Meetings by month
Yang Yang, Nathan J. Oldenhuis and Stephen L. Buchwald
A wide range of biaryls were synthesized by palladium-catalyzed Negishi cross-couplings at ambient temperature or with low catalyst loading. This protocol features the use of a recently reported aminobiphenyl palladacycle precatalyst to generate the catalytically active XPhosPd0 species. Significantly, a wide range of challenging heterocyclic and polyfluorinated aromatic substrates can be employed to give products in excellent yields.
Shenci Lu, Si Bei Poh, Woon-Yew Siau and Yu Zhao
Enantioselective: The first highly enantioselective kinetic resolution of 3-hydroxy-3-substituted oxindoles has been developed through oxidative esterification catalyzed by a N-heterocyclic carbene (see picture). This method uses a simple procedure and provides 3-hydroxy-oxindoles with various substituents at the 3-position in excellent enantiopurity. S=selectivity.
Philippe Hermange, François Portalier, Christine Thomassigny and Christine Greck
A practical one-pot three-step sequence is reported for the asymmetric synthesis of α-benzoyloxylated alcohols from primary alcohols. Good overall yields (36–52%) and enantioselectivities (91–94% e.e.) are obtained using a commercial organocatalyst in the key oxylation reaction. A simple modification in the protocol allows the formation of enantioenriched γ-benzoyloxylated α,β-unsaturated ester from alcohol. Synthetic utility has been harnessed to the easy preparation of (−)-γ-octalactone from hexan-1-ol.
Bill Morandi, Zachary K. Wickens and Robert H. Grubbs
Make it simple! A convenient and general palladium-catalyzed oxidation of internal olefins to ketones is reported. The transformation occurs at room temperature and shows wide substrate scope. Applications to the oxidation of seed-oil derivatives and a bioactive natural product (see scheme) are described, as well as intriguing mechanistic features.
Ian B. Seiple, Shun Su, Rodrigo A. Rodriguez, Ryan Gianatassio, Yuta Fujiwara, Adam L. Sobel andPhil S. Baran
A direct arylation of a variety of electron-deficient heterocycles with arylboronic acids has been developed. This new reaction proceeds readily at room temperature using inexpensive reagents: catalytic silver(I) nitrate in the presence of persulfate co-oxidant. The scope with respect to heterocycle and boronic acid coupling partner is broad, and sensitive functional groups are tolerated. This method allows for rapid access to a variety of arylated heterocycles that would be more difficult to access with traditional methods.
Russell J. Wakeham, James E. Taylor, Steven D. Bull, James A. Morris and Jonathan M. J. Williams
Acid chlorides can be activated using a simple iodide source to undergo nucleophilic attack from a variety of relatively weak nucleophiles. These include Friedel–Crafts acylation of N-methylpyrroles, N-acylation of sulfonamides, and acylation reactions of hindered phenol derivatives. The reaction is believed to proceed through a transient acid iodide intermediate.
Bingnan Du, Xiaoqing Jiang and Peipei Sun
A palladium-catalyzed ortho-halogenation (I, Br, Cl) of arylnitrile is described. The optimal reaction conditions were identified after examining various factors such as catalyst, additive, solvent, and reaction temperature. Using cyano as the directing group, the halogenation reaction gave good to excellent yields. The method is compatible to the arylnitriles with either electron-withdrawing or electron-donating groups. The reaction is available to the substrate in at least gram scale. The present method was successfully applied to the synthesis of the precursors of paucifloral F and isopaucifloral F.
Qiao Yan Toh, Andrew McNally, Silvia Vera, Nico Erdmann and Matthew J. Gaunt
An organocatalytic aldehyde C–H bond arylation process for the synthesis of complex heteroaryl ketones has been developed. By exploiting the inherent electrophilicity of diaryliodonium salts, we have found that a commercial N-heterocyclic carbene catalyst promotes the union of heteroaryl aldehydes and these heteroaromatic electrophile equivalents in good yields. This straightforward catalytic protocol offers access to ketones bearing a diverse array of arene and heteroarene substituents that can subsequently be converted into molecules displaying structural motifs commonly found in medicinal agents.
