Diversity-Oriented Enantioselective Construction of Atropisomeric Heterobiaryls and N -Aryl Indoles via Vinylidene Ortho -Quinone Methides

Open AccessCCS ChemistryRESEARCH ARTICLE5 Aug 2022Diversity-Oriented Enantioselective Construction of Atropisomeric Heterobiaryls and N-Aryl Indoles via Vinylidene Ortho-Quinone Methides Da Xu†, Shengli Huang†, Fangli Hu, Lei Peng, Shiqi Jia, Hui Mao, Xiangnan Gong, Fenglan Li, Wenling Qin and Hailong Yan Da Xu† Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 †D. Xu and S. Huang contributed equally to this work.Google Scholar More articles by this author , Shengli Huang† Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 †D. Xu and S. Huang contributed equally to this work.Google Scholar More articles by this author , Fangli Hu Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 Google Scholar More articles by this author , Lei Peng Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 Google Scholar More articles by this author , Shiqi Jia Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 Google Scholar More articles by this author , Hui Mao College of Pharmacy, Jinhua Polytechnic, Jinhua, Zhejiang Province 321007 Google Scholar More articles by this author , Xiangnan Gong Analytical and Testing Center of Chongqing University, Chongqing University, Chongqing 401331 Google Scholar More articles by this author , Fenglan Li Anqiu Women and Children’s Hospital, Anqiu, Shandong Province 262102 Google Scholar More articles by this author , Wenling Qin Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 Google Scholar More articles by this author and Hailong Yan *Corresponding author: E-mail Address: [email protected] Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101154 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail An atroposelectively diversity-oriented synthetic strategy was developed for the divergent synthesis of axially chiral heterocycles through organocatalytic asymmetric intramolecular annulation of alkyne via vinylidene ortho-quinone methides ( VQMs). The methodology reported herein was characterized by rapid reactions (most completed in seconds), high stereocontrol (up to 98% ee), and broad substrate scope (60 examples of different skeletal types, stereogenic elements, and ring sizes). With this methodology, a vast array of axially chiral heterobiaryls bearing silicon, oxygen, nitrogen, and boron heterocycles were successfully constructed with high efficiency and stereoselectivities. In addition, different stereogenic elements, including the C–C and C–N, were successfully formed atroposelectively. This method was applicable to the synthesis of axially chiral heterocycles with different ring sizes as well (five-, six-, and seven-membered rings). More importantly, the stereodivergent synthesis of the axially chiral aryl-indole framework bearing both stereogenic C–C and C–N axes was achieved with a single organocatalyst and simple starting materials. Download figure Download PowerPoint Introduction Atropisomeric heterobiaryl motifs are commonly found in natural products,1,2 pharmaceuticals, and bioactive molecules.3 They are also used as ligands or organocatalysts in asymmetric reactions.4,5 Thus, the stereoselective construction of axially chiral heterobiaryl motifs is important in synthetic organic chemistry and other fields. To date, the catalytic asymmetric construction of axially chiral heterobiaryl scaffolds has involved asymmetric cross-coupling,6,7 C–H arylation,8,9 transformations of prochiral or racemic heterobiaryls through C–H activation,10–13 desymmetrization,14–17 (dynamic) kinetic resolution,18–21 central-to-axial chirality transfer,22–24 and ring construction.25–32 In the reports about these processes, the case-by-case substrate preparation and corresponding asymmetric catalytic model were only applicable to the synthesis of atropisomeric heterobiaryl motifs containing specific heteroatoms (such as oxygen or nitrogen) or rings of a certain size. In contrast, the diversity-oriented synthesis (DOS) strategy33,34 that we report here represents the most powerful synthetic method for the collective preparation of small-molecule libraries with the structural diversity from similar substrates and catalytic systems. Therefore, a DOS of atropisomeric heterobiaryl motifs