Asymmetric Spirocyclization Enabled by Iridium and Brønsted Acid-Catalyzed Formal Reductive Cycloaddition

Open AccessCCS ChemistryRESEARCH ARTICLE1 Jul 2021Asymmetric Spirocyclization Enabled by Iridium and Brønsted Acid-Catalyzed Formal Reductive Cycloaddition Nan-Fang Mo†, Le Yu†, Ying Zhang, Ya-Hong Yao, Xun Kou, Zhi-Hui Ren Zheng-Hui Guan Mo† Key Laboratory of Synthetic Natural Functional Molecule Ministry Education, Department Chemistry & Materials Science, Northwest University, Xi’an 710127 †N.-F. Mo L. Yu contributed equally to this work.Google Scholar More articles author , Yu† Zhang Google Yao Kou *Corresponding author: E-mail Address: [email protected] https://doi.org/10.31635/ccschem.020.202000415 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd favoritesTrack Citations ShareFacebookTwitterLinked InEmail A catalytic, enantioselective spirocyclization formanilides or formylindolines enamides has been developed herein. The reaction proceeds through a sequential iridium-catalyzed hydrosilylation tertiary chiral phosphoric acid-catalyzed formal cycloaddition exocyclic enamides, thus providing straightforward access diverse array enantioenriched azaspirocycles under mild conditions. new bowl-shaped acid bearing an o-CF3-aryl on the H8-BINOL-framework OCF-CPA (CPA18) as effective, multipoint-controlled catalyst for reaction. And mechanistic investigations reveal presence crucial C–H?F hydrogen bonding in enantiodetermining transition states. Download figure PowerPoint Introduction Spirocycles are not only important structural motifs wide natural products bioactive compounds1,2 but also privileged scaffolds modern drug discovery. Their rigid unique three-dimensional diversity is used efficiently designing pharmacophores recognize target proteins.3–5 Among different spirocyclic subclasses, 1-azaspirocycles one most discovery, which their well-defined spatial arrangements often beneficial binding.2–6 importance subclass spirocycles can be gleaned its appearance pentacyclic core pyrroindomycins, NK1 tachykinin receptor antagonist, antimalarial cipargamin, U.S. Food Drug Administration (FDA)-approved rolapitant (Scheme 1a). However, due intrinsic complexity challenge stereocontrolled construction sterically congested nitrogen-constrained quaternary spirocenters,7–9 synthesis involves multistep sequences,2,10–13 making them underrepresented chemical libraries. Facile, synthetic framework class spirocycle remains organic chemistry.14–22 Scheme 1 | Selective examples (a) 1-azaspirocycles, (b) reductive functionalization amides, (c) our work. readily available amides become promising method substituted amines.23,24 In context, owing stability amide group, two-step process reduction–activation nucleophilic substitution addition generally involved. Therefore, stoichiometric activating agents reductants, including triflic anhydride (Tf2O),25–27 DIBAL-H,28,29 Schwartz’s reagent (Cp2ZrHCl),30,31 NaH32 have successfully motivate 1b). Tf2O-mediated cycloadditions with alkynes alkenes one-pot manner give azaheterocycles reported.33–35 Particularly, interesting l-proline-catalyzed bis-functionalization secondary 2,2-disubstituted 3-iminoindoline recently.36 Alternatively, seminal catalytic silane reagents emerged. IrCl(CO)(PPh3)237–44 Mo(CO)645–47 effective catalysts diversifying significantly. Despite these notable achievements, reduction-initiated transformation rarely explored. development asymmetric enantiomerically pure highly desirable. Since O-silylated hemiaminal proposed intermediate amides,37–44 we hypothesized that desilanolation silyl ether I would initiate 1c). As such, 1-azaspirocycle constructed accordingly. case, phosphate counterion resulting iminium II might impart chirality ion-pairing interaction.48–50 Simultaneously, hydrogen-bonding interaction between Lewis basic site proton enamide enhance enantioinduction reaction.51,52 present herein transformation: formanilide Experimental Methods General procedure formanilides: 10 mL tube (tube A), was charged (0.12 mmol, 1.2 equiv), IrCl(CO)(PPh3)2 (0.9 mg, 1.0 mol %), dry o-xylene (1.0 mL), 1,1,3,3-tetramethyldisiloxane (TMDS) (26.8 2.0 equiv) added stirred 0.5 h. Another B) (0.1 CPA18 (OCF-CPA) (10 (2.0 mL). solution transferred into B, then, mixture B at –25 °C. After completion, warmed room temperature. crude directly purified flash column chromatography silica gel (CH2Cl2/ethyl acetate = 8?1 3?1 eluent) afford corresponding product. experimental details characterization Supporting Information. Computational All calculations were performed Gaussian 09 package. stable structures states fully optimized unrestrainedly dispersion-corrected density functional theory (DFT) using B3LYP (B3LYP-D3) 6-31G(d) basis set. Normal vibrational mode analysis same level confirmed minima (zero imaginary frequency) saddle points (one frequency). Furthermore, coordinate (IRC) applied identify connecting reactants products. Corrected single-point energies solvent computed B3LYP-D3 6-311G(d,p) set solvation model based density. relative zero-point energy (ZPE) correction free (at 298.15 K) kcal/mol. Results Discussion Reaction conditions outcome We began identification N-methyl 1. It found 1? quantitatively generated ambient temperature Vaska’s