Meetings by month
Cheng-Hao Ying , Shao-Bai Yan , and Wei-Liang Duan
A series of bidentate monoanionic nitrogen ligands were designed and applied in the Pd-catalyzed oxidative Heck reaction of arenes with alkenes. Significant ligand-accelerated effects were observed, and direct C–H functionalized products were formed in high yields with meta-selectivity.
Louis K. M. Chan, Darren L. Poole, Di Shen, Mark P. Healy and Timothy J. Donohoe
The rhodium-catalyzed methylation of ketones has been accomplished using methanol as the methylating agent and the hydrogen-borrowing method. The sequence is notable for the relatively low temperatures that are required and for the ability of the reaction system to form α-branched products with ease. Doubly alkylated ketones can be prepared from methyl ketones and two different alcohols by using a sequential one-pot iridium- and rhodium-catalyzed process.
Chunlin Wu and Jianrong Zhou(Steve)
The asymmetric intermolecular Heck reaction has been limited to aryl and vinyl triflates. Herein, we extend the reaction to aryl and vinyl bromides. Various cyclic olefins coupled with high enantioselectivity. Only bisphosphine oxides on a spiro backbone formed highly stereoselective Pd catalysts. The use of alcoholic solvents and alkylammonium salts were essential to promote halide dissociation from neutral arylpalladium complexes.
Marta G. Núñez , Alistair J. M. Farley , and Darren J. Dixon
The design, synthesis, and development of a new class of modular, strongly basic, and tunable bifunctional Brønsted base/H-bond-donor organocatalysts are reported. These catalysts incorporate a triaryliminophosphorane as the Brønsted basic moiety and are readily synthesized via a last step Staudinger reaction of a chiral organoazide and a triarylphosphine. Their application to the first general enantioselective organocatalytic nitro-Mannich reaction of nitromethane to unactivated ketone-derived imines allows the enantioselective construction of β-nitroamines possessing a fully substituted carbon atom. The reaction is amenable to multigram scale-up, and the products are useful for the synthesis of enantiopure 1,2-diamine and α-amino acid derivatives.
Sara Morales , Fernando G. Guijarro , José Luis García Ruano *, and M. Belén Cid
A general and efficient biomimetic method for the synthesis of aldimines from aldehydes and compounds bearing the NH2 group in the presence of pyrrolidine as a catalyst has been developed. These organocatalytic reactions, based on the application of the concept of nucleophilic catalysis, proceed with outstanding yields in the absence of acids and metals under simple conditions and minimum experimental manipulation. The method has been mainly applied to the synthesis of N-sulfinyl and N-sulfonyl imines, but its general validity has been proven with the preparation of representative N-phosphinoyl, N-alkyl, and N-aryl imines. These unprecedented reactions, which presumably occur via iminium activation without requiring acidic conditions, are an interesting and competitive alternative to the classical methods for preparing aldimines.
The range of visible light has been explained by the knowledge available of gas-phase thermochemistry and chemical kinetics. The C, C–π bond dissociation energy at the 11 and 12 positions of the rhodopsin complex is estimated to be approximately 37.4±1.5 kcal/mol. This energy is just equivalent to wavelength of the red limit of the visible light. The photons of the violet limit (approx. 75.2 kcal/mol) can break the weakest C–C and H–C bonds in important species involved in the photo-induced cis–trans isomerization cycle and can stop the visual cycle.
Jianping Qu , Lydia Roßberg , and Günter Helmchen
A highly enantioselective and regioselective Ir-catalyzed allylic esterification is described, in which branched allylic esters are synthesized directly. Carboxylates were used as nucleophiles and linear allylic phosphates as electrophiles. In some cases the allylic substitution reaction was found to be accompanied by a kinetic resolution process, which causes a change of the enantiomeric excess.
Zhibin Shu, Wenzhi Ji, Xi Wang, Yujing Zhou, Yan Zhang, Jianbo Wang
A direct oxidative cyanation of arenes under FeII catalysis with 3,5-di(trifluoromethyl)phenyl(cyano)iodonium triflate (DFCT) as the cyanating agent has been developed. The reaction is applicable to wide range of aromatic substrates, including polycyclic structures and heteroaromatic compounds.
Honglei Liu , Yang Wu , Yan Zhao , Zhen Li , Lei Zhang , Wenjun Yang , Hui Jiang , Chengfeng Jing ,Hao Yu , Bo Wang , Yumei Xiao , and Hongchao Guo
The first metal-catalyzed [6 + 3] cycloaddition of tropone with azomethine ylides has been developed. With the use of a chiral ferrocenylphosphine–copper(I) complex as the catalyst, the asymmetric variant of the [6 + 3] cycloaddition has also been successfully achieved. The reactions proceeded smoothly under mild conditions, affording piperidine-fused bicyclic heterocycles in moderate to high yields with good to excellent diastereo- and enantioselectivies. The procedures are operationally simple and the catalysts are cheap and readily accessible, thus providing a practical approach to piperidine-fused bicyclic heterocycles.
Michal Szostak, Malcolm Spain, Andrew J. Eberhart and David J. Procter
Highly chemoselective direct reduction of primary, secondary, and tertiary amides to alcohols using SmI2/amine/H2O is reported. The reaction proceeds with C–N bond cleavage in the carbinolamine intermediate, shows excellent functional group tolerance, and delivers the alcohol products in very high yields. The expected C–O cleavage products are not formed under the reaction conditions. The observed reactivity is opposite to the electrophilicity of polar carbonyl groups resulting from the nX → π*C═O (X = O, N) conjugation. Mechanistic studies suggest that coordination of Sm to the carbonyl and then to Lewis basic nitrogen in the tetrahedral intermediate facilitate electron transfer and control the selectivity of the C–N/C–O cleavage. Notably, the method provides direct access to acyl-type radicals from unactivated amides under mild electron transfer conditions.
