Asymmetric Suzuki-Miyaura Coupling Research Articles

Palladium/Azaphos-Catalyzed Asymmetric Suzuki–Miyaura Coupling

AbstractA palladium-catalyzed asymmetric Suzuki–Miyaura coupling is described with a unique monophosphine ligand, Azaphos. This method provides a new ligand framework that could be used in asymmetric Suzuki–Miyaura coupling reactions to prepare the axially chiral compounds.

Facile Assembly of Modular-Type Phosphines for Tackling Modern Arylation Processes.

ConspectusThis Account presents an overview of a promising collection of phosphine ligands simply made from the modular Fischer indolization process and their applications in modern arylation processes. Using one easily accessible 2-arylindole scaffold, three major phosphino-moiety-positioned ligand series can be readily generated. We have attempted to explore challenging electrophilic and nucleophilic partners for the coupling reaction using the modular ligand tool. For the electrophilic partner study, CM-phos-type ligands, where the phosphino group is located at the 2-arene position of 2-arylindole, allow the successful cross-coupling of aryl mesylates. The CM-phos ligand forms a palladacycle before entering the cross-coupling catalytic cycle. For the nucleophilic partner investigation, the indole C3-positioned phosphines show the first accomplishment of Pd-catalyzed organotitanium nucleophile arylation. Indeed, the aryl-titanium nucleophile undergoes cross-coupling more efficiently than does the organoboron coupling partner in particular cases. Moreover, in the indole C3-positioned phosphine series, the -PPh2-containing ligands perform better in the highly sterically hindered cross-coupling of aryl chlorides than do ligands containing the -PCy2 moiety. The catalyst loading can even be reduced to 0.2 mol % Pd for tetra-ortho-substituted biaryl synthesis. This finding offers a new perspective on the next-generation design of phosphine ligands in which the sterically bulky and electron-rich -PR2 group (R = alkyl) may not be necessary for the cross-coupling of aryl chlorides. In general, we hypothesize that a good balance of steric and electronic properties for entertaining the oxidative addition and reductive elimination steps is crucial to the success of the reaction. For the steric factor, the highly sterically congested -PR2 group normally favors the reductive elimination, yet we conjecture that this sterically bulky group would serve as an obstacle for the incoming aryl halides. For the electronic factor, the electron rich -PR2 group is believed to support the oxidative cleavage of the C(Ar)-Cl bond by donating more electron density to the corresponding σ* orbital. Nevertheless, the high electron richness of the -PR2 group may disfavor the reductive elimination electronically. Overall, an appropriate balance of both electron density and steric bulkiness is suggested to allow the sterically hindered cross-coupling to proceed smoothly. We have found that the -PPh2-containing ligand is a good starting point for this investigation. The formation of aromatic carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds from aryl chlorides was successfully realized using our proprietary phosphines.In addition to the indole-core-bearing ligand skeleton, we also explored the relevant imidazolyl and carbazolyl phosphines for their unique applications. Interestingly, the carbazolyl ligand, having more flexible C-N axial chirality, displays particular interchangeable Pd-N and Pd-arene coordination, which facilitates both oxidative addition and reductive elimination processes. Moreover, this C-N axially chiral ligand allows the successful asymmetric Suzuki-Miyaura coupling for attaining the most sterically hindered tetra-ortho-substituted biaryls with excellent enantioselectivity. The rationale behind these scientifically interesting findings is presented in detail.

A General Catalyst Controlled Route to Prostaglandin F2α.

We report a general, catalyst-controlled route to prostaglandin F2α and its analogues. The approach uses a Rh-catalyzed dynamic kinetic asymmetric Suzuki-Miyaura coupling reaction between a racemic bicyclic allyl chloride and alkenyl boronic esters bearing chiral alcohols to give cyclopentyl intermediates bearing 3 contiguous stereocenters. The route provides advanced intermediates in 99% ee as a single diastereoisomer in all cases examined, with the absolute stereochemistry of the cyclopentane core controlled by the ligand. Intermediates that could be used to produce prostaglandin analogues such as bimatoprost, latanoprost, fluprostenol, and cloprostenol were synthesized. The final two stereocenters were installed via Pd-catalyzed Tsuji-Trost alkylation and iodolactonization. The synthesis of PG F2α was achieved in 19% yield in 16 longest linear steps.

