motif will undergo oxidation to form an oxindole simultaneously to access compound 2 , which in turn could undergo an intramolecular cyclization to access tetracyclic spirooxindole 3 . Chemo-selective dearomatization of the pyridinium moiety will generate the tetracyclic spiro[indolizidine-1,3´-oxindole] skeleton 4 , which is prevalent in hundreds of spirooxindole alkaloids with broad bioactivities. 14 , 16 The presence of multiple stereogenic centers, including one spiro quaternary center and various functional groups on the piperidine, presents challenges in synthesizing these spirooxindole alkaloids. 17 – 33 Herein, we present our approach for a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization for the efficient assembly of the tetracyclic spirooxindole skeleton. The application of this reaction cascade was demonstrated in the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of 7( R )-geissoschizol oxindole/7( S )-geissoschizol oxindole. Results Optimization of the Proposed Reaction Cascade We first explored the impact of different oxidants on our proposed reaction cascade using 1a as the model substrate. When subjected to m -CPBA oxidation, 34 compound 5 was observed where the amino linker was oxidized to the N -oxide (Table 1 , entry 1). When using oxone as the oxidant, 35 the furan moiety was not oxidized and oxindole 6 was obtained as the sole product (Table 1 , entry 2). NBS with sodium acetate (which is frequently used in aza-Achmatowicz rearrangement) 11 , 12 , 36 was unsuitable for this transformation (Table 1 , entry 3). Switching to bromine as the oxidant in acetic acid, we first obtained compound 2a which features a tertiary bromine at the 3-position of the oxindole. 37 After exposure to the NaHCO 3 aqueous solution, 37 – 40 3a was successfully accessed in a 20% yield (Table 1 , entry 4). The acid was essential in this process: it assists the oxidative rearrangement of the indole moiety and protonates the amino linker, avoiding the formation of the unwanted N -oxide. Finally, NBS with HCl was tested and a 27% yield of 3a was obtained after exposure to the NaHCO 3 aqueous solution (Table 1 , entry 5). Encouraged by these results, we then optimized various parameters of the reaction cascade using NBS as the oxidant. Different acids were screened, but no obvious reactivity differences were observed (Table 2 , entries 1–5). Next, increasing the amount of acid improved the reaction yield (Table 2 , entries 6–7). In addition, 3.1 equiv. of NBS proved more effective as it led to complete consumption of the starting material (Table 2 , entry 8). Moreover, different solvents were tested; however, no improvement was obtained (Table 2 , entries 9–12). Finally, we explored the impact of different bases used in the cyclization step (Table 2 , entries 13–16) and found Cs 2 CO 3 was the optimal base (Table 2 , entry 15). Investigation of the Substrate Scope Having established the optimal reaction conditions, we then examined the scope of this reaction cascade (Table 3 ). Exploration of tolerance for different substituents on the indole motif ( 3a - 3i ) showed that the desired products could be obtained in moderate to excellent yields (42–83%) with substrates bearing either an electron-withdrawing group (EWG) or an electron-donating group (EDG). Several substrates ( 3g , 3i ) required reactions to be performed at -5°C to minimize the side reaction of the electrophilic substitution on the 5-position of indole. Substrates with different EDGs on the furan motif ( 3j - 3p ) furnished the desired products in good to excellent yields (60–88%); however, when an EWG such as an ester was on the furan, no corresponding desired product was obtained. Instead, indole oxidative rearrangement and nucleophilic addition of amine product 3w was detected, presumably owing to the inert aza-Achmatowicz rearrangement of EWG-substituted furan derivatives. Moreover, the increase of the carbon on the side chain did not influence the efficiency and 3q could be accessed in an 89% yield. Substrates in which both indole and furan have substituents ( 3r - 3v ) were also readily converted to the desired products in good to excellent yields (58–83%). Regarding functional group tolerance, a series of substituents including alkyl ( 3h - 3l , 3q , 3s , 3u ), halogen ( 3a - 3c , 3e , 3r , 3t ), methoxyl ( 3f , 3v ) and ester ( 3d , 3s ) were all tolerated. Notably, free alcohols were also compatible with both the oxidation and the subsequent cyclization step ( 3m - 3p , 3r , 3t - 3v ). Formal Synthesis of Rhynchophylline and Isorhynchophylline To demonstrate the practical utility of this reaction cascade, we pursued the synthesis of rhynchophylline and isorhynchophylline, that were isolated from Uncaria rhynchophylla. 41 Starting with the pyridinium 3l (Table 3 ), we focused on the chemo-selective dearomatization of the pyridinium moiety in the presence of the benzene ring (Fig. 2 ). Pyridine dearomatization is of immense practical for the efficient installation of molecular complexity 42 – 50 and has been elegantly demonstrated in the total synthesis of complex alkaloids. 51 – 55 Different dearomatization methods were screened: the desired compounds 8 and 9 were obtained when using PtO 2 as a catalyst in the presence of HCl under a hydrogen atmosphere. 56 , 57 Moreover, when 2 equiv. of HCl was used in MeOH, the benzene ring was reduced exclusively to access 7 . Additionally,when 3l was treated with NaBH 4 in dioxane/H 2 O, 24,58 10 (confirmed by X-ray crystallography, CCDC 2282806) and 11 were obtained where the positions of the hydroxy and ethyl group were interchanged relative to 8 and 9 . The formation of 10 and 11 presumably involves a ring-opening process followed by stepwise dearomatization of the pyridinium moiety 47 to yield an iminium intermediate (see 2nb in Fig. 4 a), which subsequently undergoes recyclization through a Mannich reaction. After accessing 8 with the desired spiro[indolizidine-1,3´-oxindole] skeleton, our next focus was the installation of the side chain on the piperidine. As the hydroxy group was already attached to C14, we employed this group as a tether for selective C-H functionalization. 59 – 61 The nitrogen of the oxindole was protected by Boc 2 O and the diazo compound 14 was obtained by condensation with 12 followed by diazo transfer (Table 4 ). Subsequently, various transition metal catalysts were screened using 14 as the carbene precursor. The challenge was the selectivity towards the three tertiary (red) and four secondary (blue) C-H bonds on the piperidine ring. Firstly, we tested Pd(OAc) 2 and Cu(acac) 2 but did not access the desired product (Table 4 , entries 1–2). Switching the catalyst to [Rh(OAc) 2 ] 2 provided a 44% yield of desired compound 15 (confirmed by X-ray crystallography, CCDC 2282684), in which the vicinal, equatorial C15-H bond was inserted exclusively (Table 4 , entry 3). The regio- and stereoselectivity are presumably attributed to the preference for the formation of a 5-membered ring during the intramolecular carbene insertion 62 , 63 to the least sterically hindered equatorial C15-H bond. Moreover, in this way, the more thermodynamically favored trans-fused 5–6 ring system will be generated dominantly. Subsequently, a variety of rhodium (II) carboxylate catalysts were tested (Table 4 , entries 4–8) and the ones with electron-rich ligands (Table 4 , entries 7–8) were much more reactive than those with electron-deficient ligands, presumably due to the increasing nucleophilicity of the corresponding carbenoid for the selective insertion to the C15-H bond with lower electron density. 64 Finally, [Rh(Piv) 2 ] 2 was the optimal catalyst to access 15 with excellent regio- and stereoselectivity (Table 4 , entry 7). Pentacyclic compound 15 underwent ring opening to furnish methyl ester 16 when treated with NaOMe. 