Pentanidium-Catalyzed Direct Assembly of Vicinal All-Carbon Quaternary Stereocenters through C(sp 3 )–C(sp 3 ) Bond Formation

Open AccessCCS ChemistryRESEARCH ARTICLE1 Oct 2021Pentanidium-Catalyzed Direct Assembly of Vicinal All-Carbon Quaternary Stereocenters through C(sp3)–C(sp3) Bond Formation Xu Ban, Yifan Fan, Tuan-Khoa Kha, Richmond Lee, Choon Wee Kee, Zhiyong Jiang and Choon-Hong Tan Xu Ban International Scientific and Technological Cooperation Base of Chiral Chemistry, Henan University, Kaifeng 475004 Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore 637371 Google Scholar More articles by this author , Yifan Fan International Scientific and Technological Cooperation Base of Chiral Chemistry, Henan University, Kaifeng 475004 Google Scholar More articles by this author , Tuan-Khoa Kha Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore 637371 Google Scholar More articles by this author , Richmond Lee School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522 Molecular Horizons, University of Wollongong, Wollongong, NSW 2522 Google Scholar More articles by this author , Choon Wee Kee Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore 637371 Process & Catalysis Research, Institute of Chemical and Engineering Sciences, Singapore 627899 Google Scholar More articles by this author , Zhiyong Jiang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] International Scientific and Technological Cooperation Base of Chiral Chemistry, Henan University, Kaifeng 475004 Google Scholar More articles by this author and Choon-Hong Tan *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore 637371 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101013 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The stereoselective construction of vicinal all-carbon quaternary stereocenters has long been a formidable synthetic challenge. Direct asymmetric coupling of a tertiary carbon nucleophile with a tertiary carbon electrophile is the most straightforward approach, but it is sterically and energetically disfavored. Herein, we describe a catalytic asymmetric substitution, where racemic tertiary bromides coupled directly with racemic secondary or tertiary carbanion, creating a series of congested C(sp3)–C(sp3) bonds, including isolated all-carbon quaternary stereocenters, vicinal tertiary/all-carbon quaternary stereocenters and vicinal all-carbon quaternary stereocenters. Using pentanidium as a catalyst, this double stereoconvergent process afforded substituted products in good enantioselectivities and diastereoselectivities. Download figure Download PowerPoint Introduction The use of high-throughput synthetic practices in tandem with extensive use of Pd-coupling chemistry in medicinal chemistry laboratories worldwide has led to a propensity of achiral, aromatic compounds in screening libraries.1 Many secondary metabolites with interesting pharmacological activities contain all-carbon quaternary stereocenters.2–4 Introducing all-carbon quaternary stereocenters into molecules will improve structural diversities in screening libraries. However, the stereoselective construction of all-carbon quaternary stereocenters remains a significant challenge in synthetic chemistry.5,6 Among the limited number of strategies employed in forming this highly congested moiety, double Heck coupling,7,8 double Aldol reaction,9 and double allylation10 have been reported to be useful (Figure 1a). In contrast, using multisubstituted alkenes in [3+2] annulation,11,12 Diels–Alder,13–15 and other cycloadditions16,17 is another common approach (Figure 1a). Recent advances include dearomatization addition of β-naphthols on 3-bromooxindoles,18 Claisen rearrangement of γ,δ-unsaturated carbonyl compounds,19 dialkylation of bisoxindoles,20 phosphine-catalyzed cyclization of allenes,21 and a nucleophilic substitution at a quaternary carbon center with the concurrent opening of a cyclopropane ring.22,23 On the other hand, direct radical coupling of two C(sp3) centers is a promising possibility as it could overcome steric hindrance, but currently, it is limited to a narrow substrates scope such as bisoxindoles and chiral auxiliaries need to be deployed if enantioenriched compounds are required (Figure 1b).24–27 Thus far, there are no successful reports on the preparation of vicinal all-carbon quaternary stereocenters through