consisting of different heteroatom elements/ring sizes and different types of stereogenic axes is highly appealing since it can further enrich molecular complexity and diversity. In past years, in situ-generated chiral vinylidene ortho-quinone methides35–43 ( VQMs) have been demonstrated as a privileged intermediate for accessing diverse enantiomerically pure architectures. We speculated that its electrophilic position 4 could be utilized to undertake an intramolecular annulation with a variety of nucleophilic heteroatoms to form different types of axially chiral heterocycles. Moreover, through controlling the chain length between heteroatoms and the preinstalled rings, five-, six-, and seven-membered axially chiral heterocycles could be afforded (Schemes 1a–1c), thus realizing the DOS of diverse atropisomeric heterobiaryl skeletons. Herein, we report a diversity-oriented organocatalytic asymmetric intramolecular annulation reaction to access a variety of atropisomeric heterobiaryl motifs. This report provides a diverse synthetic method to construct up to five types of axially chiral heterobiaryl motifs containing different skeletons (benzo[c][1,2]oxasilines, isocoumarins, and indoles), ring sizes (five-, six-, and seven-membered rings) and different types of axial chirality (C–C and C–N axial chirality). Moreover, most reactions were completed within 1 min. This is an extremely rare instance of organocatalytic asymmetric transfomation completed within seconds with excellent stereocontrol. Scheme 1 | (a–c) Axially chiral heterobiaryl molecules and reaction development. Download figure Download PowerPoint Experimental Methods Synthesis of (R)-2 by asymmetric intramolecular annulation 1 (0.1 mmol, 1.0 equiv), N-Iodosuccinimide (NIS) (0.11 mmol, 1.1 equiv), and catalyst E (0.01 mmol, 10 mol %) in the mixed solvents CH3CN/CH3OH (4:1 vol/vol, 1.0 mL) at 25 °C for 1 min. After completion of the reaction [monitored by thin-layer chromatography (TLC)], the solution was directly purified by flash column chromatography (Petroleum ether (PE)/acetone, 10:1 vol/vol) to afford product (R)- 2. Synthesis of (S)-4 by asymmetric intramolecular annulation 3 (0.1 mmol, 1.0 equiv), NIS (0.11 mmol, 1.1 equiv), and catalyst D (0.01 mmol, 10 mol %) in CH2Cl2 (4.0 mL) at −45 °C for 3 min. After completion of the reaction (monitored by TLC), the solution was directly purified by flash column chromatography (PE/acetone, 10:1 vol/vol) to afford product (S)- 4. Synthesis of (1R,2S)-6 by asymmetric intramolecular annulation 5 (0.1 mmol, 1.0 equiv), NIS (0.11 mmol, 1.1 equiv), and catalyst C (0.01 mmol, 5 mol %) in toluene (2.0 mL) at 90 °C for 1 min. After completion of the reaction (monitored by TLC), the solution was directly purified by flash column chromatography (PE/CH2Cl2, 4:1 vol/vol) to afford product (1R,2S)- 6. Results and Discussion As a continuation of our interest in developing VQM chemistry for asymmetric synthesis, diverse heteroatoms were designed as nucleophiles to implement an intramolecular attack of VQM intermediates to furnish diverse axially chiral heterobiaryls. First, nucleophilic silanol was used to construct silicon-containing six-membered heterocycle 2a via intramolecular annulation reaction (Table 1). Organosilicon is the key structural motif predominantly found in the fields of synthetic chemistry,44 materials chemistry,45 and pharmaceutical chemistry.46 Particularly, chiral organosilicon compounds are famous for their unique properties as carbon isosteres in pharmaceutical chemistry. Despite the fact that enormous effort has been dedicated to the enantioselective construction of organosilicon compounds bearing a stereogenic center,47 to the best of our knowledge, synthetic methods for the atroposelective construction of axially chiral silicon-containing heterobiaryls have not been investigated yet. Herein, we report the atroposelective construction of axially chiral silicon-containing heterobiaryls through intramolecular annulation of VQM intermediates. Table 1 | Optimization of the Reaction Conditionsa Entry Catalyst Solvent Yield (%)b ee (%)c 1 A Toluene 97 2 2 B Toluene 95 3 3 C Toluene 97 14 4 D Toluene 96 14 5 E Toluene 97 54 6 E CH2Cl2 78 −22 7 E CHCl3 85 −34 8 E EA 95 −11 9 E CH3CN 98 86 10 E CH3OH 97 81 11 E C2H5OH 95 76 12d E CH3CN/CH3OH 