65 With the correct configuration of 16 in hand, we pursued deoxygenation to remove the hydroxy group. After reprotection of the nitrogen in the oxindole, a three-step sequence was adopted for this transformation: esterification of the hydroxy followed by nucleophilic substitution with LiBr furnished bromo-substrate 19 , then debromination was performed under a hydrogen atmosphere to deliver 21 , which is the common intermediate adopted in Oishi’s and Tong’s total synthesis. 19 , 26 In addition, the C-N migration product 22 was also detected in the process of hydrogenation, which was probably attributed to an aziridinium intermediate 20 (Fig. 3 ). Total Synthesis of 7( R )-Geissoschizol Oxindole and 7( S )-Geissoschizol Oxindole Based on the result of the selective dearomatization process for 10 / 11 , we pursued the synthesis of 7( R )-geissoschizol oxindole and 7( S )-geissoschizol oxindole, that were isolated from the Malayan Tabernaemontana corymbose . 66 Indole derivative 1n was chosen as the starting material for the reaction cascade. For the NaBH 4 -induced dearomatization process, we observed that the efficiency for cyclized substrate 3n (Table 3 ) is lower than the ring-opening intermediate 2n , so we separated 2n in a 5:1 mixture with the bromination side product 2na , instead of 3n , for the following transformations (Fig. 4 a). Subsequently, 2n and 2na were both treated with NaBH 4 and then debromination under a hydrogen atmosphere to obtain two diastereoisomers 23 (confirmed by X-ray crystallography, CCDC 2283109) and 24 . After selective protection of the primary alcohol and oxidation of the secondary alcohol, 23 and 24 were both transformed to ketone 25 (the cis configuration of H3 and H15 was confirmed by NOESY analysis). Subjecting 25 to a Julia olefination 67 followed by a silyl deprotection with NH 4 F, the final 27 and 28 (dr = 2.8:1) were successfully obtained. The NMR spectroscopy of 27 and 28 matched the reported data for the natural samples of 7( R )-geissoschizol oxindole and 7( S )-geissoschizol oxindole, respectively. 66 However, their crystallographic structures revealed a H3, H15- trans configuration instead of the originally proposed H3, H15- cis configuration. To verify the structures of 7( R )-geissoschizol oxindole and 7( S )-geissoschizol oxindole, we also pursued an alternative route involving oxidative rearrangement of 30 / 31 with opposite relative configurations of C3 and C15, which is generated from the intramolecular 1,4-addition of the vinyl iodide of 29 68 (Fig. 4 b). However, the corresponding oxidative rearrangement also yielded the same 27 and 28 (in terms of their 1 H NMR spectrum), failing to produce the products with H3, H15- cis configuration. These results were in accordance with the report by Martin et al. 69 that the similar spiro oxindoles with an ethylidene group are prone to be epimerized rapidly at C3 position due to the retro-Mannich/Mannich process via the ring-opening intermediate 32 and generates the H3, H15- trans epimers dominantly 69 , 70 (Fig. 4 c). We next conducted a series of quantum mechanical (QM) computations to probe into the reason for the C3 epimerization that was observed on the ethylidene substrates 27 / 28 but not on the ketone substrate 25 (Fig. 4 c). We performed conformational searches for each molecule using molecular dynamics simulations and multi-level optimization (details in the supplemental information). For the ketones, the computed free energy indicates that 25´ is more stable than 3- epi -25´ by 3.25 kcal/mol. In 25´ , the optimized structure shows that the piperidine is in a chair conformation, with the hydroxyethyl group at C15 in an equatorial position. However, in 3- epi -25´ , the piperidine adopted a boat conformation to avoid the 1,3-diaxial interactions between the hydroxyethyl group and H3/H21 β , resulting in a 3.25 kcal/mol increase in free energy. When the ketone in 25´ was changed to an ethylidene group, the conformational preferences also changed: the 1,3-allylic strain is dominant over the 1,3-diaxial interactions, causing the hydroxyethyl group at C15 to adopt an axial position. In this case, only when H3 and H15 are in a trans orientation could the piperidine maintain a chair conformation. Thus, the calculations indicate that 27 has a 3.38 kcal/mol lower free energy than 3- epi -27 , supporting the experimentally observed epimerization. Moreover, we also evaluated the free energy of C7 epimers and the result show that the free energy of 28 was higher than 27 by 0.72 kcal/mol, supporting the experimental results in which 27 is the thermodynamically favored product. This could be attributed to the stabilizing effect of an intramolecular hydrogen bond between the oxindole carbonyl and the protonated N4 in acidic condition. 70 Based on the observed epimerization of C3 in two different synthetic routes (Fig. 4 a and 4 b), along with the comparison of the NMR data of synthetic and natural samples, X-ray crystallographic structures and DFT calculations, it suggests that the relative configurations for 27 and 28 represent the correct ones of 7( R )-geissoschizol oxindole and 7( S )-geissoschizol oxindole, respectively. Conclusions In summary, a reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization was developed to construct tetracyclic spirooxindole system with pyridinium. Chemo-selective dearomatization of the pyridinium moiety using PtO 2 /H 2 and NaBH 4 respectively furnished the spiro[indolizidine-1,3´-oxindole] skeleton with regioselective establishment of the hydroxy group. Subsequently, the hydroxy group was further utilized as either a tether to introduce the carbene precursor thereby achieving the formal synthesis of rhynchophylline/isorhynchophylline, or was converted to the ethylidene group for the total synthesis of 7( R )-geissoschizol oxindole/7( S )-geissoschizol oxindole. Moreover, the structures of geissoschizol oxindoles were revised to the H3, H15- trans epimers according to NMR spectrum, crystallographic structures and DFT calculations. Our synthesis provides an illustrative example that the spirooxindole alkaloids are prone to undergo epimerization to adopt a thermodynamically favored configuration and demonstrates that the retro-Mannich/Mannich cascade is an inherent process in the total synthesis of spirooxindole alkaloids. In addition, this study showcases the power of rearrangement cascades for the assembly of the polycyclic skeletons present in complex natural products. Further explorations into the enantioselective rearrangement cascades are underway in the lab. Methods General methods Reactions were monitored by UPLC/MS and thin layer chromatography (TLC) and visualization was accomplished with a 254 nm UV light and by staining with phosphomolybdic acid solution with heating. All Flash silica gel column chromatography was performed using silica gel with particle size of 300–400 mesh. 1 H and 13 C NMR spectra were recorded on Varian Inova-400 spectrometers. Data for 1 H NMR spectra are reported relative to CDCl 3 (7.26 ppm), CD 3 OD (3.31 ppm), or DMSO-d 6 (2.50 ppm) as an internal standard and are reported as follows: chemical shift ( δ ppm), multiplicity ( s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, br = broad), coupling constant J (Hz), and integration. Data for 13 C NMR spectra are reported relative to CDCl 3 (77.00 ppm), CD 3 OD (49.00 ppm), DMSO-d 6 (39.52 ppm) as an internal standard and are reported in terms of chemical shift ( δ ppm). UPLC-MS analyses were performed on a Waters system (Column: BEH C18, 1.7 µm, 2.1*50 mm) with a Photodiode Array (PDA) detector and a Single Quadrupole (SQ) detector. High Resolution Mass spectra were obtained from on an Agilent 1290 LC-6540 QTOF Mass Spectrometer or an Agilent Technologies 7250 GCQTOF. HPLC analyses were carried out on Waters (Column Atlanits® HILIC Silica, 5 µm, 4.6*150 mm and 19*150 mm) with 2998PDA and 3100MS detectors. For NMR spectra of synthetic intermediates, see Supplementary Figures. For the experimental procedures and spectroscopic and physical data of compounds and the crystallographic data of compound 3g , 10 , 15 , 23 , 27 and 28 see Supplementary Methods. Declarations Data availability: The authors declare that all the data supporting this study, including the experimental procedures and compounds characterization, see Supplementary Files. All data are also available from the unstructured public depository figshare. (https://figshare.com/articles/dataset/Total_Synthesis_of_Tetracyclic_Spirooxindole_Alkaloids_via_a_Double_Oxidative_Rearrangement_Cyclization_Cascade/23849226). Energy data for the calculated structures are available in Supplementary Data. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 3g (CCDC 2282680), 10 (CCDC 2282806), 15 (CCDC 2282684), 23 (CCDC 2283109), 27 (CCDC 2283107), and 28 (CCDC 2283108). These data are provided free of charge by the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper. Acknowledgments: This work was supported by the National Natural Science Foundation of China (21971018 and 82225041). The authors gratefully acknowledge the Beijing Municipal Government and Tsinghua University for the financial support. We thank Dr. Toh-Seok Kam and Dr. Yun-Yee Low from Universiti Malaya for graciously providing us with the original samples of 7( R )-geissoschizol oxindole and 7( S )-geissoschizol oxindole. We thank Songlin Bai for the support on DFT calculations. Author contributions: X.Q. conceived the study; X.W. and M. Z. carried out most of the chemical synthesis; X.L. and M.L. helped synthesize some of the substrates; X.W., and X.Q. prepared the manuscript; X.W. collected the data and prepared the supplemental information; X.W., M.Z., X.L., M.L. and G.L. analyzed the data; All authors discussed the results and commented on the manuscript. Correspondence and requests for materials should be addressed to Xiangbing Qi. References Vitaku E, Smith DT, Njardarson JT. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014). De S, et al. Pyridine: the scaffolds with significant clinical diversity. RSC Adv. 12, 15385–15406 (2022). Frolov NA, Vereshchagin AN. Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications. Int. J. Mol. Sci. 24, 2937 (2023). Fu P, et al. 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Indol-2-one intermediates: mechanistic evidence and synthetic utility. Total syntheses of (±)-flustramines A and C. Org. Lett. 7, 677–680 (2005). Wei H, et al. The catalytic asymmetric dearomatization of tryptamine for accessing meso-contiguous quaternary carbon centers of oligomeric cyclotryptamine alkaloids: a formal synthesis of hodgkinsine B. Org. Chem. Front. 8, 3255–3259 (2021). Zhang H, Hong L, Kang H, Wang R. Construction of vicinal all-carbon quaternary stereocenters by catalytic asymmetric alkylation reaction of 3-bromooxindoles with 3-substituted indoles: total synthesis of (+)-perophoramidine. J. Am. Chem. Soc. 135, 14098–14101 (2013). Kondo H, Fukuda T, Tomita M. Alkaloids of Ouronparia rhynchophylla Matsum. Yakugaku Zasshi Yakugaku Zasshi 48, 321–327 (1928). Legault CY, Charette AB. Catalytic asymmetric hydrogenation of N-iminopyridinium ylides: expedient approach to enantioenriched substituted piperidine derivatives. J. Am. Chem. Soc. 127, 8966–8967 (2005). Rueping M, Antonchick AP. Organocatalytic enantioselective reduction of pyridines. Angew. Chem. Int. Ed. 46, 4562–4565 (2007). Ye ZS, Chen MW, Chen QA, Shi L, Duan Y, Zhou YG. Iridium-catalyzed asymmetric hydrogenation of pyridinium salts. Angew. Chem. Int. Ed. 51, 10181–10184 (2012). Chang M, et al. Asymmetric hydrogenation of pyridinium salts with an iridium phosphole catalyst. Angew. Chem. Int. Ed. 53, 12761–12764 (2014). Qu B, et al. Synthesis of Enantioenriched 2-Alkyl Piperidine Derivatives through Asymmetric Reduction of Pyridinium Salts. Org. Lett. 18, 4920–4923 (2016). Liu ZY, Wen ZH, Wang XC. B(C 6 F 5 ) 3 -Catalyzed Cascade Reduction of Pyridines. Angew. Chem. Int. Ed. 56, 5817–5820 (2017). Zhang X, Ling L, Luo M, Zeng X. Accessing Difluoromethylated and Trifluoromethylated cis-Cycloalkanes and Saturated Heterocycles: Preferential Hydrogen Addition to the Substitution Sites for Dearomatization. Angew. Chem. Int. Ed. 58, 16785–16789 (2019). Wagener T, Luckemeier L, Daniliuc CG, Glorius F. Interrupted Pyridine Hydrogenation: Asymmetric Synthesis of delta-Lactams. Angew. Chem. Int. Ed. 60, 6425–6429 (2021). Wu J, et al. Synthesis of chiral piperidines from pyridinium salts via rhodium-catalysed transfer hydrogenation. Nature Catalysis 5, 982–992 (2022). James MJ, Grant ND, O'Brien P, Taylor RJ, Unsworth WP. Catalytic Dearomatization Approach to Quinolizidine Alkaloids: Five Step Total Synthesis of (±)-Lasubine II. Org. Lett. 18, 6256–6259 (2016). Kerkovius JK, Stegner A, Turlik A, Lam PH, Houk KN, Reisman SE. A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids. J. Am. Chem. Soc. 144, 15938–15943 (2022). Landwehr EM, Baker MA, Oguma T, Burdge HE, Kawajiri T, Shenvi RA. Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction. Science 375, 1270–1274 (2022). Larson KK, Sarpong R. Total synthesis of alkaloid (±)-G. B. 13 using a Rh(I)-catalyzed ketone hydroarylation and late-stage pyridine reduction. J. Am. Chem. Soc. 131, 13244–13245 (2009). Woo S, Shenvi RA. Synthesis and target annotation of the alkaloid GB18. Nature 606, 917–921 (2022). Scapecchi S, et al. Molecular modulation of muscarinic antagonists. Synthesis and affinity profile of 2,2-diphenyl-2-ethylthio-acetic acid esters designed to probe the binding site cavity. Farmaco 59, 971–980 (2004). van der Heijden G, et al. Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides. Eur. J. Org. Chem. 2019, 5313–5325 (2019). Takayama H, Maeda M, Ohbayashi S, Kitajima M, Sakai S-i, Aimi N. The first total synthesis of (–)-mitragynine, an analgesic indole alkaloid in mitragyna speciosa. Tetrahedron Lett. 36, 9337–9340 (1995). Hughes JME, Gleason JL. A Concise Enantioselective Total Synthesis of (–)-Virosaine A. Angew. Chem. Int. Ed. 56, 10830–10834 (2017). Kawasumi M, Kanoh N, Iwabuchi Y. Concise entry to both enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one based on novel oxidative etherification: formal synthesis of (+)-sundiversifolide. Org. Lett. 13, 3620–3623 (2011). Mogi Y, et al. Rapid Assembly of Protoilludane Skeleton through Tandem Catalysis: Total Synthesis of Paesslerin A and Its Structural Revision. Org. Lett. 21, 3954–3958 (2019). Doyle MP, et al. Electronic and steric control in carbon-hydrogen insertion reactions of diazoacetoacetates catalyzed by dirhodium(II) carboxylates and carboxamides. J. Am. Chem. Soc. 115, 958–964 (1993). Taber DF, Ruckle RE. Cyclopentane construction by dirhodium tetraacetate-mediated intramolecular C-H insertion: steric and electronic effects. J. Am. Chem. Soc. 108, 7686–7693 (1986). Ohira S, Yoshihara N, Hasegawa T. Synthesis of (–)-Gleenol via C-H Insertion Reaction of Alkylidenecarbene. Chem. Lett. 27, 739–740 (1998). Padwa A, Austin DJ. Ligand Effects on the Chemoselectivity of Transition Metal Catalyzed Reactions of α-Diazo Carbonyl Compounds. Angew. Chem. Int. Ed. 33, 1797–1815 (1994). Lim KH, Sim KM, Tan GH, Kam TS. Four tetracyclic oxindole alkaloids and a taberpsychine derivative from a Malayan Tabernaemontana. Phytochemistry 70, 1182–1186 (2009). Ando K, Kawano D, Takama D, Semii Y. 1-Methyl-1H-tetrazol-5-yl (MT) sulfones in the Julia-Kocienski olefination: Comparison with the PT and the TBT sulfones. Tetrahedron Lett. 60, 1566–1569 (2019). Jarret M, et al. Bioinspired Divergent Oxidative Cyclizations of Geissoschizine: Total Synthesis of (–)-17-nor-Excelsinidine, (+)-16-epi-Pleiocarpamine, (+)-16-Hydroxymethyl-Pleiocarpamine and (+)-Taberdivarine H. Eur. J. Org. Chem. 2020, 6340–6351 (2020). Ito M, Clark CW, Mortimore M, Goh JB, Martin SF. Biogenetically inspired approach to the Strychnos alkaloids. Concise syntheses of (±)-akuammicine and (±)-strychnine. J. Am. Chem. Soc. 123, 8003–8010 (2001). Laus G, Brössner D, Senn G, Wurst K. Analysis of the kinetics of isomerization of spiro oxindole alkaloids. J. Chem. Soc. Perkin Trans. 2 , 1931–1936 (1996). Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files CrystalData.zip Crystal data NCSI.pdf Supplementary Information OriginalData.zip Original data Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3336630","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":234629487,"identity":"422f7b8e-60ef-41e4-a0ed-0ebfac321ea0","order_by":0,"name":"Xiangbing Qi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIie2RvQrCMBRGbwnEJW3XiIqvEPEB+ioVQZciQsHFH5zi1N1HcUwJ6FJwc9GhLk46iFNBwdR2tdVNMAc+EkjOTS4XQKP5RRCAUIuLAYwYmPhOQewzJcdVwTTTS7A2pCWS1XRg1Ra78XB4cKAiY0hW75WqxG4YRBsf16PRfslOnTnpMSOI3itMIiFMvu5w6vX2hEn1Qw+QwYsUYx4+csVXigP2uUxBQpp8opT+GpG0Ai15Je1FNrjwMfVQjaheOD2xMChQrG3Uvl74bNBc9o83cj84tt09xkmBkg9CqhD22mIom052OlOpxIUXNRqN5n95ArpHVH4EtzNvAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7139-5164","institution":"National Institute of Biological Sciences, Beijing","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xiangbing","middleName":"","lastName":"Qi","suffix":""},{"id":234629488,"identity":"b791061e-e043-4e4f-a313-b65d37fc3cc4","order_by":1,"name":"Xin Wang","email":"","orcid":"","institution":"National Institute of Biological Sciences, Beijing","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Wang","suffix":""},{"id":234629489,"identity":"55819805-25d3-4c99-bca1-80f44a00b72f","order_by":2,"name":"Mengjiao Zhang","email":"","orcid":"","institution":"National Institute of Biological Sciences, Beijing","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mengjiao","middleName":"","lastName":"Zhang","suffix":""},{"id":234629490,"identity":"c07fa010-8a57-4d49-92d9-ec356587966d","order_by":3,"name":"Xiaolei liu","email":"","orcid":"","institution":"Institute for Smart Materials \u0026 Engineering, University of Jinan,","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaolei","middleName":"","lastName":"liu","suffix":""},{"id":234629491,"identity":"09f36358-0e05-44a1-afb6-57b50a795e90","order_by":4,"name":"Mingliang Lou","email":"","orcid":"","institution":"National Institute of Biological Sciences,Beijing","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mingliang","middleName":"","lastName":"Lou","suffix":""},{"id":234629492,"identity":"0c92e100-0097-4f3a-adf4-677b1deaecc0","order_by":5,"name":"gen Li","email":"","orcid":"","institution":"National Institute of Biological Sciences, Beijing","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"gen","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2023-09-08 07:35:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3336630/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3336630/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":43443243,"identity":"bec3604c-13e9-4a33-8230-bbb4391e684f","added_by":"auto","created_at":"2023-09-20 23:27:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95109,"visible":true,"origin":"","legend":"\u003cp\u003eApplications of Aza-Achmatowicz Rearrangement and our design. NBS =\u003cem\u003e N\u003c/em\u003e-bromosuccinimide, TFA = trifluoroacetic acid.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/5cc95d41758333b5f3b76133.png"},{"id":43443242,"identity":"a2788ec2-2c8e-4fe2-a5bc-066d71e293b7","added_by":"auto","created_at":"2023-09-20 23:27:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33794,"visible":true,"origin":"","legend":"\u003cp\u003eSelective dearomatization of the pyridinium moiety\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/058bcadbea8c62ce29cdb28d.png"},{"id":43443245,"identity":"cbfdd949-825f-4341-87bd-0071ea9bfa2b","added_by":"auto","created_at":"2023-09-20 23:27:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":56127,"visible":true,"origin":"","legend":"\u003cp\u003eFormal Synthesis of rhynchophylline and isorhynchophylline. BzCl = benzoyl chloride.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/a6b97662748c5f2b653c88c4.png"},{"id":43445027,"identity":"10bcc836-d78b-4a87-b17c-d08d5957a348","added_by":"auto","created_at":"2023-09-20 23:35:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":117279,"visible":true,"origin":"","legend":"\u003cp\u003eTotal synthesis of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole and 7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole. TBDPSCl = tert-butylchlorodiphenylsilane, DMF = N, N-dimethylformamide, DMSO = dimethyl sulfoxide, DIEA = N, N-diisopropylethylamine, LiHMDS = lithium bis(trimethylsilyl)amide.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/6a73fcbdbf52e5f979882bbf.png"},{"id":44904972,"identity":"cd1ba075-9b73-470a-abc1-a6fcf4745fd4","added_by":"auto","created_at":"2023-10-19 07:53:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":683702,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/09232f61-577c-4e0e-901d-53e01dcd5b5e.pdf"},{"id":43443246,"identity":"6540f02f-a5cd-4d54-b8e6-c5894fb01686","added_by":"auto","created_at":"2023-09-20 23:27:00","extension":"zip","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1668592,"visible":true,"origin":"","legend":"Crystal data","description":"","filename":"CrystalData.zip","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/b3e5262dce3c4332161fa659.zip"},{"id":43443248,"identity":"113f713d-704f-45cf-958a-3fdfd4ce614f","added_by":"auto","created_at":"2023-09-20 23:27:00","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18508714,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Information\u003c/p\u003e","description":"","filename":"NCSI.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/1c8704d4a64e3ad31596f7c1.pdf"},{"id":43443250,"identity":"bb62f2e7-ab3f-49a0-83fe-43e7f9d799a0","added_by":"auto","created_at":"2023-09-20 23:27:02","extension":"zip","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":87247996,"visible":true,"origin":"","legend":"\u003cp\u003eOriginal data\u003c/p\u003e","description":"","filename":"OriginalData.zip","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/88e69d7832b991b8e7a18ca6.zip"},{"id":43443247,"identity":"3cb6e734-0b3c-495b-9a3b-bd9f2deafc3b","added_by":"auto","created_at":"2023-09-20 23:27:00","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":366843,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-3336630/v1/c26713bd53274f83c140d17a.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePiperidine and pyridine are frequently observed pharmacophores in drug molecules.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Statistically, over 20% of FDA-approved drugs containing a nitrogen heterocycle were derived from piperidine or pyridine (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, piperidine ranks No. 1 and pyridine ranks No. 2 respectively).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Moreover, they serve as fundamental motifs broadly embedded in bioactive natural products.\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Accordingly, the efficient synthetic methods for the construction of compounds with these two motifs are of great value. One convenient method for this is aza-Achmatowicz rearrangement, in which both piperidine and pyridine derivatives can be accessed from the furfuryl amines (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e It is a widely studied and practical reaction based on oxidative ring enlargement, in which the resulting products depend on the substituents connected to the nitrogen.\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e The piperidine derivatives are the products of this transformation when an electron-withdrawing group (EWG) is connected to the nitrogen. In contrast, the intermediate with electron-donating group (EDG) on the nitrogen is not stable and prone to undergo dehydration to form pyridinium derivatives. Both pathways tolerate various functional groups that can be further modified to piperidine and pyridinium derivatives. This enables them to function as an intermediate incorporated into a reaction cascade with other transformations such as cycloaddition and cyclization for the synthesis of polycyclic skeletons of complex alkaloids (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Gin \u003cem\u003eet al.