a catalytic asymmetric coupling of two tertiary C(sp3) centers, which should be the most direct and convenient, and yet, conceivably, the most sterically challenging approach. Nucleophilic substitution at a quaternary carbon center is difficult and improbable to achieve if the nucleophile is also a bulky tertiary carbanion. Figure 1 | (a–c) Major strategies for the construction of vicinal all-carbon quaternary stereocenters. Download figure Download PowerPoint We have been developing chiral cationic salts such as pentanidium ( PN1) and bisguanidinium ( BG1) as phase transfer and ion-pair catalysts.28 Using these catalysts, we recently reported an enantioconvergent halogenophilic nucleophilic substitution (SN2X) to generate enantioenriched quaternary stereocenters using thiols and azides.29–31 In a conventional SN2 substitution, the nucleophile displaces a carbon-bound, leaving group X, often a halogen, by attacking the carbon face opposite the C–X bond; while in the SN2X reaction, the nucleophile approach a carbon-bound leaving group X from the front, making it an ideal sterically-immune synthetic approach. Soon afterward, a more in-depth investigation of the azide substitution with tertiary bromide revealed a dynamic kinetic resolution modulated by a base present in the reaction.32 Herein, we report our recent progress into using nucleophilic substitutions to construct vicinal all-carbon quaternary stereocenters, using insights from our previous reports, through direct coupling of racemic tertiary electrophiles with racemic tertiary nucleophiles using chiral cations as catalysts (Figure 1c). Experimental Methods General procedure for the synthesis of chiral isolated all-carbon quaternary stereocenters The racemic tertiary bromide 1d (1.0 equiv), dimethyl carbonate (1.2 equiv), and BG1 (5 mol %) were dissolved in toluene, cooling down the reaction mixture to −30 °C, and then 4 M aq. KOH was added using a microsyringe. The mixture was stirred at −30 °C for 2–3 days until reaction completion. Thin-layer chromatography (TLC) monitored the process. The reaction was quenched with NH4Cl (1 mL), and then water (10 mL) was added. The organic phase was separated from the aqueous phase using dichloromethane (DCM) extraction. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (hexane:ether = 5:1 as the eluent) to get the chiral isolated all-carbon quaternary stereocenters. General procedure for the synthesis of vicinal tertiary and quaternary stereocenters The racemic tertiary bromide (1.0 equiv), dimethyl carbonate (1.2 equiv), and PN1 (5 mol %) were dissolved in toluene, cooling down the reaction mixture to −20 °C, and then 4 M aq. KOH was added using a microsyringe. The mixture was stirred at −20 °C for 3–4 days until reaction completion. TLC was utilized to monitor the process. The reaction was quenched with NH4Cl (1 mL), and then water (10 mL) was added. Separate the organic phase and extract the aqueous phase with DCM. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (hexane:ether = 5:1 as the eluent) to obtain the chiral vicinal tertiary and quaternary stereocenters. One of the chiral centers which bore an acidic proton was not stable and readily racemized with excess base. After purification, the sample should be kept at −20 °C. General procedure for the synthesis of vicinal all-carbon quaternary stereocenters The racemic tertiary bromide 1d (1.0 equiv), dimethyl carbonate (1.2 equiv), and PN1 (5 mol %) were dissolved in toluene, cooling down the reaction mixture to −20 °C, and then Cs2CO3 (1.5 equiv) was added in one portion. The mixture was stirred at −20 °C for 3–4 days until reaction completion. TLC was utilized to monitor the process. The reaction was quenched with NH4Cl (1 mL), and then water (10 mL) was added. The organic phase was separated from the aqueous phase by DCM extraction. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and membrane filtered to concentrate. The residue was purified by flash chromatography (hexane:ether = 5:1 as the eluent) to obtain the chiral vicinal all-carbon quaternary stereocenters. Results and Discussion Synthesis of isolated all-carbon quaternary stereocenters We began our investigation by extending our previous work on enantioconvergent SN2X substitution. Instead of thiols and azides, we embarked on demonstrating that carbon nucleophiles could add to racemic tertiary bromides. First, methyl 2-bromo-2-cyanoacetate 1a was chosen as the model, and various carbon pronucleophiles were activated by an electron-withdrawing group such as acetophenone isobutyronitrile and 2-nitropropane, were examined under basic conditions (Scheme 1a). We found that only protonated product 1a-H was obtained via a base-mediated SN2X debromination process. Further exploration revealed that carbon pronucleophiles with two electron-withdrawing groups, such as malononitrile and dialkyl malonate, afforded the desired substituted products (Scheme 1b). Scheme 1 | (a and b) Investigation of carbon pronucleophilies addition to racemic tertiary bromides. Download figure Download PowerPoint Subsequently, we found that in the presence of pentanidium PN1- 3 or bisguanidinium BG1- 3 as a catalyst, substituted product 2a was obtained with moderate yields and ee values (Table 1, entries 1–6). Bisguanidinium BG1, bearing 3,5-bis(trifluoromethyl)benzyl groups, provided the most promising results (entry 4). Further optimization by investigating various bases (entries 7 and 8), solvents (entries 9–11), and temperature (entries 12 and 13) revealed that the ideal reaction conditions involved using BG1 as catalyst, 4M aq. KOH (1.5 equiv) as base in toluene at −30 °C. Lowering the reaction temperature further to −40 °C led to a significantly decreased yield due to the formation of increased protonated product 1a-H (entry 13). When methyl ester 1a was changed to ethyl ester 1b, the ee value of adduct 2b improved to 84% (entry 14). Further increase in steric bulk of the tertiary bromides led to the formation of isopropyl ester 2c and tert-butyl ester 2d with even higher ee values (entries 15 and 16; 89% and 95%, respectively). However, changing dimethyl malonate to diethyl malonate or diisopropyl malonate only led to an increased formation of 1a-H, thereby decreasing the yield. Table 1 | Optimization of Reaction Conditions for Isolated all-carbon Quaternary Stereocentersa Entry Catalyst Base Solvent 1 Yield (%)b ee (%)c 1 PN1 K2CO3 Toluene 1a 78 57 2 PN2 K2CO3 Toluene 1a 80 54 3 PN3 K2CO3 Toluene 1a 82 46 4 BG1 K2CO3 Toluene 1a 82 62 5 BG2 K2CO3 Toluene 1a 80 55 6 BG3 K2CO3 Toluene 1a 82 45 7 BG1 Cs2CO3 Toluene 1a 84 62 8 BG1 4M aq. KOH Toluene 1a 85 67 9 BG1 4M aq. KOH Et2O 1a 84 56 10 BG1 4M aq. KOH Tetrahydrofuran 1a 85 25 11 BG1 4M aq. KOH DCM 1a 78 20 12d BG1 4M aq. KOH Toluene 1a 85 75 13e BG1 4M aq. KOH Toluene 1a 47 78 14d BG1 4M aq. KOH Toluene 1b 84 86 15d BG1 4M aq. KOH Toluene 1c 80 89 16d BG1 4M aq. KOH Toluene 1d 78 94 aUnless otherwise noted, reactions were carried out with catalyst (5 mol %), 1a– 1d (0.05 mmol), dimethyl malonate (0.06 mmol), base (0.07 mmol) in the solvent (2 mL) at room temperature. bIsolated yield of 2a– 2d. cDetermined by HPLC using a chiral column. dReactions for 2 days at −30 °C. eReactions for 2 days at −40 °C. Under the ideal set of conditions developed above, various tertiary bromides 3d– 16d were further evaluated (Figure 2). Both electron-withdrawing and -donating groups of the benzyl-substituted substrates were tolerated ( 2e– 2i). Replacing the phenyl group with a naphthyl group, thiophene or pyridine also resulted in good yields and ee values of the adducts 2j and 2k, 2l, (88%, 92%, and 88%, respectively. Tertiary bromides with alkyl groups can afford the desired substituted adducts in good yields and ee ( 2m and 2n, 42% yield, 88% ee, respectively). The reaction was also effective for tertiary bromides bearing allylic or alkene substituents ( 2o– 2q, 13% yield, 74% ee, respectively). Figure 2 | Synthesis of isolated all-carbon quaternary stereocenters. Unless otherwise noted, the reactions were carried out with BG1 (5 mol %), 4M aq. KOH (0.07 mmol), tertiary bromides 3d–16d (0.05 mmol), dimethyl malonate (0.06 mmol) in toluene (2 mL) at −30 °C for 2–3 days. Isolated yields are reported. The ee values were determined by HPLC analysis on the chiral stationary phase. The absolute configuration was determined using an X-ray crystal structure of 2l·HCl (see Supporting Information, page S80). Download figure Download PowerPoint Synthesis of vicinal tertiary/all-carbon quaternary stereocenters Following the success of generating enantioenriched quaternary carbon centers through the addition of dimethyl malonate to racemic tertiary bromides, we wondered if