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