Shuhei Uesugi, Zhao Li, Ryo Yazaki and Takashi Ohshima
A highly chemoselective conjugate addition of alcohols in the presence of amines is described. The cooperative nature of the catalyst enabled chemoselective activation of alcohols over amines, allowing the conjugate addition to soft Lewis basic α,β-unsaturated nitriles. Divergent transformation of the nitrile functionality highlights the utility of the present catalysis.
James Y. Hamilton , David Sarlah , and Erick M. Carreira
The direct Ir-catalyzed cross-coupling between branched, racemic allylic alcohols and simple olefins is described. This transformation is catalyzed by an Ir–(P,olefin) complex and proceeds with high site selectivity and excellent enantioselectivity. The method allows rapid access to various 1,5-dienes or trienes and was used in the catalytic asymmetric synthesis of the γ-secretase modulator JNJ-40418677.
Michelle M. Claffey *, Christopher J. Helal *, Patrick R. Verhoest , Zhijun Kang , Kristina S. Fors ,Stanley Jung , Jiaying Zhong , Mark W. Bundesmann , Xinjun Hou , Shenping Lui , Robin J. Kleiman ,Michelle Vanase-Frawley , Anne W. Schmidt , Frank Menniti , Christopher J. Schmidt , William E. Hoffman , Mihaly Hajos , Laura McDowell , Rebecca E. O’Connor , Mary MacDougall-Murphy , Kari R. Fonseca , Stacey L. Becker , Frederick R. Nelson , and Spiros Liras
Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer’s disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
Qingjiang Li and Gregory P. Tochtrop
A carefully designed three-step unsaturation of carboxylic acids is described. Briefly, carboxylic acids were converted to the trifluoromethyl ketone. Subsequent treatment with selenium dioxide followed by hydrolysis afforded α,β-unsaturated carboxylic acids. The mechanism of the reported transformation was investigated, which led us to propose a novel explanation featuring selenium dioxide assisted enolizaion of a trifluoromethyl ketone followed by β-deprotonation.
Emma L. McInturff, Khoa D. Nguyen and Michael J. Krische
Direct ruthenium-catalyzed C-C coupling of alkynes and vicinal diols to form β,γ-unsaturated ketones occurs with complete levels of regioselectivity and good to complete control over the alkene geometry. Exposure of the reaction products to substoichiometric quantities of p-toluenesulfonic acid induces cyclodehydration to form tetrasubstituted furans. These alkyne-diol hydrohydroxyalkylations contribute to a growing body of merged redox-construction events that bypass the use of premetalated reagents and, hence, stoichiometric quantities of metallic by-products.
Anthony R. Mazzotti , Michael G. Campbell ,Pingping Tang , Jennifer M. Murphy , and Tobias Ritter
A practical, palladium-catalyzed synthesis of aryl fluorides from arylboronic acid derivatives is presented. The reaction is operationally simple and amenable to multigram-scale synthesis. Evaluation of the reaction mechanism suggests a single-electron-transfer pathway, involving a Pd(III) intermediate that has been isolated and characterized.
Bromo- and thiomaleimides are shown to serve as highly effective quenchers of a covalently attached fluorophore. Reactions with thiols that lead to removal of the maleimide conjugation, or detachment of the fluorophore from the maleimide, result in ‘turn-on’ of the fluorescence. These reagents thus offer opportunities in thiol sensing and intracellular reporting.
Eric P. A. Talbot, Talita de A. Fernandes,Jeffrey M. McKenna and F. Dean Toste
A mild catalytic asymmetric direct fluoro-arylation of styrenes has been developed. The palladium-catalyzed three-component coupling of Selectfluor, a styrene and a boronic acid, provides chiral monofluorinated compounds in good yield and in high enantiomeric excess. A mechanism proceeding through a Pd(IV)-fluoride intermediate is proposed for the transformation and synthesis of an sp3 C–F bond.
Christopher J. White , Jennifer L. Hickey , Conor C. G. Scully and Andrei K. Yudin
The concept of site-specific integration of fragments into macrocyclic entities has not yet found application in the realm of synthetic chemistry. Here we show that the reduced amidicity of aziridine amide bonds provides an entry point for the site-specific integration of amino acids and peptide fragments into the homodetic cyclic peptide architecture. This new synthetic operation improves both the convergence and divergence of cyclic peptide synthesis.
Suttipol Radomkit and Amir H. Hoveyda
The first examples of Lewis base catalyzed enantioselective boryl conjugate additions (BCAs) that generate products containing boron-substituted quaternary carbon stereogenic centers are disclosed. Reactions are performed in the presence of 1.0–5.0 mol % of a readily accessible chiral accessible N-heterocyclic carbene (NHC) and commercially available bis(pinacolato)diboron; cyclic or linear α,β-unsaturated ketones can be used and rigorous exclusion of air or moisture is not necessary. The desired products are obtained in 63–95 % yield and 91:9 to >99:1 enantiomeric ratio (e.r.). The special utility of the NHC-catalyzed approach is demonstrated in the context of an enantioselective synthesis of natural product antifungal (−)-crassinervic acid.
Thomas H. West, David S. B. Daniels, Alexandra M. Z. Slawin and Andrew D. Smith
Benzotetramisole promotes the catalytic asymmetric [2,3]-rearrangement of allylic quaternary ammonium salts (either isolated or prepared in situ from p-nitrophenyl bromoacetate and the corresponding allylic amine), generating syn-α-amino acid derivatives with excellent diastereo- and enantioselectivity (up to >95:5 dr; up to >99% ee).