97 88 13e E CH3CN/CH3OH 97 92 14f E CH3CN/CH3OH 97 86 aReaction conditions: 1a (0.1 mmol, 1.0 equiv), catalyst (0.01 mmol, 10 mol %), and NIS (0.11 mmol, 1.1 equiv) in solvent (1.0 mL) at 25 °C for 1 min. bYields of isolated products. cThe ee values were determined by high-performance liquid chromatography (HPLC) analysis. dCH3CN/CH3OH (19∶1, 1.0 mL). eCH3CN/CH3OH (4∶1, 1.0 mL). fCH3CN/CH3OH (1∶4, 1.0 mL). First, a series of chiral Brønsted base catalysts at 10 mol % were examined for the annulation reaction with silanol 1a as the substrate, followed by the addition of NIS as the bulky electrophile. Quinine-derived thiourea bifunctional catalyst A was initially investigated (Table 1). The reaction went smoothly to give the desired atropisomeric silicon-containing heterobiaryl 2a in a high yield within an extremely short time (1 min), albeit only 2% ee was obtained (Table 1, entry 1). Next, we decided to test some cinchona-squaramide catalysts, which have been successfully applied in a wide range of asymmetric reactions as hydrogen-bond donor catalysts. Cinchona-squaramide catalysts B– D were screened (Table 1, entries 2–4) and delivered higher enantiomeric excess with similar reaction yields. This occurred despite the fact that squaramide-derived catalyst E gave the better enantioselectivity, which was still not satisfactory (Table 1, entry 5). To further improve the enantioselectivity, a series of solvents were screened. Disappointingly, product 2a was obtained in lower enantioselectivity in fewer polar solvents such as dichloromethane (CH2Cl2), chloroform, and ethyl acetate (EA) (Table 1, entries 6–8). Next, we turned our attention to examine some polar solvents. Acetonitrile was demonstrated to be able to increase the enantioselectivity and yield of this transformation (Table 1, entry 9). Methanol and ethanol showed no improvement in the reaction performance (Table 1, entries 10 and 11). Encouraged by the significant improvement in enantioselectivity after the solvent optimization, we further tested some combined solvent systems. To our delight, the reaction went smoothly with improved ee values by the combination of acetonitrile and methanol according to a proper ratio (Table 1, entries 12–14). Thus, the optimal reaction conditions were identified as 1a (0.1 mmol, 1.0 equiv), NIS (0.11 mmol, 1.1 equiv), and catalyst E (0.01 mmol, 10 mol %) in the mixed solvents of acetonitrile/methanol (4:1 vol/vol, 1.0 mL) at 25 °C for 1 min (Table 1, entry 13; see Supporting Information Table S1 for details). With the optimal reaction conditions in hand, we explored the generality of different R1 groups at substrate 1. Substrates with electron-donating groups such as methyl and methoxyl at different positions successfully afforded products 2b– 2d with high yields and good enantioselectivities (up to 94% yield, 95% ee, Table 2). Next, a variety of electron-withdrawing groups were installed at different positions of substrates 1e– 1h. Products 2e– 2h were obtained in high yields with up to 95% ee, indicating that substituents with different electron properties or different positions of phenyl ring had no influence on the yields or enantioselectivities. Next, a series of R2 groups at naphthol were evaluated. When R2 groups were phenyl and substituted phenyl groups, products 2i– 2l were successfully formed in up to 94% yield with up to 95% ee (Table 2). Meanwhile, bromide, ethyl, and methoxyl groups were also demonstrated as suitable R2 groups at the naphthol part of the substrates and gave products 2m– 2p with high yields and up to 94% ee. Replacing the naphthyl with quinoline scaffold, the corresponding substrate 1q successfully gave product 2q in high yield with 90% ee. It is worth noting that when the R3 group was methyl substituted, product 2r was successfully afforded in 81% yield with decreased enantioselectivity (78% ee). The structure of 2n was confirmed by X-ray single-crystal diffraction, and its absolute configuration was determined by circular dichroism spectroscopy (see Supporting Information Figures S5 and S6 for details). The structures and absolute configurations of other products were deduced analogously. Table 2 | Substrate Scopea aReaction conditions: 1 (0.1 mmol, 1.0 equiv), NIS (0.11 mmol, 1.1 equiv), and catalyst E (0.01 mmol, 10mol %) in the mixed solvents of CH3CN/CH3OH (4∶1, 1.0 mL) at 25 °C for 1 min. Isolated yields. The ee values were determined by HPLC analysis. To investigate the scope of this DOS strategy via de novo construction of heterocycles in an axially chiral skeleton, we explored the protocol for atroposelective formation of axially chiral oxygen-containing heterobiaryls via intramolecular annulation. We envisioned that o-alkynylbenzamides could be suitable substrates for a nucleophilic O-attack to VQM intermediates for furnishing six-membered oxygen-containing heterocycles named isocoumarin-1-imines. Isocoumarin derivatives are interesting oxygen-containing heterocycles, widely found in a variety of natural products, biologically active compounds, and pharmaceuticals with significant bioactivities,48 and chiral architectures bearing an isocoumarin moiety would be attractive for activity investigations. Preliminary attempts were carried out with o-alkynylbenzamide 3a as the substrate in the presence of NIS and catalyst D. To improve the enantioselectivity and yield of this reaction, we optimized reaction parameters and identified the best conditions as follows: 3a (0.1 mmol, 1.0 equiv), catalyst D (0.01 mmol, 10 mol %), and NIS (0.11 mmol, 1.1 equiv) in CH2Cl2 (4.0 mL) at −45 °C for 3 min (see Supporting Information Table S2 for details). Product 4a was formed in 97% yield with 94% ee under the optimal reaction conditions. With the optimal conditions in hand, we started the substrate scope investigation by exploring the generality for different R1 groups at the phenyl part of substrate 3. Products 4b– 4d were obtained in high yields with excellent enantioselectivities (up to 96% ee, Table 3). Direct hydrolysis of 4b with acidic condition produced a lactone 11 in 85% yield. Next, substitution groups (R2) at the naphthol moiety of the substrate were also found to be suitable for our reaction system and gave corresponding adducts 4e– 4f in high yields (96% yield) with excellent enantioselectivities (up to 97% ee, Table 3). Furthermore, we investigated different N-substitution groups (R3) at substrates 3. N-methyl-substituted substrate 3g was tolerated to the above reaction conditions and gave product 4g in 95% yield with 86% ee. Moreover, R3 substituents with different electrophicities at ortho, meta, and para positions of phenyl ring on nitrogen atom of substrates 3h– 3q were successfully used as the substrates to afford products 4h– 4q with high yields and enantioselectivities (up to 98% yields, 90% ee, Table 3). The absolute configuration of 4q was determined by X-ray crystallographic analysis and other products were assigned analogously (see Supporting Information Figure S7 for details). Table 3 | Substrate Scopea aReaction conditions: 3 (0.1 mmol, 1.0 equiv), catalyst D (0.01 mmol, 10 mol %), and NIS (0.11 mmol, 1.1 equiv) in CH2Cl2 (4.0 mL) at −45 °C for 3 min. Condition A: 4b (0.2 mmol, 1.0 equiv), HCl (1.0 M, 1.2 mL) in tetrahydrofuran (THF) (6.0 mL) was heated at reflux for 5 h. Isolated yields. The ee values were determined by HPLC analysis. Axially chiral N-aryl indole systems represent novel architectures displaying significant properties in asymmetric synthesis and medicinal chemistry.49 To further demonstrate the broad application of this DOS strategy, we applied our methodology in the atroposelective preparation of axially chiral nitrogen-containing heterobiaryls with amine as the nucleophile for the construction of aryl-indole skeletons. To obtain an axially chiral naphthyl-indole scaffold bearing C–N axis, we designed 2-alkynylnaphthol bearing a secondary aniline with a bulky substitution ( 5a) as the substrate to furnish an intramolecular annulation in one step to construct two types of axially chiral elements. Despite great effort has been devoted to enantioselectively synthesis of atropisomers.50–54 Stereoselective methods toward the preparation of individual compound with multiple stereogenic axes are highly desirable.55–63 As a result, with 5a as the substrate and NIS as the iodation agent, the reaction proceeded smoothly to give the corresponding product 6a bearing both C–C and C–N axes in good yield by using cinchona-squaramide catalysts. After screening reaction conditions, catalyst C was identified as the optimal catalyst, and high