Hui Zhou and Christina Moberg
In the presence of Pd(0) and a phosphine, hydrosilylation of 1,3-enynes with Me2SiHCl proceeds to yield dienylsilanes with the silicon function added to the internal alkyne carbon atom and with (E)-configuration of newly formed olefinic bond. The silanols isolated after hydrolysis of the primarily obtained products serve as precursors to conjugated dienes with different substitution patterns.
Zhenqian Fu, Jeongbin Lee, Byungjoon Kang and Soon Hyeok Hong
A new atom-economical strategy to amide linkage from an azide and alcohol liberating hydrogen and nitrogen was developed with an in situ generated ruthenium catalytic system. The reaction has broad substrate generality including diols for the synthesis of cyclic imides.
Sarah E. Walker, Julian Boehnke, Pauline E. Glen, Steven Levey, Lisa Patrick, James A. Jordan-Horeand Ai-Lan Lee
A simple change of solvent allows controlled and efficient switching between oxidative Heck and conjugate addition reactions on cyclic Michael acceptor substrates, catalyzed by a cationic Pd(II) catalyst system. Both reactions are ligand- and base-free and tolerant of air and moisture, and the controlled switching sheds light on some of the factors which favor one reaction over the other.
Jia Jia Dong, Martín Fañanás-Mastral, Paul L. Alsters, Wesley R. Browne and Ben L. Feringa
An aldol alternative: The palladium(II)-catalyzed anti-Markovnikov oxidation of allylic esters to aldehydes at room temperature provides a viable alternative to valuable cross aldol products. High regioselectivity towards the aldehyde product was achieved using the ester protecting group for the allylic alcohol. Rapid isomerization and the much higher rate of oxidation of the branched isomer result in the same product forming from both linear and branched allylic esters.
Mathieu P. Lalonde, Meredeth A. McGowan, Naomi S. Rajapaksa and Eric N. Jacobsen
A highly enantio- and diastereoselective synthesis of indolo- and benzoquinolizidine compounds has been developed through the formal aza-Diels–Alder reaction of enones with cyclic imines. This transformation is catalyzed by a new bifunctional primary aminothiourea that achieves simultaneous activation of both the enone and imine reaction components.
Meng Gao, Chuan He, Hongyi Chen, Ruopeng Bai, Ben Cheng and Aiwen Lei
Just click with silver: Pyrroles are prepared by the co-cyclization of terminal alkynes and isocyanides in a silver-catalyzed click reaction. This protocol represents an extremely simple, efficient, and atom-economic approach to substituted pyrroles in good yields with high selectivity, thus complementing the click method for the rapid formation of multifunctional heterocycles.
Ludo K. Frevel
Hui-Xiong Dai, Gang Li, Xing-Guo Zhang, Antonia F. Stepan and Jin-Quan Yu
A combination of weakly coordinating auxiliaries and ligand acceleration allows for the development of both ortho- and meta-selective C–H olefination of phenol derivatives. These reactions demonstrate the feasibility of directing C–H functionalizations when functional groups are distal to target C–H bonds. The meta-C–H functionalization of electron-rich phenol derivatives is unprecedented and orthogonal to previous electrophilic substitution of phenols in terms of regioselectivity. These methods are also applied to functionalize α-phenoxyacetic acids, a fibrate class of drug scaffolds.
Dan-Tam D. Tang, Karl D. Collins, and Frank Glorius
The first completely selective C3 C–H arylation of benzo[b]thiophenes is reported, demonstrating previously unexploited reactivity of palladium. Benzo[b]thiophenes are coupled with readily available aryl chlorides using a ligand-free, dual catalytic system of heterogeneous Pd/C and CuCl. The reaction is operationally simple and insensitive to air and moisture, and it provides valuable products with complete selectivity. Significant investigations into the nature of the active catalytic species and mechanistic considerations are discussed.
Gregor Kiefer, Loïc Jeanbourquin and Kay Severin
Catalysis with laughing gas: N2O in combination with transition-metal catalysts allow the oxidative homo- and cross-coupling of Grignard reagents. The reactions can be performed under mild conditions despite the inert character of N2O.