Victor Blanco, David A. Leigh, Vanesa Marcos, José A. Morales-Serna and Alina L. Nussbaumer
A rotaxane-based switchable asymmetric organocatalyst has been synthesized in which the change of the position of the macrocycle reveals or conceals an acyclic, yet still highly effective, chiral organocatalytic group. This allows control over both the rate and stereochemical outcome of a catalyzed asymmetric Michael addition.
Miles W. Johnson, Scott W. Bagley, Neal P. Mankad, Robert G. Bergman, Vincent Mascitti,* andF. Dean Toste
The development of a gold(I)-catalyzed sulfination of aryl boronic acids is described. This transformation proceeds through an unprecedented mechanism which exploits the reactivity of gold(I)–heteroatom bonds to form sulfinate anions. Further in situ elaboration of the sulfinate intermediates leads to the corresponding sulfones and sulfonamides, two pharmacophores routinely encountered in drug discovery.
Bijie Li, Matthias Driess and John F. Hartwig
We report Ir-catalyzed intramolecular silylation of secondary alkyl C–H bonds. (Hydrido)silyl ethers, generated in situ by dehydrogenative coupling of a tertiary or conformationally restricted secondary alcohol with diethylsilane, undergo regioselective silylation at a secondary C–H bond γ to the hydroxyl group. Oxidation of the resulting oxasilolanes in the same vessel generates 1,3-diols. This method provides a strategy to synthesize 1,3-diols through a hydroxyl-directed, functionalization of secondary alkyl C–H bonds. Mechanistic studies suggest that the C–H bond cleavage is the turnover-limiting step of the catalytic cycle. This silylation of secondary C–H bonds is only 40–50 times slower than the analogous silylation of primary C–H bonds.
Igors Sokolovs, Dmitrijs Lubriks and Edgars Suna
A one-pot two-step method for intermolecular C–H amination of electron-rich heteroarenes and arenes has been developed. The approach is based on a room-temperature copper-catalyzed regioselective reaction of the in situ formed unsymmetrical (hetero)aryl-λ3-iodanes with a wide range of primary and secondary aliphatic amines and anilines.
Cynthia Ghobril, Kristie Charoen, Edward K. Rodriguez, Ara Nazatian and Mark W. Grinstaff
Washable wound dressing: A dissolvable dendritic thioester hydrogel for wound closure has been developed. The hydrogel sealant adheres strongly to tissues, closes an ex vivo vein puncture, and withstands high pressures placed on a wound. This material can be washed off upon exposure to thiolates because a thiol–thioester exchange takes place, and gradual wound re-exposure may be achieved during surgical care.
Jack A. Terrett, Michael D. Clift and David W. C. MacMillan
Direct β-alkylation of saturated aldehydes has been accomplished by synergistically combining photoredox catalysis and organocatalysis. Photon-induced enamine oxidation provides an activated β-enaminyl radical intermediate, which readily combines with a wide range of Michael acceptors to produce β-alkyl aldehydes in a highly efficient manner. Furthermore, this redox-neutral, atom-economical C–H functionalization protocol can be achieved both inter- and intramolecularly. Mechanistic studies by various spectroscopic methods suggest that a reductive quenching pathway is operable.
Daniel M. Allwood, David C. Blakemore and Steven V. Ley
Preparation of ketones by insertion of diazo compounds into the formyl C–H bond of an aldehyde is an attractive procedure, but use of structurally diverse diazo compounds is hampered by preparation and safety issues. A convenient procedure for the synthesis of unsymmetrical ketones from bench-stable tosylhydrazones and aryl aldehydes is reported. The procedure can be performed in one pot from the parent carbonyl compound and needs only a base, with no additional promoters being required.
Matthew J. Hesse, Stephanie Essafi, Charlotte G. Watson, Jeremy N. Harvey, David Hirst, Christine L. Willis and Varinder K. Aggarwal
α,α-Disubstituted allylic pinacol boronic esters undergo highly selective allylborations of aldehydes to give tetrasubstituted homoallylic alcohols with exceptional levels of anti-Z-selectivity (>20:1). The scope of the reaction includes both acyclic and cyclic allylic boronic esters which lead to acyclic and exocyclic tetrasubstituted homoallylic alcohols. The use of β-borylated allylic boronic esters gave fully substituted alkenes bearing a boronic ester which underwent further cross-coupling enabling a highly modular and stereoselective approach to the synthesis of diaryl tetrasubstituted alkenes. Computational analysis revealed the origin of the remarkable selectivity observed
Denis A Malyshey, Kirandeep Dhami, Thomas Lavergne, Tingjian Chen, Nan Dai, Jeremy M. Foster, Ivan R. Corrêa and Floyd E. Romesberg
Organisms are defined by the information encoded in their genomes, and since the origin of life this information has been encoded using a two-base-pair genetic alphabet (A–T and G–C). In vitro, the alphabet has been expanded to include several unnatural base pairs (UBPs)1, 2, 3. We have developed a class of UBPs formed between nucleotides bearing hydrophobic nucleobases, exemplified by the pair formed between d5SICS and dNaM (d5SICS–dNaM), which is efficiently PCR-amplified1 and transcribed4, 5 in vitro, and whose unique mechanism of replication has been characterized6, 7. However, expansion of an organism’s genetic alphabet presents new and unprecedented challenges: the unnatural nucleoside triphosphates must be available inside the cell; endogenous polymerases must be able to use the unnatural triphosphates to faithfully replicate DNA containing the UBP within the complex cellular milieu; and finally, the UBP must be stable in the presence of pathways that maintain the integrity of DNA. Here we show that an exogenously expressed algal nucleotide triphosphate transporter efficiently imports the triphosphates of both d5SICS and dNaM (d5SICSTP and dNaMTP) into Escherichia coli, and that the endogenous replication machinery uses them to accurately replicate a plasmid containing d5SICS–dNaM. Neither the presence of the unnatural triphosphates nor the replication of the UBP introduces a notable growth burden. Lastly, we find that the UBP is not efficiently excised by DNA repair pathways. Thus, the resulting bacterium is the first organism to propagate stably an expanded genetic alphabet.