significant diastereoselectivity could be observed if the ester groups on malonates were different. Thus, tertiary ,bromide 1a was treated with ethyl methyl malonate 18a (Table 2, entry 1); it was found, after screening our catalyst library, that PN1 can provide adduct 19a with moderate enantioselectivity and some diastereoselectivity. By introducing iPr ( 18b), Bn ( 18c), or tBu ( 18d) groups to monomethyl malonates to increase steric discrimination, we found that diastereoselectivities increased correspondingly (entries 2–4). However, using ethyl isopropyl malonate 18e did not improve the diastereoselectivity further, and the yield decreased dramatically (entry 5). When ethyl tert-butyl malonate 18f was used, mostly protonated product 1a-H was obtained (entry 6). Thiolate 18g produced the corresponding adduct, but the ee and dr values obtained were moderate (entry 7). Amide 18h was also examined, but no desired adduct was observed (entry 8). Further investigations were conducted with methyl tert-butyl malonate 18d (entries 9–11) by varying different bromides and found 1d gave 19k the best results with 90% ee and 49:1 dr (entry 11). Table 2 | Optimization of Reaction Conditions for Vicinal Tertiary and all-carbon Quaternary Stereocentersa Entry 1 18 Yield (%)b ee (%)c drd 1 1a 18a 87 60 1.2:1 2 1a 18b 82 72 2:1 3 1a 18c 85 55 2:1 4 1a 18d 85 78 4:1 5 1a 18e 60 76 2:1 6 1a 18f Trace — — 7 1a 18g 81 54 4:1 8 1a 18h Trace — — 9 1b 18d 82 84 8:1 10 1c 18d 80 89 9:1 11 1d 18d 80 90 49:1 aUnless otherwise noted, reactions were carried out with PN1 (5 mol %), bromide 1a– 1d (0.05 mmol), malonate 18a–18h (0.0.06 mmol), 4M aq. KOH (0.05 mmol) in toluene (2 mL) at −20 °C for 2 days. bIsolated yield of 19. cDetermined by HPLC using a chiral column. dDetermined HPLC analysis. With these optimized reaction conditions in hand, various tertiary bromides were studied (Figure 3). Tertiary bromides with benzylic substitutions, heterocycles, alkyl, and allylic substituents that were investigated afforded their corresponding adducts 19l– 19s in good yields and stereoselectivity. Figure 3 | Synthesis of vicinal tertiary and all-carbon quaternary stereocenters. Unless otherwise noted, the reactions were carried out with PN1 (5 mol %), 4M aq. KOH (0.05 mmol), tertiary bromides (0.05 mmol), malonate 18d (0.06 mmol) in toluene (2 mL) at −20 °C for 3–4 days. Isolated yields are reported. The dr value was determined by HPLC analysis. The ee values were determined by HPLC analysis on the chiral stationary phase. The absolute configuration was determined using an X-ray crystal structure of a derivative and density functional theory (DFT) calculation (see Supporting Information, page S81). Download figure Download PowerPoint Synthesis of vicinal all-carbon quaternary stereocenter As far as we know, there are no successful reports regarding the formation of vicinal all-carbon quaternary stereocenters through the direct catalytic asymmetric coupling of two C(sp3) centers. After our initial success, we were keen on investigating the formation of vicinal all-carbon quaternary stereocenters using this methodology. When we treated tertiary bromide 1a with 1-ethyl 3-methyl 2-methylmalonate 20 (Scheme 2), we obtained protonated product of 1a-H. This debromination indicated that the SN2X occurred between the bromide 1a and tertiary carbon anion from 1-ethyl 3-methyl 2-methylmalonate 20, while the C–C bond formation was depressed. Similar results were observed when several other tertiary carbon nucleophiles were investigated. Scheme 2 | Testing of tertiary carbon nucleophiles for vicinal all-carbon quaternary stereocenters. Download figure Download PowerPoint Subsequently, we identified cyclic β-ketone ester 21a as a suitable model to study this reaction (Table 3). It allowed the coupling with tertiary bromide 1a to proceed (entry 1). Based on our previous studies, we concluded that the steric effect played a crucial role in enantioselectivity and diastereoselectivity. When we investigated tertiary bromide 1b, we found that it led to an increased yield of protonated product, while with tertiary bromide 1c, no desired product was obtained. On the other hand, changing cyclic β-ketone ester 21 led to more interesting results. When tert-butyl ester 21c was used, both the ee and dr values of the corresponding adduct were increased (Table 