Yushang Shao, Kai Zhu, Zhengchen Qin, Ende Li and Yanzhong Li
A highly efficient BF3·Et2O-catalyzed cascade reaction of enaminones with propargylic alcohols under mild reaction conditions has been developed. This methodology offers regioselective access to multisubstituted 1,2-dihydropyridines in good to excellent yields.
Junmin Zhang , Chong Xing , Bhoopendra Tiwari and Yonggui Robin Chi
We disclose the first catalytic activation of carbohydrates as formaldehyde equivalents to generate acyl anions as one-carbon nucleophilic units for a Stetter reaction. The activation involves N-heterocyclic carbene (NHC)-catalyzed C–C bond cleavage of carbohydrates via a retro-benzoin-type process to generate the acyl anion intermediates. This Stetter reaction constitutes the first success in generating formal formaldehyde-derived acyl anions as one-carbon nucleophiles for non-self-benzoin processes. The renewable nature of carbohydrates, accessible from biomass, further highlights the practical potential of this fundamentally interesting catalytic activation.
Marinus A. Bigi and M. Christina White
Development of a mild (35 °C, no Brønsted acids) tandem Wacker oxidation–dehydrogenation of terminal olefins was accomplished using palladium(II) and hypervalent iodine co-catalysis. The reaction affords linear aryl and alkyl α,β-unsaturated ketones directly from readily available terminal olefins in good yields (average 75% per step) with excellent functional group tolerance and chemo- and stereoselectivities. The hypervalent iodine co-catalyst was found to be critical for dehydrogenation but was not effective as a stoichiometric oxidant.
Jiajing Tan, Matsujiro Akakura and Hisashi Yamamoto
Silyl superpowers: The supersilyl group was investigated as a superior carboxylic acid protecting group. Supersilyl esters were also utilized as stable carboxylic acid synthetic equivalents in highly stereoselective aldol and Mannich reactions (see scheme). The value of this method lies in easy photodeprotection and in the rapid synthesis of polyketide subunits.
Isabelle Aillaud , David M. Barber , Amber L. Thompson and Darren J. Dixon
A Michael addition/iminium ion cyclization cascade of enones with tryptamine-derived ureas under BINOL phosphoric acid (BPA) catalysis is reported. The cascade reaction tolerates a wide variety of easily synthesized tryptamine-derived ureas, including those bearing substituents on the distal nitrogen atom of the urea moiety, affording polyheterocyclic products in good yields and good to excellent enantioselectivities.
Erqing Li, You Huang, Ling Liang and Peizhong Xie
The first phosphine-catalyzed [4 + 2] annulation of γ-substituted allenoates with 2-arylidene-1H-indene-1,3(2H)-diones is disclosed. In the reaction, the γ-substituted allenoate serves as a new type of 1,4-dipolar synthon; this broadens the application of γ-substituted allenoates. This method also offers a powerful approach to the construction of highly substituted spiro[4.5]dec-6-ene skeletons in excellent yields, and with complete regioselectivity and high diastereoselectivity.
Sara Meninno, Gianluca Croce, and Alessandra Lattanzi
The stereoselective synthesis of highly functionalized tetrahydrothiophenes bearing three contiguous stereocenters, one of them quaternary, can be achieved by reacting trans-α-cyano-α,β-unsaturated ketones and trans-tert-butyl 4-mercapto-2-butenoate in the presence of a readily available amine thiourea. The products are obtained in high yield, good diastereoselectivity, and excellent enantioselectivity. The overall formation of tetrahydrothiophenes occurs via a cascade double Michael reaction involving a highly efficient process of dynamic kinetic resolution.
Tien M. Nguyen and David A. Nicewicz
Herein we report a metal-free method for the direct anti-Markovnikov hydroamination of unsaturated amines. Irradiation of the amine substrates with visible light in the presence of catalytic quantities of easily synthesized 9-mesityl-10-methylacridinium tetrafluoroborate and thiophenol as a hydrogen-atom donor furnished the nitrogen-containing heterocycles with complete regiocontrol. Two examples of intermolecular anti-Markovnikov alkene hydroamination are also disclosed.
Patrizia Mamone, Grégory Danoun and Lukas J. Gooßen
New directions: The carboxylic acid functional group directs the ortho acylation of benzoic acids with carboxylic anhydrides in the presence of a rhodium catalyst (see scheme; cod=cyclo-1,5-octadiene). The acylation at the ortho position is complementary to the meta selectivity of Friedel–Crafts reactions. The resulting products can undergo protodecarboxylation to deliver an aryl ketone.