Qiaoyi Wang, Stephen E. Motika, Novruz G. Akhmedov, Jeffrey L. Petersen and Xiaodong Shi
The first catalytic alkyne hydroboration of propargyl amine boranecarbonitriles is accomplished with triazole-AuI complexes. While the typical [L-Au]+ species decomposes within minutes upon addition of amine boranecarbonitriles, the triazole-modified gold catalysts (TA-Au) remained active, and allowed the synthesis of 1,2-BN-cyclopentenes in one step with good to excellent yields. With good substrate tolerability and mild reaction conditions (open-flask), this new method provides an alternative route to reach the interesting cyclic amine borane with high efficiency.
Hester Dang, Melrose Mailig and Gojko Lalic
A chemoselective catalytic fluorination of alkyl triflates is described using potassium fluoride as a fluoride source. Excellent yields of the desired alkyl fluorides are obtained after one hour at 45 °C using 2 mol % of the copper catalyst. With 10 mol % of the catalyst, full conversion can be achieved in less than 10 minutes at 45 °C, and thus makes this procedure potentially suited for the preparation of 18F-labeled PET probes. As a result of the mild reaction conditions, only the substitution products are observed with no evidence of common side reactions, such as elimination. Reported is a preliminary study of the reaction scope, which demonstrates that the fluorination can be performed in the presence of a wide range of functional groups. Evidence suggests an unusual role of the [IPrCuOTf] catalyst as a phase-transfer catalyst and points to [IPrCuF] as the active fluorinating reagent (IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene).
Michael R. Harris, Mikhail O. Konev and Elizabeth R. Jarvo
Enantioenriched methylenecyclopentanes are synthesized by stereospecific, nickel-catalyzed Heck cyclizations of secondary benzylic ethers. The reaction proceeds in high yield and enantiospecificity for benzylic ethers of both π-extended and simple arenes. Ethers with pendant 1,2-disubstituted olefins form trisubstituted olefins with control of both absolute configuration and alkene geometry. Diastereoselective synthesis of a polycyclic furan is demonstrated.
Jan van Dijken, John M. Belerie, Marc C.A. Stuart, Wiktor, Szymanski, Wesley R. Browne and Ben L. Feringa
The novel concept for the autoamplification of molecular chirality, wherein the amplification proceeds through the induction of supramolecular chirality, is presented. A solution of prochiral, ring-open diarylethenes is doped with a small amount of their chiral, ring-closed counterpart. The molecules co-assemble into helical fibers through hydrogen bonding and the handedness of the fibers is biased by the chiral, ring-closed diarylethene. Photochemical ring closure of the open diarylethene yields the ring-closed product, which is enriched in the template enantiomer.
Eric M Woerly, Jahnabi Roy and Martin D. Burke
The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin β-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.
Vincent James Gray, James Cuthbertson and Jonathan D. Wilden
We present here valuable extensions to our previous work in preparing highly functionalized, heteroatom-substituted alkynes via displacement at an sp center. Our results show that a wide range of ynol ethers can be prepared by the same methodology and that the same protocol can be applied to the synthesis of synthetically useful thioynol ethers. We also present new observations that have led us to revise our original hypothesis in favor of a pathway involving radical intermediates.
Valer Jeso , Claudio Aquino , Xiayun Cheng ,Haruki Mizoguchi , Mika Nakashige and Glenn C. Micalizio
Angularly substituted trans-fused hydroindanes are now accessible by the direct and convergent union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-enynes by a process that forges three C–C bonds, one C–H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti–alkyne complex (with a TMS-alkyne) followed by regioselective alkoxide-directed coupling with the enyne, stereoselective intramolecular cycloaddition, elimination of phenoxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. Several examples are given to demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substituents, and an empirical model is presented to accompany the stereochemical observations.
Fengzhi Zhang , Shoubhik Das , Andrew J. Walkinshaw , Alicia Casitas , Michael Taylor ,Marcos G. Suero , and Matthew J. Gaunt
Copper-catalyzed cascade reactions between alkenes or alkynes and diaryliodonium salts form carbocyclic products in a single step. Arylation of the unsaturated functional group is proposed to form a carbocation intermediate that facilitates hydride shift pathways to translocate the positive charge to a remote position and enables ring formation via a Friedel–Crafts-type reaction.
Apiwat Wangweerawong, Robert G. Bergman and Jonathan A. Ellman
The first asymmetric intermolecular addition of non-acidic C–H bonds to imines is reported. The use of the activating N-perfluorobutanesulfinyl imine substituent is essential for achieving sufficient reactivity and provides outstanding diastereoselectivity (>98:2 dr). Straightforward removal of the sulfinyl group with HCl yields the highly enantiomerically enriched amine hydrochlorides.
Frank Maier and Oliver Trapp
Stereolabile interconverting catalysts open up the possibility of directing enantioselectivity in asymmetric synthesis by formation of diastereomeric complexes with chiral auxiliaries and deracemization. However, the stoichiometrically used auxilliaries can significantly limit the potential applications of such systems. We synthesized a new BIPHEPO tropos ligand containing achiral selectands in the backbone, which forms transient diastereomeric associates with amylose-tris-3,5-dimethylphenyl carbamate as a selector and thus deracemizes. The enantiomerically enriched BIPHEPO obtained was successfully used in the organocatalytic asymmetric double aldol addition of substituted methyl ketones to form benzaldehyde. This strategy combines an on-column deracemization with the high stereoinduction of chiral biarylphosphineoxides and opens up new possibilities in the field of self-amplified asymmetric syntheses.