complex, IrCl(CO)(PPh3)2, (Me2HSi)2O (TMDS). Having obtained N-phenyl precursor, next examined whether 2 could engineered (Table 1). Many commonly steric electronic properties screened; tested promoted desired product 3 high yield, low-to-moderate enantiomeric excess (ee) 1, CPA1– CPA16). These preliminary results revealed associated accomplishing Table Optimization Conditionsa aConditions: mmol), TMDS (0.2 mmol) mL) Then, CPA %) 0 °C Isolated yields andee determined high-performance liquid (HPLC). bToluene solvent. cCH2Cl2 dThe carried out weaker less directional nature electrostatic counteranion substrate key factor effectiveness enantiocontrol.53 Inspired state-of-the-art design incorporating fluorine effects,54–58 speculated enantiocontrol enhanced additional attraction substrate.59,60 CPA17 either o-F-aryl substitutions 3,3?-positions first synthesized subsequently delighted observe enantioselectivity indeed gave rise improvement, achieving 72% ee 80% CPA18. Moreover, increased 83% lowering ?25 CPA18, no further improvement modifying ( CPA19– CPA25) parameters. Because substituent N-aryl ion may alter cationic counteranion, then tuned substituents improve (Figure respect, 2,4,6-trimethylbenzyl protected 1-G8 provided 4,4?-spiro-tetrahydroquinoline 3-G8 97% 94% yield. group conveniently removed N–H 8 90% yield without loss purity via Pd/C-catalyzed hydrogenation 1b), demonstrating utility addition, formylindoline 4 displayed reactivity This result valuable indoline-fused method. 4% observed when acyclic 5 employed reaction, albeit obtained. Figure Asymmetric N-alkyl alkyl groups from optimization studies; *reaction run o-xylene/toluene (v/v 1/2) ?78 Removal Scope established optimal conditions, investigated scope 2a). Formanilides electron-donating substituents, such methoxy, underwent reduction smoothly excellent enantioselectivities 9– 19, 95–98% ee, 87–97% yield). Specifically, 3,4-dimethoxy single regioselective 17 89% halide F, Cl, Br, compatible both 20– 22, 92–94% 80–91% Notably, formyl-2-naphthylamine produced exclusively 23 95% 93% Enamidesa 12 2b) ability tolerate component remarkable. Enamides electron-neutral aryl rings, methyl all tetrahydroquinolines 24– 28, 93–98% 88–95% 1,3-Benzodioxole-containing participated produce tetrahydroquinoline 29 82% Enamide strong electron-withdrawing nitro converted 30 96% 75% chloro position 31– 34, 96–98% 93–97% containing fluoro trifluromethyl well tolerated form 35– 37, 97–98% 90–92% indicate property little influence demonstrated late-stage functionalizations 2c). To satisfaction, family steroid vitamin E-containing substrates generating cholesterol, ?-sitosterol, estrone, trans-dehydroandrosterone, tocopherol-containing diastereoselectivities good 38– 42, >20?1 dr, 62–73% alkenyl electrophilic ketone chemoselectivity indoline nucleus ubiquitous motif pharmaceutical targets, accessible indolines particularly attractive synthesis. installation stereocenter C7-position especially challenge. An advantage system construct C7 bound nitrogen spirocenters, easily achieved alternative protocol 3). 4-, 5-, 6-position particular, hindered 6-methyl-substituted 45 99% Like tolerance noted earlier, methyl, fluro, chloro, bromo, formylindolines, spirocyclization. absolute configuration 56 unambiguously X-ray crystallographic diffraction. Formylindolines aReaction conditions: Formylindoline [IrCl(CO)(PPh3)2] toluene –78 Mechanistic investigation gain insight cycle, conducted control experiments. did proceed absence acid, occurred p-toluene sulfonic 2). experiments suggest plays vital role generate active cycloaddition. investigation: catalysis. obviously intramolecular cyclization III, isolated trapped, DFT better understand origin uncover special CF3 during induction (simple model). free-energy profile complex III R given 3a. calculated activation reactive onto isoindolone-ium im1 state TS-1 6.8 Subsequently, deprotonative rearomatization exothermic TS-2 barrier 0.1 kcal/mol im2. Release final requires 5.6 DFT. Calculated Gibbs profiles PCM(o-xylene)B3LYP-D3/6-311G(d,p)//B3LYP-D3/6-31G(d) theory. lowest-energy CPA7 selected distances bonds ?-stacking shown (c). Enantiodetermining explored two 3b (the comparative depicted Information). reactant docked mainly N–H?O C–H?O bonds. TS1-R-CPA7, there sigma–? methylene H ?-benzene CPA7,61,62 while TS1-S-CPA7, weak bond exits carbonyl O reactant. result, ?G values TS1-R-CPA7 (8.5 kcal/mol) TS1-S-CPA7 (8.6 almost identical, agrees low experiment (16% ee). contrast, shows geometry TS-1, formed o-CF3 TS1-R-CPA18 TS1-S-CPA18, play roles holding back side make reactant–catalyst much stronger,56,59–60 comparison CPA7. force multiple allows generation parallel-displaced moiety o-CF3-benzene aniline TS1-S-CPA18.61,62 imide interacting phosphate; respective makes H-bonds stronger. According coupling interactions, 1.6 ??G (6.8 TS1-S-CPA18 (8.4 predicts toward formation (R)- 3, consistent result. effect G8 3c). TS1-R-CPA18, stronger stabilizes TS1-R-CPA18(G8) gives lowered (?G kcal/mol). TS1-S-CPA18(G8), side-CH3 rotates weakens P=O?H–C C–H bond. distorted center (eight-membered ring) 8.8 compared TS1-S-CPA18. experimentally higher 2,4,6-trimethylbenzyl-substituted substrates. 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