Pd(II)-immobilized on a novel covalent imine framework (COF-BASU1) as an efficient catalyst for asymmetric Suzuki coupling

This study reports the synthesis of a new imine-based covalent organic framework (COF) stabilizer through the reaction between 1,4-phenylenediamine and 4,4′,4″-(benzene-1,3,5-triyltris(oxy))tribenzaldehyde (COF-BASU1). Next, palladium (Pd) species were decorated on the synthesized COF, and the obtained Pd/COF-BASU1 composite was used as a heterogeneous catalyst in the asymmetric Suzuki-Miyaura coupling (SMC) reaction. The easily prepared imine-linked COF-BASU1 possesses a two-dimensional eclipsed layered-sheet structure, making its incorporation with metal ions feasible. Via a simple post-treatment, a Pd(II)-containing COF, Pd/COF-BASU1, was accordingly synthesized, which showed excellent catalytic activity in catalyzing the asymmetric Suzuki-Miyaura coupling reaction with high stereoselectivity. The eclipsed imine structure provide chiral environment to achieve the asymmetric Suzuki-Miyaura coupling reactionplay. Afterward, the chiral high-performance liquid chromatography (HPLC) was conducted to examine the axially chiral products generated through these reactions. These products were separated via the HPLC method. This technique is based on the function of some columns whose packing groups can segregate chiral products. The fabricated nanocatalyst was structurally authenticated using various analytical techniques such as FT-IR, XRD, FE-SEM, TGA, EDS, ICP-AES, and BET. The outcomes indicated that Pd/COF-BASU1 nanocomposite is a suitable catalyst to synthesis axially chiral biaryl derivatives with high stereoselectivity (up to 85.37% ee).

The Catalytic Formation of Atropisomers and Stereocenters via Asymmetric Suzuki–Miyaura Couplings

Although Suzuki–Miyaura cross-coupling is one of the most convenient and well-developed cross-coupling reactions, its applications to the asymmetric version to deliver highly functionalized atropisomers or nonracemic coupling products have been less explored. Besides some excellent work reported intermittently, the asymmetric Suzuki–Miyaura reaction remains a significant challenge, particularly for preparing highly functionalized heterocyclic atropisomers. A concise but critical knowledge on this topic may further inspire researchers across various subdisciplines to develop innovative and practical solutions to tackle this problem. Therefore, this concise Review aims to summarize the pioneering work on asymmetric Suzuki–Miyaura cross-couplings and cover the implementations via homogeneous and heterogeneous catalysis reported during recent years. Most notably, the use of transition metals other than palladium is also described.

Synthesis and Evaluation of Novel Planar‐Chiral Monophosphine Ligands Bearing Ferrocene‐Triazole Backbones

We prepared novel planar chiral monophosphine ligands bearing ferrocene-triazole backbones. These ligands were produced in a series of steps that included triazole synthesis by diastereoselective azidation and Huisgen cycloaddition of (S)-Ugi's amine, followed by methylation and phosphine introduction. This method was applicable to the preparation of various analogues due to the wide substrate scope of the Huisgen cycloaddition reaction. These ligands showed good catalytic activity in Suzuki–Miyaura coupling reactions, especially those involving bulky substrates. Furthermore, the optically active versions of these ligands were used in the asymmetric Suzuki–Miyaura coupling reaction to produce the axial chiral binaphthyl compound with moderate enantioselectivity. The ligand developed in this study is the first triazole-type biaryl- monophosphine ligand that can be used in asymmetric reactions, and it is expected to be a new tool for the accessing chiral compounds.

Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides

Understanding how catalytic asymmetric reactions with racemic starting materials can operate would enable new enantioselective cross-coupling reactions that give chiral products. Here we propose a catalytic cycle for the highly enantioselective Rh(i)-catalysed Suzuki–Miyaura coupling of boronic acids and racemic allyl halides. Natural abundance 13C kinetic isotope effects provide quantitative information about the transition-state structures of two key elementary steps in the catalytic cycle, transmetallation and oxidative addition. Experiments with configurationally stable, deuterium-labelled substrates revealed that oxidative addition can happen via syn- or anti-pathways, which control diastereoselectivity. Density functional theory calculations attribute the extremely high enantioselectivity to reductive elimination from a common Rh complex formed from both allyl halide enantiomers. Our conclusions are supported by analysis of the reaction kinetics. These insights into the sequence of bond-forming steps and their transition-state structures will contribute to our understanding of asymmetric Rh–allyl chemistry and enable the discovery and application of asymmetric reactions with racemic substrates. A major drive in current chemistry research is to develop asymmetric versions of widely used carbon–carbon bond-forming reactions, such as Suzuki-Miyaura cross-couplings. Now, the origins of diastereo- and enantioselectivity in a Rh-catalysed cross-coupling of boronic acid and racemic allyl halides have been established.

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

Summary Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

Pd-catalyzed asymmetric Suzuki-Miyaura coupling reactions for the synthesis of chiral biaryl compounds with a large steric substituent at the 2-position.

Pd-catalyzed asymmetric Suzuki–Miyaura couplings of 3-methyl-2-bromophenylamides, 3-methyl-2-bromo-1-nitrobenzene and 1-naphthaleneboronic acids have been successfully developed and the corresponding axially chiral biaryl compounds were obtained in very high yields (up to 99%) with good enantioselectivities (up to 88% ee) under mild conditions. The chiral-bridged biphenyl monophosphine ligands developed by our group exhibit significant superiority to the naphthyl counterpart MOP in both reactivity and enantioselectivity control. The large steric hindrance from π-conjugated ortho-substituents of the bromobenzene substrates and the Pd···O interaction between carbonyl and palladium seem essential to achieve high enantioselectivity.

Enantioselective assembly of multi-layer 3D chirality.

The first enantioselective assembly of sandwich-shaped organo molecules has been achieved by conducting dual asymmetric Suzuki-Miyaura couplings and nine other reactions. This work also presents the first fully C-C anchored multi-layer 3D chirality with optically pure enantiomers. As confirmed by X-ray diffraction analysis that this chiral framework is featured by a unique C2-symmetry in which a nearly parallel fashion consisting of three layers: top, middle and bottom aromatic rings. Unlike the documented planar or axial chirality, the present chirality shows its top and bottom layers restrict each other from free rotation, i.e., this multi-layer 3D chirality would not exist if either top or bottom layer is removed. Nearly all multi-layered compounds showed strong luminescence of different colors under UV irradiation, and several randomly selected samples displayed aggregation-induced emission (AIE) properties. This work is believed to have broad impacts on chemical, medicinal and material sciences including optoelectronic materials in future.

Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides

Although Csp2-Csp2 Suzuki-Miyaura couplings (SMCs) are widely used in small-molecule synthesis, related methods that allow the incorporation of Csp3-hybridized coupling partners, particularly in an asymmetric manner, are less developed. This protocol describes catalytic asymmetric SMC reactions that provide access to enantiomerically enriched cyclic allylic products. The method couples racemic allyl halide starting materials with sp2-hybridized boronic acid derivatives and is compatible with heterocyclic coupling partners. These reactions are catalyzed by a rhodium-ligand complex and typically display very high levels of enantioselectivity (>95% enantiomeric excess (ee)). In this protocol, we detail a procedure using a dihydropyridine-derived allyl chloride for the synthesis of (-)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, an intermediate in the synthesis of the anticancer drug niraparib. This procedure affords 1.17 g (86% yield) of the coupling product with 96% ee. The initial experimental setup of the reaction takes 45-50 min, and the reaction is complete within 4-5 h.

Facilitating the transmetalation step with aryl-zincates in nickel-catalyzed enantioselective arylation of secondary benzylic halides

Nickel-catalyzed asymmetric cross-coupling of secondary alkyl electrophiles with different nucleophiles represents a powerful strategy for the construction of chiral tertiary carbon centers. Yet, the use of aryl Grignard reagents or aryl zinc halides in many reactions typically resulted in low enantioselectivity, mainly due to their slow transmetalation step in the catalytical cycle and consequently the requirement of relatively high temperature. Here we report that the use of lithium aryl zincate [Ph2ZnBr]Li facilitates the transmetalation step of the nickel-catalyzed cross-coupling reaction. Based on this discovery, a highly enantioselective construction of fluoroalkyl-substituted stereogenic center by a nickel-catalyzed asymmetric Suzuki-Miyaura coupling of α-bromobenzyl trifluoro-/difluoro-/mono- fluoromethanes with a variety of lithium aryl zincates [Ph2ZnBr]Li that were in situ generated from the reaction of lithium organoboronate with 1.0 equivalent of ZnBr2 was described.