\u003c/em\u003e combined the aza-Achmatowicz rearrangement with an intramolecular dipolar cycloaddition, efficiently accessing the aza-tricyclo[5.2.1.0\u003csup\u003e3,8\u003c/sup\u003e]decane skeleton of hetisine alkaloids through a pyridinium intermediate.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e In our previous studies, we developed an aza-Achmatowicz rearrangement/indole nucleophilic cyclization cascade to generate an indole-fused azabicyclo-[3.3.1]nonane skeleton through a piperidine intermediate and completed the asymmetric total synthesis of (\u0026ndash;)-trinervine and other four indole alkaloids.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Zhang \u003cem\u003eet al.\u003c/em\u003e developed an aza-Achmatowicz rearrangement/Mannich-type cyclization cascade to access the highly functional 9-azabicyclo-[3.3.1]nonane skeleton, thereby achieving the asymmetric total synthesis of vinorine.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOxindole is another privileged motif commonly found in biologically active molecules and natural products.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Theoretically, the oxidative rearrangement of electron-rich furfuryl amine and indole can lead to the simultaneous generation of pyridine and oxindole motifs under identical reaction conditions. Accordingly, the designed compound \u003cb\u003e1\u003c/b\u003e, which has a nitrogen tether connecting the furan and indole motifs, could potentially be utilized as a substrate for a reaction cascade (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). The furan motif will be transformed into a pyridinium while the indole motif will undergo oxidation to form an oxindole simultaneously to access compound \u003cb\u003e2\u003c/b\u003e, which in turn could undergo an intramolecular cyclization to access tetracyclic spirooxindole \u003cb\u003e3\u003c/b\u003e. Chemo-selective dearomatization of the pyridinium moiety will generate the tetracyclic spiro[indolizidine-1,3\u0026acute;-oxindole] skeleton \u003cb\u003e4\u003c/b\u003e, which is prevalent in hundreds of spirooxindole alkaloids with broad bioactivities.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e The presence of multiple stereogenic centers, including one spiro quaternary center and various functional groups on the piperidine, presents challenges in synthesizing these spirooxindole alkaloids.\u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Herein, we present our approach for a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization for the efficient assembly of the tetracyclic spirooxindole skeleton. The application of this reaction cascade was demonstrated in the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole/7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eOptimization of the Proposed Reaction Cascade\u003c/h2\u003e\n \u003cp\u003eWe first explored the impact of different oxidants on our proposed reaction cascade using \u003cstrong\u003e1a\u003c/strong\u003e as the model substrate. When subjected to \u003cem\u003em\u003c/em\u003e-CPBA oxidation,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e compound \u003cstrong\u003e5\u003c/strong\u003e was observed where the amino linker was oxidized to the \u003cem\u003eN\u003c/em\u003e-oxide (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 1). When using oxone as the oxidant,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e the furan moiety was not oxidized and oxindole \u003cstrong\u003e6\u003c/strong\u003e was obtained as the sole product (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 2). NBS with sodium acetate (which is frequently used in aza-Achmatowicz rearrangement)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e was unsuitable for this transformation (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 3). Switching to bromine as the oxidant in acetic acid, we first obtained compound \u003cstrong\u003e2a\u003c/strong\u003e which features a tertiary bromine at the 3-position of the oxindole.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e After exposure to the NaHCO\u003csub\u003e3\u003c/sub\u003e aqueous solution,\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e\u003cstrong\u003e3a\u003c/strong\u003e was successfully accessed in a 20% yield (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 4). The acid was essential in this process: it assists the oxidative rearrangement of the indole moiety and protonates the amino linker, avoiding the formation of the unwanted \u003cem\u003eN\u003c/em\u003e-oxide. Finally, NBS with HCl was tested and a 27% yield of \u003cstrong\u003e3a\u003c/strong\u003e was obtained after exposure to the NaHCO\u003csub\u003e3\u003c/sub\u003e aqueous solution (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, entry 5).\u003c/p\u003e\n \u003cp\u003eEncouraged by these results, we then optimized various parameters of the reaction cascade using NBS as the oxidant. Different acids were screened, but no obvious reactivity differences were observed (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, entries 1\u0026ndash;5). Next, increasing the amount of acid improved the reaction yield (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, entries 6\u0026ndash;7). In addition, 3.1 equiv. of NBS proved more effective as it led to complete consumption of the starting material (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, entry 8). Moreover, different solvents were tested; however, no improvement was obtained (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, entries 9\u0026ndash;12). Finally, we explored the impact of different bases used in the cyclization step (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, entries 13\u0026ndash;16) and found Cs\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e was the optimal base (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, entry 15).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eInvestigation of the Substrate Scope\u003c/h2\u003e\n \u003cp\u003eHaving established the optimal reaction conditions, we then examined the scope of this reaction cascade (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Exploration of tolerance for different substituents on the indole motif (\u003cstrong\u003e3a\u003c/strong\u003e-\u003cstrong\u003e3i\u003c/strong\u003e) showed that the desired products could be obtained in moderate to excellent yields (42\u0026ndash;83%) with substrates bearing either an electron-withdrawing group (EWG) or an electron-donating group (EDG). Several substrates (\u003cstrong\u003e3g\u003c/strong\u003e, \u003cstrong\u003e3i\u003c/strong\u003e) required reactions to be performed at -5\u0026deg;C to minimize the side reaction of the electrophilic substitution on the 5-position of indole. Substrates with different EDGs on the furan motif (\u003cstrong\u003e3j\u003c/strong\u003e-\u003cstrong\u003e3p\u003c/strong\u003e) furnished the desired products in good to excellent yields (60\u0026ndash;88%); however, when an EWG such as an ester was on the furan, no corresponding desired product was obtained. Instead, indole oxidative rearrangement and nucleophilic addition of amine product \u003cstrong\u003e3w\u003c/strong\u003e was detected, presumably owing to the inert aza-Achmatowicz rearrangement of EWG-substituted furan derivatives. Moreover, the increase of the carbon on the side chain did not influence the efficiency and \u003cstrong\u003e3q\u003c/strong\u003e could be accessed in an 89% yield. Substrates in which both indole and furan have substituents (\u003cstrong\u003e3r\u003c/strong\u003e-\u003cstrong\u003e3v\u003c/strong\u003e) were also readily converted to the desired products in good to excellent yields (58\u0026ndash;83%). Regarding functional group tolerance, a series of substituents including alkyl (\u003cstrong\u003e3h\u003c/strong\u003e-\u003cstrong\u003e3l\u003c/strong\u003e, \u003cstrong\u003e3q\u003c/strong\u003e, \u003cstrong\u003e3s\u003c/strong\u003e, \u003cstrong\u003e3u\u003c/strong\u003e), halogen (\u003cstrong\u003e3a\u003c/strong\u003e-\u003cstrong\u003e3c\u003c/strong\u003e, \u003cstrong\u003e3e\u003c/strong\u003e, \u003cstrong\u003e3r\u003c/strong\u003e, \u003cstrong\u003e3t\u003c/strong\u003e), methoxyl (\u003cstrong\u003e3f\u003c/strong\u003e, \u003cstrong\u003e3v\u003c/strong\u003e) and ester (\u003cstrong\u003e3d\u003c/strong\u003e, \u003cstrong\u003e3s\u003c/strong\u003e) were all tolerated. Notably, free alcohols were also compatible with both the oxidation and the subsequent cyclization step (\u003cstrong\u003e3m\u003c/strong\u003e-\u003cstrong\u003e3p\u003c/strong\u003e, \u003cstrong\u003e3r\u003c/strong\u003e, \u003cstrong\u003e3t\u003c/strong\u003e-\u003cstrong\u003e3v\u003c/strong\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eFormal Synthesis of Rhynchophylline and Isorhynchophylline\u003c/h2\u003e\n \u003cp\u003eTo demonstrate the practical utility of this reaction cascade, we pursued the synthesis of rhynchophylline and isorhynchophylline, that were isolated from \u003cem\u003eUncaria rhynchophylla.