Chada Raji Reddy, Reddi Rani Valleti, and Motatipally Damoder Reddy
A new protocol has been developed for the synthesis of substituted thiophenes under mild and metal-free reaction conditions via the base-promoted thioannulation of Morita–Baylis–Hillman acetates of acetylenic aldehydes with potassium thioacetate involving a tandem allylic substitution/deacetylative 5-exo-dig-thiocycloisomerization. The obtained products provide an entry to 4H-thieno[3,2-c]chromene and thieno[3,2-c]dihydroquinoline.
Orazio A. Attanasi , Luca Bianchi , Linda A. Campisi , Lucia De Crescentini , Gianfranco Favi , andFabio Mantellini
A very simple domino reaction under solvent-free conditions of various pyridine-like heterocycles with 1,2-diaza-1,3-dienes produces in good yields imidazo[1,2-a]pyridines, imidazo[1,2-a]quinolines, and imidazo[2,1-a]isoquinolines. The advantage of this one-pot transformation lies in the use of simple pyridine-like compounds without prefunctionalization of the starting heterocycles.
Andrew J. Perkowski and David A. Nicewicz
A direct catalytic anti-Markovnikov addition of carboxylic acids to alkenes is reported. The catalyst system is comprised of the Fukuzumi acridinium photooxidant (1) and a substoichiometric quantity of a hydrogen-atom donor. Oxidizable olefins, such as styrenes, trisubstituted aliphatic alkenes, and enamides, can be employed along with a variety of carboxylic acids to afford the anti-Markovnikov addition adducts exclusively. A deuterium-labeling experiment lends insight to the potential mechanism.
Song Zhang , Lian-Yan Liao , Fang Zhang , and Xin-Fang Duan
A facile arylation, alkenylation, and alkylation of functionalized 2-halopyridine N-oxides with various Grignard reagents was developed. It represented a highly efficient and selective C–H bond functionalization of pyridine derivatives in the presence of reactive C–Cl or C–Br bonds. Using Cl or Br as a blocking group, C2/C6 site-controllable functionalization of pyridine derivatives has been achieved. Various pyridine compounds can be prepared as illustrated in the total syntheses of Onychine, dielsine, and PARP-1 inhibitor GPI 16539.
Qing Xiao, Binglong Wang, Leiming Tian, Yang Yang, Jian Ma, Yan Zhang, Shufeng Chen and Jianbo Wang
'Diene' to know: The title reaction leads to the formation of 1,3-dienes in high yields (see scheme). The reaction also proceeds with the use of N-tosylhydrazone substrates. Carbopalladation to the allene and palladium carbene migratory insertion are proposed to play the key role in this transformation.
Andrew J. Walkinshaw , Wenshu Xu , Marcos G. Suero , and Matthew J. Gaunt
Copper-catalyzed arylation of electron rich alkynes reveals stabilized trisubstituted vinyl cation equivalents that react with pendant arene nucleophiles to form all carbon tetrasubstituted alkenes. The new process streamlines the synthesis of important medicinally relevant molecules.
Yongbing Liu and Haifeng Du
A metal-free direct hydrogenation of pyridines was successfully realized by using homogeneous borane catalysts generated from alkenes and HB(C6F5)2 via in situ hydroboration. The reaction affords a broad range of piperidines in high yields with excellent cis stereoselectivities.
Paolo Ricci , Katrina Krämer , Xacobe C. Cambeiro , and Igor Larrosa
Current approaches to facilitate C–H arylation of arenes involve the use of either strongly electron-withdrawing substituents or directing groups. Both approaches require structural modification of the arene, limiting their generality. We present a new approach where C–H arylation is made possible without altering the connectivity of the arene via π-complexation of a Cr(CO)3 unit, greatly enhancing the reactivity of the aromatic C–H bonds. We apply this approach to monofluorobenzenes, highly unreactive arenes, which upon complexation become nearly as reactive as pentafluorobenzene itself in their couplings with iodoarenes. DFT calculations indicate that C–H activation via a concerted metalation–deprotonation transition state is facilitated by the predisposition of C–H bonds in (Ar–H)Cr(Co)3 to bend out of the aromatic plane.