P-Chiral Phosphorus Ligands Based on a 2,3-Dihydrobenzo[ d][1,3]oxaphosphole Motif for Asymmetric Catalysis.

Despite the rapid progress in the field of asymmetric catalysis, the search for new, efficient, and practical asymmetric catalytic transformations to facilitate the green synthesis of chiral natural products and drugs will continue to be a major ongoing effort in organic chemistry. Chiral phosphorus ligands have played a significant role in recent advances in transition-metal-catalyzed asymmetric transformations. However, there remain numerous challenging issues of reactivity and selectivity in catalysis. The development of new and efficient chiral phosphorus ligands with new structural motifs remains highly desirable. P-Chiral phosphorus ligands have been overlooked and are underdeveloped, except for the early success of DIPAMP, introduced first by Knowles in the early 1970s. It was not until the late 1990s that the development of P-chiral phosphorus ligands regained attention with the advent of bisP*, TangPhos, etc. Nonetheless, most P-chiral phosphorus ligands were either difficult to prepare or operationally inconvenient. The development of efficient, practical, and operationally convenient P-chiral phosphorus ligands with new structural motifs remains an important subject of research. This Account introduces the design and development of a series of practical and efficient P-chiral bis- and monophosphorus ligands based on a 2,3-dihydrobenzo[ d][1,3]oxaphosphole motif. Their unique structural and physical properties include conformational unambiguousness, high tunability of electronic and steric properties, and operational simplicity as air-stable solids, which make them practical and exceptional ligands for asymmetric catalysis. Chiral bisphosphorus ligands such as MeO-BIBOP (L3), WingPhos (L4), and iPr-BABIBOP (L7) have demonstrated excellent enantioselectivities and unprecedented turnover numbers (TONs) in various asymmetric hydrogenations and other transformations, providing practical and efficient solutions leading to chiral amines, alcohols, carboxylic acids, and α- and β-amino acids. Chiral biaryl monophosphorus ligands, including BI-DIME (L9), AntPhos (L15), iPr-BI-DIME (L11), etc., have proven to be a class of versatile and powerful ligands for a number of catalytic asymmetric transformations, including asymmetric Suzuki-Miyaura coupling, asymmetric palladium-catalyzed dearomative cyclization, asymmetric hydroboration/diboration, asymmetric nickel-catalyzed reductive coupling, asymmetric palladium-catalyzed intramolecular arylation, asymmetric alkene aryloxyarylation, asymmetric α-arylation, asymmetric Heck reaction, and asymmetric nucleophilic addition, providing efficient solutions leading to various synthetically challenging chiral structures such as chiral biaryls, chiral tertiary alcohols, chiral α-amino tertiary boronic esters, and chiral all-carbon quaternary stereocenters. The high enantioselectivities and TONs obtained with these ligands have resulted in the syntheses of several chiral natural products and therapeutic agents in concise and highly efficient manners. While our efforts on the development of P-chiral phosphorus ligands are ongoing, it should be emphasized that the development of ligands and catalysts with new structural motifs should continue in the search for new reactivity and selectivity to tackle current synthetic challenges. Such effort is destined to promote the advances of asymmetric catalysis as well as synthetic organic chemistry.

Enantioselective synthesis of chiral heterocyclic biaryls via asymmetric Suzuki-Miyaura cross-coupling of 3-bromopyridine derivatives.

A series of chiral heterocyclic biaryls with a pyridyl moiety were prepared in moderate to good yields with up to 92% ee via asymmetric Suzuki-Miyaura coupling. The chiral-bridged biphenyl monophosphine ligand L1 was found to be much more effective in the reaction enantioselection than its counterpart binaphthyl monophosphine ligands.