\u003c/em\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e Starting with the pyridinium \u003cstrong\u003e3l\u003c/strong\u003e (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), we focused on the chemo-selective dearomatization of the pyridinium moiety in the presence of the benzene ring (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Pyridine dearomatization is of immense practical for the efficient installation of molecular complexity\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e and has been elegantly demonstrated in the total synthesis of complex alkaloids.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e Different dearomatization methods were screened: the desired compounds \u003cstrong\u003e8\u003c/strong\u003e and \u003cstrong\u003e9\u003c/strong\u003e were obtained when using PtO\u003csub\u003e2\u003c/sub\u003e as a catalyst in the presence of HCl under a hydrogen atmosphere.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e Moreover, when 2 equiv. of HCl was used in MeOH, the benzene ring was reduced exclusively to access \u003cstrong\u003e7\u003c/strong\u003e. Additionally,when \u003cstrong\u003e3l\u003c/strong\u003e was treated with NaBH\u003csub\u003e4\u003c/sub\u003e in dioxane/H\u003csub\u003e2\u003c/sub\u003eO,\u003csup\u003e24,58\u003c/sup\u003e\u003cstrong\u003e10\u003c/strong\u003e (confirmed by X-ray crystallography, CCDC 2282806) and \u003cstrong\u003e11\u003c/strong\u003e were obtained where the positions of the hydroxy and ethyl group were interchanged relative to \u003cstrong\u003e8\u003c/strong\u003e and \u003cstrong\u003e9\u003c/strong\u003e. The formation of \u003cstrong\u003e10\u003c/strong\u003e and \u003cstrong\u003e11\u003c/strong\u003e presumably involves a ring-opening process followed by stepwise dearomatization of the pyridinium moiety\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e to yield an iminium intermediate (see \u003cstrong\u003e2nb\u003c/strong\u003e in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea), which subsequently undergoes recyclization through a Mannich reaction.\u003c/p\u003e\n \u003cp\u003eAfter accessing \u003cstrong\u003e8\u003c/strong\u003e with the desired spiro[indolizidine-1,3\u0026acute;-oxindole] skeleton, our next focus was the installation of the side chain on the piperidine. As the hydroxy group was already attached to C14, we employed this group as a tether for selective C-H functionalization.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e The nitrogen of the oxindole was protected by Boc\u003csub\u003e2\u003c/sub\u003eO and the diazo compound \u003cstrong\u003e14\u003c/strong\u003e was obtained by condensation with \u003cstrong\u003e12\u003c/strong\u003e followed by diazo transfer (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Subsequently, various transition metal catalysts were screened using \u003cstrong\u003e14\u003c/strong\u003e as the carbene precursor. The challenge was the selectivity towards the three tertiary (red) and four secondary (blue) C-H bonds on the piperidine ring. Firstly, we tested Pd(OAc)\u003csub\u003e2\u003c/sub\u003e and Cu(acac)\u003csub\u003e2\u003c/sub\u003e but did not access the desired product (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, entries 1\u0026ndash;2). Switching the catalyst to [Rh(OAc)\u003csub\u003e2\u003c/sub\u003e]\u003csub\u003e2\u003c/sub\u003e provided a 44% yield of desired compound \u003cstrong\u003e15\u003c/strong\u003e (confirmed by X-ray crystallography, CCDC 2282684), in which the vicinal, equatorial C15-H bond was inserted exclusively (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, entry 3). The regio- and stereoselectivity are presumably attributed to the preference for the formation of a 5-membered ring during the intramolecular carbene insertion \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e to the least sterically hindered equatorial C15-H bond. Moreover, in this way, the more thermodynamically favored trans-fused 5\u0026ndash;6 ring system will be generated dominantly. Subsequently, a variety of rhodium (II) carboxylate catalysts were tested (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, entries 4\u0026ndash;8) and the ones with electron-rich ligands (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, entries 7\u0026ndash;8) were much more reactive than those with electron-deficient ligands, presumably due to the increasing nucleophilicity of the corresponding carbenoid for the selective insertion to the C15-H bond with lower electron density.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e Finally, [Rh(Piv)\u003csub\u003e2\u003c/sub\u003e]\u003csub\u003e2\u003c/sub\u003e was the optimal catalyst to access \u003cstrong\u003e15\u003c/strong\u003e with excellent regio- and stereoselectivity (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, entry 7).\u003c/p\u003e\n \u003cp\u003ePentacyclic compound \u003cstrong\u003e15\u003c/strong\u003e underwent ring opening to furnish methyl ester \u003cstrong\u003e16\u003c/strong\u003e when treated with NaOMe.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e With the correct configuration of \u003cstrong\u003e16\u003c/strong\u003e in hand, we pursued deoxygenation to remove the hydroxy group. After reprotection of the nitrogen in the oxindole, a three-step sequence was adopted for this transformation: esterification of the hydroxy followed by nucleophilic substitution with LiBr furnished bromo-substrate \u003cstrong\u003e19\u003c/strong\u003e, then debromination was performed under a hydrogen atmosphere to deliver \u003cstrong\u003e21\u003c/strong\u003e, which is the common intermediate adopted in Oishi\u0026rsquo;s and Tong\u0026rsquo;s total synthesis.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e In addition, the C-N migration product \u003cstrong\u003e22\u003c/strong\u003e was also detected in the process of hydrogenation, which was probably attributed to an aziridinium intermediate \u003cstrong\u003e20\u003c/strong\u003e (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTotal Synthesis of 7(\u003c/strong\u003e \u003cstrong\u003eR\u003c/strong\u003e \u003cstrong\u003e)-Geissoschizol Oxindole and 7(\u003c/strong\u003e \u003cstrong\u003eS\u003c/strong\u003e \u003cstrong\u003e)-Geissoschizol Oxindole\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eBased on the result of the selective dearomatization process for \u003cstrong\u003e10\u003c/strong\u003e/\u003cstrong\u003e11\u003c/strong\u003e, we pursued the synthesis of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole and 7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole, that were isolated from the Malayan \u003cem\u003eTabernaemontana corymbose\u003c/em\u003e.