Stereodivergent Pd/Cu Catalysis for the Dynamic Kinetic Asymmetric Transformation of Racemic Unsymmetrical 1,3-Disubstituted Allyl Acetates

Journal of the American Chemical Society, Journal Year: 2020, Volume and Issue: 142(18), P. 8097 - 8103

Published: April 19, 2020

A stereodivergent Pd/Cu catalyst system has been developed for the unprecedented dynamic kinetic asymmetric transformation (DyKAT) of racemic unsymmetrical 1,3-disubstituted allylic acetates with prochiral aldimine esters. series α,α-disubstituted α-amino acids bearing vicinal stereocenters were easily prepared excellent enantioselectivities (up to >99% ee) and diastereoselectivities >20:1 dr). Moreover, all four stereoisomers product can be readily obtained simply by switching configurations two chiral metal catalysts. Furthermore, present work highlights power synergistic catalysis consisting common bidentate ligands synthesis.

Language: Английский

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Nickel‐Catalyzed Asymmetric Reductive Arylalkylation of Unactivated Alkenes

Angewandte Chemie International Edition, Journal Year: 2019, Volume and Issue: 58(20), P. 6722 - 6726

Published: March 20, 2019

Abstract Reported is an asymmetric reductive dicarbofunctionalization of unactivated alkenes. Under the catalysis a Ni/BOX system, various aryl bromides, incorporating pendant olefinic unit, were successfully reacted with array primary alkyl bromides in presence Zn as reductant, furnishing series benzene‐fused cyclic compounds bearing quaternary stereocenter high enantioselectivities. Notably, this reaction avoids use pregenerated organometallics and demonstrates tolerance sensitive functionalities. The preliminary mechanistic investigations reveal that Ni‐catalyzed proceeds cascade consisting migratory insertion cross‐coupling nickel(I)‐mediated intramolecular 5‐ exo cyclization enantiodetermining step.

Language: Английский

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Enantio‐ and Diastereodivergent Synthesis of Spirocycles through Dual‐Metal‐Catalyzed [3+2] Annulation of 2‐Vinyloxiranes with Nucleophilic Dipoles

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(47), P. 24941 - 24949

Published: Sept. 17, 2021

The development of efficient and straightforward methods for obtaining all optically active isomers structurally rigid spirocycles from readily available starting materials is great value in drug discovery chiral ligand development. However, the stereodivergent synthesis bearing multiple stereocenters remains an unsolved challenge owing to steric hindrance ring strain. Herein, we report enantio- diastereodivergent through dual-metal-catalyzed [3+2] annulation oxy π-allyl metallic dipoles with less commonly employed nucleophilic (imino esters). A series spiro compounds a pyrroline olefin were easily synthesized manner (up 19:1 dr, >99 % ee), which showed promise as new type N-olefin ligand. Preliminary mechanistic studies also carried out understand process this bimetallic catalysis.

Language: Английский

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Organoelectrophotocatalytic Generation of Acyl Radicals from Formamides and Aldehydes: Access to Acylated 3-CF₃-2-Oxindoles

Organic Letters, Journal Year: 2023, Volume and Issue: 25(38), P. 7014 - 7019

Published: Sept. 18, 2023

Organoelectrophotocatalytic generation of acyl radicals from formamides and aldehydes to synthesize acylated 3-CF3-2-oxindoles has been developed. This protocol features a monocatalytic system using 9,10-phenanthrenequinone (PQ) both as catalyst hydrogen atom transfer (HAT) reagent, which avoids the use an external HAT metal oxidant. A variety have obtained in satisfactory yields CF3-substituted N-arylacrylamides via tandem radical cyclization.

Language: Английский

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Organophotoelectrochemical silylation cyclization for the synthesis of silylated 3-CF₃-2-oxindoles

Organic Chemistry Frontiers, Journal Year: 2023, Volume and Issue: 10(14), P. 3585 - 3590

Published: Jan. 1, 2023

An organophotoelectrochemical approach for silylation cyclization of CF3-substituted N -arylacrylamides with organosilanes under transition-metal-free and oxidant-free conditions has been developed.