enantioselectivity was achieved with toluene as the solvent at 25 °C (Table 4a, entry 10), albeit the diastereoselectivity of the transformation was not satisfactory (dr = 7∶1) under current reaction conditions. To improve the diastereoselectivity of this reaction, according to the usual strategy, we decreased the reaction temperature to −20 °C. However, to our disappointment, the diastereomeric ratio of the products was changed from 7∶1 to 1∶2, and the major diastereomer was determined to be (1R,2R)- 6a by X-ray crystallographic analysis. To our surprise, however, when the reaction temperature was raised to 90 °C, the dr value was increased to 27∶1, and in this case the structure of the major diastereomer was assigned to be (1R,2S)- 6a by X-ray crystallographic analysis. Even the catalyst loading decreased to 5 mol %, and the desired asymmetric annulation proceeded smoothly (95% yield, 94% ee, dr > 20∶1) (see Supporting Information Table S3 for details). This result revealed that in the presence of catalyst C, remarkable stereoselectivity for C–N axis formation could be achieved through adjusting the reaction temperature. Next, enantiomerically pure (1R,2S)- 6a was isolated from the reaction mixture and subjected to different conditions to test its optical stability. Indeed, (1R,2S)- 6a was demonstrated to be stable at 90 °C, but it could be converted into (1S,2S)- 6a when the temperature rose to 110 °C. Interestingly, catalyst C could dramatically accelerate this conversion process [kD/kC = 6.8∶1, (see Supporting Information Figure S3 for details)], indicating that the C–N axis was more thermodynamically stable than C–C axis. The absolute configurations of the C–C axis were interchangeable at 110 °C. These remarkable results enabled us to develop a method for arbitrary access to four isomers with a single organocatalyst by controlling the reaction temperature and a facile treatment of isolated products. Table 4 | Optimization of the Reaction Conditionsa aReaction conditions: 5a (0.1 mmol, 1.0 equiv), catalyst (0.01 mmol, 10 mol %), and NIS (0.11 mmol, 1.1 equiv) in solvent (2.0 mL) at 25 °C for 1 min. bYields of isolated products. cThe ee values were determined by HPLC analysis. dThe dr was determined by 1H NMR. Inspired by the foregoing phenomena (Schemes 2a and 2b), we attempted to test whether all stereoisomers could be obtained through a single organocatalyst. Indeed, product (1R,2S)- 6a could be enantioselectively prepared from substrate 5a under Condition A at 90 °C in 95% yield with 94% ee. Isomer (1S,2S)- 6a could be afforded in 41% yield over two steps with good enantioselectivity (95% ee; Condition A, and then Condition D; Scheme 2c). Next, (1R,2R)- 6a could be obtained from substrate 5a in a moderate yield (58%) at −20 °C with excellent enantiopurity (91% ee; Condition B, Scheme 2c). Moreover, isomer (1S,2R)- 6a could be obtained in 30% yield over two steps with good enantioselectivity (91% ee; Condition B, and then Condition C, Scheme 2c) (See Supporting Information Figure S1 for details). The absolute configuration of each product was confirmed by X-ray crystallographic analysis (see Supporting Information Figure S8–S11 for details). Thus, a predictable and practical procedure for the access of specific isomers bearing both C–C and C–N stereogenic axes was realized by using a single organocatalyst. To the best of our knowledge, most of the available procedures for accessing each diastereomer from products bearing multiple stereogenic elements depend on each elaborated catalyst or the appropriate combination of two different catalysts.64,65 Scheme 2 | (a–c) Stereodivergent synthesis. Download figure Download PowerPoint After the optimization of reaction conditions and the exploration of the efficiency of our catalyst in the stereoselective preparation of each single isomer of products, the scope and limitations of this transformation were evaluated. First, a series of substituted phenyl groups (R2) were installed into the seven-position of naphthol in substrates 5b– 5i. Products 6b– 6i were obtained in high yields with up to 97% ee, and the diastereoselectivities were excellent as well (dr > 20∶1). Notably, heterocycles such as thiophene could also be attached to the seven-position of naphthol and give the desired product 6j with high