Ashley Brewer and Anthony Davis
The route by which the complex and specific molecules of life arose from the 'prebiotic soup' remains an unsolved problem. Evolution provides a large part of the answer, but this requires molecules that can carry information (that is, exist in many variants) and can replicate themselves. The process is commonplace in living organisms, but not so easy to achieve with simple chemical systems. It is especially difficult to contemplate in the chemical chaos of the prebiotic world. Although popular in many quarters, the notion that RNA was the first self-replicator carries many difficulties. Here, we present an alternative view, suggesting that there may be undiscovered self-replication mechanisms possible in much simpler systems. In particular, we highlight the possibility of information coding through stereochemical configurations of substituents in organic polymers. We also show that this coding system leads naturally to enantiopurity, solving the apparent problem of biological homochirality.
Junfei Luo , Sara Preciado , and Igor Larrosa
The direct functionalization of phenols at the ortho and para position is generally facilitated by the electron-donating nature of the hydroxyl group. Accessing meta-functionalized phenols from the parent phenols, on the other hand, generally requires lengthy synthetic sequences. Here, we report the first methodology for the one-pot direct meta-selective arylation of phenols. This methodology is based on a traceless directing group relay strategy. In this process carbon dioxide is used as a transient directing group which facilitates a palladium catalyzed arylation meta to the phenol hydroxyl group with iodoarenes. This transformation proceeds with complete meta-selectivity and is compatible with a variety of functional groups both in the phenol and in the iodoarene coupling partner.
Xiaojian Jiang, Sekarpandi Sakthivel, Kseniya Kulbitski, Gennady Nisnevich and Mark Gandelman
Organofluorine compounds have found extensive applications in various areas of science. Consequently, the development of new efficient and selective methods for their synthesis is an important goal in organic chemistry. Here, we present the first Suzuki cross-coupling reaction which utilizes dihalo compounds for the preparation of secondary alkyl fluorides. Namely, an unprecedented use of simple 1-halo-1-fluoroalkanes as electrophiles in Csp3-Csp3 and Csp3-Csp2 cross-couplings allows for the formal site-selective incorporation of F-group in the alkyl chain with no adjacent activating functional groups. Highly effective approach to the electrophilic substrates, 1-halo-1-fluoroalkanes, via iododecarboxylation of the corresponding α-fluorocarboxylic acids is also presented. The conceptually new route to organofluorides was used for the facile preparation of biomedically valuable compounds. In addition, we demonstrated that an asymmetric version of the developed reaction for the stereoconvergent synthesis of chiral secondary alkyl fluorides is feasible.
Roohollah Kazem Shiroodi, Mohammad Soltani and Vladimir Gevorgyan
An efficient, regioselective gold-catalyzed 1,3-transposition reaction of ynones and diynones has been developed. It was found that stereoelectronic (interrupted conjugation) and electronic (extended conjugation) factors could efficiently govern the regioselectivity of this thermodynamically controlled transformation. The produced conjugated diynones were efficiently transformed into diverse alkyne-substituted five- and six-membered heterocycles.
Eric T. Parker, Manshui Zhou, Aaron S. Burton, Daniel P. Glavin, Jason P. Dworkin, Ramanarayanan Krishnamurthy, Facundo M. Fernández and Jeffrey L. Bada
Following his seminal work in 1953, Stanley Miller conducted an experiment in 1958 to study the polymerization of amino acids under simulated early Earth conditions. In the experimen t, Miller sparked a gas mixture of CH4, NH3, and H2O, while intermittently adding the plausible prebiotic condensing reagent cyanamide. For unknown reasons, an analysis of the samples was not reported. We analyzed the archived samples for amino acids, dipeptides, and diketopiperazines by liquid chromatography, ion mobility spectrometry, and mass spectrometry. A dozen amino acids, 10 glycine-containing dipeptides, and 3 glycine-containing diketopiperazin es were detected. Miller’s experiment was repeated and similar polymerization products were observed. Aqueous heating experiments indicate that Strecker synthesis intermediates play a key role in facilitating polymerization. These results highlight the potential importance of condensing reagents in generating diversity within the prebiotic chemical inventory.
Kai Hong, Xun Liu and James P. Morken
The reaction of 1,1-bis(pinacolboronate) esters with alkyl halides can be effected by metal alkoxides and provides a strategy for the construction of organoboronate compounds. The reaction is found to occur by alkoxide-induced deborylation and generation of a boron-stabilized carbanion.
Arkady L. Krasovskiy, Stephen Haley, Karl Voigtritter and Bruce H. Lipshutz
Stereoselective palladium-catalyzed Kumada–Corriu reactions of functionalized alkenyl halides and a variety of Grignard reagents, including those bearing β-hydrogen atoms and sensitive functional groups, can be carried out at room temperature using a new combination of reagents.
Veronica Santacroce , Emanuele Paris, Giovanni Sartori, Raimondo Maggi and Giovanni Maestri
It has been recently reported that the reaction of α,β-unsaturated carbonyl derivatives with epoxides in the presence of a homogeneous acid catalyst readily delivers the corresponding dioxepines via formal (4 + 3) cycloaddition. We report herein that the same apparent reactivity can be triggered via heterogeneous catalysis. Characterization of products by means of NMR correlation experiments and DFT modeling revealed, however, that products are the acetals of the unsaturated reagent rather than the desired heterocycles.