3, entries 1–3). We hypothesized that the protonated product could be suppressed by water removal from the reaction condition. Thus, to improve the yield of adduct 22, we needed to choose a more suitable base. We investigated a series of bases ranging from powdered hydroxides salts to carbonates (Table 3, entries 4–10). We found that carbonate salts gave reproducible results with high yields and stereoselectivities; in particular, Cs2CO3 proved to be more reliable (entry 9), yielding ideal reaction conditions at a lower reaction temperature (-20 °C, entry 11). Table 3 | Optimization of Reaction Conditions for Vicinal all-carbon Quaternary Stereocentersa Entry 21 Base Yield (%)b ee (%)c drd 1 21a 4M aq. KOH 60 45 2:1 2 21b 4M aq. KOH 50 53 2:1 3 21c 4M aq. KOH 53 62 6:1 4 21c LiOH 34 60 5:1 5 21c NaOH 17 56 6:1 6 21c KOH 23 67 6:1 7 21c Na2CO3 45 70 5:1 8 21c K2CO3 76 70 5:1 9 21c Cs2CO3 84 72 6:1 10 21c K3PO4 78 70 6:1 11e 21c Cs2CO3 83 84 10:1 aUnless otherwise noted, reactions were carried out with PN1 (5 mol %), 1a (0.1 mmol), 21a– 21c (0.12 mmol), base (0.15 mmol) in toluene (2 mL) at room temperature for 3–4 days. bIsolated yield. cDetermined by HPLC using a chiral column. dDetermined HPLC analysis. eReaction temperature is −20 °C. With the goldilocks zone identified, we expanded our investigation on the scope of the tertiary bromides that could be used. We reported successful cases in which the reaction proceeded smoothly with good yields and stereoselectivities (Figure 4, 22d– 22w). For benzyl substitutions in bromides, both electron-withdrawing and -donating groups were tolerated ( 22d– 22k). Heterocycle such as thiophene was well tolerated ( 22l). Also, simple alkyl groups produced good results ( 22m– 22p). Olefins containing alkyl chains were transformed into the desired product with good yields and stereoselectivities ( 22q). Substitution on cyclic β−ketone ester 21e and 22f was also well tolerated ( 22r– 22w). Attempts to expand to other tertiary carbon nucleophiles such as tert-butyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate, and tert-butyl 2-oxocyclopentane-1-carboxylate were unsuccessful. We continued to explore other potential tertiary carbon nucleophiles, including bearing less electron donating groups and linear vicinal all-carbon quaternary stereocenters. Figure 4 | Synthesis of vicinal all-carbon quaternary stereocenters. Unless otherwise noted, the reactions were carried out with PN1 (5 mol %), Cs2CO3 (0.07 mmol), 1a (0.05 mmol), 21c (0.06 mmol) in toluene (2 mL) at −20 °C for 3–4 days. Isolated yield. The dr value was determined by HPLC analysis. The ee value was determined by HPLC analysis on the chiral stationary phase. The absolute configuration was determined using an X-ray crystal structure of 22c (see Supporting Information, page S85). Download figure Download PowerPoint To gain a better understanding of the mechanism, control experiments were designed accordingly. First, a carbanion-exchange experiment was conducted between tertiary bromide 1a and cyclic β-ketone ester 21c. The reaction temperature was lowered from −20 to −40 °C and quenched using saturated NH4Cl after 8 h. The transfer of Br atom from 1a to 21c was evident through the significant production of bromide 23 (Scheme 3a). However, both protonated product 1a-H and bromide 23 were obtained as racemic mixtures. Moreover, a carbanion-trapping experiment using acrylonitrile further substantiated the presence of a carbanion intermediate generated from tertiary bromide 1d (Scheme 3b). The conjugated addition product 24 was obtained with moderate enantioselectivity, pointing to close ion-pair interaction of the carbanion with bisguanidinium BG1. Next, we prepared the enantioenriched tertiary bromide 23 using preparative high-performance liquid chromatography (HPLC) and subjected them to our conditions independently (Scheme 3c). We found that both enantioenriched tertiary bromides 23 were transformed to the same stereoisomer 22c. Finally, base-mediated racemization was observed when treated enantioenriched bromides 23 with Cs2CO3, indicating that the Cs2CO3 induced dynamic kinetic resolution before the C–C bond coupling thereby contributing to the high stereoselectivity (Scheme 3d). Scheme 3 | (a–d) Control experiments performed to understand the mechanism of formation of vicinal all-carbon quaternary