Language: Английский

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Diastereodivergent Synthesis of β‐Amino Alcohols by Dual‐Metal‐Catalyzed Coupling of Alkoxyallenes with Aldimine Esters

Angewandte Chemie International Edition, Journal Year: 2020, Volume and Issue: 60(12), P. 6545 - 6552

Published: Dec. 4, 2020

Abstract Both syn ‐ and anti ‐β‐amino alcohols are common structural motifs in natural products, drug molecules, chiral ligands catalysts. However, the currently available methods for synthesizing these limited to generate only one diastereoisomer. Therefore, development of a unified method stereoselective access complementary diastereomers would be highly desirable. Herein, we report dual‐metal‐catalyzed diastereodivergent coupling alkoxyallenes with aldimine esters. By carefully selecting two metals appropriate ligands, could synthesize both alcohol high enantioselectivity diastereoselectivity from same set starting materials. Furthermore, stereodivergent syntheses all four stereoisomers β‐amino achieved. We demonstrated synthetic utility this by concisely mycestericins F G.

Language: Английский

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Palladium‐Catalyzed Enantioselective Heck Carbonylation with a Monodentate Phosphoramidite Ligand: Asymmetric Synthesis of (+)‐Physostigmine, (+)‐Physovenine, and (+)‐Folicanthine

Angewandte Chemie International Edition, Journal Year: 2020, Volume and Issue: 59(29), P. 12199 - 12205

Published: April 2, 2020

Abstract Reported herein is the development of first enantioselective monodentate ligand assisted Pd‐catalyzed domino Heck carbonylation reaction with CO. The highly N ‐aryl acrylamides and various nucleophiles, including arylboronic acids, anilines, alcohols, in presence CO was achieved. A novel phosphoramidite ligand, Xida‐Phos, has been developed for this it displays excellent reactivity enantioselectivity. employs readily available starting materials, tolerates a wide range functional groups, provides straightforward access to diverse array enantioenriched oxindoles having β‐carbonyl‐substituted all‐carbon quaternary stereocenters, thus providing facile complementary method asymmetric synthesis bioactive hexahydropyrroloindole its dimeric alkaloids.

Language: Английский

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Asymmetric Cobalt‐Catalyzed Regioselective Hydrosilylation/Cyclization of 1,6‐Enynes

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(21), P. 12046 - 12052

Published: March 8, 2021

Abstract We report an enantioselective cobalt‐catalyzed hydrosilylation/cyclization reaction of 1,6‐enynes with secondary and tertiary hydrosilanes employing a catalyst generated in situ from the combination Co(acac) 2 ( R , S p )‐Josiphos. A wide range oxygen‐, nitrogen‐, carbon‐tethered reacted Ph SiH (EtO) 3 SiH, or (RO) MeSiH to afford corresponding chiral organosilane products high yields up >99 % ee . This also occurred prochiral hydrosilane PhMeSiH yield alkylsilanes containing both carbon‐ silicon‐stereogenic centers excellent enantioselectivity, albeit modest diastereoselectivity. The this asymmetric could be converted variety five‐membered heterocyclic compounds by stereospecific conversion their C−Si Si−H bonds without loss enantiopurity.

Language: Английский

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Pd-Catalyzed Enantioselective Tandem C–C Bond Activation/Cacchi Reaction between Cyclobutanones and o-Ethynylanilines

Organic Letters, Journal Year: 2021, Volume and Issue: 23(4), P. 1309 - 1314

Published: Feb. 4, 2021

A palladium-catalyzed asymmetric tandem C–C bond activation/Cacchi reaction between cyclobutanones and o-ethynylanilines was reported. The transient chiral σ-alkylpalladium species generated via enantioselective C(sp3)–C(sp2) activation of promotes cyclization o-ethynylanilines, leading to one-carbon-tethered indanone-substituted indoles. Two bonds one C–N are created with concomitant formation an all-carbon quaternary stereocenter. Furthermore, a C2-aryl axis can be in 2,3-disubstituted indole moiety, indoles both central axial stereogenic elements.