Christophe Deraedt, Noël Pinaud and Didier Astruc
Upon catalyst and substrate encapsulation, an amphiphilic dendrimer containing 27 triethylene glycol termini and 9 intradendritic triazole rings serves as a catalytic nanoreactor by considerably accelerating the CuI-catalyzed alkyne–azide cycloaddition (CuAAC) “click” reactions of various substrates in water using the catalyst Cu(hexabenzyltren)Br (tren = triaminoethylamine). Moreover this recyclable nanoreactor with intradendritic triazole rings strongly also activates the simple Sharpless–Fokin catalyst CuSO4 + sodium ascorbate in water under ambient conditions leading to exceptional TONs up to 510 000. This fully recyclable catalytic nanoreactor allows to considerably decrease the amount of this cheap copper catalyst down to industrially tolerable residues, and some biomedical and cosmetic applications are exemplified.
Rebecca A. Green and John F. Hartwig
We report the palladium-catalyzed coupling of aryl halides withammonia and gaseous amines as their ammonium salts. The coupling of arylchlorides and ortho-substituted aryl bromides with ammonium sulfate formsanilines with higher selectivity for the primary arylamine over the diarylaminethan couplings with ammonia in dioxane. The resting state for the reactions ofaryl chlorides is different from the resting state for the reactions of aryl bromides, and this change in resting states is proposed toaccount for a difference in selectivities for reactions of the two haloarenes.
Junwon Choi, Pablo Martín-Gago and Gregory C. Fu
The development of efficient methods for the generation of enantioenriched sulfonamides and sulfones is an important objective for fields such as organic synthesis and medicinal chemistry; however, there have been relatively few reports of direct catalytic asymmetric approaches to controlling the stereochemistry of the sulfur-bearing carbon of such targets. In this report, we describe nickel-catalyzed stereoconvergent Negishi arylations and alkenylations of racemic α-bromosulfonamides and -sulfones that furnish the desired cross-coupling product in very good ee and yield for an array of reaction partners. Mechanistic studies are consistent with the generation of a radical intermediate that has a sufficient lifetime to diffuse out o f the solvent cage and to cyclize onto a pendant olefin.
Andrew J. Musacchio, Lucas Q. Nguyen, G. Hudson Beard and Robert R. Knowles
While olefin amination with aminium radical cations is a classical method for C–N bond formation, catalytic variants that utilize simple 2° amine precursors remain largely undeveloped. Herein we report a new visible-light photoredox protocol for the intramolecular anti-Markovnikov hydroamination of aryl olefins that proceeds through catalytically generated aminium radical intermediates. Mechanistic studies are consistent with a process involving amine oxidation via electron transfer, turnover-limiting C–N bond formation, and a second electron transfer step to reduce a carbon-centered radical, rendering the overall process redox-neutral. A range of structurally diverse N-aryl heterocycles can be prepared in good to excellent yields under conditions significantly milder than those required by conventional aminium-based protocols.
Yifeng Han, Yun Ma, Ivan Keresztes, David B. Collum and E. J. Corey
Benzylic C–H lithiation of 3,4-benzothiophane and subsequent treatment with triphenyl- or trimethylchlorosilane under a variety of conditions leads to α,α- rather than α,α′-bis-silylation products as a consequence of anion stabilization by R3Si and very fast deprotonation of the intermediate monosilylated product, even with a sterically bulky base such as lithium diisopropylamide.
Zhankui Sun, Grace A. Winschel, Paul M. Zimmerman and Pavel Nagorn
An enantioselective intramolecular chiral phosphoric acid-catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two-step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous SN2′-like displacement to yield the product with stereoselectivity in agreement with experimental observations.
Olesya M. Kuzmina and Paul Knochel*
We report a CrCl2-catalyzed oxidative arylation of various pyridines, aryl oxazolines, and aryl imines using aromatic Grignard reagents in the presence of 2,3-dichlorobutane (DCB). Most of the reactions proceed rapidly at 25 °C and do not require any additional ligand. Benzo[h]quinoline, 2-arylpyridine, aryl oxazoline, and imines were successfully arylated in good yields under these conditions. A TMS-substituent was used to prevent double arylation. After oxidative cross-coupling the TMS-group was further converted to a second ortho-aryl substituent. Remarkably, inexpensive aryl N-butylimine derivatives are excellent substrates for this oxidative arylation.
Charles S. Yeung, Robert E. Ziegler, John A. Porco , Jr. and Eric N. Jacobsen
We report the development of a catalytic method for the enantioselective addition of indoles to pyrone-derived electrophiles. Arylpyrrolidino-derived thioureas catalyze the addition with high stereoselectivity in the presence of catalytic quantities of an achiral Brønsted acid. The indole–pyrone adducts feature a quaternary stereocenter and represent an unusual class of indolines bearing structural resemblance to the hybrid natural product pleiocarpamine.
Joseph S. Bair, York Schramm, Alexey G. Sergeev, Eric Clot, Odile Eisenstein and John F. Hartwig
We report a series of hydroarylations of unactivated olefins with trifluoromethyl-substituted arenes that occur with high selectivity for the linear product without directing groups on the arene. We also show that hydroarylations occur with internal, acyclic olefins to yield linear alkylarene products. Experimental mechanistic data provide evidence for reversible formation of an alkylnickel–aryl intermediate and rate-determining reductive elimination to form the carbon–carbon bond. Labeling studies show that formation of terminal alkylarenes from internal alkenes occurs by initial establishment of an equilibrating mixture of alkene isomers, followed by addition of the arene to the terminal alkene. Computational (DFT) studies imply that the aryl C–H bond transfers to a coordinated alkene without oxidative addition and support the conclusion from experiment that reductive elimination is rate-determining and forms the anti-Markovnikov product. The reactions are inverse order in α-olefin; thus the catalytic reaction occurs, in part, because isomerization creates a low concentration of the reactant α-olefin.