Ningning Zhang, Rui Yang, Daisy Zhang-Negrerie, Yunfei Du and Kang Zhao
Treatment of N-alkoxyamides with NBS in toluene was found to conveniently afford the corresponding carboxylic esters, including those bearing a bulky or long-chain substituent, in satisfactory to excellent yields. This approach not only represents a convenient and economic approach to a direct transformation of an alkoxyamide moiety into the carboxylic ester functional group, via oxidative homocoupling and the subsequent thermal denitrogenation, but also facilitates the synthesis of sterically hindered carboxylic esters.
Arvind Jaganathan, Richard J. Staples and Babak Borhan
The first example of a kinetic resolution via chlorofunctionalization of olefins is reported. The enantiomers of racemic unsaturated amides were found to have different hydrogen-bonding affinities for chiral Lewis bases in numerous solvents. This interaction was exploited in developing a kinetic resolution of racemic unsaturated amides via halocyclization. The same catalyst serves to both ‘sense chirality’ in the substrate as well as mediate a highly face-selective chlorine delivery on to the olefin functionality resulting in stereotriad products in up to 99:1 dr and up to 98.5:1.5 er. The selectivity factors were typically greater than 50 to allow for the simultaneous synthesis of both the products and unreacted substrates in highly enantioenriched form at yields approaching 50%. The reaction employs catalytic amounts (≤ 0.50 mol%) of a commercially available and recyclable organocatalyst.
Longyong Xie, Yundong Wu, Weiguo Yi, Lei Zhu, Jiannan Xiang and Weimin He
A general atom-economical approach for the synthesis of α-halomethyl ketones is demonstrated through hydration of a wide range of haloalkynes. Other outstanding features include excellent yields from both alkyl- and aryl-substituted haloalkynes and wide functional group tolerance. This protocol is an alternative to conventional α-halogenation of ketones.
Andrew J. Neel , Jörg P. Hehn , Pascal F. Tripet and F. Dean Toste
This report describes the development of an enantioselective C–N bond-forming reaction to produce 1,2,3,4-tetrahydroisoquinoline-derived cyclic aminals catalyzed by chiral phosphate anions. Central to the success of this goal was the design of a library of 3,3′-triazolyl BINOL-derived phosphoric acids capable of forming attractive hydrogen-bonding interactions with the peptide-like substrate. We envision this work will offer an alternative to the conventional strategy of increasing catalyst steric bulk to improve enantioselectivity with BINOL-derived phosphoric acids.
Flavio S. P. Cardoso , Khalil A. Abboud and Aaron Aponick
A new strategy for increasing the barrier to rotation in biaryls has been developed that allows for the incorporation of 5-membered aromatic heterocycles into chiral atropisomers. Using this concept, an imidazole-based biaryl P,N-ligand has been designed and prepared as a single enantiomer. This ligand performs exceptionally well in the enantioselective A3-coupling, demonstrating the potential of this new design element.
John R. Huckins, Eric A. Bercot, Oliver R. Thiel, Tsang-Lin Hwang and Matthew M. Bio
A general Rh(III)-catalyzed synthesis of naphthyridinone derivatives is described. It relies on a double-activation and directing approach leveraging nicotinamide N-oxides as substrates. In general, high yields and selectivities can be achieved using low catalyst loadings and mild conditions (room temperature) in the couplings with alkynes, while alkenes require slightly more elevated temperatures.
Han Yong Bae, Jae Hun Sim, Ji-Woong Lee, Benjamin List and Choong Eui Son
Copycat: A highly enantioselective biomimetic aldol reaction of malonic acid half thioesters with a variety of aldehydes affords optically active β-hydroxy thioesters by employing the cinchona-derived sulfonamide organocatalyst 1. The synthetic utility of this protocol was demonstrated by performing formal syntheses of the antidepressants (R)-fluoxetine, (R)-tomoxetine, (−)-paroxetine, and (R)-tomoxetine, (−)-paroxetine, and (R)-duloxetine.