Language: Английский

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Stereodivergent Pd/Cu Catalysis for Asymmetric Desymmetric Alkylation of Allylic Geminal Dicarboxylates

CCS Chemistry, Journal Year: 2021, Volume and Issue: 4(5), P. 1720 - 1731

Published: May 26, 2021

Open AccessCCS ChemistryRESEARCH ARTICLE1 May 2022Stereodivergent Pd/Cu Catalysis for Asymmetric Desymmetric Alkylation of Allylic Geminal Dicarboxylates Xiaohong Huo, Ling Zhao, Yicong Luo, Yue Wu, Yuwen Sun, Guanlin Li, Tatiana Gridneva, Jiacheng Zhang, Yong Ye and Wanbin Zhang Huo Shanghai Key Laboratory Molecular Engineering Chiral Drugs, Frontiers Science Center Transformative Molecules, School Chemistry Chemical Engineering, Jiao Tong University, 200240 , Zhao Luo Wu Sun Li Gridneva College Chemistry, Zhengzhou 450052 *Corresponding author: E-mail Address: [email protected] https://doi.org/10.31635/ccschem.021.202101044 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail A stereodivergent catalyst system asymmetric desymmetric alkylation allylic geminal dicarboxylates has been developed, which was successfully applied the synthesis β-hydroxycarbonyl motifs bearing a versatile carbon–carbon double bond in an enantio- diastereodivergent manner. wide scope substrates including challenging alkyl-substituted, 2-substituted, 3,3′-disubstituted species are compatible with this catalytic system, delivering substituted products high excellent yields diastereo- (up >20:1 dr) enantioselectivities >99% ee). Furthermore, mechanism dual including: (1) desymmetrization process dicarboxylates; (2) origin regioselectivity (branched or linear); (3) diastereoselectivity observed by changing combinations two chiral metal catalysts, have carefully investigated theoretical calculations. Download figure PowerPoint Introduction β-Hydroxycarbonyl vicinal stereogenic centers privileged structural motifs, exist many bioactive molecules natural pharmaceuticals (Erythromycin, Discodermolide, Epothilone C, etc.) (Scheme 1a).1–5 Their stereochemistries important influence on their chemical biological properties.6–9 Therefore, development efficient access all stereoisomers these is significant research topic as well great challenge field. Catalytic aldol reactions, most method synthesizing β-hydroxycarbonyls, typically only generate one diastereoisomer (syn anti). In fact, much effort devoted complementary diastereomers. However, methods mainly limited auxiliary-based approaches10,11 careful choices additives, reaction conditions.12–14 Thus, general unified that achieves urgently needed but remains underdeveloped. Scheme 1 | Stereodivergent catalysis dicarboxylates. The Pd-catalyzed (AAA) serves powerful tools construction bond.15–22 range functionalized electrophiles developed rapid complex atom- step-economical Since pioneering works Lu Trost, carbonyl surrogates attracted increasing attention due efficiency preparation alcohol derivatives 1b).23–30 Combined suitable prochiral enolate nucleophile, AAA dicarboxylate provide direct convenient route diastereoselective carbon-carbon bond. currently available mostly generation single stereocenter report reported favored being obtained. addition, ratio (dr) value sensitive steric hindrance substrate.26 Enantio- substitution common