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e Indole derivative \u003cstrong\u003e1n\u003c/strong\u003e was chosen as the starting material for the reaction cascade. For the NaBH\u003csub\u003e4\u003c/sub\u003e-induced dearomatization process, we observed that the efficiency for cyclized substrate \u003cstrong\u003e3n\u003c/strong\u003e (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) is lower than the ring-opening intermediate \u003cstrong\u003e2n\u003c/strong\u003e, so we separated \u003cstrong\u003e2n\u003c/strong\u003e in a 5:1 mixture with the bromination side product \u003cstrong\u003e2na\u003c/strong\u003e, instead of \u003cstrong\u003e3n\u003c/strong\u003e, for the following transformations (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea). Subsequently, \u003cstrong\u003e2n\u003c/strong\u003e and \u003cstrong\u003e2na\u003c/strong\u003e were both treated with NaBH\u003csub\u003e4\u003c/sub\u003e and then debromination under a hydrogen atmosphere to obtain two diastereoisomers \u003cstrong\u003e23\u003c/strong\u003e (confirmed by X-ray crystallography, CCDC 2283109) and \u003cstrong\u003e24\u003c/strong\u003e. After selective protection of the primary alcohol and oxidation of the secondary alcohol, \u003cstrong\u003e23\u003c/strong\u003e and \u003cstrong\u003e24\u003c/strong\u003e were both transformed to ketone \u003cstrong\u003e25\u003c/strong\u003e (the \u003cem\u003ecis\u003c/em\u003e configuration of H3 and H15 was confirmed by NOESY analysis). Subjecting \u003cstrong\u003e25\u003c/strong\u003e to a Julia olefination\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e followed by a silyl deprotection with NH\u003csub\u003e4\u003c/sub\u003eF, the final \u003cstrong\u003e27\u003c/strong\u003e and \u003cstrong\u003e28\u003c/strong\u003e (dr\u0026thinsp;=\u0026thinsp;2.8:1) were successfully obtained. The NMR spectroscopy of \u003cstrong\u003e27\u003c/strong\u003e and \u003cstrong\u003e28\u003c/strong\u003e matched the reported data for the natural samples of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole and 7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole, respectively.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e However, their crystallographic structures revealed a H3, H15-\u003cem\u003etrans\u003c/em\u003e configuration instead of the originally proposed H3, H15-\u003cem\u003ecis\u003c/em\u003e configuration. To verify the structures of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole and 7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole, we also pursued an alternative route involving oxidative rearrangement of \u003cstrong\u003e30\u003c/strong\u003e/\u003cstrong\u003e31\u003c/strong\u003e with opposite relative configurations of C3 and C15, which is generated from the intramolecular 1,4-addition of the vinyl iodide of \u003cstrong\u003e29\u003c/strong\u003e\u003csup\u003e68\u003c/sup\u003e (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb). However, the corresponding oxidative rearrangement also yielded the same \u003cstrong\u003e27\u003c/strong\u003e and \u003cstrong\u003e28\u003c/strong\u003e (in terms of their \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH NMR spectrum), failing to produce the products with H3, H15-\u003cem\u003ecis\u003c/em\u003e configuration. These results were in accordance with the report by Martin \u003cem\u003eet al.\u003c/em\u003e\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e that the similar spiro oxindoles with an ethylidene group are prone to be epimerized rapidly at C3 position due to the retro-Mannich/Mannich process via the ring-opening intermediate \u003cstrong\u003e32\u003c/strong\u003e and generates the H3, H15-\u003cem\u003etrans\u003c/em\u003e epimers dominantly\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e69\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ec).\u003c/p\u003e\n \u003cp\u003eWe next conducted a series of quantum mechanical (QM) computations to probe into the reason for the C3 epimerization that was observed on the ethylidene substrates \u003cstrong\u003e27\u003c/strong\u003e/\u003cstrong\u003e28\u003c/strong\u003e but not on the ketone substrate \u003cstrong\u003e25\u003c/strong\u003e (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ec). We performed conformational searches for each molecule using molecular dynamics simulations and multi-level optimization (details in the supplemental information). For the ketones, the computed free energy indicates that \u003cstrong\u003e25\u0026acute;\u003c/strong\u003e is more stable than \u003cstrong\u003e3-\u003c/strong\u003e\u003cstrong\u003eepi\u003c/strong\u003e\u003cstrong\u003e-25\u0026acute;\u003c/strong\u003e by 3.25 kcal/mol. In \u003cstrong\u003e25\u0026acute;\u003c/strong\u003e, the optimized structure shows that the piperidine is in a chair conformation, with the hydroxyethyl group at C15 in an equatorial position. However, in \u003cstrong\u003e3-\u003c/strong\u003e\u003cstrong\u003eepi\u003c/strong\u003e\u003cstrong\u003e-25\u0026acute;\u003c/strong\u003e, the piperidine adopted a boat conformation to avoid the 1,3-diaxial interactions between the hydroxyethyl group and H3/H21\u003cem\u003e\u0026beta;\u003c/em\u003e, resulting in a 3.25 kcal/mol increase in free energy. When the ketone in \u003cstrong\u003e25\u0026acute;\u003c/strong\u003e was changed to an ethylidene group, the conformational preferences also changed: the 1,3-allylic strain is dominant over the 1,3-diaxial interactions, causing the hydroxyethyl group at C15 to adopt an axial position. In this case, only when H3 and H15 are in a \u003cem\u003etrans\u003c/em\u003e orientation could the piperidine maintain a chair conformation. Thus, the calculations indicate that \u003cstrong\u003e27\u003c/strong\u003e has a 3.38 kcal/mol lower free energy than \u003cstrong\u003e3-\u003c/strong\u003e\u003cstrong\u003eepi\u003c/strong\u003e\u003cstrong\u003e-27\u003c/strong\u003e, supporting the experimentally observed epimerization. Moreover, we also evaluated the free energy of C7 epimers and the result show that the free energy of \u003cstrong\u003e28\u003c/strong\u003e was higher than \u003cstrong\u003e27\u003c/strong\u003e by 0.72 kcal/mol, supporting the experimental results in which \u003cstrong\u003e27\u003c/strong\u003e is the thermodynamically favored product. This could be attributed to the stabilizing effect of an intramolecular hydrogen bond between the oxindole carbonyl and the protonated N4 in acidic condition.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eBased on the observed epimerization of C3 in two different synthetic routes (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea and \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb), along with the comparison of the NMR data of synthetic and natural samples, X-ray crystallographic structures and DFT calculations, it suggests that the relative configurations for \u003cstrong\u003e27\u003c/strong\u003e and \u003cstrong\u003e28\u003c/strong\u003e represent the correct ones of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole and 7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole, respectively.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, a reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization was developed to construct tetracyclic spirooxindole system with pyridinium. Chemo-selective dearomatization of the pyridinium moiety using PtO\u003csub\u003e2\u003c/sub\u003e/H\u003csub\u003e2\u003c/sub\u003e and NaBH\u003csub\u003e4\u003c/sub\u003e respectively furnished the spiro[indolizidine-1,3\u0026acute;-oxindole] skeleton with regioselective establishment of the hydroxy group. Subsequently, the hydroxy group was further utilized as either a tether to introduce the carbene precursor thereby achieving the formal synthesis of rhynchophylline/isorhynchophylline, or was converted to the ethylidene group for the total synthesis of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole/7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole. Moreover, the structures of geissoschizol oxindoles were revised to the H3, H15-\u003cem\u003etrans\u003c/em\u003e epimers according to NMR spectrum, crystallographic structures and DFT calculations. Our synthesis provides an illustrative example that the spirooxindole alkaloids are prone to undergo epimerization to adopt a thermodynamically favored configuration and demonstrates that the retro-Mannich/Mannich cascade is an inherent process in the total synthesis of spirooxindole alkaloids. In addition, this study showcases the power of rearrangement cascades for the assembly of the polycyclic skeletons present in complex natural products. Further explorations into the enantioselective rearrangement cascades are underway in the lab.