Susannah C. Coote and Thorsten Bach
The first examples of enantioselective intermolecular [2+2] photocycloadditions of isoquinolone with alkenes are reported. Photoreactions were carried out at low temperature in the presence of a chiral hydrogen-bonding template, which effectively shields one face of the substrate through formation of a hydrogen-bonded supramolecular complex. Functionalized cyclobutane products were obtained in excellent yields (86–98%) and with outstanding regio-, diastereo-, and enantioselectivity (88–99% ee).
Zhibin Shu, Yuxuan Ye, Yifan Deng, Yan Zhang and Jianbo Wang
From methyl to nitrile: A mild ammoxidation method, which directly converts methyl arenes into aromatic nitriles, has been developed by using Pd(OAc)2 and N-hydroxyphthalimide (NHPI) as the catalysts, and tert-butyl nitrite as the nitrogen source and oxidant.
Bo Peng , Danny Geerdink , and Nuno Maulide
A one-pot protocol for the asymmetric α-allylation reaction is reported relying on a key efficient asymmetric Claisen rearrangement, triggered by electrophilic activation of chiral pseudoephedrine amides. Subsequent reduction or hydrolysis of the resulting iminium ions provides highly enantioenriched α-allylic aldehydes or carboxylic acids in a traceless manner. Compared to traditional alternatives which make use of strongly basic conditions, the work presented herein displays unprecedented functional group tolerance.
Dr. Enoch Mensah, Nicole Camasso, Will Kaplan, Prof. Dr. Pavel Nagorny
In control: A chiral phosphoric acid catalyst (see scheme) significantly enhances or completely overrides the inherent regioselective acetalization profiles exhibited by monosaccharide-derived 1,2-diol substrates. This study represents the first example of chiral-catalyst-directed regio- and enantioselective intermolecular acetalizations, which are complementary to existing methods for substrate-controlled functionalization of polyols.
Hao Hu , Fan Yang and Yangjie Wu
An efficient and general protocol for the deacetonative Sonogashira coupling of aryl propargyl alcohols with aryl chlorides is described. The reaction proceeded smoothly with the catalyst system of palladacycle/Xphos. This result represents the first successful deacetonative Sonogashira version for electron-poor, electron-neutral, and even inactive sterically hindered electron-rich aryl chlorides.
Reaction of 2-(trimethylsilyl)aryl triflates 1 with N-aryl-α-amino ketones 2 afforded N-aryl-2,3-disubstituted indoles in good to excellent yields with complete control of the substitution patterns. This methodology allowed for the first time a one-step synthesis of unsymmetrical 2,3-di alkyl subs tituted indoles in a regiospecific manner.
Abel Ros, Beatriz Estepa, Pedro Ramírez-López, Eleuterio Álvarez, Rosario Fernández and José M. Lassaletta
A dynamic kinetic asymmetric transformation (DYKAT) technique has been designed for the synthesis of 2′-substituted 2-aryl pyridines/isoquinolines and related heterobiaryls. In this way, the Pd(0)-catalyzed coupling of racemic 2-triflates with aryl boroxines using a TADDOL-derived phosphoramidite as the ligand provides the corresponding coupling products with good to excellent enantioselectivities. Structural studies support that the formation of configurationally labile oxidative addition palladacycles is the key for the success of the methodology.
Zachary K. Wickens, Bill Morandi and Robert H. Grubbs
Breaking the rules: Reversal of the high Markovnikov selectivity of Wacker-type oxidations was accomplished using a nitrite co-catalyst. Unbiased aliphatic alkenes can be oxidized with high yield and aldehyde selectivity, and several functional groups are tolerated. 18O-labeling experiments indicate that the aldehydic O atom is derived from the nitrite salt.
Gregory L. Lackner , Kyle W. Quasdorf and Larry E. Overman
A convenient method for the direct construction of quaternary carbons from tertiary alcohols by visible-light photoredox coupling of tert-alkyl N-phthalimidoyl oxalate intermediates with electron-deficient alkenes is reported.
Andreas K. Steib, Olesya M. Kuzmina, Sarah Fernandez, Dietmar Flubacher and Paul Knochel
Low-toxicity chromium(II) chloride catalyzes at 25 °C within minutes the coupling reactions of various (hetero)arylmagnesium reagents with N-heterocyclic halides, aromatic halogenated ketones or imines, and alkenyl iodides. Remarkably, much lower amounts of homo-coupling side products are obtained compared to related iron, cobalt, or manganese cross-couplings.
