Stereodivergent Synthesis of Tertiary Fluoride-Tethered Allenes via Copper and Palladium Dual Catalysis

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(19), С. 7285 - 7291

Опубликована: Май 10, 2021

Herein we describe a protocol for the unprecedented stereodivergent synthesis of tertiary fluoride-tethered allenes bearing stereogenic center and axis via Cu/Pd synergistic catalysis. A broad scope conjugated enynes are coupled with various α-fluoroesters in high yields diastereoselectivities generally >99% ee. In addition, four stereoisomers allene products ensure precise access to corresponding fluorinated hydrofurans novel axial-to-central chirality transfer process.

Язык: Английский

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Enantio- and Diastereodivergent Construction of 1,3-Nonadjacent Stereocenters Bearing Axial and Central Chirality through Synergistic Pd/Cu Catalysis

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(32), С. 12622 - 12632

Опубликована: Авг. 5, 2021

In contrast to the widely explored methods for asymmetric synthesis of molecules bearing a single stereocenter or adjacent stereocenters, concurrent construction 1,3-stereogenic centers in an enantio- and diastereoselective manner remains challenge, especially acyclic systems. Herein, we report diastereodivergent 1,3-nonadjacent stereocenters allenyl axial central chirality through synergistic Pd/Cu-catalyzed dynamic kinetic allenylation with racemic allenylic esters. The protocol is suitable wide range substrates including challenging esters less sterically bulky substituents provided chiral products high levels diastereoselectivities (up >20:1 dr >99% ee). Furthermore, several representative transformations involving axial-to-central transfer were conducted, affording useful structural motifs containing nonadjacent manner.

Язык: Английский

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Bimetallic Catalysis in Stereodivergent Synthesis

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(45)

Опубликована: Авг. 2, 2022

Abstract Bimetallic catalysis has emerged as an efficient strategy for the development of new chemical reactions. Importantly, this also provides a simple and powerful platform stereodivergent synthesis, whereby all possible stereoisomers products bearing two stereocenters can be easily prepared from same set starting materials. In Minireview, allylic substitution, propargylic hydrofunctionalization, annulation based on bimetallic been summarized. It is expected that more catalytic systems will developed applied synthesis valuable molecules.

Язык: Английский

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Synergistic Pd/Amine-Catalyzed Stereodivergent Hydroalkylation of 1,3-Dienes with Aldehydes: Reaction Development, Mechanism, and Stereochemical Origins

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(29), С. 10948 - 10962

Опубликована: Июль 15, 2021

Metal-hydride-catalyzed hydroalkylation of 1,3-dienes with enolizable carbonyl compounds is an atom- and step-economical method for preparing chiral molecules allylic stereocenters. Although high diastereo- enantioselectivities have been achieved many coupling partners, aldehydes not yet used this purpose because they are less stable than other under basic conditions the potential to rapidly epimerize at α-position. Moreover, stereodivergent reactions access complementary diastereomers vicinal stereocenters challenging. Herein, we describe a synergistic palladium/amine catalyst system that allowed us achieve first aldehydes. By choosing appropriate combination palladium amine catalysts, could obtain either syn or anti products, therefore provides highly enantioselective α,β-vicinal Density functional theory calculations revealed mechanism involving PdH formation migratory insertion into alkene, followed by C–C bond formation. The origin stereoselectivities was investigated means distortion/interaction analysis.

Язык: Английский

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Dispersion and Steric Effects on Enantio-/Diastereoselectivities in Synergistic Dual Transition-Metal Catalysis

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(4), С. 1971 - 1985

Опубликована: Янв. 20, 2022

Comprehensive computational studies were carried out to explore the mechanisms of enantioselective Cu/Pd and stereodivergent Cu/Ir dual-catalytic syntheses α,α-disubstituted α-amino acids (α-AAs). A chiral copper azomethine ylide undergoes facile α-allylation with racemic π-allylpalladium species or stereopure π-allyliridium complex stereoconvergently stereodivergently furnish single/double stereocenters, respectively. Stereoselectivity at α-center is controlled by facial selectivity respect prochiral nucleophile. Despite apparently similar transition-state assemblies, models distortion/interaction analyses disclose versatile modes stereoinduction wherein can face-selectively intercept metal−π-allyl intermediates utilizing attractive dispersion interactions and/or sterically caused distortions. Generation β-stereocenter in system relies on a stereospecifically generated allyliridium electronically branched-to-linear selectivity, while dual yields linear monochiral product due steric factors π–π stacking interactions. The demonstrate molecular level how ligand-encoded information transferred α-/β-sites resulting α-AAs mode regio-/stereoselection altered differences transition-metal-stabilized coupling partners. To facilitate stereoselective catalysis, suite analytical tools extract controlling for asymmetric induction demonstrated.

Язык: Английский

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Stereodivergent Construction of 1,4‐Nonadjacent Stereocenters via Hydroalkylation of Racemic Allylic Alcohols Enabled by Copper/Ruthenium Relay Catalysis

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(36)

Опубликована: Июнь 28, 2022

An unprecedented hydroalkylation of racemic allylic alcohols and ketimine esters enabled by Cu/Ru relay catalysis has been developed via merging the ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with a copper-catalyzed Michael addition in one-pot procedure. The current method enables efficient preparation highly functionalized δ-hydroxyesters bearing 1,4-nonadjacent stereocenters good yields high levels diastereoselectivity excellent enantioselectivity under mild conditions. full complement four stereoisomers products could be readily accessed orthogonal permutations two chiral metal catalysts. work highlights power for stereodivergent construction that were otherwise inaccessible.

Язык: Английский

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Synergistic Dual Catalysis in Stereodivergent Synthesis

ACS Catalysis, Год журнала: 2024, Номер 14(6), С. 3812 - 3844

Опубликована: Фев. 23, 2024

Chiral skeletons with multiple stereogenic centers widely reside in nature and drugs, their relative absolute configuration often determine physiological or pharmacological properties. Stereodivergent synthesis of chiral molecules is not only great significance, but also highly challenging since the formation one diastereomers inherently preferred most asymmetric reactions. dual catalysis, introduced 2013 by Carreira group, perfectly catered to all requirements for full stereoselectivity control given reactions two catalysts are utilized a synergistic way act independently, has now been arguably efficient strategy realize stereodivergent synthesis. This comprehensive review presents an overview development enabled catalysis past ten years, providing readers fundamental attributes as well ability, scope, mechanism, limitations this strategy.

Язык: 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, Год журнала: 2020, Номер 60(12), С. 6545 - 6552

Опубликована: Дек. 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.

Язык: Английский

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

CCS Chemistry, Год журнала: 2021, Номер 4(5), С. 1720 - 1731

Опубликована: Май 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. 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Язык: Английский

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Asymmetric transformations enabled by synergistic dual transition-metal catalysis

Chem Catalysis, Год журнала: 2022, Номер 3(1), С. 100455 - 100455

Опубликована: Ноя. 17, 2022

Язык: Английский

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