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eGeneral methods\u003c/p\u003e \u003cp\u003eReactions were monitored by UPLC/MS and thin layer chromatography (TLC) and visualization was accomplished with a 254 nm UV light and by staining with phosphomolybdic acid solution with heating. All Flash silica gel column chromatography was performed using silica gel with particle size of 300\u0026ndash;400 mesh. \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH and \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003eC NMR spectra were recorded on Varian Inova-400 spectrometers. Data for \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH NMR spectra are reported relative to CDCl\u003csub\u003e3\u003c/sub\u003e (7.26 ppm), CD\u003csub\u003e3\u003c/sub\u003eOD (3.31 ppm), or DMSO-d\u003csub\u003e6\u003c/sub\u003e (2.50 ppm) as an internal standard and are reported as follows: chemical shift (\u003cem\u003eδ\u003c/em\u003e ppm), multiplicity (\u003cem\u003es\u003c/em\u003e\u0026thinsp;=\u0026thinsp;singlet, \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;doublet, \u003cem\u003et\u003c/em\u003e\u0026thinsp;=\u0026thinsp;triplet, \u003cem\u003eq\u003c/em\u003e\u0026thinsp;=\u0026thinsp;quartet, \u003cem\u003esept\u003c/em\u003e\u0026thinsp;=\u0026thinsp;septet, \u003cem\u003em\u003c/em\u003e\u0026thinsp;=\u0026thinsp;multiplet, \u003cem\u003ebr\u003c/em\u003e\u0026thinsp;=\u0026thinsp;broad), coupling constant \u003cem\u003eJ\u003c/em\u003e (Hz), and integration. Data for \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003eC NMR spectra are reported relative to CDCl\u003csub\u003e3\u003c/sub\u003e (77.00 ppm), CD\u003csub\u003e3\u003c/sub\u003eOD (49.00 ppm), DMSO-d\u003csub\u003e6\u003c/sub\u003e (39.52 ppm) as an internal standard and are reported in terms of chemical shift (\u003cem\u003eδ\u003c/em\u003e ppm). UPLC-MS analyses were performed on a Waters system (Column: BEH C18, 1.7 \u0026micro;m, 2.1*50 mm) with a Photodiode Array (PDA) detector and a Single Quadrupole (SQ) detector. High Resolution Mass spectra were obtained from on an Agilent 1290 LC-6540 QTOF Mass Spectrometer or an Agilent Technologies 7250 GCQTOF. HPLC analyses were carried out on Waters (Column Atlanits\u0026reg; HILIC Silica, 5 \u0026micro;m, 4.6*150 mm and 19*150 mm) with 2998PDA and 3100MS detectors.\u003c/p\u003e \u003cp\u003eFor NMR spectra of synthetic intermediates, see Supplementary Figures. For the experimental procedures and spectroscopic and physical data of compounds and the crystallographic data of compound \u003cb\u003e3g\u003c/b\u003e, \u003cb\u003e10\u003c/b\u003e, \u003cb\u003e15\u003c/b\u003e, \u003cb\u003e23\u003c/b\u003e, \u003cb\u003e27\u003c/b\u003e and \u003cb\u003e28\u003c/b\u003e see Supplementary Methods.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that all the data supporting this study, including the experimental procedures and compounds characterization, see Supplementary Files. All data are also available from the unstructured public depository figshare. (https://figshare.com/articles/dataset/Total_Synthesis_of_Tetracyclic_Spirooxindole_Alkaloids_via_a_Double_Oxidative_Rearrangement_Cyclization_Cascade/23849226). Energy data for the calculated structures are available in Supplementary Data. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers \u003cstrong\u003e3g\u003c/strong\u003e (CCDC 2282680), \u003cstrong\u003e10\u003c/strong\u003e (CCDC 2282806), \u003cstrong\u003e15\u003c/strong\u003e (CCDC 2282684), \u003cstrong\u003e23\u003c/strong\u003e (CCDC 2283109), \u003cstrong\u003e27\u003c/strong\u003e (CCDC 2283107), and \u003cstrong\u003e28\u003c/strong\u003e (CCDC 2283108). These data are provided free of charge by the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (21971018 and 82225041). The authors gratefully acknowledge the Beijing Municipal Government and Tsinghua University for the financial support. We thank Dr. Toh-Seok Kam and Dr. Yun-Yee Low from Universiti Malaya for graciously providing us with the original samples of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole and 7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole. We thank Songlin Bai for the support on DFT calculations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.Q. conceived the study; X.W. and M. Z. carried out most of the chemical synthesis; X.L. and M.L. helped synthesize some of the substrates; X.W., and X.Q. prepared the manuscript; X.W. collected the data and prepared the supplemental information; X.W., M.Z., X.L., M.L. and G.L. analyzed the data; All authors discussed the results and commented on the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence and requests for materials\u003c/strong\u003e should be addressed to Xiangbing Qi.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVitaku E, Smith DT, Njardarson JT. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257\u0026ndash;10274 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe S, \u003cem\u003eet al.\u003c/em\u003e Pyridine: the scaffolds with significant clinical diversity. 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Perkin Trans. \u003cem\u003e2\u003c/em\u003e, 1931\u0026ndash;1936 (1996).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3336630/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3336630/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePiperidine and pyridine are the most significant structural components of bioactive molecules. Aza-Achmatowicz rearrangement is a broadly appliable approach to access piperidine or pyridine derivatives owing to the easily adjustable electronic properties of the amino group. When combined with other chemical transformations, such as nucleophilic cyclization or cycloaddition, it provides entries to a variety of polycyclic skeletons present in naturally-derived alkaloids. Herein, we developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole/7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole. The reaction cascade has a broad substrate scope, with a variety of substitutions on the indoles and furans. Other innovative features include the chemo-selective dearomatization of the pyridinium moiety to form the C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-enriched, three-dimensional spiro[indolizidine-1,3\u0026acute;-oxindole] skeleton and a late-stage, regio- and stereoselective carbene insertion into a C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-H bond that enabled the successful installation of the adjacent carbon functionality for rhynchophylline and isorhynchophylline. In addition, 7(\u003cem\u003eR\u003c/em\u003e)-geissoschizol oxindole/7(\u003cem\u003eS\u003c/em\u003e)-geissoschizol oxindole were revised to their C-3 epimers and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by the DFT calculations.\u003c/p\u003e","manuscriptTitle":"Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-20 23:26:55","doi":"10.21203/rs.3.rs-3336630/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0a7d1897-145b-4b2b-9287-bbf777997a4e","owner":[],"postedDate":"September 20th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":24851954,"name":"Physical sciences/Chemistry/Chemical synthesis/Natural product synthesis"},{"id":24851955,"name":"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2023-10-19T07:45:13+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-20 23:26:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3336630","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3336630","identity":"rs-3336630","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}