Yougui Zhou, Shouliang Wang, Wenhao Wu, Qing Li, Yuwei He, Yue Zhuang, Lanning Li, Jiyan Pang ,Zhongyuan Zhou and Liqin Qiu
Substituted 2-formylarylboronic acids were successfully employed as substrates for asymmetric Suzuki–Miyaura coupling. By virtue of the coupling with dialkoxyphosphinyl substituted naphthyl bromides and 2-nitronaphthalen-1-yl triflouromethanesulfonate, a series of novel multifunctionalized axially chiral biaryls were prepared in 53–97% yields with up to 97% ee using palladium-Cy-MOP as the catalyst. The methodology provides a highly efficient and practical strategy for the synthesis of novel multifunctionalized axially chiral biaryls.
Alexander M. Spokoyny, Yekui Zou, Jingjing J. Ling, Hongtao Yu, Yu-Shan Lin and Bradley L. Pentelute
We report the discovery of a facile transformation between perfluoroaromatic molecules and a cysteine thiolate, which is arylated at room temperature. This new approach enabled us to selectively modify cysteine residues in unprotected peptides, providing access to variants containing rigid perfluoroaromatic staples. This stapling modification performed on a peptide sequence designed to bind the C-terminal domain of an HIV-1 capsid assembly polyprotein (C-CA) showed enhancement in binding, cell permeability, and proteolytic stability properties, as compared to the unstapled analog. Importantly, chemical stability of the formed staples allowed us to use this motif in the native chemical ligation-mediated synthesis of a small protein affibody that is capable of binding the human epidermal growth factor 2 receptor.
Xisheng Wang, Larry Truesdale and Jin-Quan Yu
A Pd(II)-catalyzed C−H activation/trifluoromethylation of arenes with an electrophilic trifluoromethylation reagent using diverse heterocycle directing groups is reported. The presence of trifluoroacetic acid is crucial for this catalytic reaction
Jaime Rojas-Martín, Marcos Veguillas, María Ribagorda and M. Carmen Carreño
Indole substituted twistane-like derivatives resulted in a reaction between 3,5-dimethyl-2-quinonyl boronic acid and 2-alkenyl indoles. Their MCPBA oxidation gave 6/6/9 caged systems. Boronic acid acts as a temporal promoter allowing a site-selective conjugate addition of the heteroaromatic system to the methyl substituted C-3 quinone carbon, giving an intermediate diene which is regioselectively trapped by intramolecular [4 + 2] cycloaddition.
Vikram Bhat, Su Wang, Brian M. Stoltz and Scott C. Virgil
A palladium-catalyzed, atroposelective C–P coupling process has been developed for the asymmetric synthesis of QUINAP and its derivatives in high enantiomeric excess. Bromide, triflate (OTf) and 4-methanesulfonylbenzenesulfonate (OSs) precursors were studied, leading in the case of the triflate to a novel dynamic kinetic resolution involving isomerization of an arylpalladium intermediate. The operationally simple methods described in this communication afford these important ligands in good to high yields and selectivity using low catalyst loading (≤3 mol % Pd).
Wen-Bo Liu, Corey M. Reeves and Brian M. Stoltz
The first regio-, diastereo-, and enantioselective allylic alkylation of acyclic β-ketoesters to form vicinal tertiary and all-carbon quaternary stereocenters is reported. Critical to the successful development of this method was the employment of iridium catalysis in concert with N-aryl-phosphoramidite ligands. Broad functional group tolerance is observed at the keto-, ester-, and α-positions of the nucleophile. Various transformations demonstrating the utility of this method for rapidly accessing complex enantioenriched compounds are reported.
Liviana L. Limacher, François D. Delay, Nicole Bédert and Paul Tissot
Ring enlargement of bicyclo[10.3.0]pentadec-1(12)-en-13-one p-toluenesulfonylhydrazone into cyclopentadec-4-yn-l-one was accomplished under mild and controlled anodic oxidation conditions. The mechanism of this fragmentation is reconsidered.