Qilong Shen

Angewandte Chemie International EditionVolume 58, Issue 23 p. 7524-7524 Author ProfileFree Access Qilong Shen First published: 25 October 2018 https://doi.org/10.1002/anie.201811328AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “My favorite food is steamed whole fish. If I were not a scientist, I would be a writer …” Find out more about Qilong Shen in his Author Profile. Qilong Shen The author presented on this page has published more than 10 articles in Angewandte Chemie in the last 10 years, most recently: “Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel-Catalyzed Asymmetric Suzuki–Miyaura Coupling of Secondary Benzyl Bromides”: W. Huang, X. Wan, Q. Shen, Angew. Chem. Int. Ed. 2017, 56, 11986; Angew. Chem. 2017, 129, 12148. The work of Q. Shen has been featured on the back cover of Angewandte Chemie: “An Electrophilic Hypervalent Iodine Reagent for Trifluoromethylthiolation”: X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2013, 52, 3457; Angew. Chem. 2013, 125, 3541. Date of birth: October 4, 1974 Position: Professor, Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS) E-mail: shenql@mail.sioc.ac.cn Homepage: http://shenqilong.sioc.ac.cn ORCID: 0000-0001-5622-153X Education: 1996 BS, Nanjing University 1999 MSc, SIOC, CAS 2002 MSc, University of Massachusetts, Dartmouth 2007 PhD with Prof. John F. Hartwig, Yale University 2007–2010 Postdoc with Prof. Jeffrey S. Moore, University of Illinois at Urbana-Champaign Awards: 2016 National Natural Science Fund for Distinguished Young Scholars, NSFC; 2018 Roche Chinese Young Investigator Award Current research interests: Organofluorine chemistry; electrophilic fluoroalkylating reagents; organometallic fluorine chemistry Hobbies: Hiking, reading My favorite food is steamed whole fish. If I were not a scientist, I would be a writer. If I won the lottery, I would set up my own research institute. The most important thing I learned from my parents is to stand up straight and do your best. I chose chemistry as a career because I was chosen as a member of my high-school chemistry olympiad team and I fell love with the subject. My greatest achievement has been the development of a family of electrophilic fluoroalkylating reagents. My favorite author (fiction) is Romain Rolland (who wrote the novel Jean Christophe). My favorite piece of music is Beethoven's “Moonlight” Sonata. My favorite quote is “If winter comes, can spring be far behind?” (Percy Bysshe Shelley). The most significant scientific advance of the last 100 years has been the discovery of the DNA structure. My 5 top papers: 1“Copper-Catalyzed Trifluoromethylation of Aryl and Vinyl Boronic Acids with An Electrophilic Trifluoromethylating Reagent”: T. Liu, Q. Shen, Org. Lett. 2011, 13, 2342. (Site-specific trifluoromethylation made easy.) 2“N-Trifluoromethylthiosaccharin: An Easily Accessible, Shelf-Stable, Broadly Applicable Trifluoromethylthiolating Reagent”: C.-F. Xu, B.-Q. Ma, Q. Shen, Angew. Chem. Int. Ed. 2014, 53, 9316; Angew. Chem. 2014, 126, 9470. (With a sweet component, this reagent makes trifluoromethylthiolated compounds readily accessible.) 3“Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides”: Y. Gu, X. Leng, Q. Shen, Nat. Commun. 2014, 5, 5405. (A two-catalyst relay led to the first reported transition-metal-catalyzed difluoromethylation reaction.) 4“N-Difluoromethylthiophthalimide: A Shelf-Stable Electrophilic Regent for Difluoromethylthiolation”: D. Zhu, Y. Gu, L. Lu, Q. Shen, J. Am. Chem. Soc. 2015, 137, 10547. (A stable yet reactive “one-stop-shop” reagent for difluoromethylthiolation.) 5“Direct of Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide”: J. Zhu, Y. Liu, Q. Shen, Angew. Chem. Int. Ed. 2016, 55, 9050; Angew. Chem. 2016, 128, 9196. (Umpolung reactivity in a sulfonium ylide—now it is electrophilic.) Volume58, Issue23June 3, 2019Pages 7524-7524 ReferencesRelatedInformation

Development of New Chiral Phosphine Ligands with Helical Environments and Their Application in Asymmetric Catalytic Reactions