yield and stereoselectivity. Substrates with different substituted phenyl groups (R2) at the six-position of naphthol underwent cyclization smoothly to give products 6k– 6o in high yields (up to 98%, Table 5). Meanwhile, high stereoselectivities were obtained (up to 96% ee, dr > 20∶1). Substrates bearing the substituents R1 with different electronic properties and positions took part in the transformation ( 6p– 6t), and R1, R2 di-substituted substrates were tolerated under the reaction conditions and afforded products 6u– 6w with high yields and stereoselectivities (up to 97% ee, dr > 20∶1). After the exploration of the substrate scope of this DOS strategy for the construction of three types of axially chiral heterobiaryls, we performed several experiments to further demonstrate the practicability of current methodology. The catalysis efficiency and the facile operation process of this reaction were evaluated by continuous loading of starting materials. To our delight, the catalyst was still efficient, and product (1R,2S)- 6a was afforded with 81% ee after six continuous feedings of substrate 5a and NIS (Scheme 3a). This preliminary study demonstrated the potential of our method in a continuous flow process for the production of axially chiral heterocycles (see Supporting Information Figure S2 for details). To explore the application scope of our method, a gram-scale reaction of substrates with NIS under standard reaction conditions was performed (Scheme 3b). Highly stereoretentive transformations from 1i to (R)- (91% yield and ee), from to (S)- 4b yield and 95% ee), and from 5a to (1R,2S)- 6a yield and 94% were To further explore the generality of this divergent synthetic strategy, we constructed more axially chiral architectures (Scheme First, heterobiaryl was successfully formed and atroposelectively installed into an axially chiral and product (S)- 8 was obtained in yield with ee (see Supporting Information Table for details). an axially chiral seven-membered was successfully via an asymmetric intramolecular annulation and product (R)- 10 was afforded in yield with satisfactory enantiopurity (see Supporting Information Table S5 for details). Table 5 | Substrate Scopea aReaction conditions: 5 (0.1 mmol, 1.0 equiv), catalyst C mmol, 5 mol %), and NIS (0.11 mmol, 1.1 equiv) in toluene (2.0 mL) at 90 °C for 1 min. of isolated products. The ee values were determined by HPLC and the dr was determined by 1H analysis of the reaction Scheme 3 | (a–c) Download figure Download PowerPoint To an into the reaction we performed experiments to the reaction After the groups of the compounds and were to the formation of VQM the corresponding substrates were not able to afford the axially chiral in the presence of the catalyst and NIS (see Supporting Information Figure for details). These results that VQM intermediates were involved in the reaction and a key in this atroposelective We have developed an atroposelectively diversity-oriented synthetic for a variety of axially chiral heterobiaryls through organocatalytic asymmetric intramolecular annulation of VQM intermediates with nucleophilic This method not and products with a broad range of different skeletal Axially chiral heterobiaryls containing oxygen, nitrogen, and heterobiaryls were successfully constructed with high efficiency and stereoselectivities. Moreover, stereogenic C–C and C–N axes were also atroposelectively constructed with this methodology. this method was applicable to construct axially chiral heterobiaryls in different ring Particularly, the stereoselective access of each four isomers in a chiral structure bearing both stereogenic C–C and C–N axes was achieved with only one organocatalyst. In addition, the conditions and extremely short reaction time its application in continuous flow for The of this divergent atroposelective method in the synthesis of biologically active compounds and of natural products as well as other axially chiral heterobiaryls with different ring sizes are in our Supporting Information Supporting Information is available and and of is no of interest to Information was by the Zhejiang Natural of the of and and the for the 1. Synthesis of Axially Natural Google Scholar 2. of an from a Google Scholar 3. S. in and Google Scholar 4. in Google Scholar the of of with by a