stereocenters. Download figure Download PowerPoint To gain a better understanding of the mechanism, control experiments were designed accordingly. First, a carbanion-exchange experiment was conducted between tertiary bromide 1a and cyclic β-ketone ester 21c. The reaction temperature was lowered from −20 to −40 °C, and the reaction was quenched using saturated NH4Cl after 8 h. The transfer of Br atom from 1a to 21c was evident through the significant production of bromide 23 (Scheme 3a). However, both protonated product 1a-H and bromide 23 were obtained as racemic mixtures. Further, a carbanion-trapping experiment using acrylonitrile substantiated the presence of a carbanion intermediate generated from tertiary bromide 1d (Scheme 3b). The conjugated addition product 24 was obtained with moderate enantioselectivity, pointing to close ion-pair interaction of the carbanion with the bisguanidinium BG1. Next, we prepared the enantioenriched tertiary bromide 23 using preparative HPLC and subjected them to our conditions independently (Scheme 3c). We found that both enantioenriched tertiary bromides 23 were transformed to the same stereoisomer 22c. Finally, base-mediated racemization was observed when enantioenriched bromide 23 was treated with Cs2CO3; this indicated that Cs2CO3 induced dynamic kinetic resolution prior to the C–C bond coupling, contributing to the high stereoselectivity (Scheme 3d). Based on previous investigations (Scheme 4a) and our preliminary studies, we proposed that cyclic β-ketone ester 21c and tertiary bromide underwent carbanion-exchange through SN2X (Scheme 4b). Cyclic β-ketone ester bromide 23, generated at this step, could undergo further racemization through SN2X, modulated by a base. Finally, SN2 substitution occurred between the PN1 paired carbanion generated from tertiary bromide A and cyclic β-ketone ester bromide 23 to install the vicinal all-carbon quaternary stereocenters through the coupling of two C(sp3) centers. Scheme 4 | (a and b) Proposed mechanism for construction of vicinal all-carbon quaternary stereocenters. Download figure Download PowerPoint Conclusion We have successfully developed a pentanidium-catalyzed direct coupling of tertiary carbon nucleophiles and tertiary carbon electrophiles through C(sp3)–C(sp3) bond formation. These reactions allowed the direct construction of the challenging vicinal all-carbon quaternary stereocenters at high efficiencies. This transformation is so far the most efficient approach for assembling this congested C(sp3)–C(sp3) bond. Synthetic application of this new methodology is currently ongoing in our group. Supporting Information Supplementary Information is available and include X-ray crystallographic data. Conflict of Interest The authors declare no competing interests. Funding Information The authors gratefully acknowledge financial support from Nanyang Technological University for Tier 1 grants (RG1/19 and RG2/20) and Ministry of Education (Singapore) Tier 2 grants (no. MOE2019-T2-1-091). The authors also like to acknowledge financial support obtained from the University of Wollongong (VC Fellowship) and the Australian Research Council (DECRA DE210100053). This work was supported by the A*STAR Computational Resource Centre through its high-performance computing facilities. Preprint Acknowledgment Research presented in this article was posted on a preprint server before publication in CCS Chemistry. The corresponding preprint article can be found here: DOI: 10.21203/rs.3.rs-250161/v1; direct link: https://www.researchsquare.com/article/rs-250161/v. References 1. Lovering F.; Bikker J.; Humblet C.Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical SuccessJ. Med. Chem.2009, 52, 6752–6756. Google Scholar 2. 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Google Scholar Previous articleNext article FiguresReferencesRelatedDetailsCited ByLi M and Wang J (2022) Nickel-Catalyzed Enantioselective C(sp3)–H Arylation of Ketones with Aryl Ethers via Selective CAr–O Cleavage to Construct All-Carbon Quaternary Stereocenters, CCS Chemistry, , (1-9) Issue AssignmentVolume 3Issue 10Page: 2192-2200Supporting Information Copyright & Permissions© 2021 Chinese Chemical SocietyKeywordsasymmetric substitutionSN2X substitutionion-paired catalystSN2 substitutionall-carbon quaternary stereocenters Downloaded 1,735 times PDF DownloadLoading ...