Yi-Lin Huang and Jeffrey W. Bode
Microbial fermentation can rapidly provide potent compounds that can be easily screened for biological activity, and the active components can be isolated. Its success in drug discovery has inspired extensive efforts to modulate and control the products. In this Article, we document a ‘synthetic fermentation’ of bioactive, unnatural peptides ‘grown’ from small building blocks in water using amide-forming ligations. No organisms, enzymes or reagents are needed. The sequences, structures and compositions of the products can be modulated by adjusting the building blocks and conditions. No specialized knowledge of organic chemistry or handling of toxic material is required to produce complex organic molecules. The ‘fermentations’ can be conducted in arrays and screened for biological activity without isolation or workup. As a proof-of-concept, about 6,000 unnatural peptides were produced from just 23 building blocks, from which a hepatitis C virus NS3/4A protease inhibitor with a half-maximum inhibitory concentration of 1.0 μM was identified and characterized.
Lisa Candish , Alison Levens , and David W. Lupton
The enantioselective vinylogous Michael/aldol cascade is an underdeveloped approach to cyclohexenes. Herein we describe a highly enantioselective (most ≥98:2 er) and diastereoselective (all ≥15:1 dr) N-heterocyclic carbene catalyzed cycloisomerization of acyclic dienyl esters to cyclohexyl β-lactones. Derivatizations avail cyclohexenes bearing four contiguous stereogenic centers, while mechanistic studies support olefin isomerization prior to cyclization.
Alan H. Cherney and Sarah E. Reisman
A Ni-catalyzed asymmetric reductive cross-coupling between vinyl bromides and benzyl chlorides has been developed. This method provides direct access to enantioenriched products bearing aryl-substituted tertiary allylic stereogenic centers from simple, stable starting materials. A broad substrate scope is achieved under mild reaction conditions that preclude the pregeneration of organometallic reagents and the regioselectivity issues commonly associated with asymmetric allylic arylation.
Nicholas A. White and Tomislav Rovis
A novel oxidative N-heterocyclic carbene-catalyzed reaction pathway has been discovered. Alkyl and aryl enals undergo β-hydroxylation via oxygen atom transfer from electron-deficient nitrobenzenes, followed by trapping of the resultant acyl azolium by the solvent. The proposed mechanism involves a single electron transfer event to initiate the reaction followed by radical recombination. This represents a profound mechanistic departure from the established two-electron disconnects in NHC catalysis.
Sichang Wang , Zhangqin Ni , Xin Huang , Jichao Wang , and Yuanjiang Pan
A highly efficient amidation reaction of heterocycles with N-fluorobenzenesulfonimide (NFSI) has been developed, presumably proceeding via C–H bond activation. Cuprous iodide was employed as the catalyst, and various α-amidated heterocycle derivatives have been generated in good to excellent yields. This chemistry endowed an economic method of synthesis of valuable amidated heterocycles through a direct C–N bond-coupling processes.
David Tejedor, Leandro Cotos, Gabriela Mendez-Abt, and Fernando García-Tellado
A general and practical metal-free protocol forthe synthesis of 1,2-dihydropyridines with wide structural/functional diversity at the ring and featuring mono, double, orspiro substitution at the sp3 position is described. The protocolentails a microwave-assisted domino reaction of a propargylvinyl ether (secondary or tertiary) and a primary amine(aliphatic or aromatic) in toluene or methanol.
Ming Shang, Shang-Zheng Sun, Hui-Xiong Dai and Jin-Quan Yu
Cu-catalyzed coupling of aryl C–H bonds with arylboron reagents was accomplished using a readily removable directing group, which provides a useful method for the synthesis of biaryl compounds. The distinct transmetalation step in this Cu-catalyzed C–H coupling with aryl borons provides unique evidence for the formation of an aryl cupperate intermediate.
Victor Blanco, David A. Leigh, Urszula Lewandowska, Bartosz Lewandowski and Vanesa Marcos
The reactivity of a rotaxane that acts as an aminocatalyst for the functionalization of carbonyl compounds through HOMO and LUMO activation pathways has been studied. Its catalytic activity is explored for C–C and C–S bond forming reactions through iminium catalysis, in nucleophilic substitutions and additions through enamine intermediates, in Diels–Alder reactions via trienamine catalysis, and in a tandem iminium-ion/enamine reaction. The catalyst can be switched “on” or “off”, effectively controlling the rate of all of these chemical transformations, by the in situ change of the position of the macrocycle between two different binding sites on the rotaxane thread.
Marco Notarianni, Jinzhang Liu, Francesca Mirri, Matteo Pasquali and Nunzio Motta
Flexible graphene-based thin film supercapacitors were made using carbon nanotube (CNT) films as current collectors and graphene films as electrodes. The graphene sheets were produced by simple electrochemical exfoliation, while the graphene films with controlled thickness were prepared by vacuum filtration. The solid-state supercapacitor was made by using two graphene/CNT films on plastic substrates to sandwich a thin layer of gelled electrolyte. We found that the thin graphene film with thickness <1 μm can greatly increase the capacitance. Using only CNT films as electrodes, the device exhibited a capacitance as low as ~0.4 mF cm−2, whereas by adding a 360 nm thick graphene film to the CNT electrodes led to a ~4.3 mF cm−2 capacitance. We experimentally demonstrated that the conductive CNT film is equivalent to gold as a current collector while it provides a stronger binding force to the graphene film. Combining the high capacitance of the thin graphene film and the high conductivity of the CNT film, our devices exhibited high energy density (8–14 Wh kg−1) and power density (250–450 kW kg−1).