nucleophiles remain formidable no examples yet 1c). recent years, since seminal studies carried out Carreira,31,32 cooperative metal/organo catalysis,31–39 bimetallic catalysis,40–50 organo/organo catalysis51 become synthesis.52–55 As result our continued interest synthesis,40–43,56 we envisioned using strategy address same starting materials. This involves concurrent activation independent stereocontrol reactants different catalysts. If configurations stereocenters adamantly fixed ligands, can easily control configuration (RR, RS, SR, SS) Considering highly building blocks target importance stereochemical diversity, methodology may diversity-oriented design compound libraries drug discovery.57–59 Herein, utilized through manner accommodate species, corresponding 95% yield) (ee) diastereoselectivities ee dr). Additionally, enantio-, diastereodivergence were computationally investigated. predicted regio-, consistent experimental results. Experimental Methods General procedure esters Pd catalyst: [Pd(η3-allyl)Cl]2 (2.5 mol %), (S)- L4 (R)- (5.5 %) stirred tetrahydrofuran (THF; 1.0 mL) Schlenk flask under nitrogen atmosphere at room temperature (RT) 40 min. Cu [Cu(MeCN)4]PF6 (5.0 (S,Sp)-L5 (R,Rp)-L5 THF (1.0 RT flame dried tube cooled filled N2. To imino ester (0.20 mmol, equiv) base (0.28 1.4 added. Next, diacetates then added, mixture 0 °C 12 h. After complete, filtered small pad silica washed EtOAc. dr determined 1H NMR analysis crude mixture. Purification gel column chromatography [petroleum ether (PE)/ethyl acetate (EA) = 5:1–10:1] afforded desired product (see Supporting Information more details experimentation characterization data). Results Discussion Initial trials (E)-3-phenylprop-2-ene-1,1-diyldiacetate ( 1a) cyclic 2a) model (Table 1).60–81 When combination Pd/(R,R)- L1 Cu/(S,Sp)- L5) used RT, 6% isolated yield 3aa obtained 1.3:1 (entry 1). poor activity might be mismatch between (R,R)- (S,Sp)- L5. Trost's ligand big "chiral pocket" nucleophilic attack metalated ester. Then, three classic axially-chiral ligands dihedral angles screened (entries 2–4).82 (S,S)- could smoothly enantioselectivity (>20:1 ee) low (38–45% yield). Careful revealed 2a completely consumed considerable amount disubstituted by-product generated. inhibit process, decreased °C. Positively, increased 71% 5). further increase 3aa, phosphino-oxazoline (PHOX) methyl tert-butyl group also explored 6 7). It found L5 iso-propyl proved best reaction. Imino modified examined 8 9). Different results observed: 2a′) 2a″) gave its 17% 8:1 ee. absolute reversed, (R,S)- satisfactory stereoselectivity (87% yield, dr, 10). These suggested palladium copper catalysts independently both substrate Table Optimization Reaction Conditions Diastereodivergent Synthesisa Entry 2 L Yield (%)b Drc (%)d (Config.) 97 (S,S)/66 L2 38 >99 (S,S) 3 L3 43 4 45 5e 71 6e L6 75 12:1 7e L7 13:1 8e 2a' 70 9e 2a″ 17 95 10 87 (R,S) 11f 12e No nr — 13e 14e,g Trace aReaction conditions: 1a equiv), 2a-2a″ [Pd(allyl)Cl]2 L1–L4 (5 L5–L7 K3PO4 (1.5 (2 mL), h, RT. bIsolated diastereoisomers based material 2. 