Brendan L. Quigley and
The Z-selective cross metathesis of allylic-substituted olefins is explored with recently developed ruthenium-based metathesis catalysts. The reaction proceeds with excellent stereoselectivity for the Z-isomer (typically >95%) and yields of up to 88% for a variety of allylic substituents. This includes the first synthesis of Z-α,β-unsaturated acetals by cross metathesis and their elaboration to Z-α,β-unsaturated aldehydes. In addition, the reaction is tolerant of a variety of cross partners, varying in functionality and steric profile.
Li Wan , Navid Dastbaravardeh , Gang Li and Jin-Quan Yu
meta-C–H arylation and methylation of 3-phenylpropanoic acid and phenolic derivatives were developed using an easily removable nitrile template. The combination of a weakly coordinating U-shaped template and mono-protected amino acid ligand was crucial for the cross-coupling of C–H bonds with organoborons.
Leah S. Witus, Chawita Netirojjanak, Kanwal S. Palla, Ellen M. Muehl, Chih-Hisang Weng, Anthony T. Iavarone and Matthew B. Francis
The controlled attachment of synthetic groups to proteins is important for a number of fields, including therapeutics, where antibody–drug conjugates are an emerging area of biologic medicines. We have previously reported a site-specific protein modification method using a transamination reaction that chemoselectively oxidizes the N-terminal amine of a polypeptide chain to a ketone or an aldehyde group. The newly introduced carbonyl can be used for conjugation to a synthetic group in one location through the formation of an oxime or a hydrazone linkage. To expand the scope of this reaction, we have used a combinatorial peptide library screening platform as a method to explore new transamination reagents while simultaneously identifying their optimal N-terminal sequences. N-Methylpyridinium-4-carboxaldehyde benzenesulfonate salt (Rapoport’s salt, RS) was identified as a highly effective transamination reagent when paired with glutamate-terminal peptides and proteins. This finding establishes RS as a transamination reagent that is particularly well suited for antibody modification. Using a known therapeutic antibody, herceptin, it was demonstrated that RS can be used to modify the heavy chains of the wild-type antibody or to modify both the heavy and the light chains after N-terminal sequence mutation to add additional glutamate residues.
Sean M. Preshlock, Donald L. Plattner, Peter E. Maligres, Shane W. Krska, Robert E. Maleczka Jr.,Milton R. Smith III
Not a trace: Borylation of the nitrogen in nitrogen heterocycles or anilines provides a traceless directing group for subsequent catalytic C-H borylation. Selectivities that previously required Boc protection can be achieved; furthermore, the NBpin directing group can be installed and removed in situ, and product yields are substantially higher. Boc=tert-butoxycarbonyl, pin=pinacolato.
John C. Lukesh III, Brett VanVeller and Ronald T. Raines
Pass them on! Dithiobutylamine immobilized on a resin is a useful reagent for the reduction of disulfide bonds. Its ability to reduce a disulfide bond in a protein is enhanced greatly if used along with a soluble strained cyclic disulfide or mixed diselenide that relays electrons from the resin to the protein. This electron-relay catalysis system provides distinct advantages over the use of excess soluble reducing agent alone.
Yuki Nagashima , Ryo Takita , Kengo Yoshida, Keiichi Hirano, and Masanobu Uchiyama
Borylzincate was generated in situ from dialkylzinc, diboron, and metal alkoxide. Model DFT calculations showed that although the formation of borylzincate is kinetically favorable, it is thermodynamically unfavorable. Therefore, we designed a successive reaction sequence that would provide a compensating energy gain. This enabled Zn-catalyzed borylation of aryl halides and borylzincation of benzynes and terminal alkyne from diborons without the need for any cocatalyst.
Xiao-Meng Cui, Yong-Hong Guan, Na Li, Hao Lv, Lin-An Fuu, Kun Guoo and Xiaohui FanGraphical Abstract
Exploration of α,α-dibromo-β-dicarbonyl compounds as novel bromine agents for the conversion of alcohols to alkyl bromides under neutral conditions has been achieved. This method can be used for acid-sensitive substrates and allows the bromination of various primary and secondary alcohols to proceed at room temperature within a very short period of time.