The design and development of new chiral ligands to enable precise stereocontrol in a wide variety of reactions is one of the most important branches of organic synthesis. To date, the development of hybrid ligands containing both σ-donating and π-donating groups has attracted considerable attention, with unprecedented reactivities and stereoselectivities being observed. Therefore to develop efficient hybrid chiral ligands with novel structural motifs, we envisage that helicene would be a suitable π-donor efficiently to construct a helical environment around a metal center. In this context, we herein describe our recent efforts to develop a series of novel chiral [5]helicene-derived phosphine ligands (L1, with a 7,8-dihydro[5]helicene core structure, and L2, with a fully aromatic [5]helicene core structure). The prepared ligands, and in particular L1, were found highly effective in the asymmetric allylation of 1,3-diphenylallyl acetate with indoles and etherification with alcohols. Furthermore, in the asymmetric Suzuki-Miyaura coupling reaction, L2 exhibited excellent enantioselectivities. Finally, density functional theory studies were employed to propose a model that accounts for the origin of such high enantioselectivity in these reactions.

Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel‐Catalyzed Asymmetric Suzuki–Miyaura Coupling of Secondary Benzyl Bromides

AbstractTrifluoromethoxy‐substituted stereogenic centers can be constructed with high enantioselectivity by a nickel‐catalyzed Suzuki–Miyaura coupling of readily available α‐bromobenzyl trifluoromethyl ethers with a variety of aryl pinacol boronates. The coupling proceeds under mild reaction conditions, and a variety of common functional groups, such as fluoride, chloride, bromide, ester, enolizable ketone, nitro, cyano, amino, and vinyl moieties, were well tolerated. Furthermore, the reaction can be easily scaled up to gram quantities without a decrease in enantioselectivity.

Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel‐Catalyzed Asymmetric Suzuki–Miyaura Coupling of Secondary Benzyl Bromides

Trifluoromethoxy-substituted stereogenic centers can be constructed with high enantioselectivity by a nickel-catalyzed Suzuki-Miyaura coupling of readily available α-bromobenzyl trifluoromethyl ethers with a variety of aryl pinacol boronates. The coupling proceeds under mild reaction conditions, and a variety of common functional groups, such as fluoride, chloride, bromide, ester, enolizable ketone, nitro, cyano, amino, and vinyl moieties, were well tolerated. Furthermore, the reaction can be easily scaled up to gram quantities without a decrease in enantioselectivity.

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

Using asymmetric catalysis to simultaneously form carbon–carbon bonds and generate single isomer products is strategically important. Suzuki-Miyaura cross-coupling is widely used in the academic and industrial sectors to synthesize drugs, agrochemicals and biologically active and advanced materials. However, widely applicable enantioselective Suzuki-Miyaura variations to provide 3D molecules remain elusive. Here we report a rhodium-catalysed asymmetric Suzuki-Miyaura reaction with important partners including aryls, vinyls, heteroaromatics and heterocycles. The method can be used to couple two heterocyclic species so the highly enantioenriched products have a wide array of cores. We show that pyridine boronic acids are unsuitable, but they can be halogen-modified at the 2-position to undergo reaction, and this halogen can then be removed or used to facilitate further reactions. The method is used to synthesize isoanabasine, preclamol, and niraparib—an anticancer agent in several clinical trials. We anticipate this method will be a useful tool in drug synthesis and discovery.

Synthesis of Chiral‐Bridged Atropisomeric Monophosphine Ligands with Tunable Dihedral Angles and their Applications in Asymmetric Suzuki–Miyaura Coupling Reactions

AbstractPrecise chiral recognition was firstly realized in the construction of diastereomeric biaryl monophosphines by means of the substrate‐directed asymmetric annulation reactions. A series of new chiral‐bridged atropisomeric biphenyl monophosphine ligands with tunable dihedral angles was accordingly synthesized successfully without a resolution step being needed. Using these ligands, different kinds of axially chiral 1,1′‐biaryl‐2‐phosphonates including the first reported quinolyl biaryl phosphonates were prepared in 42–97% yields with up to 96% ee via palladium‐catalyzed asymmetric Suzuki coupling reactions.magnified image