Daniel J. Scott, Matthew J. Fuchter and Andrew E. Ashley
Solutions of the Lewis acid B(C6F5)3 in 1,4-dioxane are found to effectively catalyze the hydrogenation of a variety of ketones and aldehydes. These reactions, the first to allow entirely metal-free catalytic hydrogenation of carbonyl groups under relatively mild reaction conditions, are found to proceed via a “frustrated Lewis pair” mechanism in which the solvent, a weak Brønsted base yet moderately strong donor, plays a pivotal role.
M. Sc Jie and Lutz Ackermann
Carboxylate assistance proved to be the key for the success of efficient cobalt(III)-catalyzed C-H cyanations. Thus, an in situ generated cationic cobalt complex was identified as a versatile catalyst for the site-selective synthesis of various aromatic and heteroaromatic nitriles with ample substrate scope.
Christopher G. Newton, Samuel L. Drew, Andrew L. Lawrence, Anthony C. Willis, Michael N. Paddon-Row and Michael S. Sherburn
The pseudopterosins are a family of diterpene marine natural products, which, by virtue of their interesting anti-inflammatory and analgesic properties, have attracted the attentions of many synthetic chemists. The most efficient syntheses reported to date are 14 and 20 steps in the longest linear sequence for chiral pool and enantioselective approaches, respectively, and all start with precursors that are easily mapped onto the natural product structure. Here, we describe an unconventional approach in which a chiral cross-conjugated hydrocarbon is used as the starting material for a series of three cycloadditions. Our approach has led to a significant reduction in the step count required to access these interesting natural products (10 steps chiral pool and 11 steps enantioselective). Furthermore it demonstrates that cross-conjugated hydrocarbons, erroneously considered by many to be too unstable and difficult to handle, are viable precursors for natural product synthesis.
Naoki Yoneda , Ayano Hotta , Keisuke Asano *, andSeijiro Matsubara
Formaldehyde was utilized as an oxygen-centered nucleophile in an asymmetric oxy-Michael addition to γ-hydroxy-α,β-unsaturated carbonyl compounds using bifunctional organocatalysts through hemiacetal intermediates. The cyclic acetal product could be further transformed into β-hydroxycarbonyl compounds, useful synthetic intermediates leading to various important target molecules. As such, this method is an example of a novel formal asymmetric hydration of α,β-unsaturated carbonyl compounds.
Chicco Manzuna Sapu, Tamás Görbe, Richard Lihammar, Jan-E. Bäckvall and Jan Deska
A novel migratory dynamic kinetic resolution based on the interplay between an enzyme acylation catalyst and a heterogeneous Brønsted acid as an isomerization/racemization catalyst gives rise to carbocyclic allylic esters with excellent stereoselectivity from readily available tertiary carbinols. An easy-to-use teabag setup combining resin-bound catalysts, a biphasic isooctane–water solvent system, and a highly lipophilic acyl donor efficiently suppresses side reactions and allows for the preparation of functionalized carbocyclic building blocks in high yields and optical purity.
Rajesh K. Yadav , Gyu Hwan Oh , No-Joong Park ,Abhishek Kumar , Ki-jeong Kong , and Jin-Ook Baeg
The successful development of a photocatalyst/biocatalyst integrated system that carries out selective methanol production from CO2 is reported herein. The fine-tuned system was derived from a judicious combination of graphene-based visible light active photocatalyst (CCG-IP) and sequentially coupled enzymes. The covalent attachment of isatin-porphyrin (IP) chromophore to chemically converted graphene (CCG) afforded newly developed CCG-IP photocatalyst for this research endeavor. The current work represents a new benchmark for carrying out highly selective methanol formation from CO2 in an environmentally benign manner.
Anna M. Goldys, Marta G. Núñez and Darren J. Dixon
An immobilized chiral bifunctional iminophosphorane superbase organocatalyst has been developed and applied in a range of challenging enantioselective reactions. A unique feature of this novel catalytic system is that the final step creation of the iminophosphorane occurs at the point of immobilization. The utility of the immobilized catalyst system was demonstrated in the nitro-Mannich reaction of ketimines as well as the conjugate addition of high pKa 1,3-dicarbonyl pro-nucleophiles to nitrostyrene. Catalyst recycling was also demonstrated.
Da-Gang Yu , Tobias Gensch , Francisco de Azambuja , Suhelen Vásquez-Céspedes and Frank Glorius
The first cobalt-catalyzed cyanation, halogenation, and allylation via C–H activation have been realized. These formal SN-type reactions generate valuable (hetero)aryl/alkenyl nitriles, iodides, and bromides as well as allylated indoles using a bench-stable Co(III) catalyst. High regio- and mono-selectivity were achieved for these reactions. Additionally, allylation proceeded efficiently with a turnover number of 2200 at room temperature, which is unprecedented for this Co(III) catalyst. Alkenyl substrates and amides have been successfully utilized in Cp*Co(III)-catalyzed C–H activation for the first time.
Peng Du, Huihuang Li, Yaxiong Wang, Jiang Cheng and Xiaobing Wan
A new radical-polar crossover reaction has been developed involving the combination of a tandem radical reaction and Kornblum–DeLaMare rearrangement in a one-pot process. This simple methodology allows for the construction of polyfunctionalized carbonyl compounds via the oxidative coupling of 1,3-dioxolanes with electron-deficient alkenes and vinylarenes in the presence of Co(salen) and TBHP under mild conditions. This reaction also exhibited high functional group tolerance, wide substrate scope, and operational simplicity.