5 % [Pd(allyl)Cl]2. cDetermined integration. dDetermined HPLC IC (CHIRALPAK® IC) column. e0 instead fA large-scale 2.0 mmol 2a. gNo K3PO4. conducted optimized conditions, providing similar 11). understand specific role experiments 12–14). did not occur absence either Cu-catalyst Pd-catalyst trace amounts detected if present, showing facilitative nature system. four materials choosing (For all, transformed into 4aa simple hydrolysis without 2). 4aa. (a) 5N HCl With conditions hand, (R)-BINAP (BINAP 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthalene) (S)-BINAP All products, regardless electronic properties substituents, prepared yields, diastereoselectivities. There obvious differences stereo-induction substrates. Specifically, (R,S)-products: fluoro- substituents 2-position, 3ab 3ac) 87% 80% 14:1 functional groups 3-position showed effect diastereoselectivity. Increasing electron-donation ability fluoro methoxyl improvements 3ad– 3ah). 3ag 3ah (both performances 4-position aryl negligible 3ai– 3am, Disubstituted 3an, Changing phenyl naphthyl 3ao, Notably, alkyl dicarboxylates, regarded reactions,83,84 reactivity 3ap– 3av). encouraging results, less substrates, such 2-substituted explored, moderate almost perfect stereoselectivities 3aw- 3ay). For (S,S)-products, trend aryl-substituted Most alkyl-substituted (S,S)-( 3ap- 3av) 57–69% 4:1–7:1 91–>99% 3av X-ray crystallography. Substrate Scope Dicarboxylatesa incorporating standard optimal 3). Various electron-withdrawing -donating furnished stereoselectivities. Overall, (R,S)-products slightly higher than 3ba– 3qa) synthesized (56–95%) furan, thiophene, pyridine conducted, affording 3ma– 3oa (12:1–20:1 98–>99% 2-Thiazoline-4-carboxylates acyclic aldimine 3pa 3qa [for 3pa: 99% ee; 56% 3:1 dr; 98% 3qa: 75% 9:1 63% 16:1 Estersa bThe after reduction NaBH4. proposed cycle presented, overview starts Pd(0)/ from interacts produce π-allyl-Pd intermediate (syn,anti)- (syn,syn)- 7 AcO− leaving via 5a 5b. another cycle, α-H 2a′ activated presence Cu/ catalyst. captures proton, giving nucleophile 17. undergo substitution, furnishing final 3. Proposed synergistic catalysis. explore diastereoselectivity, density theory (DFT) calculations (Figure At first, underlying reason Pd/(R)- L4. Two pathways intermediates proposed. originated conformations 5. 5.81 kcal/mol energy compared (syn,syn)-configuration 7.69 kcal/mol, observations. Figure Gibbs free (y-axis, kcal/mol) profile possible regarding Pd/(R)-L4 Cu/(R,Rp)-L5. established, transformation Cu/(R,Rp)- general, sites whereby benzyl position leads branched (teal pathway gray pathway) other linear (brown pale green pathway). there 7), established. reactions (Cu (R,Rp)- studied 1).85,86 suggest barrier formation 10.90 ([ 10-14]‡ vs [ 9-13]‡), 10.97 over 12–16]‡ 11–15]‡). According profiles, (S,R)-linear (the brown major lowest among pathways. Similar trends L5), (S,S)-linear S1).87–89 agree Conclusion We present reasonably explained computational study. includes information, procedures, optimization details, crystallographic data, copies high-performance liquid (HPLC) spectra. Conflict Interest conflict report. Acknowledgments work supported National Natural Foundation China (nos. 21620102003, 21831005, 21901158, 21991112), Sailing Program (no. 19YF1421900), Municipal Education Commission 201701070002E00030), R&D 2018YFE0126800), Technology Municipality 19JC1430100), Zhiyuan Scholar ZIRC2020-04). References 1. Mahrwald R.; Evans D.Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004. Google Schetter B.; R.Modern Total Synthesis Polyketides.Angew. Chem. Int. Ed.2006, 45, 7506–7525. Trost B. M.; Brindle C. S.The Direct Reaction.Chem. Soc. Rev.2010, 39, 1600–1632. 4. Stereoselective 2013. L.; Yang G.; W.Ni-Catalyzed Enantioconvergent Coupling Epoxides Alkenylboronic Acids: Construction Oxindoles Bearing Quaternary Carbons.CCS Chem.2019, 1, 623–631. 6. Jozwiak K.; Lough W. J.; Wainer I. W.Drug Stereochemistry: Analytical Pharmacology; CRC Press: Boca Raton, FL, 2012. 7. Harrison A.; Gierasch T. Neilan C.; Pasternak G. W.; Verdine L.High-Affinity Mu Opioid Receptor Ligands Discovered Screening Exhaustively Stereodiversified Library 1,5-Enediols.J. Am. Soc.2002, 124, 13352–13353. 8. Kim Y.-k.; Arai M. T.; Lamenzo J. O.; Dean E. F.; Patterson N.; Clemons P. Schreiber S. L.Relationship Stereochemical Skeletal Diversity Small Molecules Cellular Measurement Space.J. Soc.2004, 126, 14740–14745. 9. Gerard Duvall Lowe Murillo Wei Akella L. Marcaurelle A.Synthesis Stereochemically Diverse Medium-Sized Lactams Sultams SNAr Cycloetherification.ACS Comb. Sci.2011, 13, 365–374. 10. Van Draanen N. Arseniyadis S.; Crimmins Heathcock H.Protocols Preparation Each Four Possible Stereoisomeric α-Alkyl-β-hydroxy Carboxylic Acids Single Reagent.J. Org. Chem.1991, 56, 2499–2506. 11. Walker H.Acyclic Stereoselection. 54. Extending Reaction: anti "Non-Evans" syn Aldols.J. 5747–5750. 12. Denmark E.; Su X.; Nishigaichi Y.The Trichlorosilyl Enolates. Mechanistic Duality Lewis Base-Catalyzed Addition Reaction.J. Soc.1998, 120, 12990–12991. 13. Gao Bai Q.; Liu Y.; Q.Acid Controlled Diastereoselectivity Cycloketones Aldehydes Using Enamine-Based Organocatalysts.Chem. Commun.2011, 47, 6716–6718. 14. Martínez-Castañeda Á.; Rodríguez-Solla H.; Concellón del Amo V.Switching Proline-Catalyzed Reactions.J. Chem.2012, 77, 10375–10381. 15. Vranken D. L.Asymmetric Transition Metal-Catalyzed Alkylations.Chem. Rev.1996, 96, 395–422. 16. Helmchen Pfaltz A.Phosphinooxazolines-A New Class Versatile, Modular P,N-Ligands Catalysis.Acc. Res.2000, 33, 336–345. Miyabe Takemoto Y.Regio- Stereocontrolled Palladium- Iridium-Catalyzed Allylation.Synlett2005, 2005, 1641–1655. 18. Mohr T., Stoltz M.Enantioselective Tsuji Allylations.Chem. Asian J.2010, 2, 1476–1491. 19. Z.; Ma S.Metal-Catalyzed Enantioselective Allylation Synthesis.Angew. Ed.2008, 258–297. 20. Oliver A.Transition-Metal-Catalyzed Substitution Reactions: α- β-Substituted Carbonyl Compounds.Synthesis2013, 3179–3198. 21. Butt W.Transition Reactions Unactivated Substrates.Chem. Rev.2015, 44, 7929–7967. 22. Kazmaier U., Ed.; Metal Catalyzed Organic Synthesis; Springer Verlag: Berlin Heidelberg, Germany, 23. Huang Y.Palladium-Catalyzed Nucleophiles Diacetates 1,1-Diols.J. Organomet. Chem.1984, 268, 185–190. 24. Vercauteran J.Allylic Diacetates. Unusual Substitutes Reactions.Tetrahedron Lett.1985, 26, 131–134. 25. Lee Weiss M.Asymmetric gem-Dicarboxylates.J. Soc.1995, 117, 7247–7248. 26. Ariza X.Catalytic Nucleophiles: α-Alkylated Amino Acids.Angew. Ed. Eng.1997, 36, 2635–2637. 27. B.Geminal Surrogates Synthesis. Part Malonate Nucleophiles.J. Soc.2001, 123, 3671–3686. 28. II. Applications.J. 3687–3696. 29.

Language: Английский

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